Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although the association between higher physical activity and preventive effect on breast-cancer-related lymphoedema (BCRL) has been reported, it is unclear what intervention is optimal. We aimed to investigate the effect of exercise and educational programs on BCRL development. METHODS: This study was a secondary endpoint analysis from a prospective randomized controlled trial. We enrolled patients with stage 0-III breast cancer from March 2016 to March 2020 and randomly assigned them to the control (n = 111), education (n = 115), or exercise (n = 104) group. As secondary endpoint, we assessed the incidence of and preventive effect on BCRL at 12 months post-intervention. RESULTS: There were no significant differences in the incidence of BCRL at 12 months post-intervention between the exercise and control groups (9.8% and 10.8%, P = 0.83) and the education and control groups (11.6% and 10.8%, P = 1.00). There were no significant differences in time to BCRL onset from the day of surgery between the exercise and control groups (event rate at 12 months: 20.7% and 17.2%, log-rank, P = 0.54) and the education and control groups (18.8% and 17.2%, log-rank, P = 0.57). The multivariable analyses indicated that axillary dissection and obesity significantly increased the risk of BCRL [hazard ratio (HR): 2.36, 95% confidence interval (CI) 1.52-3.67 and HR: 1.68, 95% CI 1.07-2.63, respectively]. CONCLUSIONS: The intervention did not decrease the risk of BCRL, and axillary dissection and obesity were the risk factors of BCRL. TRIAL REGISTRATION NUMBER: UMIN000020595 at UMIN Clinical Trial Registry.

DOI： 10.1007/s12282-024-01610-5

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

The increasing incidence and prevalence of breast cancer alongside diagnostic and treatment technology advances have produced a debate about the financial burden cancer places on the healthcare system and concerns about access.

Methods

This study was conducted at 51 hospitals belonging to the Breast Cancer Study Group of the Japan Clinical Oncology Group using a web-based survey. The survey period conducted from July 2021 to June 2022. The study population included patients with metastatic breast cancer who received the related treatment as their first-line therapy. The proportion of patients who selected that regimen as their first-line treatment was tabulated. The total cost increase for each current standard therapy in comparison to conventional treatments was calculated.

Results

A total of 702 patients (pts) were surveyed. Of those enrolled, 342 (48.7%) received high-cost treatment [estimated monthly drug costs exceeding ~500 000 Japanese Yen (JPY)]. Of these, 16 pts (4.7%) were receiving very high-cost treatment, amounting to more than 1 000 000 JPY per month. Fifty three (15.5%) of the patients who received high-cost treatment were 75 years of age or older. Of these, 1 pt (0.3%) were receiving very high-cost treatment. Analyses of incremental costs by current drugs showed that abemaciclib was costly with total additional cost of 6 365 670 JPY per patient. The total additional cost of the regimen per patient that included palbociclib was the second highest at 4011248 JPY, followed by atezolizumab at 3209033 JPY.

Conclusions

The findings indicate that evaluating the financial implications of high-cost treatments requires considering not only drug prices but also analysis of total cost increase.

DOI： 10.1093/jjco/hyae109

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Position of the nipple-areolar complex (NAC) is an important factor in the esthetic impression of the breast, and NAC malposition is often an issue in breast reconstruction after nipple-sparing mastectomy (NSM). The purpose of this study was to evaluate the degree of NAC malposition depending on several factors using data quantified with the Mamma Balance application (Medic Engineering K.K., Kyoto, Japan). METHODS: Patients who underwent unilateral breast reconstruction after NSM at eight hospitals in Japan between 2007 and 2020 were retrospectively investigated. Using Mamma Balance, NAC malposition was quantified separately in horizontal and vertical directions using patient photographs from pre-operatively and 6-24 months post-operatively. The degree of malpositioning was then statistically compared using various factors. RESULTS: The NAC deviated more cranially and medially with implants than that with flaps. Cases with latissimus dorsi flap showed lateral malposition more often than cases with deep inferior epigastric artery perforator flap. With flaps, lateral incisions showed more lateral malposition, and peri-areolar incisions tended to show more medial NAC malposition. In cases with severe post-operative infection of the implant, the NAC tended to deviate cranially. In radiation cases, the NAC deviated cranially. No significant difference was observed according to the degree of breast ptosis or use of the pull-down operation. Only a very weak correlation was observed between a larger amount of mastectomy and more cranial NAC malposition with both flaps and implants. CONCLUSIONS: This study provides insights into the tendencies and characteristics of NAC malposition.

DOI： 10.1007/s12282-024-01578-2

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. METHODS: We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. RESULTS: ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175-0.946], P = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073-0.857], P = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. CONCLUSIONS: RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0.

DOI： 10.1007/s10549-024-07408-5

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PURPOSE: Various studies have demonstrated the causal relationship between gut microbiota and efficacy of chemotherapy; however, the impact of gut microbiota on breast cancer has not been fully elucidated. This study aimed to evaluate the associations between the gut microbiota before neoadjuvant chemotherapy and its consequent efficacy in breast cancer. METHODS: This prospective observational study included patients who received neoadjuvant chemotherapy for primary early breast cancer at eight institutions between October 1, 2019, and March 31, 2022. We performed 16S rRNA analysis of fecal samples and α and β diversity analyses of the gut microbiota. The primary endpoint was the association between the gut microbiota and pathological complete response (pCR) to neoadjuvant chemotherapy. RESULTS: Among the 183 patients, the pCR rate after neoadjuvant chemotherapy was 36.1% in all patients and 12.9% (9/70), 69.5% (41/59), and 29.6% (16/54) in those with the luminal, human epidermal growth factor receptor 2, and triple-negative types, respectively. The α diversity of the gut microbiota did not significantly differ between patients with pCR and those without pCR. Among the gut microbiota, two species (Victivallales, P = 0.001 and Anaerolineales, P = 0.001) were associated with pCR, and one (Gemellales, P = 0.002) was associated with non-pCR. CONCLUSION: Three species in the gut microbiota had potential associations with neoadjuvant chemotherapy efficacy, but the diversity of the gut microbiota was not associated with response to chemotherapy. Further research is needed to validate our findings.

DOI： 10.1007/s10549-024-07395-7

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INTRODUCTION: Involved surgical margins are risk factors for local recurrence and re-excision is often difficult, particularly in patients with breast cancer undergoing immediate breast reconstruction (IBR). However, the magnitude of the effect of radiation therapy on preventing local recurrence for breast cancers with involved margins has not been sufficiently assessed. MATERIALS AND METHODS: We retrospectively assessed sites of involved surgical margins and local recurrence after mastectomy with IBR in patients with early breast cancer between 2008 and 2016. The effect of postoperative radiation therapy was evaluated in patients with involved margins, adjusted for nuclear grade, lymphatic invasion, surgical procedures, and primary systemic therapy. RESULTS: A total of 274 (5.8 %) out of 4726 patients who underwent mastectomy with IBR had involved surgical margins: 133, 68, 88, and 26 had involvement of the skin, deep margin, lateral margins, and nipple, respectively (including duplicates). Radiation therapy was administered to 54 patients with involved margins. In patients with involved margins, 7-year cumulative incidences of local recurrence were 1.9 % and 12.6 % with and without radiation therapy, respectively (adjusted hazard ratio, 0.17; 95 % CI, 0.04-0.80). Local recurrence occurred in 28 patients, and the sites were skin, subcutaneous tissue, muscle, and nipple-areola complex in 7, 17, 1, and 3 patients, respectively. Among them, 23 (82.1 %) were associated with involved margin sites. CONCLUSIONS: Radiation therapy meaningfully reduced the incidence of local recurrence in patients with breast cancer with margin involvement after mastectomy with IBR. Most local recurrences occurred at involved margin-related sites.

DOI： 10.1016/j.ejso.2024.108360

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Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

DOI： 10.1111/pin.13442

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DOI： 10.1245/s10434-024-15529-w

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BACKGROUND: In breast cancer patients receiving neoadjuvant chemotherapy (NAC), immediate breast reconstruction (IBR) as a breast cancer treatment option remains controversial. We assessed the impact of NAC on surgical and oncological outcomes of patients undergoing IBR. METHODS: This was a retrospective multicenter study of 4726 breast cancer cases undergoing IBR. The rate of postoperative complications and survival data were compared between IBR patients who received NAC and those who did not receive NAC. Propensity score matching analysis was performed to mitigate selection bias for survival. RESULTS: Of the total 4726 cases, 473 (10.0%) received NAC. Out of the cases with NAC, 96 (20.3%) experienced postoperative complications, while 744 cases (17.5%) without NAC had postoperative complications. NAC did not significant increase the risk of complications after IBR (Odds ratio, 0.96; 95%CI 0.74-1.25). At the median follow-up time of 76.5 months, 36 patients in the NAC group and 147 patients in the control group developed local recurrences. The 5-year local recurrence-free survival rate was 93.1% in the NAC group and 97.1% in the control group. (P < 0.001). After matching, there was no significant difference between the two groups. CONCLUSION: IBR after NAC is a safe procedure with an acceptable postoperative complication profile.

DOI： 10.1007/s12282-024-01570-w

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Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the standard agents for treating patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer (ER + HER2 - ABC). However, markers predicting the outcomes of CDK4/6i treatment have yet to be identified. This study was a single-center retrospective cohort study. We retrospectively evaluated 101 patients with ER + HER2 - ABC receiving CDK4/6i in combination with endocrine therapy at Fukuyama City Hospital between November 2017 and July 2021. We investigated the clinical outcomes and the safety of CDK4/6i treatment, and the absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) as predictive markers for CDK4/6i. We defined the cut-off values as 1000/μL for ALC and 3 for NLR, and divided into "low" and "high" groups, respectively. We evaluated 43 and 58 patients who received abemaciclib and palbociclib, respectively. Patients with high ALC and low NLR had significantly longer overall survival than those with low ALC and high NLR (high vs. low; ALC: HR 0.29; 95% CI 0.12-0.70; NLR: HR 2.94; 95% CI 1.21-7.13). There was no significant difference in efficacy between abemaciclib and palbociclib and both had good safety profiles. We demonstrated that ALC and NLR might predict the outcomes of CDK4/6i treatment in patients with ER + HER2 - ABC.

DOI： 10.1038/s41598-024-60101-x

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Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

DOI： 10.1111/cas.16164

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BACKGROUND: Mastectomy has been the standard surgical treatment for ipsilateral breast tumor recurrence (IBTR). Recently, there has been growing interest in repeat breast-conserving surgery (rBCS) for IBTR among breast surgeons; however, there is currently little information regarding patient preferences for surgical procedure for IBTR. The purpose of this study was to evaluate preference for surgical procedure (mastectomy vs. rBCS) among breast cancer patients who had undergone salvage surgery for IBTR. METHODS: Overall, 100 breast cancer patients who had undergone salvage surgery for IBTR were asked about their preferred surgical methods for IBTR and the reason. The association of patient preference and the reasons related to various clinical and pathological factors were assessed. RESULTS: Of the 100 respondents, only 11 patients (11%) preferred rBCS. Patients who had undergone rBCS and radiotherapy for IBTR were significantly more likely to prefer to undergo rBCS than other groups (p = 0.030). The most frequent reason for choosing rBCS was the patient's desire to minimize breast deformity and surgical wounds. CONCLUSIONS: Our study revealed that there is a low rate of patients who opt to undergo rBCS among patients who had undergone salvage surgery for IBTR. Discrepancies in perceptions regarding the surgical procedure for IBTR between patients and their surgeons may exist.

DOI： 10.1245/s10434-024-15282-0

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Authorship：Lead author   Language：Japanese   Publisher：(一社)日本外科学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Authorship：Lead author   Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Authorship：Last author   Language：Japanese   Publisher：日本臨床外科学会  

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Authorship：Last author   Language：Japanese   Publisher：日本臨床外科学会  

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Authorship：Corresponding author   Language：English  

We report our experience with the diagnosis and treatment of an ectopic breast cancer arising within an axillary lymph node. The patient was a 65-year-old woman diagnosed breast cancer and axillary lymph node metastasis. We performed a partial mastectomy and axillary lymph node dissection. Postoperative pathology revealed no malignant lesions in the breast; however, a nodule in one of axillary lymph nodes had mixed benign and malignant components, leading to a diagnosis of invasive ductal carcinoma derived from ectopic mammary tissue. This case represents a very rare form of breast cancer, and the malignancy was difficult to distinguish from metastasis.

DOI： 10.18926/AMO/66676

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

While local treatment of metastases is considered to be unrelated to prognosis, previous studies have suggested that local treatment of isolated lung metastases may have positive prognostic impact. We designed this prospective cohort study to investigate the clinical situation and its outcomes. We enrolled patients with fewer than 3 lung nodules suspected of being oligometastases after curative breast cancer surgery. Treatments, including local and systemic therapy, were selected by the physician and patient in consultation. The primary outcome was overall survival (OS); secondary outcomes were the efficacy and the safety of the surgery for lung oligometastases. Between May 2015 and May 2019, 14 patients were enrolled. Resection of lung nodules (metastasectomy) was performed in 11 (78.6%) of 14 patients, and one of these cases was diagnosed as primary lung cancer. Metastasectomies were all performed employing video-assisted thoracic surgery (VATS) without perioperative complications. Systemic therapies were administered to all patients except one. The respective 3-year and 5-year OS rates of patients with lung oligometastases were 91.6% and 81.5%, respectively. Progression occurred in 6 patients: 3 of the 10 with metastasectomy and all 3 without this surgical procedure. Lung metastasectomy was worthwhile as a diagnostic evaluation and may provide long-term benefit in some patients.

DOI： 10.18926/AMO/66666

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BACKGROUND: Electronic patient-reported outcomes monitoring (ePROM) is a useful communication tool for patients and healthcare providers in cancer chemotherapy. In this study, we examined the feasibility of our newly developed ePROM system, which we refer to as "Hibilog". METHODS: An ePROM app was developed by extracting 18 items from the Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Symptom monitoring was conducted every two weeks for patients with metastatic breast cancer undergoing chemotherapy. The primary outcome was the response rate to the ePROM system. The secondary outcomes were response time, item missing rate, and distribution of responses for each symptom. RESULTS: A total of 71 cases (mean age 52.6 years) were analyzed. Performance status was 0 in 76% of the cases and 1 or higher in 24%. First-line treatment was being administered in 30% of cases, second-line treatment in 17%, and third-line or higher treatment in 53%. The response rate to the ePROM system from registration to week 40 remained high at around 80%, indicating good compliance. The average response time was 5.5 min and the missing rate for each item was below 0.4%. Among 1,093 responses, the top 3 symptoms causing interference with daily life were Fatigue (63%), Numbness and tingling (48%), and General pain (46%). CONCLUSION: Our developed ePROM system was able to capture symptoms accurately in patients with metastatic breast cancer undergoing chemotherapy while maintaining a high response compliance.

DOI： 10.1007/s12282-023-01537-3

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The number of breast cancer patients is increasing worldwide. Furthermore, breast cancer often develops in young people, even those only in their 30s, who play a central role in their families and society. Results from many cohort studies suggest that dietary factors, alcohol consumption, lack of physical activity, obesity, nulliparity, breastfeeding, oral contraceptive use, fertility treatment and hormone replacement therapy are risk factors for breast cancer. However, the effects of lifestyle habits on the human body are complexly intertwined with various factors, and the effects vary from person to person depending on their constitution, etc., so there is no basis for this. Therefore, primary prevention of breast cancer is still not being implemented appropriately and efficiently. Furthermore, advances in genomic technology make it possible to assess the risk of developing breast cancer in some individuals. As a result, the establishment of breast cancer prevention methods has become a health priority for high-risk individuals.Drugs such as tamoxifen and raloxifene are known to prevent the development of breast cancer, based on the results of multiple randomized controlled trials, but there are concerns regarding the side effects of these powerful agents. In addition, several clinical studies have shown that prophylactic mastectomy for women who have BRCA mutations or who are identified as being at high risk reduces the incidence of breast cancer development. However, many issues, such as changes in long-term quality of life after preventive surgery, the optimal timing of surgery and the identification of women who are at high risk but will not develop breast cancer, remain uncertain. In other words, although many researchers have focused on chemoprevention and surgical prevention and clear preventive effects of these strategies have been confirmed, it cannot be said that they are widely accepted. Therefore, the current evidence for chemoprevention and surgical prevention, as well as highlights of several interesting lines of research currently underway, are summarized in this article.

DOI： 10.1186/s41021-023-00287-0

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Immune checkpoint inhibitors (ICI) are reportedly efficacious against triple-negative breast cancer (TNBC) and are now recommended as first-line therapy. Systemic immunity markers, the absolute lymphocyte count (ALC) and the neutrophil-to-lymphocyte ratio (NLR), have been identified as predict ICI efficacy in patients with various cancers. We retrospectively enrolled 36 TNBC patients who received atezolizumab treatment between September 2019 and May 2021 at eight Japanese medical institutions. We evaluated systemic immunity markers, including dynamic changes in these markers, as predictors of survival benefit derived from atezolizumab treatment. Median time-to-treatment failure (TTF) and overall survival (OS) were 116 days and "not reached", respectively. Patients with low NLR at baseline and decreased NLR at the start of the second cycle (SO2nd) had significantly longer OS than those with high NLR at baseline and increased NLR (SO2nd) (log-rank P < 0.001 and log-rank P = 0.049, respectively). Multivariate analyses identified high ALC at baseline and decreased NLR (SO2nd) as independent predictive markers for longer TTF (P = 0.043 and P = 0.002, respectively), and low NLR at baseline and decreased NLR (SO2nd) as independent predictive markers for longer OS (P < 0.001 and P = 0.013, respectively). The safety profile was consistent with those of previous trials. This retrospective multicenter observational study showed the clinical efficacy and safety of atezolizumab treatment. Furthermore, systemic immunity markers, including their dynamic changes, were found to be associated with clinical outcomes of atezolizumab treatment in patients with advanced or metastatic TNBC.

DOI： 10.1007/s10238-023-01230-x

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Authorship：Last author   Language：Japanese   Publisher：日本臨床外科学会  

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The 2022 revision of the Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for surgical treatment of breast cancer was updated following a systematic review of the literature using the Medical Information Network Distribution Service (MINDS) procedure, which focuses on the balance of benefits and harms for various clinical questions (CQs). Experts in surgery designated by the JBCS addressed five areas: breast surgery, axillary surgery, breast reconstruction, surgical treatment for recurrent and metastatic breast cancer, and other related topics. The revision of the guidelines encompassed 4 CQs, 7 background questions (BQs), and 14 future research questions (FRQs). A significant revision in the 2022 edition pertained to axillary management after neoadjuvant chemotherapy in CQ2. The primary aim of the 2022 JBCS Clinical Practice Guidelines is to provide evidence-based recommendations to empower patients and healthcare professionals in making informed decisions regarding surgical treatment for breast cancer.

DOI： 10.1007/s12282-023-01510-0

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INTRODUCTION: Due to the increase in the number of early-stage breast cancer patients, there is growing interest in minimally invasive local therapies for breast cancer. Radiofrequency ablation (RFA) therapy is one of the most promising minimally invasive treatments. The Radiofrequency Ablation Therapy for Early Breast Cancer as Local Therapy (RAFAELO) study, a multicenter collaborative study that aims to validate the efficacy and safety of RFA and to standardize its use for early-stage breast cancer, was conducted under the Advanced Medical Care B system in 2013. This study enrolled the expected number of patients in November 2017; moreover, it is currently in the follow-up period. Some patients with early-stage breast cancer who are eligible for RFA could not receive the RFA treatment, as it is still not covered by insurance. Therefore, the Patients Offer Radiofrequency Ablation Therapy for Early Breast Cancer as Local Therapy (PO-RAFAELO) study under the Patient-proposed Health Services (PPHS) was proposed and approved in March 2019. METHODS: The PPHS is a system that allows patients to receive prompt access to advanced medical care at a medical facility close to them, starting with their request. This system is considered a part of the specific and special medical coverage. The PO-RAFAELO study is the only study in the surgical field utilizing the PPHS, aiming to help in achieving regulatory approval and insurance coverage of RFA for breast cancer. RESULTS: As of January 2023, 120 patients have undergone RFA using the PPHS and no grade 3 or higher early adverse events have occurred. CONCLUSIONS: A certain number of patients with early-stage breast cancer prefer nonsurgical treatment, and it is important to provide information regarding the availability of RFA for early-stage breast cancer under the PPHS.Trial registration: registered with Japan Registry of Clinical Trial on March 06, 2019 (Trial ID: jRCTs032180187).

DOI： 10.31662/jmaj.2023-0047

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DOI： 10.1245/s10434-023-14019-9

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DOI： 10.1245/s10434-023-13925-2

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BACKGROUND: The number of breast cancer patients in Japan undergoing immediate breast reconstruction (IBR) has increased and the postoperative follow-up period has been extended. This study was conducted to clarify the clinical aspects of, and factors associated with, local recurrence (LR) after IBR. METHODS: This was a multicenter study which included 4153 early breast cancer patients who underwent IBR. Clinicopathological characteristics were examined and factors potentially contributing to LR were analyzed. Risk factors for LR were examined separately for non-invasive and invasive breast cancers. RESULTS: The median follow-up period was 75 months. The 7-year LR rates were 2.1% and 4.3% for non-invasive and invasive cancers, respectively (p < 0.001). The proportions of LR detected by palpation, subjective symptoms, and ultrasonography were 40.0%, 27.3%, and 25.9%, respectively. Overall, 75.7% of LR were solitary, and 92.7% of these cases had no further recurrences during the observational period. Multivariate analysis of LR for invasive cancer showed that skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM), the presence of lymphovascular invasion, cancer at the surgical margin, and not receiving radiation therapy were factors related to LR. The 7-year overall survival rates of the patients with LR and non-LR of invasive cancers were 92.5% and 97.3%, respectively, (p = 0.002). CONCLUSIONS: The rate of LR after IBR was acceptably low and IBR can thus be performed safely for early breast cancer patients. Invasive cancer, SSM/NSM, lymphovascular invasion, and/or cancer at the surgical margin should prompt awareness of the possibility of LR.

DOI： 10.1245/s10434-023-13832-6

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PURPOSE: Mammography screening has increased the detection of subcentimeter breast cancers. The prognosis for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative T1a/bN0M0 breast cancers is excellent; however, the necessity of adjuvant endocrine therapy (ET) is uncertain. METHODS: We evaluated the effectiveness of adjuvant ET in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer who underwent surgery from 2008 to 2012. Standard ET was administrated after surgery. The primary endpoint was the cumulative incidence of distant metastasis. All statistical tests were 2-sided. RESULTS: Adjuvant ET was administered to 3991 (83%) of the 4758 eligible patients (1202 T1a [25.3%] and 3556 T1b [74.7%], diseases). The median follow-up period was 9.2 years. The 9-year cumulative incidence of distant metastasis was 1.5% with ET and 2.6% without ET (adjusted subdistribution hazard ratio [sHR], 0.54; 95% CI, 0.32-0.93). In multivariate analysis, the independent risk factors for distant metastasis were no history of ET, mastectomy, high-grade, and lymphatic invasion. The 9-year overall survival was 97.0% and 94.4% with and without ET, respectively (adjusted HR, 0.57; 95% CI, 0.39-0.83). In addition, adjuvant ET reduced the incidence of ipsilateral and contralateral breast cancer (9-year rates; 1.1% vs. 6.9%; sHR, 0.17, and 1.9% vs. 5.2%; sHR, 0.33). CONCLUSIONS: The prognosis was favorable in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer. Furthermore, adjuvant ET reduced the incidence of distant metastasis with minimal absolute risk difference. These findings support considering the omission of adjuvant ET, especially for patients with low-grade and no lymphatic invasion disease.

DOI： 10.1007/s10549-023-07097-6

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Authorship：Last author   Language：Japanese   Publisher：(株)篠原出版新社  

近年,乳癌診療の一部として乳房再建術が普及している.乳房再建の実態と周術期治療への影響を検討するため,大規模アンケート調査を行った.429施設より回答が得られ,乳房再建を提供している施設は73%であった.そのうち,自家組織を用いた乳房再建は75%,遊離皮弁を用いた乳房再建は48%の施設で実施されており,それぞれ形成外科医が2名以上,3名以上所属している施設が多かった.乳房再建が周術期治療に及ぼす影響は,化学療法は「変更なし」と回答した施設が94%であったのに対し,放射線療法は15%が「変更する」とし,適応症例や照射範囲を縮小する傾向があった.高度な技術を要する乳房再建術は複数の形成外科医を必要とし,周術期治療の変化が予後に与える影響を評価する必要がある.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Emojis are commonly used for daily communication and may be useful in assessing patient-reported outcomes (PROs) in breast cancer. The purpose of this study is to develop and validate a Symptom Illustration Scale (SIS) as a new PRO measurement. METHODS: Eighteen original SIS items were developed from the PRO-CTCAE. In cohort one, the SIS validity and reliability were examined in patients with breast cancer, using a semi-structured five-question survey to investigate content validity. PROs with PRO-CTCAE and SIS were examined twice to determine criteria validity and test-retest reliability. In cohort two, the responsiveness of the scales were examined in patients treated with anthracycline, docetaxel, paclitaxel, and endocrine therapy. PROs with PRO-CTCAE and SIS were investigated two or three times, depending on the therapy. RESULTS: Patients were enrolled from August 2019 to October 2020. In cohort one (n = 70), most patients had no difficulties with the SIS, but 16 patients indicated that it was difficult to understand severities in the SIS. For criterion validity, Spearman rank correlation coefficients (rs) between PRO-CTCAE and SIS items were ≥ 0.41, except for "Decreased appetite." For test-retest reliability, κ coefficients of the SIS were ≥ 0.41 for 16/18 items (88.9%). Response time was significantly shorter for the SIS than for PRO-CTCAE (p < 0.001). In cohort two (n = 106), score changes between PRO-CTCAE and SIS for relevant symptoms all had correlations with rs ≥ 0.41. CONCLUSION: An original SIS from the PRO-CTCAE for patients with breast cancer were verified the validity, reliability, and responsiveness. Further studies to improve and validate the SIS are needed.

DOI： 10.1007/s12282-023-01480-3

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The concept of oligometastases was first proposed to describe a disease state between localized cancer and extensive metastasis. After the emergence of variations in the definition of oligometastasis, in April 2020 the European Society for Radiotherapy and Oncology and the European Organization for Research and Treatment of Cancer defined oligometastases as the presence of one to five metastatic lesions that can be safely treated. However, the pathogenesis of oligometastases remains unknown, and it is uncertain which patients will benefit from metastasis-directed therapy. Breast cancer with oligometastases is generally managed with systemic therapy. Retrospective studies have suggested that the addition of metastasis-directed therapy, such as surgery, radiofrequency ablation and stereotactic body radiation therapy, may increase overall survival in breast cancer patients with oligometastases, but as yet there have been no prospective studies. Phase II trials of stereotactic body radiation therapy or fractionated irradiation for oligometastases of breast cancer have demonstrated impressive rates of local control and overall survival. Although the efficacy of stereotactic body radiation therapy in the SABR-COMET was largely anticipated, it is noteworthy that only 18% of the patient population had breast cancer. For this reason, various trials were planned or are being conducted globally to investigate the efficacy of metastasis-directed therapy for oligometastases of breast cancer. Metastasis-directed therapy for oligometastases has been shown to be effective, and stereotactic body radiation therapy and other therapies are commonly used internationally and are considered to be safe. However, the efficacy of metastasis-directed therapy for oligometastases has not yet been proven. The results of future clinical trials are thus eagerly awaited.

DOI： 10.1093/jjco/hyad077

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Although immediate breast reconstruction following mastectomy has become increasingly common, its oncological safety has been debated. We enrolled patients with breast cancer who underwent surgery at Okayama University Hospital between 2007 and 2013. The primary outcome was relapse-free survival (RFS). Secondary outcomes were overall survival and the duration from the surgery to the initiation of adjuvant chemotherapy. We divided into immediate breast reconstruction, mastectomy alone, and breast conservative surgery groups. Outcomes were compared using Cox's regression analysis. A total of 614 patients were included (reconstruction: 125, mastectomy: 128, breast conservative surgery: 361). The median follow-up duration was 79.0±31.9 months. The immediate-reconstruction patients were younger, had more lymph node metastases, and more often received postoperative chemotherapy. The RFS was better after the breast conservative surgery compared to after reconstruction (hazard ratio 0.33, 95% confidence interval: 0.144-0.763). The proportion of local recurrence was highest in the reconstruction group. No patients in the reconstruction group underwent postoperative radiation therapy. However, reconstruction did not affect overall survival or the time to the initiation of adjuvant chemotherapy. Surgeons should explain the risks of breast reconstruction to their patients preoperatively. Careful long-term follow-up is required after such procedures.

DOI： 10.18926/AMO/65493

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本乳癌学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本乳癌学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本乳癌学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本乳癌学会  

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PURPOSE: Perioperative inflammatory cytokines may be related to cancer proliferation, although few studies have investigated this issue in patients undergoing breast reconstruction surgery. METHODS: We conducted a prospective study of patients scheduled for mastectomy only, mastectomy plus deep inferior epigastric perforator flap reconstruction (DIEP), or mastectomy plus tissue expander reconstruction (TE), with or without axial dissection (Ax), for primary breast cancer. Blood samples were collected for analysis of serum IL-6 and VEGF preoperatively, then within 24 h postoperatively (POD 1), and 4-6 days postoperatively (POD 4-6). We investigated the difference in serum cytokine levels over time for each surgical procedure and the difference in serum cytokine levels among the procedures at the three measurement time points. RESULTS: There were 120 patients included in the final analysis. Serum IL-6 was significantly higher than the preoperative level on POD 1 in patients who underwent mastectomy only, DIEP, or TE and Ax (+), with higher values persisting on POD 4-6 except in those who underwent DIEP. IL-6 was significantly higher after DIEP than after mastectomy only on POD 1, but no differences were observed at POD 4-6. VEGF did not differ significantly among the surgical procedures at any time. CONCLUSIONS: The increase in IL-6 was short term and immediate breast reconstruction is considered a safe procedure.

DOI： 10.1007/s00595-023-02700-1

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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The importance of a well-fitted, comfortable brassiere to overall quality of life after breast reconstruction has not been evaluated. Our aim was to determine the impact of a semi-customized brassiere on patients' health-related quality of life after breast reconstruction. The subjects were prospective patients with mastectomy who were to undergo immediate or delayed breast reconstruction at our hospital. After surgery, a professional bra fitter sized each patient for a semi-customized brassiere and provided follow-up consultations. A self-reported questionnaire on breast aesthetics, postoperative pain, and satisfaction was used to assess the primary outcomes. Data were prospectively collected at baseline (before surgery) and at 1, 3, 6, and 12 months after surgery and analyzed. Forty-six patients (50 breasts) were included in the analysis. Consistent wearing of the brassiere reduced pain (p<0.05), with good overall satisfaction (p<0.001). Aesthetic scores on breast shape and size were higher with than without the custom brassiere at 3 months (p=0.02) and 6 months (p=0.03) after surgery. Wearing the brassiere reduced anxiety at all time points of measurement. A well-fitting brassiere ensured safety and provided a high degree of satisfaction without anxiety for patients after breast reconstruction.

DOI： 10.18926/AMO/64356

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BACKGROUND/AIM: Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery. PATIENTS AND METHODS: We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients' estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed. RESULTS: Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017). CONCLUSION: The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk.

DOI： 10.21873/invivo.13143

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BACKGROUND: One barrier to the widespread use of breast reconstruction (BR) is physicians' perception that BR adversely affects breast cancer prognosis. However, there is limited information regarding physicians' understanding of the impact of BR on patient prognosis and which physicians have misunderstandings about BR. METHODS: We conducted an e-mail survey regarding the impact of BR on the prognosis of patients with breast cancer among members of the Japanese Breast Cancer Society. RESULTS: Of 369 respondents, 99 (27%) said that they believe BR affects patient prognosis. Female respondents and those who treat fewer new breast cancer patients per year were more likely to state that they believe BR affects patient prognosis (P = 0.006 and 0.007). Respondents who believed that BR affects patient prognosis underestimated 5-year overall survival rates in patients who receive BR and subsequently have local or regional recurrence in different sites. CONCLUSION: Our survey demonstrated that a quarter of respondents believe that BR affects patient prognosis and underestimate survival rates in patients who receive BR and have subsequent local or regional recurrence. Because of the lack of evidence regarding the impact of BR on patient prognosis, educating physicians by providing accurate knowledge regarding BR and patient prognosis is highly recommended.

DOI： 10.1007/s12282-022-01421-6

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Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).

DOI： 10.18926/AMO/64116

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DOI： 10.1245/s10434-022-12773-w

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BACKGROUND: Little information is available about the clinical and pathologic characteristics of local recurrence (LR) after nipple-sparing mastectomy according to the locations of LR. METHODS: This study classified 99 patients into the following two groups according to the location of LR after nipple-sparing mastectomy: nipple-areolar recurrence (NAR) group and other locations of LR (oLR) group. The study evaluated whether the location of LR was associated with disease-free survival (DFS) after LR resection. RESULTS: For about half of the patients (44.4 %) with NAR, the primary cancer was estrogen receptor (ER)-negative and human epidermal growth factor receptor 2 (HER2)-positive. Conversely, in most of the patients with oLR (79.2 %), the primary cancer was ER-positive and HER2-negative. Among the LR tumors, the frequency of noninvasive carcinoma in the NAR tumors was significantly higher than in the oLR tumors (51.9 % vs 4.2 %, respectively). During a median follow-up period of 46 months, the location of LR was not associated with DFS after LR. In the NAR group, the presence or absence of LR tumor invasiveness was the only factor associated with DFS. In the oLR group, age at primary surgery was the only factor associated with DFS. CONCLUSION: This multi-institutional retrospective study demonstrated that the features of NAR, such as the characteristics of the primary and recurrent tumors and the prognostic factors after LR resection, were quite different from those of oLR.

DOI： 10.1245/s10434-022-12760-1

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Authorship：Lead author   Language：English   Publisher：(一社)日本癌治療学会  

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Authorship：Lead author   Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本乳房オンコプラスティックサージャリー学会  

われわれは,乳頭温存乳房全切除術施行後の乳癌患者における局所再発パターン別予後に関する論文のレビューを行ったので報告する。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J06905&link_issn=&doc_id=20221006150002&doc_link_id=10.20699%2Fjopbs.7.3_69&url=https%3A%2F%2Fdoi.org%2F10.20699%2Fjopbs.7.3_69&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Previous studies of immune genomic signatures (IGSs) in breast cancer have attempted to predict the response to chemotherapy or prognosis and were performed using different patient cohorts. The purpose of this study was to evaluate the predictive functions of various IGSs using the same patient cohort that included data for response to chemotherapy as well as the prognosis after surgery. METHODS: We applied five previously described IGS models in a public dataset of 508 breast cancer patients treated with neoadjuvant chemotherapy. The prognostic and predictive values of each model were evaluated, and their correlations were compared. RESULTS: We observed a high proportion of expression concordance among the IGS models (r: 0.56-1). Higher scores of IGSs were detected in aggressive breast cancer subtypes (basal and HER2-enriched) (P < 0.001). Four of the five IGSs could predict chemotherapy responses and two could predict 5-year relapse-free survival in cases with hormone receptor-positive (HR +) tumors. However, the models showed no significant differences in their predictive abilities for hormone receptor-negative (HR-) tumors. CONCLUSIONS: IGSs are, to some extent, useful for predicting prognosis and chemotherapy response; moreover, they show substantial agreement for specific breast cancer subtypes. However, it is necessary to identify more compelling biomarkers for both prognosis and response to chemotherapy in HR- and HER2 + cases.

DOI： 10.1007/s12282-022-01397-3

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According to a recent report, a low Ki67 level after short-term preoperative hormone therapy (post-Ki67) might suggest a more favorable prognosis compared with a high post-Ki67 level in patients with hormone receptorpositive/human epidermal growth factor 2-negative (HR+/HER2-) breast cancer with high levels of Ki67. This study aimed to evaluate the pre-treatment genetic differences between these two patient groups. Forty-five luminal B-like patients were stratified into two groups, namely, a group with high (H→H) and one with low (H→L) Ki67 levels after short-term preoperative aromatase inhibitor (AI) treatment. We compared pre-treatment gene expression profiles between the two groups. In gene level analysis, there was no significant difference between the two groups by the class comparison test. In pathway analysis, five metabolism-related gene sets were significantly upregulated in the H→L group (p≤0.05). In the search for novel targets, five genes (PARP, BRCA2, FLT4, CDK6, and PDCD1LG2) showed significantly higher expression in the H→H group (p≤0.05). Several metabolism-related pathways were associated with sensitivity to AI. In the future, it will be necessary to seek out new therapeutic strategies for the poor prognostic group with high post-Ki67.

DOI： 10.18926/AMO/63894

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Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were co-cultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including of EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer- CAF interaction.

DOI： 10.1111/cas.15502

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Japanese women have the highest life expectancy in the world and breast cancer is the most prevalent cancer among them. However, little data are available to support the evidence-based clinical management due to the fact that older adults are commonly excluded from most clinical trials. In Japan the rate of other cause of death in older patient was about a half, then we should consider whether or not breast cancer may affect the patient's life expectancy to avoid either overtreatment or undertreatment. Although management principles in older patients may be similar with those of younger age, these differences would be caused by relatively short life expectancy, some comorbidity, drug interactions and low functional status. Then, their treatment needs to be individualized. To this end, employing a comprehensive geriatric assessment may be advantageous, which enables to evaluate patient vulnerability from several different aspects, to predict adverse events of chemotherapy and to identify geriatric problems in advance so that extra support and modified treatment can be provided. Before treatment we should assess the patient's goals and values regarding the management of the cancer, especially on balancing survival benefit with immediate quality of life impairment due to anti-cancer therapy. In Japan Clinical Oncology Group (JCOG) , a randomized controlled trial for older patients with advanced stage HER2-positive breast cancer is ongoing as an inferiority design including geriatric assessment (JCOG1607, HARB TEA study). Best practice, current management and how to approach decision making in older patients with breast cancer are summarized.

DOI： 10.1093/jjco/hyac054

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本乳腺甲状腺超音波医学会  

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BACKGROUND: The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. METHODS: Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. RESULTS: Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. CONCLUSIONS: Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET.

DOI： 10.1371/journal.pone.0278344

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

DOI： 10.3390/ijms222312809

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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The standard first-line treatment for patients with human epidermal growth factor 2-positive metastatic breast cancer is a combination therapy of trastuzumab, pertuzumab and docetaxel, and the standard second-line treatment is trastuzumab emtansine. However, it may be difficult for the elderly to maintain sufficient intensity of treatment due to severe adverse events of trastuzumab, pertuzumab and docetaxel. The aim of this trial is to confirm the non-inferiority of trastuzumab emtansine over trastuzumab, pertuzumab and docetaxel in terms of overall survival in elderly (65-year-old or more) patients with human epidermal growth factor 2-positive metastatic breast cancer. If improved overall survival and fewer toxicities are observed, trastuzumab emtansine may be a feasible new standard first-line treatment for elderly patients with human epidermal growth factor 2-positive metastatic breast cancer. A planned total 330 patients will be enrolled from 45 institutions over 6.5 years. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000030783 [http://www.umin.ac.jp/ctr/index.htm].

DOI： 10.1093/jjco/hyab101

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DOI： 10.1093/jjco/hyab124

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BACKGROUND: We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS. PATIENTS AND METHODS: We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records. RESULTS: We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2-2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2-2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2-2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2-2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm. CONCLUSION: We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.

DOI： 10.1007/s12282-021-01225-0

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Language：English   Publisher：SPRINGER JAPAN KK  

DOI： 10.1007/s12282-021-01256-7

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Perioperative dose-dense chemotherapy (DDCT) with pegfilgrastim (Peg) prophylaxis is a standard treatment for high-risk breast cancer. We explored the optimal timing of administration of 3.6 mg Peg, the dose approved in Japan. In the phase II feasibility study of DDCT (adriamycin+cyclophosphamide or epirubicin+cyclophosphamide followed by paclitaxel) for breast cancer, we investigated the feasibility, safety, neutrophil transition, and optimal timing of Peg treatment by administering Peg at days 2, 3, and 4 post-chemotherapy (P2, P3, and P4 groups, respectively). Among the 52 women enrolled, 13 were aged > 60 years. The anthracycline sequence was administered to P2 (n=33), P3 (n=5), and P4 (n=14) patients, and the taxane sequence to P2 (n=38) and P3 (n=6) patients. Both sequences showed no interaction between Peg administration timing and treatment discontinuation, treatment delay, or dose reduction. However, the relative dose intensity (RDI) was significantly different among the groups. The neutrophil count transition differed significantly among the groups receiving the anthracycline sequence. However, the neutrophil count remained in the appropriate range for both sequences in the P2 group. The timing of Peg administration did not substantially affect the feasibility or safety of DDCT. Postoperative day 2 might be the optimal timing for DDCT.

DOI： 10.18926/AMO/62231

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1200/JCO.2021.39.15_suppl.TPS601

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Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.

DOI： 10.2169/internalmedicine.5089-20

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BACKGROUND: The number of patients desiring implant-based breast reconstruction has been increasing. While local recurrence is observed in patients with breast reconstruction, only a few reports have focused on the risk factors for local recurrence and the prognosis after developing local recurrence. METHODS: We analyzed 387 patients who underwent implant-based breast reconstruction during the period from 2004 to 2017 in Hiroshima City Hospital. We retrospectively examined the risk factors for local recurrence and the outcomes of patients developing such recurrence after implant-based breast reconstruction. RESULTS: The median follow-up time was 59 months. The local recurrence rate was 3.1% (n = 12). The most common reason for detecting local recurrence was a palpable mass. Four patients with local recurrence had recurrence involving the skin just above the primary lesion and needle biopsy tract. All patients with local recurrence received surgery and systemic therapy and most patients received radiation therapy, all have remained free of new recurrence to date. Multivariate analysis showed lymphatic vessel invasion (HR, 6.63; 95% CI, 1.40-31.36; p = 0.017) and positive or < 2 mm vertical margin (HR, 9.72; 95%CI, 1.23-77.13; p = 0.047) to be associated with significantly increased risk of local recurrence. CONCLUSIONS: The risk factors for local recurrence following implant-based breast reconstruction were lymphatic vessel invasion and positive or < 2 mm vertical margin. Removal of the skin just above the primary lesion and needle biopsy tract and adjuvant radiation therapy might improve local outcomes. Patients with local recurrence following implant-based breast reconstruction appear to have good outcomes with appropriate treatment.

DOI： 10.1186/s12905-021-01287-4

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BACKGROUND: Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end-of-life (EOL) communication between oncologists and patients with metastatic breast cancer. MATERIALS AND METHODS: We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39-item questionnaire that measured facility type and function; physicians' background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions. RESULTS: Ninety-eight responses concerning physicians' engagement in ACP with patients were obtained. Seventy-one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians' engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1-7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients' life expectancy was less frequent compared with other topics. CONCLUSION: The opportunity to improve EOL communication skills promoted physicians' engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists. IMPLICATIONS FOR PRACTICE: This study found that the opportunity to improve end-of-life (EOL) communication skills promoted physicians' engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment.

DOI： 10.1002/onco.13640

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Language：Japanese   Publisher：(一社)日本外科学会  

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Over the past 10 years, immunotherapy with immune checkpoint inhibitors has revolutionized the management of various cancers. However, immunotherapy in breast cancer has not been successful. Breast cancer has long been recognized as an immunologically 'cold' tumor, although a higher frequency of tumor-infiltrating lymphocytes present in certain subtypes and an association between tumor-infiltrating lymphocytes and favorable prognosis have been reported. In March 2019, the combination of atezolizumab and nanoparticle albumin-bound paclitaxel was granted accelerated approval in the United States for the treatment of programmed death-ligand 1-positive advanced or metastatic triple-negative breast cancer. This finally opened the door for immune checkpoint blockade therapy for breast cancer. Several clinical trials have been conducted using different combinations of immune checkpoint inhibitors and chemotherapy or targeted agents in various treatment settings for metastatic breast cancer and early-stage breast cancer. In this review, we summarize recent advances in immune checkpoint blockade therapy and predictive biomarkers in breast cancer.

DOI： 10.1093/jjco/hyaa230

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In April 2016, the Japanese government introduced health technology assessment as a response to rising medical expenses due to 'medical innovation'. This study investigates how Japanese breast cancer patients who received treatment in Japan consider the financial value (willingness-to-pay; WTP) for their life and health by using the contingent valuation method (CVM) prospectively. First, 168 patients (84 primary breast cancer patients and 84 metastatic breast cancer patients) were pre-examined their WTP with dichotomous-choice method survey form. Next, 1,596 patients (798 primary breast cancer patients and 798 metastatic breast cancer patients) will be surveyed to their WTP for hypothetical scenarios in CVM. Based on our results, we will construct an evaluation axis from the patients' viewpoint for the cost-effectiveness of clinical trials to establish standard treatments for breast cancer. We believe this research can contribute to create a meaningful healthcare system for patients, clinicians, industries, and healthcare policymakers.

DOI： 10.1093/jjco/hyaa241

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OBJECTIVE: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists. METHODS: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics. RESULTS: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753). CONCLUSION: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.

DOI： 10.1093/jjco/hyaa235

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Recent genome-wide association studies have shown that many single-nucleotide polymorphisms (SNPs) are associated with breast cancer risk. However, it is often unclear how these SNPs are related to breast cancer. Analysis of associations between SNPs and phenotypes may be important for determining mechanisms of action, including carcinogenesis. METHODS: In previous case-control studies, we found three SNPs (rs2046210, rs3757318, and rs3573318) associated with breast cancer risk in Japanese women. Among these SNPs, two (rs2046210 and rs3757318) are located at 6q25.1, in proximity to the estrogen receptor 1 gene (ESR1). Using data from these studies, we examined associations between factors related to breast cancer risk, such as height, weight, and breast density, and the three SNPs in cases and controls. We also investigated whether the SNPs correlated with breast cancer features, such as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type-2 (HER2) status, and clinical stage. RESULTS: There was a significant difference in mean height between risk and non-risk allele carriers for rs2046210 (156.0 ± 5.8 vs. 154.3 ± 5.5 cm, p = 0.002), and rs3757318 (155.8 ± 5.7 vs. 154.7 ± 5.6 cm, p = 0.035) in cases, but no significant associations between height and these SNPs in controls. There was also a significant difference in breast density between risk and non-risk allele carriers for rs2046210 (p = 0.040) and rs3757318 (p = 0.044) in cases. rs2046210 and rs3757318 risk allele carriers tended to have higher breast density in all subjects and in controls. In cases, rs3757318 risk allele carriers were also significantly more likely to be ER-negative compared to non-risk allele carriers (ER-positive rate: 77% vs. 84%, p = 0.036). CONCLUSIONS: SNPs rs2046210 and rs3757318, which are associated with breast cancer risk in Japanese women, were significantly associated with height and high breast density, and this association was particularly strong in those with breast cancer. These findings suggest that SNPs in the ESR1 gene region affect phenotypes such as height and breast density.

DOI： 10.1007/s12282-020-01185-x

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PURPOSE: Epidemiological studies have suggested that intake of soy isoflavones is associated with a reduced risk of development of breast cancer and an improved prognosis in patients with breast cancer. In addition, basic research has demonstrated the antitumor effects of these compounds on breast cancer cell lines. However, the detailed effects of the intake of equol, which is one of the metabolites of the soy isoflavones, are yet to be clarified on the risk of development and recurrence of breast cancer and its interactions with drugs used for treating breast cancer. This study aimed to determine the antitumor effects of equol and investigate the impact of adding equol to therapeutic agents for breast cancer using breast cancer cell lines. METHODS: We examined the antitumor effect of equol on breast cancer cell lines using MTS assay. We also studied the combined effect of equol and the existing hormonal or chemotherapeutic agents using combination index. We evaluated the expressions of the related proteins by Western blot analysis and correlated the findings with the antitumor effect. RESULTS: Equol showed bi-phasic protumor and antitumor effects; at a low concentration, it promoted the tumor growth in hormone receptor-positive cell lines, whereas antitumor effects were generally observed when an excessive amount of dose unexpected in the blood and the tissue was administered. When used with tamoxifen, equol might have some antagonistic effect, although it depends on equol concentration and the type of cancer cells. CONCLUSIONS: We confirmed that equol has dual action, specifically a tumor growth-promoting effect and an antitumor effect. Although the results suggested that equol might exert an antagonistic effect against tamoxifen depending on the concentration, equol did not exert an antagonistic effect on other therapeutic agents.

DOI： 10.1007/s10549-020-05957-z

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Differentiated thyroid carcinoma (DTC) in juvenile patients is often an extensive and aggressive disease with a high frequency of recurrence. However, the prognosis is excellent, with a low mortality rate even when advanced disease is present, although prognostic factors and treatment strategy remain uncertain. Between April 2004 and March 2017, 33 juvenile patients (< 30 years old) were diagnosed with DTC and treated at our institution. We retrospectively investigated prognosis and factors including sex, reason for discovery, treatment, pathological factors and treatment progress to clarify the risk factors. All patients underwent curative surgical treatment. Pathologically, lymph node metastasis was identified in 25 patients (75%). Thirteen patients (39%) had bilateral cervical metastasis. In addition, 9 (27%) had more than 10 metastatic lymph nodes. The 2 patients with more than 20 metastatic lymph nodes were treated with radioactive iodine (RAI). Five patients (15%) had local recurrences and received surgery. There have been no further recurrences or deaths. However, no factors were determined to significantly predict the recurrence of juvenile DTC. Local recurrent disease was treated with surgery and/or RAI until remission, and survival was excellent in juvenile DTC.

DOI： 10.18926/AMO/60799

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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PURPOSE: Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET. METHODS: This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks. RESULTS: Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6-57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6-65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0-78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1-65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6-10.6). CONCLUSION: Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.

DOI： 10.1007/s12282-020-01095-y

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BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

DOI： 10.1016/j.bbrc.2020.06.077

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Language：English   Publisher：AME PUBL CO  

DOI： 10.21037/tcr-2020-mbc-13

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2020-1884

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Metastatic breast cancer (MBC), including de novo stage IV, is regarded as being incurable and the mainstay of clinical management is systemic therapy. Traditionally, locoregional surgery is performed only for local control, such as to prevent ulceration and bleeding. In recent years, however, both retrospective and prospective studies have demonstrated the prognostic efficacy of primary surgery for de novo stage IV patients. Therefore, we conducted a meta-analysis to evaluate whether surgical therapy contributes to overall survival (OS) extension. We searched for clinical trials published in electronic databases (PubMed, Embase, and the Cochrane databases) and performed a meta-analysis of the data collected. There were five prospective randomized controlled phase III trials (RCTs). The results of three have been reported. According to our meta-analysis of these RCTs, primary surgery for de novo stage IV breast cancer patients significantly improves OS. However, the Tata trial showed that systemic therapy does not achieve a sufficient effect. Another trial, conducted in Turkey, had statistical shortcomings and patient randomization was not adequately performed The ABCSG (Austrian Breast and Colorectal Cancer Study Group) trial had too few subjects. Meta-analysis of 12 retrospective studies showed that patients with stage IV breast cancer receiving surgery as the initial treatment experienced longer OS (HR: 0.65, P<0.00001). Based on our meta-analysis of three reported 'RCTs, surgery as the primary treatment does not significantly impact the outcomes of de novo stage IV breast cancer patients. However, these trials had limitations. We await the results of the remaining two ongoing RCTs (ECOG 2108 and JCOG 1017). These trials are anticipated to resolve current controversies and provide many eagerly awaited answers.

DOI： 10.21037/tcr.2020.01.60

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PURPOSE: Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer. METHOD: We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen. RESULT: There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08). CONCLUSION: Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

DOI： 10.1007/s00280-020-04092-2

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Breast cancer is highly sensitive to systemic therapy. High probability of pathological complete response suggests a clinical question that omitting surgery is an effective alternative to surgery in breast cancer showing clinical complete response to primary systemic therapy. However, the validity of omitting surgery for early breast cancer after primary systemic therapy has not been sufficiently established; thus, even if pathological complete response is expected in patients showing clinical complete response, excision of the primary tumor site remains the standard treatment of breast cancer. Inappropriate omitting surgery increases the incidence of local recurrence, which can be the risk of a subsequent distant metastasis and reduced overall survival. To achieve acceptable local control rate, omitting surgery should be investigated in patients with early breast cancer where a high percentage of pathological complete response, a high concordance rate between clinical complete response and pathological complete response and an acceptable local control rate are expected. This review presents concept and ongoing clinical trials for omitting surgery for patients with breast cancer showing clinical complete response to primary systemic therapy.

DOI： 10.1093/jjco/hyaa055

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INTRODUCTION: Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. PATIENTS AND METHODS: We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. RESULTS: Among hormone receptor-positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node-positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. CONCLUSION: In hormone receptor-positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

DOI： 10.1016/j.clbc.2019.07.001

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Systemic therapies for operable breast cancer patients have improved outcomes and have thus become standard treatments. Recently, new molecular target drugs and regimens are being developed based on the predicted sensitivity for specific breast cancer histological types. Systemic therapy is selected according to recurrence risk, with the treatment for low-risk patients being de-escalated, while high-risk patients receive aggressive systemic treatment with an adequate dose and duration. Neoadjuvant systemic therapy has a different aim. The efficacy of systemic therapies, based on the sensitivities to drugs, is supported by improvements in the rate of breast-conserving therapy. The response to neoadjuvant systemic therapy is the most important factor for predicting outcomes and selecting the optimal adjuvant therapy. Novel biological markers unique to individual patients allow appropriate targeted therapy, which can achieve optimal efficacy.

DOI： 10.1093/jjco/hyz213

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Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

DOI： 10.1111/cas.14289

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Mammography is the standard examination for breast cancer screening of woman aged ≥ 40 years. High breast density on mammography indicates that mammary gland parenchyma occupy a high percentage of the breast. The objective of this study was to investigate factors associated with breast density and the risk of high breast density for breast cancer. METHODS: A multicenter case-control study was performed in 530 patients and 1043 controls. Breast density was classified as C1-C4 using the Breast Imaging Reporting and Data System (BI-RADS). Clinical factors were obtained from questionnaires or medical records, and the influence of each factor (breast density, menopausal status, body mass index (BMI), parity, presence or absence of breastfeeding history, age at menarche, age at first birth, and familial history of breast cancer) on breast cancer risk in all patients was calculated as an age-adjusted odds ratio (OR). Multivariate logistic regression analyses were then performed in all patients and in pre- and postmenopausal and BMI-stratified groups using factors with a significant age-adjusted OR as adjustment factors. RESULTS: Age-adjusted ORs for breast cancer were significant for breast density, BMI, parity, and breast feeding, but not for age at menarche, age at first birth, or family history of breast cancer. In multivariate analysis, there was a significant correlation between breast density and breast cancer in postmenopausal women (OR for C1 vs. C2 1.90 [95% CI 1.34-2.70]; C1 vs. C4 2.85 [95% CI 1.10-7.16]). This correlation was also significant in patients in the third BMI quartile (22.3-24.5 kg/m2) (OR for C1 vs. C4 8.76 [95% CI 2.38-42.47]); and fourth BMI quartile (>24.5 kg/m2) (OR for C1 vs. C2 1.92 [95% CI 1.17-3.15]; C1 vs. C4 11.89 [95% CI 1.56-245.17]). CONCLUSION: Breast density on mammography is a risk factor for breast cancer after adjustment for other risk factors. This risk is particularly high in postmenopausal women and those with a high BMI.

DOI： 10.1007/s12282-019-01018-6

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DOI： 10.1158/1538-7445.SABCS19-P5-13-04

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DOI： 10.1158/1538-7445.SABCS19-OT3-13-01

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DOI： 10.1158/1538-7445.SABCS19-OT3-19-01

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BACKGROUND: Angiosarcoma of the breast is very rare and can be divided into primary and secondary angiosarcoma. Radiation-induced angiosarcoma (RIAS) is classified as secondary angiosarcoma. Diagnosis of RIAS is difficult due to its rarity, and the interpretation of pathological imaging is complicated. In the National Comprehensive Care Network (NCCN) guidelines, the first choice of treatment is surgery with negative margins. Adjuvant radiotherapy (RT) for close soft tissue margins should be considered. Preoperative or adjuvant chemotherapy of nonmetastatic disease is not recommended for angiosarcoma. We report a case of RIAS, which was impossible to diagnose with core needle biopsy (CNB) but was diagnosed by excisional biopsy. The patient was then administered adjuvant chemotherapy using conjugated paclitaxel (PTX). CASE PRESENTATION: A 62-year-old woman noticed a tumor in her right breast. She had a history of right breast cancer and had undergone breast-conserving surgery, RT, and tamoxifen therapy 8 years previously. CNB, which was performed twice, was inconclusive. The tumor was surgically excised and pathological analysis yielded a diagnosis of angiosarcoma. She then underwent a right mastectomy. One month after she underwent right mastectomy, a nodule reappeared on the skin of her right breast, and excisional biopsy revealed recurrence of angiosarcoma. A few weeks later another nodule reappeared near the post-operative scar and excisional biopsy revealed recurrence of angiosarcoma. We assumed that surgical therapy was insufficient because the patient experienced relapse of angiosarcoma after complete mastectomy. After the second recurrence, we treated her with systemic chemotherapy using PTX. There was no evidence of recurrence 8 months after chemotherapy. CONCLUSION: Although angiosarcoma is difficult to diagnose, many patients have a poor prognosis. Therefore, prompt treatment intervention is desired. Moreover, there is little evidence regarding adjuvant therapy of angiosarcoma since it is a rare disease. We consider that adjuvant therapy helped to effectively prevent recurrence in the patient after complete excision.

DOI： 10.1186/s40792-020-0790-7

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We have prepared the Japanese Breast Cancer Society clinical practice guidelines (CPGs) for surgical treatment of breast cancer, 2018 update after a systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. The CPG committee for surgical treatment of breast cancer, composed of breast surgeons and plastic surgeons treating breast cancer, has developed the CPGs. Eight clinical questions (CQs) were selected and divided roughly into the following five categories: (1) breast surgery in initial therapy (CQs 1-3); (2) axillary surgery in initial therapy (CQs 4-5); (3) breast reconstruction in initial therapy (CQ 6); (4) surgical treatment for recurrent and metastatic breast cancer (CQs 7-8); and (5) others. Recommendations for these CQs were decided by the GRADE grid method. In addition, 4 outlines, 14 background questions (BQs), and 12 future research questions (FQs) were also selected. Statements for these BQs and FQs are provided. We developed the updated CPGs for surgical treatment of breast cancer, 2018, which include 8 CQs and recommendations. As a decision-making tool for the understanding and treatment of breast cancer, these guidelines will help surgical oncologists dealing with breast cancer, medical staff, and patients, along with their family members.

DOI： 10.1007/s12282-019-01030-w

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Language：English   Publisher：CHURCHILL LIVINGSTONE  

DOI： 10.1016/S0960-9776(19)30746-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.

DOI： 10.1038/s41598-019-50099-y

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2019.37.15_suppl.TPS603

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Language：English   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2019.37.15_suppl.e14182

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

BACKGROUND: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. MATERIALS AND METHODS: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition. RESULTS: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. CONCLUSION: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

DOI： 10.21873/anticanres.13283

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The eighth editions of the primary tumor, lymph node and metastasis classifications for breast cancer issued by the American Joint Commission of Cancer and the Union for International Cancer Control were revised in 2017. The major change made by the American Joint Commission of Cancer is to incorporate biological factors such as estrogen and progesterone receptor, human epidermal growth factor receptor 2, histological grade and multigene prognostic assays, into the staging system. Tumor biomarkers and low recurrence scores confirmed by multigene prognostic assays change the staging. Minor changes are to add the post-neoadjuvant therapy clinical and pathological classification and to define the size of tumor, lymph node and metastasis components more precisely. Little has changed in the Union for International Cancer Control. We have identified key points of change in both eighth editions of the tumor, lymph node and metastasis classifications and we discuss possible problems which may arise when they are adopted in Japanese practice, as well as future directions.

DOI： 10.1093/jjco/hyy182

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Language：English   Publisher：AME PUBL CO  

DOI： 10.21037/tcr.2018.11.19

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

The value of assessing tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive/human epidermal growth factor receptor type 2 (HER2) negative breast cancer has yet to be determined. In the present study, a total of 184 cases with early distant recurrence detected within 5 years following the primary operation, 134 with late distant recurrence diagnosed following 5 years or longer and 321 controls without recurrence for >10 years following starting the initial treatment for ER-positive/HER2 negative breast cancer, registered in 9 institutions, were analyzed. The distributions of TILs and their clinical relevance were investigated. TIL distributions did not differ significantly among the early, late and no recurrence groups, employing a 30% cut-off point as a dichotomous variable. In those who had received adjuvant chemotherapy as well as endocrine therapy, a trend toward higher TIL proportions was detected when the early recurrence group was compared with the no recurrence group employing the 30% cut-off point (P=0.064). The TIL distributions were significantly associated with nodal metastasis (P=0.004), ER status (P=0.045), progesterone receptor (PgR) status (P=0.002), tumor grade (P=0.021), and the Ki67 labeling index (LI) (P=0.002) in the no recurrence group and with the Ki67 LI in the recurrence groups (P=0.002 in early recurrence group, P=0.023 in late recurrence group). High TIL distributions also predicted shorter survival time following the detection of recurrence (P=0.026). However, these prognostic interactions were not significant in multivariate analysis (P=0.200). The present retrospective study demonstrated no significant interaction between TIL proportions and the timing of recurrence. However, higher TIL proportions were observed in breast cancer patients with aggressive biological phenotypes, which tended to be more responsive to chemotherapy. The clinical relevance of stromal TILs for identifying patients who would likely benefit from additional therapies merits further investigation in a larger patient population.

DOI： 10.3892/ol.2018.9853

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Marine-Lenhart syndrome is rare disease defined as coexistence of Graves' disease and autonomously functioning thyroid nodule. We will introduce a case of Marine-Lenhart with a huge goiter.

DOI： 10.1002/jgf2.220

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

BACKGROUND: Perioperative dose-dense chemotherapy (DDCT) with granulocyte-colony stimulating factor (G-CSF) prophylaxis is a standard treatment for patients with high-risk breast cancer. The approval of this approach in Japan led to the widespread adoption of DDCT, despite limited efficacy and safety data among Japanese patients. We evaluated the efficacy and safety of neoadjuvant DDCT for Japanese patients with breast cancer. METHODS: This prospective, multicenter, phase II study evaluated 52 women with operable human epidermal growth factor receptor 2-negative breast cancer and axillary lymph node metastasis. Neoadjuvant DDCT (adriamycin plus cyclophosphamide or epirubicin plus cyclophosphamide followed by paclitaxel) was administrated every 2 weeks with G-CSF support. The study endpoints were the rates of pathological complete response (pCR), febrile neutropenia, treatment completion, toxicities, and the relative dose intensity (RDI). RESULTS: The pCR rate was 21.9% (9/41) and the triple-negative (TN) subtype was significantly associated with a high pCR rate (triple-negative: 53.3% vs. luminal A: 7.7% and luminal B: 0%; p = 0.003). The treatment completion rate was 80.8% (42/52) and the average RDI was 98.9%. Most adverse events were manageable and tolerable. Six patients (11.5%) developed febrile neutropenia. Grade 3-4 adverse events were slightly more common among older patients (57%) with a low protocol completion rate (≥ 65 years: 42.9% vs. <65 years: 86.7%, p = 0.0062). CONCLUSION: The pCR rate for DDCT was similar to that of standard chemotherapy, although it was remarkably effective for the TN subtype. DDCT may be feasible for Japanese patients with breast cancer although caution is needed for older patients.

DOI： 10.1007/s12282-018-0877-1

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Language：English   Publisher：FUTURE MEDICINE LTD  

DOI： 10.2217/bmt-2018-0020

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Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

DOI： 10.1111/cas.13763

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Language：Japanese   Publisher：日本臨床外科学会  

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A 19-year-old girl complained of an enlarged cervical mass. Based on clinical and cytological assessments, it was diagnosed as thyroid follicular carcinoma and left thyroidectomy was performed. Although thyroid neoplasms are rare in young people, differentiation is needed when the rapid growth of a goiter is detected.

DOI： 10.1002/jgf2.185

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s12282-018-0855-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

DOI： 10.18926/AMO/56172

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Adverse effects on fertility are a significant problem for premenopausal breast cancer patients. Since April 2009, we have been referring young patients for fertility counseling provided by a multidisciplinary team. Here we evaluated the efficacy and safety of our current fertility preservation approach. We retrospectively analyzed the cases of 277 patients < 45 years old at diagnosis, which was made between 2009 and 2016. Seventy-two (26%) patients received fertility counseling. Seventeen (6%) of the 277 patients decided to preserve their fertility before starting adjuvant systemic therapy. Six (35%) patients underwent oocyte cryopreservation, and 11 (65%) married patients opted for embryo cryopreservation. There were no pregnancies among the patients undergoing oocyte cryopreservation, whereas 3 (27%) of the patients who opted for embryo cryopreservation became pregnant. Two (12%) patients stopped endocrine therapy after 2 years in an effort to become pregnant, but their breast cancers recurred. Though the problem of fertility loss for breast cancer patients is important and we should assess the infertility risk for all patients, we should also consider the prognosis. In June 2016, we launched a prospective multicenter cohort study to evaluate the efficacy and safety of fertility preservation in greater detail.

DOI： 10.18926/AMO/55854

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

? 2018 Shimoi et al. Background: This is a randomized, multicenter, open-label, Phase II study designed to evaluate the efficacy of everolimus added to continuous aromatase inhibitor (AI) administration in patients who had maintained stable disease or a better response for at least 5 months. Patients and methods: Patients will be randomized to everolimus and standard therapy groups (1:1 ratio). In the everolimus group, patients will receive everolimus in addition to the AI agent. The standard therapy group will continue AI alone treatment. The primary endpoint is progression-free survival. Target accrual is 130 patients with a two-sided type I error rate of 10% and 80% power to detect 35% risk reduction. Conclusion: The Chloe trial will provide important information about the efficacy and safety of adding everolimus to AI in patients with estrogen receptor-positive and human epidermal growth factor 2-negative metastatic breast cancer.

DOI： 10.2147/OAJCT.S155706

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Verlag  

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

DOI： 10.1007/s00280-017-3491-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

PURPOSE: The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. METHODS: We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. RESULTS: Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30-3.14, P = 0.025). CONCLUSIONS: TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.

DOI： 10.1007/s10549-017-4502-3

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PURPOSE: Though advanced and metastatic epidermal growth factor receptor 2 (HER2)-positive disease is not curable, a small proportion of patients with HER2-positive metastatic breast cancer remain in prolonged complete remission with anti-HER2 treatment. We hypothesized that some cases of HER2-positive metastatic breast cancer may be curable. In this large, multicenter retrospective study, we aimed to assess the long-term outcomes for patients with a durable response to trastuzumab. METHODS: We retrospectively evaluated the data of patients diagnosed with HER2-positive metastatic breast cancer who received trastuzumab for more than 2 years as the first-line treatment. Patients diagnosed between April 1, 2001 and December 31, 2014 at 19 institutions in Japan were included in the analysis. From 124 potential subjects, 16 were excluded and 108 were evaluated. RESULTS: The median follow-up length was 7.7 years. Disease progression occurred in 44/108 (40.7%) patients and 13/108 (12%) patients died. The median progression-free survival was 11.2 years, and as more than 80% of patients were alive 10 years after metastatic breast cancer diagnosis. Of the 108 patients, 57 achieved a clinical complete response. Trastuzumab therapy was interrupted for 27 (47.4%) of these patients (based on the doctor's recommendation for 19 patients, owing to adverse events for 4 patients, owing to unknown reasons for 3 patients, and at the request of 1 patient). Disease progression occurred in 4 of the 27 patients after the interruption of trastuzumab treatment. The median duration of trastuzumab therapy for all 27 patients was 5.1 years (0.9-9.3 years). CONCLUSION: We found that some patients showed no evidence of disease after the interruption of trastuzumab therapy. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while awaiting a global collaborative effort for a randomized trial.

DOI： 10.1007/s10549-017-4489-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

DOI： 10.21037/tcr.2018.05.28

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Objective: To clarify how breast cancer patients undergoing post-surgical hormone therapy cope with changes in their sexual lives and support themselves and their partners during these changes.Methods: Participants were 37 breast cancer patients undergoing post-surgical hormone therapy and attending mammary outpatient clinics. In-depth interviews and grounded theory were used to collect and analyze data, respectively.Results: First, sexual life was divided into four groups: “No complaint” regarding sexual activity, “Slight discord”, “Handicapped in meeting a life partner” and “Uninterested” in sexual activity. Sexual life during surgical-hormone therapy did not change significantly from sexual life before breast cancer. Second, meanings of sexual activity for breast cancer patients were divided into five, “Regaining femininity”, “Confirming love”, “Sharing pleasure”, “Response to partner’s higher desire” and “Procreation”. They differed by group. Third, coping strategies were divided into six, “Virtuous cycle to confirm love and regain lost femininity”, “Struggle to avoid relationship crisis”, “Reconfirmation of partner’s affection by his abstinence”, “Attempt to recover the sexual activity they hope for”, “Pursuing children or assuaging partner’s desire by other means” and “Difficulty making a partner continue to have sexual activity”.Conclusions: Nurses should screen breast cancer patients for changes in their sexual lives and to ascertain what sexual activity means to patients, and support them in selecting appropriate coping methods.

DOI： 10.5430/cns.v6n1p61

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

DOI： 10.1007/s12282-017-0771-2

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2017-5592

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Systemic treatment with drugs is administered to prolong survival and palliate symptoms in Stage IV breast cancer patients who have distant metastases at diagnosis. Surgical procedures for the primary tumor are not actively recommended in guidelines due to lack of evidence indicating prognostic benefit. Recently, several retrospective studies have shown primary tumor resection to prolong overall survival in patients with Stage IV breast cancer. Prospective randomized trials began enrolling patients to examine this possibility and two have already reported results. However, the results of these two trials were discordant. The first trial, conducted in India, reported negative effects of primary tumor resection after primary systemic therapy. A Turkish trial then obtained a positive effect of surgery as primary treatment. Several questions regarding the effects, timing, methods and eligibility for primary surgery have yet to be answered. Robust evidence, which is anticipated from other ongoing trials examining surgery for metastatic breast cancer, is eagerly awaited.

DOI： 10.1093/jjco/hyx027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Sentinel lymph node biopsy (SLNB) alone has been compared with SLNB followed by axillary lymph node dissection (ALND) in sentinel lymph node (SLN)-positive breast cancer patients in randomized phase III trials: the addition of ALND did not further improve the patient's outcome. However, there is still some controversy, regarding the clinical application of SLNB alone. To identify the optimal axillary treatment in the era of SLNB, the Japanese Breast Cancer Society conducted a group study of SLNB in 2014. METHODS: A questionnaire on axillary surgery and radiation therapy was sent to 432 Japanese institutes in December 2014, and 309 (72 %) completed the questionnaire. RESULTS: SLNB was performed at 98 % of the institutes, and 77 % offered irradiation for cancer treatment. Regarding breast-conserving surgery (BCS), SLNB alone was indicated at 41 % of the institutes in the cases of SLN with micrometastases. However, in the cases of SLN with macrometastases, ALND was performed at 64 %. The proportion of ALND seemed to be higher in total mastectomy than in BCS regardless of the SLN-positive status. In the cases of SLN with micrometastases, the radiation field was localized in the conserved breast at about half of the institutes. On the other hand, in the cases of SLN with macrometastases, it was extended to axillary and/or supraclavicular lesions beyond the conserved breast at about 70 % of the institutes. CONCLUSIONS: Japanese breast physicians were conservative with respect to the omission of ALND in SLN-positive breast cancer, especially in the cases of SLN with macrometastases.

DOI： 10.1007/s12282-016-0721-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. METHODS: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. RESULTS: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. CONCLUSION: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

DOI： 10.1007/s12282-016-0730-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

BACKGROUND: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers. RESULTS: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). Post-Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P < 0.001 and 0.041, respectively). MATERIALS AND METHODS: Core needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed. CONCLUSIONS: IHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

DOI： 10.18632/oncotarget.15385

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Recent studies have suggested that the association between smoking and breast cancer risk might be modified by polymorphisms in the N-acetyltransferase 2 gene (NAT2). Most of these studies were conducted in Western countries, with few reports from East Asia. METHODS: We conducted a case-control study of 511 breast cancer cases and 527 unmatched healthy controls from December 2010 to November 2011 in Japan. Unconditional logistic regression was used to analyze the association of smoking with breast cancer risk stratified by NAT2 phenotype. RESULTS: In this population, 11 % of the cases and 10 % of the controls were classified as a slow acetylator phenotype. Compared to never smokers, current smokers had an increased breast cancer risk in multivariate analysis [odds ratio (OR) = 2.27, 95 % confidence interval (95 %CI) = 1.38-3.82]. Subgroup analyses of menopausal status indicated the same tendency. Subgroup analyses of NAT2 phenotype, the ORs in both of rapid and slow acetylator phenotype subgroups were comparable, and no interactions were observed between smoking status and NAT2 phenotype (p = 0.97). A dose-dependent effect of smoking on breast cancer risk was seen for the rapid acetylator phenotype, but not for the slow acetylator phenotype. CONCLUSION: Given the high frequency of the rapid acetylator phenotype, these results show that smoking is a risk factor for breast cancer among most Japanese women. It may be of little significance to identify the NAT2 phenotype in the Japanese population.

DOI： 10.1007/s12282-016-0696-1

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Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem cell (CSC) marker that is easily evaluable. The expression and clinical significance of ALDH1 in ipsilateral breast tumor recurrence (IBTR) has yet to be investigated. In the present study, the expression profile of ALDH1 and its correlation with prognosis in IBTR tissues was examined. Patients with IBTR from eight institutions were retrospectively enrolled in the study. Immunohistochemistry was used to examine ALDH1 expression patterns in the tissue specimens of primary cancers and IBTRs. ALDH1 expression levels were investigated in 182 IBTR tumors, which included cases of invasive carcinoma selected from 271 consecutive patients with IBTR. ALDH1 was expressed in 23% of the IBTR tissue samples. The rate of concordant expression between primary cancer and IBTR tissues was 68%. There was no significant association between disease-free survival (DFS) and ALDH1 expression levels in IBTR. IBTRs that expressed ALDH1 and Ki-67 had a poorer prognosis and this expression pattern was significantly associated with DFS (P=0.0073). The percentages of ALDH1 positive expression in each tissue subtype were as follows: Luminal A, 20%; luminal B, 24%; human epidermal growth factor 2 (HER2), 35%; triple-negative, 21%. There was a significant correlation between DFS and ALDH1 expression levels in HER2-type IBTR tissue specimens (P=0.034). In conclusion, it is possible that ALDH1 and Ki-67 expression levels may be useful for predicting prognosis in patients with HER2-type tumors.

DOI： 10.3892/ol.2016.5538

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: An understanding of health-related quality of life (HRQOL) is of utmost importance in both oncological and esthetic breast surgery. The BREAST-Q is a patient-reported outcome (PRO) measure that investigates HRQOL and patient satisfaction before and after breast surgery. The aim of this study was to develop a Japanese version of the BREAST-Q including the mastectomy module, the reconstruction module, the augmentation module and the reduction/mastopexy module, and to assess the psychometric properties of the mastectomy module among Japanese women. METHODS: The Japanese version of the BREAST-Q was developed through forward translation, backward translation and patient testing. Traditional psychometric testing of the mastectomy module was administered to 45 post-mastectomy patients. RESULTS: The mastectomy, reconstruction, augmentation and reduction/mastopexy modules were formally developed into Japanese. Despite cultural difference between Japanese women and original target population, the contents were considered to be valid among Japanese woman. With the exception of the sexual well-being subscale, good reliability and validity were evident for the mastectomy module (Test-retest reliability 0.76-0.95, Chronbach's alpha coefficient 0.77-0.98). CONCLUSIONS: The BREAST-Q Japanese version is a useful PRO measure for investigating the impact of breast surgery on HRQOL and patient satisfaction. Further validation in younger Japanese women is needed to determine the usefulness of the sexual well-being subscale.

DOI： 10.1007/s12282-016-0703-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. METHODS: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than 10 years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. RESULTS: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. CONCLUSION: Predictors of early and late distant recurrence might differ according to menopausal status and age.

DOI： 10.1007/s12282-015-0649-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.

DOI： 10.18926/AMO/54607

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PURPOSE: Gemcitabine (Gem) with paclitaxel (Pac) is used for patients with metastatic breast cancer who require cytoreduction with manageable toxicities. Nanoparticle albumin-bound (nab)-Pac exhibits better efficacy and reduces the risk of hypersensitivity reactions associated with solvent-based Pac. Therefore, Gem plus nab-Pac (GA) therapy may be effective for metastatic breast cancer. The purpose of this study was to determine the maximum tolerated dose for GA therapy. METHODS: The subjects were patients with metastatic breast cancer with performance status 0 or 1 and normal hepatic, renal and marrow function. Leukopenia, neutropenia or thrombocytopenia of grade 4, neutropenic fever, or non-hematological toxicity of grade 3 or higher during the 1st cycle, and chemotherapy-induced peripheral neurotoxicity of grade 2 or higher at the end of the 1st cycle were defined as dose-limiting toxicities (DLTs). Gem (1250 mg/m(2)) was administered on days 1 and 8. nab-Pac was administered at a starting dose of 180 mg/m(2) (cohort 1) and escalated to 220 mg/m(2) (cohort 2) and 260 mg/m(2) (cohort 3) on day 1 of the 21-day cycle, using a 3 + 3 design. RESULTS: Nine patients (n = 3, 3, and 3 in cohorts 1, 2, and 3, respectively) were included in the study (median age 56 years; range 43-75 years). DLTs did not occur in any cohorts. CONCLUSIONS: The initial recommend dose in GA therapy is 1250 mg/m(2) Gem and 260 mg/m(2) nab-Pac. It is well known that nab-Pac has cumulative toxicities, and thus the efficacy and safety of GA therapy require validation in a phase 2 study.

DOI： 10.1007/s00280-016-3091-x

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A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8＋ T cells, which produce multiple cytokines.

DOI： 10.18926/AMO/54514

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

BACKGROUND: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. METHODS: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. RESULTS: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). CONCLUSIONS: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

DOI： 10.1186/s13058-016-0731-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown.
Methods: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group.
Results: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18. 4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p &lt; 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p &lt; 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059).
Conclusions: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

DOI： 10.1186/s13058-016-0731-3

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INTRODUCTION: Breast-conserving surgery is a standard treatment for early breast cancer. For ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery, salvage mastectomy is the current standard surgical procedure. However, it is not rare for patients with IBTR who have received salvage mastectomy to develop local recurrence. In this study, we examined the risk factors of local recurrence after salvage mastectomy for IBTR. PATIENTS AND METHODS: A total of 118 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent salvage mastectomy without irradiation for IBTR between 1989 and 2008 were included from eight institutions in Japan. The risk factors of local recurrence were assessed. RESULTS: The median follow-up period from salvage mastectomy for IBTR was 4.6 years. Patients with pN2 or higher on diagnosis of the primary tumor showed significantly poorer local recurrence-free survival than those with pN0 or pN1 at primary tumor (p < 0.001). Multivariate analysis showed that the lymph node status of the primary tumor was a significantly independent predictive factor of local recurrence-free survival (p = 0.02). CONCLUSION: The lymph node status of the primary tumor might be a predictive factor of local recurrence-free survival after salvage mastectomy for IBTR. Further research and validation studies are needed. (UMIN-CTR number UMIN000008136).

DOI： 10.1016/j.ejso.2016.03.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells, and the expression of ALDH1 may be a prognostic factor of poor clinical outcome. The epithelial-mesenchymal transition may produce cells with stem-cell-like properties promoted by transcription factors. We investigated the expression of ALDH1 and transcription factors in both primary and metastatic lesions, and prognostic value of them in breast cancer patients with axillary lymph node metastasis (ALNM). METHOD: Forty-seven breast cancer patients with ALNM who underwent surgery at Okayama University Hospital from 2002 to 2008 were enrolled. We retrospectively evaluated the levels of ALDH1 and transcription factors, such as Snail, Slug and Twist, in both primary and metastatic lesions by immunohistochemistry. RESULTS: In primary lesions, the positive rate of ALDH1, Snail, Slug and Twist was 19, 49, 40 and 26%, respectively. In lymph nodes, that of ALDH1, Snail, Slug and Twist was 21, 32, 13 and 23%, respectively. The expression of ALDH1 or transcription factors alone was not significantly associated with a poor prognosis. However, co-expression of ALDH1 and Slug in primary lesions was associated with a shorter DFS (P = 0.009). CONCLUSIONS: The evaluation of the co-expression of ALDH1 and transcription factors in primary lesions may be useful in prognosis of node-positive breast cancers.

DOI： 10.1007/s12282-015-0583-1

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BACKGROUND: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, first-generation genomic signatures serve predominately as prognostic biomarkers and secondarily as predictors of response to chemotherapy. We compared both the prognostic and predictive value of histologic grades and genomic markers. METHODS: We retrieved publicly available cDNA microarray data from 1373 primary ER(+)/HER2(-) breast cancers and developed a genomic signature simulated from Recurrence Online (http://www.recurrenceonline.com/) to calculate the recurrence score and risk using predefined sets of genes in the cDNA microarray. We then compared the prognostic and predictive information provided by histologic grade and genomic signature. RESULTS: Based on genomic signatures, 55%, 28%, and 17% of breast cancers were classified as low, intermediate, and high risk, respectively, whereas the histologic grades were I, II, and III in 22%, 59%, and 19% of breast cancers, respectively. Univariate analysis in the untreated cohort revealed that both histologic grade (overall P = .007) and genomic signature (P < .001) could predict prognosis. Results were similar using the genomic signature, with pathologic complete response rates of 4.6%, 5.7%, and 16.5% for low-, intermediate-, and high-risk cancers, respectively. Neither biomarker was statistically significant in multivariate analysis for predictive response to neoadjuvant chemotherapy (NAC). CONCLUSION: Genomic signature was better at identifying low-risk cases compared to histologic grade alone, but both markers had similar predictive values for NAC response. Better predictive biomarkers for NAC response are still needed.

DOI： 10.1016/j.clbc.2015.10.004

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INTRODUCTION: Mastectomy is the current standard surgical procedure for ipsilateral breast tumor recurrence (IBTR). However, there is little evidence about the prognostic impact of the surgical procedure (mastectomy versus repeat lumpectomy) for IBTR. PATIENTS AND METHODS: A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for IBTR between 1989 and 2008 were included from eight institutions in Japan. The impact of the surgical procedure for IBTR on distant disease-free survival (DDFS) and overall survival (OS) was evaluated using and multivariable proportional hazards regression and propensity score matching methods. RESULTS: Of the 271 patients, 149 patients (55%) underwent repeat lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. The median follow-up period from definitive surgery for IBTR was 55 months. There was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR, adjusted for various clinical and tumor characteristics. In addition, for the matched patient cohort, no difference in DDFS and OS was seen between the 2 groups. CONCLUSION: In our study, both multivariate analysis and the propensity score matching method demonstrated that there was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR. Further studies are warranted (UMIN-CTR number UMIN000008136).

DOI： 10.1016/j.ejso.2016.01.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER MEDICAL ASSOC  

DOI： 10.1001/jamadermatol.2015.2507

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A 52-year-old woman presented with stage IIB primary breast cancer (cT2N1M0), which was treated using neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and paclitaxel). However, the tumor persisted in patchy areas; therefore, we performed modified radical mastectomy and axillary lymph node dissection. Routine endoscopy at 8 months revealed a depressed lesion on the gastric angle's greater curvature, and histology revealed signet ring cell proliferation. We performed endoscopic submucosal dissection for gastric cancer, although immunohistochemistry revealed that the tumor was positive for estrogen receptor, mammaglobin, and gross cystic disease fluid protein-15 (E-cadherin-negative). Therefore, we revised the diagnosis to gastric metastasis from the breast cancer.

DOI： 10.1155/2016/2085452

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Operative stress causes various changes in the body, and immunological hypofunction and malnutrition increase complications and adversely affect long-term prognosis. Therefore, reducing operative stress as much as possible, minimizing complications after surgery, and aiming for a satisfactory postoperative course are important. However, difficult and unresolvable situations often arise when only the conventional Western medicine approach is used because the situation and condition varies for each patient. We believe that Kampo medicine is very useful in diverse situations. Particularly, Kampo medicine has been used more frequently in recent years, with the expectation of numerous effects, because the effectiveness of Kampo medicine on various disease states has been proven and the pharmacological ingredients and the mechanisms by which Kampo medicine exerts its effects have been better clarified scientifically. Kampo medicine will have an effect in various situations, and we think that Kampo medicine occupies an important position in team-based medical care with multiple specialists. Kampo medicine compounds have been reported to be useful for the following conditions: Hochuekkito and Juzentaihoto for improving immunocompetence after operative stress, Daikenchuto and Rikkunshito for improving postoperative gastrointestinal motility, Shakuyakukanzoto for postoperative wound pain control, Yokukansan for postoperative delirium, and Inchinkoto for postoperative liver dysfunction. The availability of numerous treatment choices that work well in specific situations would be useful for cancer patients during the perioperative period.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: Young breast cancer survivors have specific needs related to age. Clarifying the relationships between unmet information needs and quality of life (QOL) in young breast cancer survivors can contribute to constructing a support system to enhance QOL in patients.
Objective: This study aimed to identify the unmet information needs and examine the relationships between unmet information needs and QOL in young breast cancer survivors in Japan.
Methods: Participants completed an information needs questionnaire containing 26 items, the World Health Organization Quality of Life Instrument-Short Form (WHOQOL-BREF), and a demographic and medical information questionnaire.
Results: Fifty participants (30.7%) were unsatisfied with overall communication with medical professionals. The mean scores on all subscales of the WHOQOL-BREF of the participants who were satisfied with overall communication with medical professionals were significantly higher than those of the unsatisfied group. follow-up tests, treatment for recurrence of breast cancer, strategies about communication with medical staff, and nutrition were significantly related with all subscales in the WHOQOL-BREF. Secondary menopause caused by hormonal therapy was significantly related with physical and psychological health.
Conclusions: Japanese young breast cancer survivors have unmet information needs, including age-specific issues. These unmet information needs are related to QOL. In particular, overall communication with medical professionals, which is the most unmet information need, is related to QOL.
Implications for Practice: Oncology nurses should teach patients communication skills, provide adequate information, and provide education and emotional support to medical professionals to improve QOL in young breast cancer survivors.

DOI： 10.1097/NCC.0000000000000201

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The primary purpose of this large cohort study is to investigate the effects on breast cancer outcomes of modifiable lifestyle factors after breast cancer diagnosis. These factors include physical activity, smoking, alcohol consumption, obesity and weight gain after diagnosis, alternative medicine and dietary factors. Women diagnosed with Stage 0 to III breast cancer are eligible for participation to this study. Lifestyle, use of alternative medicine, psychosocial factors, reproductive factors and health-related quality of life will be assessed using a questionnaire at the time of breast cancer diagnosis (baseline), and 1, 2, 3 and 5 years after diagnosis. Clinical information and breast cancer outcomes will be obtained from a breast cancer database. The primary endpoint will be disease-free survival. Secondary endpoints are overall survival, health-related quality of life, breast cancer-related symptoms and adverse events. Patient recruitment commenced in February 2013. Enrollment of 2000 breast cancer patients is planned during the 5-year recruitment period. The concept of the study is described in this article.

DOI： 10.1093/jjco/hyv033

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.SABCS14-P6-01-09

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INTRODUCTION: Changes in the biological marker status between primary and recurrent tumors are observed in breast cancer. However, their clinical significance is still uncertain, especially for patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. PATIENTS AND METHODS: A total of 117 patients with IBTR without distant metastases were enrolled in this study. All patients were examined for estrogen receptor (ER), HER2, and Ki-67 in both the primary tumors and paired IBTR. We evaluated the impact of changes in these biomarkers between primary tumors and IBTR on the prognosis after IBTR. RESULTS: There were no associations of changes in the ER, HER2 status with distant disease-free survival (DDFS) after surgical resection of IBTR, whereas the change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS (unadjusted: p = 0.0094; adjusted: p = 0.013). Patients in the "increased or remained high" Ki-67 group had a significantly shorter DDFS than those in the "decreased or remained low" Ki-67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p = 0.0084 by log-rank test). CONCLUSION: An increased or persistently high Ki-67 status in the IBTR was significantly correlated with a poorer prognosis after IBTR.

DOI： 10.1016/j.ejso.2015.01.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We evaluated the usefulness of preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) examinations to predict the pathological features in primary breast cancer. In particular, we evaluated the correlation between the maximum standardized uptake values (SUVmax) obtained by 18F-FDG PET/CT and the Ki67 expression in estrogen receptor (ER)-positive invasive ductal carcinoma (IDC). Primary IDC patients operated between March 2009 and July 2013 at Okayama University Hospital were enrolled. We evaluated the correlations between the SUVmax and age, postoperative pT, histological grade, lymph vascular invasion, status of hormone receptor, human epidermal growth factor receptor 2 (HER2), Ki67 expression and node status. The Ki67 expression was classified as high (＞ 14%) versus low (< 14%). We enrolled 138 patients with IDC. Their median SUVmax was 3.85 (range:0-52.57). In a univariate analysis, the SUVmax was significantly related to age, pT, histological grade, lymphovascular invasion, hormone receptor status, HER2 status, node status and Ki67. In the 113 patients with ER-positive IDC, there was a significant correlation between Ki67 and SUVmax (p ＝ 0.0030). The preoperative 18F-FDG PET/CT results of IDC patients had significant relationships with pathological status parameters. The determination of the preoperative SUVmax might help classify Luminal A and Luminal B patients among luminal-type breast cancer patients.

DOI： 10.18926/AMO/53907

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Cancer subtype has recently become an increasingly important consideration when deciding the treatment strategy for breast cancer. For the estrogen receptor positive (ER+) subtype, the efficacy of adjuvant endocrine therapy is definitive, but that of adjuvant chemotherapy is controversial.
In order to evaluate the effect of adding doxorubicin (A) and cyclophosphamide (C) to tamoxifen (TAM) (ACT) on the overall survival (OS) of node-positive postmenopausal breast cancer (PMBC) patients, we conducted a randomized trial. Eligibility criteria included pathologically node-positive (n = 1-9) PMBC, stage I-IIIA disease. Patients were randomized to receive either TAM (20 mg daily) for 2 years or A (40 mg/m(2)) and C (500 mg/m(2)) plus TAM (ACT) as adjuvant therapy following surgery.
One hundred twenty-nine patients were recruited (TAM 64, ACT 65) between October 1994 and July 1999. The hazard ratios for OS and relapse-free survival (RFS) were 0.58 (95 % CI 0.24-1.39; log-rank p = 0.22) and 0.45 (95 %CI 0.24-0.86; log-rank p = 0.013), respectively, in favor of ACT. The 5-year OS and RFS were 76.9 % (ER+ 87.1 %, ER- 53.3 %) and 54.9 % (ER+ 59.3 %, ER- 42.9 %) for TAM and 85.0 % (ER+ 90.0 %, ER- 77.1 %) and 76.7 % (ER+ 76.9 %, ER- 76.0 %) for ACT. A higher proportion of the patients receiving ACT than those receiving TAM experienced grade 3 decreased white blood cell count and grade 2-3 nausea.
The efficacy of adding AC to TAM was not high for ER+, node-positive PMBC. However, adjuvant ACT therapy was considered to be effective for ER-, node-positive PMBC.

DOI： 10.1007/s10147-013-0657-z

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There are limited data on the outcomes of patients treated with repeat lumpectomy at the time of ipsilateral breast tumor recurrence (IBTR). Especially, the impact of radiotherapy (RT) on a second IBTR is unknown.
We retrospectively analyzed 143 patients from 8 institutions in Japan who underwent repeat lumpectomy after IBTR. The risk factors of a second IBTR were assessed.
The median follow-up period was 4.8 years. The 5-year second IBTR-free survival rate was 80.7 %. There was a significant difference in the second IBTR-free survival rate according to RT (p = 0.0003, log-rank test). The 5-year second IBTR-free survival rates for patients who received RT after initial surgery, RT after salvage surgery, and no RT were 78.0, 93.5, and 52.7 %, respectively. Multivariate analysis revealed that RT was a significantly independent predictive factor of second IBTR-free survival.
Repeat lumpectomy plus RT is a reasonable option in patients who did not undergo RT at the initial surgery. In contrast, caution is needed when RT is omitted in patients who have undergone repeat lumpectomy.

DOI： 10.1007/s12282-013-0454-6

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We evaluated the expression of aldehyde dehydrogenase 1 (ALDH1) between primary breast lesions and pulmonary metastatic (PM) lesions in breast cancer patients.
We retrospectively analyzed the clinicopathological features and the expression statuses of ER, PR, HER2, Ki-67 and ALDH-1 in both primary and metastatic breast cancer lesions and evaluated the discordance rates in the expressions of these markers between the primary and metastatic lesions, and also the prognostic value of these factors.
None of the PM patients had metastases at any other sites, and all had undergone curative breast cancer surgery. The pulmonary operation was partial resection in 15 (88 %) patients and lobectomy in 2 (12 %) patients. The median overall survival (OS) after resection of the PNs (OS) was 48 months. The discordance rates in the expressions of ER, PR, HER2, Ki67 and ALDH-1 between the primary and metastatic lesions were 0, 29, 21, 43 and 50 %, respectively.
There was significant discordance in the biomarkers between the primary tumors and the metastatic lesions.

DOI： 10.1007/s12282-013-0445-7

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To clarify the clinicopathological features of breast cancer in young females, surveillance data of the Registration Committee of the Japanese Breast Cancer Society were analyzed.
The clinicopathological characteristics were compared between young (&lt; 35) patients and non-young (a parts per thousand yen35) patients among 109,617 records registered between 2004 and 2009.
The numbers of young and non-young patients were 2,982 (2.7 %) and 106,295 (97.0 %), respectively. The young patients had more cases of a familial history of breast cancer, more subjective symptoms, fewer bilateral tumors, lower BMIs, larger tumors, more positive lymph nodes, fewer instances of an ER-positive status, more instances of an HER2-positive status, more triple-negative tumors and more advanced TNM stages. The young patients more frequently received neoadjuvant chemotherapy and breast-conserving therapy (BCT) compared with the non-young patients. Eighty percent of all patients received adjuvant therapy. The young patients were more frequently treated with chemotherapy, molecular targeted therapy and radiation therapy than the non-young patients.
In this study, young patients with breast cancer were diagnosed at more advanced stages and had more endocrine-unresponsive tumors than non-young patients. Further prognostic analyses should be conducted in this cohort.

DOI： 10.1007/s12282-013-0466-2

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Systemic therapies have been shown to effectively improve prognosis in patients with breast cancer. However, such therapies also become increasingly harmful as their duration increases, and they have adverse effects on fertility and ovarian function. Fertility preservation (FP) is important in young adult cancer survivors who may wish to have children. In Japan, some cancer societies recommend that the potentially serious effects of systemic therapy on ovarian function should be explained to women with cancer, and they should be encouraged to undergo FP prior to commencing treatment. Still, as there are no official guidelines, many oncologists lack the required knowledge and mind-set to advise young breast cancer patients on fertility issues. Counseling of patients and their families might improve their understanding about the influence of such treatment on fertility and ensure effective FP. There are several FP methods that can be selected before beginning treatment, and these methods have both advantages and disadvantages. Young adults with breast cancer who want to bear children in the future must be provided with FP counseling, in addition to advice about breast cancer treatment and prognosis.

DOI： 10.1007/s12282-013-0463-5

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PURPOSE: A prospective randomized clinical trial was conducted to evaluate the efficacy of tamoxifen plus doxorubicin and cyclophosphamide compared to tamoxifen plus tegafur-uracil as an adjuvant therapy to treat node-positive premenopausal breast cancer (PreMBC). METHODS: Eligibility criteria included pathologically node-positive (n = 1-9) preMBC with curative resection, in stages I-IIIA. Patients were randomized to receive either tamoxifen 20 mg/day plus tegafur-uracil 400 mg/day (TU) for 2 years or six courses of a 28-day cycle of doxorubicin 40 mg/m(2) plus cyclophosphamide 500 mg/m(2) on day 1 along with tamoxifen (ACT) given for 2 years as adjuvant therapy. Primary endpoint was overall survival (OS), and secondary endpoint was recurrence-free survival (RFS). RESULTS: In total, 169 patients were recruited (TU arm 87, ACT arm 82) between October 1994 and September 1999. The HR for OS was 0.76 (95 % CI 0.35, 1.66, log-rank p = 0.49) and that for RFS was 0.77 (95 % CI 0.44, 1.36, log-rank p = 0.37), with ACT resulting in a better HR. The 5-year OS was 79.7 % for patients in the TU arm and 83 % for those in the ACT arm. The 5-year RFS was 66.1 % for patients in the TU arm and 70.6 % for those in the ACT arm. A higher proportion of patients in the ACT arm experienced grade 3 leucopenia (0 % in the TU arm, 4 % in the ACT arm). CONCLUSIONS: There were no significant differences in the efficacy of TU and ACT as adjuvant therapy.

DOI： 10.1007/s00280-014-2545-2

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Language：English   Publisher：PIONEER BIOSCIENCE PUBL CO  

DOI： 10.3978/j.issn.2072-1439.2014.06.13

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Co., Limited  

Stage IV breast cancer refers to breast cancer that has already metastasized to distant regions when initially diagnosed. Treatment for stage IV is intended to "prolong survival and palliate symptoms". Resection of a primary tumor is considered to be "effective only at alleviating chest symptoms and providing local control" in spite of the advances of imaging examination and medication for breast cancer. Molecular target and endocrine drugs are very effective and useful to tailor-make a treatment strategy according to breast cancer subtypes. Positron emission tomography-computed tomography can detect and diagnose the very small metastases and recurrences which can potentially be cured even if they are distant metastases. Recently, many retrospective studies have reported the survival benefit of surgery for breast cancer patients with metastases and some clinical trials which confirm the surgical prognostic benefit for them have started to enrol patients. The goal of treatment has to be clearly identified: increase the patient's survival time, provide local control or perform histology to determine the cancer's properties. The best evidence is absolutely essential to treat patients who need surgery at the right time. We need to evaluate the treatment strategy, including primary resection for stage IV breast cancer particularly, and find new evidence by prospective analysis.

DOI： 10.5306/wjco.v5.i2.82

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

A 55-year-old woman underwent a total thyroidectomy for carcinoma showing thymus-like differentiation (CASTLE). The patient was referred to our hospital after the tumor was found to have directly invaded the cervical esophagus and the entire circumference of the trachea. A total thyroidectomy was performed, followed by end-to-end anastomosis of the trachea, suprahyoid release and dissection of bilateral pulmonary ligaments. No major complications, including anastomotic dehiscence or stenosis, were observed. The patient experienced some swallowing disturbances and hoarseness during the perioperative period but fully recovered. Radiotherapy to the neck was performed as an adjuvant therapy. Eleven months after surgery, lower back pain and right leg numbness developed and led to gait inability. Multiple lung and bone recurrences were observed, but no local recurrence. Palliative radiotherapy to the bone metastasis was performed. The patient died of pleural metastasis 14 months after the initial diagnosis of CASTLE.

DOI： 10.1159/000370306

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Recently, evidence in support of the cancer stem cell (CSC) hypothesis has been accumulating. On the other hand, it has been reported that the expression of aldehyde dehydrogenase 1 (ALDH1) in primary breast cancer is a powerful predictor of a poor clinical outcome, and that breast cancer stem cells express ALDH1. According to the CSC hypothesis, development of metastases requires the dissemination of CSC that may remain dormant and be reactivated to cause tumor recurrence. In this study, we investigated whether the detection of CSC in axillary lymph node metastases (ALNM) might be a significant prognostic factor in patients with breast cancer.
From 1998 to 2006, 40 primary breast cancer patients with ALNM, the number of metastatic nodes varying in number from 1 to 3, underwent surgery at Okayama University; of these, 15 patients developed tumor recurrence. We retrospectively evaluated the common clinicopathological features and the expression of ER, HER2, ALDH1, and Ki67 in both the primary lesions and the ALNM, and analyzed the correlations between the expression of these biological markers and the disease-free survival (DFS).
Expression of ALDH1 in the ALNM was significantly associated with the DFS (P = 0.037).
Evaluation of biomarker expression in ALNM could be useful for prognosis in breast cancer patients with 1-3 metastatic lymph nodes.

DOI： 10.1007/s12282-012-0350-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

We examined estrogen receptor (ER) mRNA expression and molecular subtypes in stage I-III breast cancers that are progesterone receptor (PR) positive but ER and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization. The ER, PR, and HER2 status was determined by IHC as part of routine clinical assessment (N = 501). Gene expression profiling was done with the Affymetrix U133A gene chip. We compared expressions of ESR1 and MKI67 mRNA, distribution of molecular subtypes by the PAM50 classifier, the sensitivity to endocrine therapy index, and the DLDA30 chemotherapy response predictor signature among ER/PR-positive (n = 223), ER-positive/PR-negative (&lt;Emphasis Type="ItalicUnderline"&gt;n = 73), ER-negative/PR-positive (n = 20), and triple-negative (n = 185) cancers. All patients received neoadjuvant chemotherapy with an anthracycline and taxane and had adjuvant endocrine therapy only if ER or PR &gt; 10 % positive. ESR1 expression was high in 25 % of ER-negative/PR-positive, in 79 % of ER-positive/PR-negative, in 96 % of ER/PR-positive, and in 12 % of triple-negative cancers by IHC. The average MKI67 expression was significantly higher in the ER-negative/PR-positive and triple-negative cohorts. Among the ER-negative/PR-positive patients, 15 % were luminal A, 5 % were Luminal B, and 65 % were basal like. The relapse-free survival rate of ER-negative/PR-positive patients was equivalent to ER-positive cancers and better than the triple-negative cohort. Only 20-25 % of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers. In this rare subset of patients (i) a second RNA-based assessment may help identifying the minority of ESR1 mRNA-positive, luminal-type cancers and (ii) the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy.

DOI： 10.1007/s10549-013-2763-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Lifestyle factors, including food and nutrition, physical activity, body composition and reproductive factors, and single nucleotide polymorphisms (SNPs) are associated with breast cancer risk, but few studies of these factors have been performed in the Japanese population. Thus, the goals of this study were to validate the association between reported SNPs and breast cancer risk in the Japanese population and to evaluate the effects of SNP genotypes and lifestyle factors on breast cancer risk.
Methods: A case-control study in 472 patients and 464 controls was conducted from December 2010 to November 2011. Lifestyle was examined using a self-administered questionnaire. We analyzed 16 breast cancer-associated SNPs based on previous GWAS or candidate-gene association studies. Age or multivariate-adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were estimated from logistic regression analyses.
Results: High BMI and current or former smoking were significantly associated with an increased breast cancer risk, while intake of meat, mushrooms, yellow and green vegetables, coffee, and green tea, current leisure-time exercise, and education were significantly associated with a decreased risk. Three SNPs were significantly associated with a breast cancer risk in multivariate analysis: rs2046210 (per allele OR = 1.37 [95% CI: 1.11-1.70]), rs3757318 (OR = 1.33[1.05-1.69]), and rs3803662 (OR = 1.28 [1.07-1.55]). In 2046210 risk allele carriers, leisure-time exercise was associated with a significantly decreased risk for breast cancer, whereas current smoking and high BMI were associated with a significantly decreased risk in non-risk allele carriers.
Conclusion: In Japanese women, rs2046210 and 3757318 located near the ESR1 gene are associated with a risk of breast cancer, as in other Asian women. However, our findings suggest that exercise can decrease this risk in allele carriers.

DOI： 10.1186/1471-2407-13-565

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

BACKGROUND: There is little information about the impact of breast cancer subtype on prognosis after ipsilateral breast tumor recurrence (IBTR). METHODS: One hundred eighty-five patients were classified according to breast cancer subtype, as approximated by estrogen receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67, of IBTR, and we evaluated whether breast cancer subtype was associated with distant recurrence after IBTR. RESULTS: There was a significant difference in distant disease-free survival (DDFS) after IBTR according to breast cancer subtype defined by a cutoff of the Ki-67 index of 20 % (p = 0.0074, log-rank test). The 5-year DDFS rates for patients with luminal A, luminal B, triple-negative, and HER2 types were 86.3, 57.1, 56.6, and 65.9 %, respectively. In addition, breast cancer subtype was significantly associated with distant recurrence after IBTR on adjustment for various clinicopathologic factors (p = 0.0027, Cox proportional hazards model). CONCLUSIONS: Our study suggests that breast cancer subtype based on immunohistochemical staining predicts the outcomes of patients with IBTR. Further analyses are needed (UMIN-CTR number UMIN000008136).

DOI： 10.1245/s10434-012-2825-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

While clinical and pathologic responses are important prognostic parameters, biological markers from core needle biopsy (CNB) are needed to predict neoadjuvant chemotherapy (NAC) response, to individualize treatment, and to achieve maximal efficacy. We retrospectively evaluated the cases of 183 patients with primary breast cancer who underwent surgery after NAC (anthracycline and taxane) at the National Cancer Center Hospital (NCCH). We analyzed EGFR, HER2, and p53 expression and common clinicopathological features from the CNB and surgical specimens of these patients. These biological markers were compared between sensitive patients (pathological complete response; pCR) and insensitive patients (clinical no change; cNC and clinical progressinve disease; cPD). In a comparison between the 9 (5%) sensitive patients and 30 (16%) insensitive patients, overexpression of p53 but not overexpression of either HER2 or EGFR was associated with a good response to NAC. p53 = 0.045) and histological grade 3 (p = 0.011) were important and significant predictors of the response to NAC. The correspondence rates for histological type, histological grade 3, ER, PgR, HER2, p53, and EGFR in insensitive patients between CNB and surgical specimens were 70%, 73%, 67%, 70%, 80%, 93%, and 73%. The pathologic response was significantly associated with p53 expression and histological grade 3. The correspondence rate of p53 expression between CNB and surgical specimens was higher than that of other factors. We conclude that the level of p53 expression in the CNB was an effective and reliable predictor of treatment response to NAC.

DOI： 10.18926/AMO/50409

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

A high mammographic breast density is considered to be a risk factor for breast cancer. However, only a small number of studies on the association between breast density and lifestyle have been per- formed. A cross-sectional study was performed using a survey with 29 questions on life history and lifestyle. The breast density on mammography was classified into 4 categories following the BI-RADS criteria. The subjects were 522 women with no medical history of breast cancer. The mean age was 53.3 years old. On multivariate analysis, only BMI was a significant factor determining breast density in premenopausal women (parameter estimate, 0.403
p value, 0.0005), and the density decreased as BMI rose. In postmenopausal women, BMI (parameter estimate, 0.196
p value, 0.0143) and number of deliveries (parameter estimate, 0.388
p value, 0.0186) were significant factors determining breast density
breast density decreased as BMI and number of deliveries increased. Only BMI and number of deliveries were identified as factors significantly influencing breast density. BMI was inversely cor- related with breast density before and after menopause, whereas the influence of number of deliveries on breast density was significant only in postmenopausal women in their 50 and 60s. © 2013 by Okayama University Medical School.

DOI： 10.18926/AMO/50407

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

This trial is being conducted to confirm the superiority, in terms of overall survival, of primary tumour resection plus systemic therapy to systemic therapy alone in patients with Stage IV breast cancer who are not refractory to primary systemic therapy. The inclusion criteria for the study are as follows: untreated patients with histologically confirmed invasive breast cancer with one or more measurable metastatic lesions diagnosed by radiological examination. All patients receive primary systemic therapy according to the estrogen receptor and human epidermal growth factor receptor type-2 status of the primary breast cancer after the first registration. After 3 months, the patients without disease progression are randomized to the primary tumour resection plus systemic therapy arm or the systemic therapy alone arm. The primary endpoint is the overall survival, and the secondary endpoints are proportion of patients without tumour progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumour resection-free survival, adverse events of chemotherapy, operative morbidity and serious adverse events. The patient recruitment was commenced in May 2011. Enrolment of 410 patients for randomization is planned over a 5 year recruitment period. We hereby report the details of the study.

DOI： 10.1093/jjco/hys120

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Ectopic thymoma is considered to arise from ectopic thymus tissue deposited as a result of the abnormal mislocalization of thymus tissue during the embryonic stage. An 86-year-old man visited our hospital with chief complaints of hoarseness and a mass in his anterior neck. A preoperative needle biopsy of the mass did not yield a definitive diagnosis. A positron emission tomography (PET) study revealed heterogeneous accumulation of F-18-fluorodeoxyglucose (FDG) in the tumor. The tumor, affecting the left sternocleidomastoid muscle, the recurrent laryngeal nerve, the internal carotid vein, and the brachiocephalic vein, was resected using a combination of a collar incision in the neck and a median incision in the sternum. Immunohistochemically, the tumor was diagnosed as an ectopic thymoma of the neck. To date, only a few cases of ectopic thymoma presenting with FDG accumulation have been reported. Our experience indicates that ectopic thymoma should be kept in mind during the differential diagnosis of neck tumors with FDG accumulation appearing on PET images.

DOI： 10.18926/AMO/48691

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies.
We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed.
The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group.
REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies.

DOI： 10.1007/s00432-012-1158-6

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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A spiculated mass on a mammogram is highly suggestive of malignancy. We report the case of a 32-year-old woman with a radial sclerosing lesion that mimicked breast cancer on mammography. She visited her physician after palpating a lump in her left breast. Mammography showed architectural distortion in the upper inner quadrant of the left breast. Ultrasonography showed a low echoic area with an ambiguous boundary. Core needle biopsy was performed because of the suspicion of malignancy. Histological examination did not reveal any malignant cells. After 6 months, the breast lump became larger and the patient was referred to our hospital. Mammography performed in our hospital showed a spiculated mass, and therefore mammotome biopsy was performed. Histological examination revealed dense fibroelastic stroma with a wide variety of mastopathic changes, leading to a diagnosis of a radial sclerosing lesion. One year after the biopsy, the lump on her left breast had disappeared and mammography showed no spiculated mass. Copyright © 2012 S. Karger AG, Basel.

DOI： 10.1159/000337024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo. (Cancer Sci 2011; 102: 2038-2042)

DOI： 10.1111/j.1349-7006.2011.02050.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Estrogen is involved in the development and progression of breast cancer. Here we investigated the effect of fibroblast growth factor (FGF)-8 on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptor (ER)alpha, ER beta, FGF receptors, and Smad signaling molecules. Estradiol stimulated MCF-7 cell proliferation in a concentration-responsive manner, whereas BSA-bound estradiol had a weak effect on MCF-7 cell mitosis compared with the effect of free estradiol. It is notable that estrogen-induced cell proliferation was enhanced in the presence of FGF-8 and that the combined effects were reversed in the presence of an FGF-receptor kinase inhibitor or an ER antagonist. It was also revealed that FGF-8 increased the expression levels of ER alpha, ER beta and aromatase mRNAs, while estradiol reduced the expression levels of ERs, aromatase and steroid sulfatase in MCF-7 cells. FGF-8-induced phosphorylation of FGF receptors was augmented by estradiol, which was reversed by an ER antagonist. FGF-8-induced activation of MAPKs and AKT signaling was also upregulated in the presence of estrogen. On the other hand, FGF-8 suppressed BMP-7 actions that are linked to mitotic inhibition by activating the cell cycle regulator cdc2. FGF-8 was revealed to inhibit BMP receptor actions including Id-1 promoter activity and Smad1/5/8 phosphorylation by suppressing expression of BMP type-II receptors and by increasing expression of inhibitory Smads. Collectively, the results indicate that FGF-8 acts to facilitate cell proliferation by upregulating endogenous estrogenic actions as well as by suppressing BMP receptor signaling in ER-expressing breast cancer cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2011.05.037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Combined low-dose therapy of oral capecitabine (Xeloda) and cyclophosphamide (XC) has been demonstrated to be useful for long-term control of lesions in patients with metastatic breast cancer (MBC) and is aimed at symptomatic alleviation and prolongation of survival. Here, a retrospective review was conducted of MBC patients administered XC at the Okayama University Hospital (OUH), to evaluate responses to XC, adverse events and time to progression (TTP). Twenty patients with MBC received XC between 2006 and 2009. With the exception of 2 elderly patients who were over the age of 70 at the initial examination, all of the patients had received prior treatment with an anthracycline and/or a taxane. No complete response (CR) cases were observed, but partial response (PR) was achieved in 6 patients (30%) and SD in 9 (45%), of whom 5 (20%) sustained SD status for &gt;= 12 months. The median TTP was 6 months (range: 3-27 mo.). Three patients developed Grade 3 adverse events (diarrhea, nausea and stomatitis), but no other patients developed adverse reactions causing interruption of the therapy. XC was safe even in previously treated and elderly MBC patients; moreover, it yielded remarkable clinical responses.

DOI： 10.18926/AMO/46848

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Hepatitis B virus (HBV) reactivation is a serious clinical problem for HBV infected patients, and one of its possible causes is chemotherapy for malignant disease. At the onset of active hepatitis, planned chemotherapy should be discontinued and acute or fetal fulminant hepatitis must be induced in some cases. Therefore, it is desirable to prevent virus reactivation during chemotherapy in HBV-positive patients. We report a case in which adjuvant chemotherapy for a breast cancer patient was accomplished safely by using entecavir. The patient was a 48-year-old woman with breast cancer whose HBV infection had been pointed out when she was 20 years old. Breast reconstruction was performed, followed by mastectomy. Pathological findings were invasive ductal carcinoma, three positive nodes, estrogen and progesterone receptor-positive, and HER2-negative. An adjuvant chemotherapy with anthracycline followed by taxane was planned. Blood chemistry revealed the seroconversion of HBV and the quantity of HBV-DNA was 2. 8 log copies/mL. Administration of the anti-virus agent, entecavir, was started three weeks before chemotherapy. The HBV-DNA was decreased under the titer of detection and no re-increase in HBV-DNA was found during chemotherapy. Planned chemotherapy was accomplished safely without HBV reactivation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Introduction: Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.
Methods: The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT-and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.
Results: mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-beta-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.
Conclusions: Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT-and ER-positive breast cancer cells.

DOI： 10.1186/bcr2598

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

This study examined postmenopausal estrogen receptor-positive breast cancer patients who received prospective neoadjuvant endocrine therapy (NAET) with tamoxifen or anastrozole to determine if the 21-gene recurrence score (RS) predicts NAET responses. RS scores were determined from pretreatment core biopsy specimens. Although half of the specimens yielded insufficient RNA, the remaining samples were highly representative. Patients with a low RS tended to respond better than those with an intermediate or high RS (n = 43). Response rates by RS were similar between the tamoxifen and anastrozole groups. Patients with a low RS tended to have better relapse-free Survival (RFS) than those with ail intermediate or high RS (5y-RFS; 100% vs. 84% and 73%, respectively). These results suggest that RS predicts responses to NAET with tamoxifen or anastrozole. Because this pilot study examined a small sample size, these results should be validated in larger studies. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.breast.2009.03.005

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Current treatments for metastatic breast cancer (MBC) include palliation with chemotherapy and/or hormone therapy, neither of which has the effect of adequately improving survival. Local surgery to remove the primary breast tumor is performed to improve local control and prevent uncontrolled chest wall disease (UCD). From June 1962 to February 2007 7 344 patients with MBC were treated at National Cancer Center Hospital. In our review of these cases, we evaluated the prognostic impact of local surgery and other clinicopathological features. One hundred and sixty patients (47%) underwent resection of primary breast tumor, while 184 (53%) patients were treated without surgery. Overall survival (OS) was prolonged in patients treated with surgery (p=0.049), younger patients (age &lt; 50, p=0.023), and patients with bone or soft tissue metastases (p=0.013). While surgery significantly improved OS in young patients (p=0.021), it did not increase OS in older patients (age &gt; 51, p=0.665) or patients with visceral metastasis (p=0.797). This study demonstrated that local surgery improved OS of patients with MBC; local surgery should therefore be considered, especially in young patients. Prospective studies are required to validate these findings and evaluate the impact of surgical intervention.

DOI： 10.3892/or_00000291

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Background The aim of this study was to apply perfusion techniques to breast tumors using a prototype 256-row multislice computed tomography (CT) scanner (which allows a wide range of 128 mm to be scanned and can provide whole-breast perfusion maps without any dead angles) to improve contrast and assess the possibility of precisely depicting the extent of breast cancer.
Patients and methods The study group included seven patients with breast cancer who were scheduled to undergo radical surgery and radiotherapy. Dynamic scanning was performed using a 256-row multislice CT scanner during normal respiration. Volume perfusion images of the entire breast were obtained using the maximum slope method. Perfusion map images and early-phase breast CT images at 54 s were compared by means of pathological examination.
Results All breast cancers could be distinguished from normal mammary glands based on the perfusion value. The extent of cancer depicted in perfusion images showed excellent agreement with the pathology findings for invasive ductal carcinoma and ductal carcinoma in situ. In three patients, all ductal spread, parts of which were not visualized by early-phase CT, were depicted in volume perfusion images. Simulation analysis suggested that perfusion maps could be generated with fewer scanning points.
Conclusion The results of the present study suggest that volume perfusion imaging may be useful for depicting the extent of breast cancer, with excellent sensitivity. Further research is needed to determine the clinical relevance of these findings.

DOI： 10.1007/s12282-008-0076-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Primary small cell carcinoma of the breast is a very rare disease, and only a few case reports have described small cell carcinoma of the breast that responds to chemotherapy. Here, we report a case of primary small cell carcinoma of the breast that was treated with surgery and chemotherapy for postoperative local recurrence in the chest wall and metastasis to the liver. The metastatic lesions showed a partial response (PR) to carboplatin and irinotecan, but did not respond to subsequent Taxotere and doxifluridine (5&apos;-DFUR) treatment. We then treated the metastatic lesions with CBDCA and etoposide (VP-16), and were able to stop disease progression. Small cell carcinoma of the breast is as aggressive as its pulmonary counterpart. Therefore, the best therapy for primary small cell carcinoma of the breast may be surgery followed by adjuvant therapy similar to that recommended for small cell lung carcinoma.

DOI： 10.1007/s12282-008-0057-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Background The present study was conducted to assess the clinical usefulness of multidetector-row CT (MDCT) in determining the extent of invasive lobular carcinoma (ILC) and especially the extent of residual tumor after neoadjuvant chemotherapy (NAC).
Patients and methods The subjects were 24 patients with primary ILC who underwent surgery without NAC and 17 patients with ILC who underwent surgery after NAC at National Cancer Center Hospital (NCCH) between April 1999 and December 2005. The extent of primary ILC was assessed by ultrasound, mammography, and MDCT before surgery, and the results obtained using each modality were compared with the results of pathological examination after surgery. In addition, the characteristic findings of ILC obtained by MDCT were assessed. Similarly, the extent of residual tumor after NAC was evaluated using ultrasound, mammography, and MDCT before surgery in the subjects who underwent NAC, and the results obtained by each modality were compared with the results of pathological examination after surgery.
Results The findings of primary ILC obtained by MDCT showed that the carcinoma was the non-localized type rather than the localized type in 63% of the subjects. In addition, with regard to the pattern of time-sequential contrast enhancement, the persistent pattern (in which tumor enhancement is strong in the late phase rather than in the early phase) was observed in 46% of the subjects, and the plateau pattern (in which contrast enhancement is weak in both the early phase and the late phase) was observed in 38% of the subjects. These trends were significant in the subjects who underwent NAC and in whom tumor enhancement could not be clearly observed by MDCT. Assessment of the extent of carcinoma showed that the diagnostic accuracy of MDCT was 79%, as compared with 71% for either ultrasound or mammography. Assessment of the extent of carcinoma after NAC also showed that the diagnostic accuracy of MDCT was 71%, as compared with 48% for ultrasound and 53% for mammography, indicating that MDCT provided the highest accuracy. It should be noted that for all modalities, the extent of ILC was not overestimated as compared with the tumor diameter measured during pathological examination.
Conclusion Assessment by MDCT showed that ILC tends to be diffuse, tumor enhancement tends to be very weak, and the rate of enhancement tends to be low. In addition, MDCT was found to be useful for determining the extent of carcinoma, and the diagnostic accuracy of MDCT, especially in determining the extent of carcinoma after NAC, was much higher than that of ultrasound or mammography.

DOI： 10.1007/s12282-008-0044-1

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Neoadjuvant chemotherapy (NAC) is increasingly used for operable disease. However there are several pathological response classification systems and the correlation between the pathological response to NAC according to each system and the patient outcome is still under debate. From 1998 to 2006, 370 primary breast cancer patients underwent curative surgical treatment after NAC containing both anthracycline and taxane at the National Cancer Center Hospital. We retrospectively evaluated the clinical and pathological response using the cTMN, Fisher&apos;s, Chevailler&apos;s, and the Japanese Breast Cancer Society classification systems (JBCS) respectively, and analyzed the correlation between each pathological response and disease free survival (DFS). Ninety-five (26%) patients had tumor recurrence. The five-year DFS according to Fisher&apos;s system was pCR, 80% and pINV, 63%. The five-year DFS according to Chevallier&apos;s system was Grade 1, 83%, Grade 2, 85%, Grade 3, 62%, and Grade 4, 65%. The five-year DFS according to the JBSC system was Grade 3, 77%, Grade 2, 68%, Grade 1a, 68%, Grade 1b, 58%, and Grade 0, 52%. None of the pathological response systems reached a statistically significant difference. In the classification by the post-treatment number of metastatic axillary lymph nodes, the 5-year DFS was n = 0, 86%; n = 1-3, 64%; n = 4-9, 44%; and n &gt; 10 positive: 25% (P &lt; .0001). In pathologically node negative patients, there were no significant differences in the DFS among all the classification systems. All three classifications analyzed were considered inadequate as the prognostic marker of the long-term outcome after NAC and further studies are warranted to optimize the prediction.

DOI： 10.1007/s10549-008-9935-2

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To evaluate the clinicopathological features of intracystic papillary carcinoma (ICPC), which have not been established given its rarity and lack of standard diagnostic criteria.
We reviewed the clinicopathological findings and treatment outcomes of 14 patients with ICPC diagnosed between 2002 and 2006.
Intracystic papillary carcinoma was diagnosed by fine-needle aspiration biopsy in three patients and by core-needle biopsy in six patients. A preoperative diagnosis was not made in five patients. Three patients underwent magnetic resonance imaging preoperatively, which helped to differentiate benign tumors and maintain free surgical margins. The final pathological diagnosis was invasive carcinoma in 2 (14.2%) of the 14 patients. The patients were followed up for 1-72 months, during which time only one died, of a cancer-unrelated cause.
Our results show that ICPC is more difficult to diagnose than common breast cancer preoperatively. Excisional biopsy was necessary when fine-needle aspiration and core-needle biopsy could not provide a diagnosis. Magnetic resonance imaging is helpful to differentiate a benign tumor from invasive disease.

DOI： 10.1007/s00595-008-3792-9

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Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. Clinical and pathological responses are important prognostic parameters for NC, which aims to achieve a pathological complete response or tumor reduction to reduce the volume of subsequent breast resection. Clinicopathological markers that predict patient response to NC are needed to individualize treatment.
From 1998 to 2006, 368 patients with primary breast cancer underwent curative surgical treatment after NC (anthracycline and/or taxane without trastuzumab). We retrospectively evaluated the clinicopathological features and classification of the tumors using computed tomography (CT) before NC and analyzed the correlation with the pathological complete response (pCR) and reduction of tumor size after treatment.
The overall response and pCR rates in these patients were 86% and 17%, respectively. In multivariate analysis, classification as a scirrhous-type tumor was an independent predictor of reduced likelihood of pCR (p = 0.0115; odds ratio 0.21). For tumor reduction, histological grade 3 (p = 0.0002; odds ratio 3.3) and localized tumors identified by using CT imaging (p = 0.0126; odds ratio 2.4) were independent predictors in multivariate analysis.
In this study, NC often did not result in pCR for breast cancers classified as scirrhous. Furthermore, tumor type classification using CT imaging and histological grading was effective to predict tumor reduction in response to NC that included an anthracycline and/or a taxane.

DOI： 10.1007/s00268-008-9800-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Background. In recent years, the surgical management of patients with breast cancer has shifted to a locoregional approach, and evaluating the patient's axillary lymph node status is of the greatest importance in determining the appropriate treatment strategy. We evaluated on the efficacy of preoperative axillary staging using contrast-enhanced computed tomography (CE-CT).
Methods. Between 2000 and 2003, 235 patients with operable breast cancer who underwent CE-CT before surgery and 137 patients who received neoadjuvant chemotherapy (NAC) and underwent CE-CT before NAC and surgery were enrolled in this study. The axillary status was evaluated based on three criteria (short-axis diameter, shape, and enhancement type), and the diagnosis was correlated with the histopathological results.
Results. In patients who did not receive NAC, the size criterion of a short-axis diameter of more than 5 mm provided a sensitivity of 78%, a specificity of 75%, and an accuracy of 76% in predicting node-positive status. According to the size criterion of a short-axis diameter of more than 5 mm and the shape criterion of the absence of intranodal fat density, the specificity and accuracy were 90% and 81%, respectively, and according to the enhancement type criterion of early enhancement, the corresponding values were 89% and 78%. Evaluation was more difficult in patients who received NAC and the sensitivity of the size-based criterion in the patients who received NAC was lower than in those who did not.
Conclusion. These findings suggest that CE-CT based on size criteria is useful for evaluating the preoperative axillary status of breast cancer patients, but that evaluation is more difficult and the sensitivity is reduced in patients who have received NAC.

DOI： 10.1007/s10147-007-0753-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background: S-1, an oral fluoropyrimidine carbamate, is an active and well-tolerated agent against solid cancer. However, the clinical efficacy of S-1 in patients with metastatic breast cancer has not been determined.
Methods: We retrospectively evaluated the efficacy of S-1 and identified its adverse effects in patients with metastatic breast cancer who had failed to respond to prior chemotherapy regimens. All the patients were treated at the National Cancer Center Hospital and received S-1 twice daily at a dose of 80 mg/m(2) for 4 weeks, followed by a 2-week rest interval.
Results: Between 2003 and 2007, 37 women with metastatic breast cancer received S-1 as a third line or greater chemotherapy regimen. All the patients had been previously treated with both anthracyclines and taxanes prior to S-1 chemotherapy. The median order of S-1 administration was as a fifth-line treatment, and 23 patients (62%) received S-1 as their final anticancer drug. One (3%) partial response and two (5%) stable diseases were observed. The median time to progression (TTP) was 84 days. Grade 2 adverse events, such as diarrhea, stomatitis and neutropenia occurred in 5 (16%), 1 (3%) and 1 (3%) patients, respectively.
Conclusions: S-1 was safety administered to heavily treated metastatic breast cancer patients with limited efficacy. Further evaluation of S-1 is necessary to elucidate its clinical role in breast cancer treatment.

DOI： 10.1093/jjco/hyn001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

Neoadjuvant endocrine therapy (NAET) can expand the number of breast cancer patients who can be treated with breast-conserving surgery and can predict benefit from adjuvant endocrine therapy. Because no validated surrogate markers for long-term outcome have been established, we conducted prospective trials to evaluate pathological response and Ki-67 index following treatment with tamoxifen or anastrozole. The study population included postmenopausal women with operable breast tumors that were both estrogen and progesterone receptor-positive and larger than 3 cm. Response was classified as pathological response (minimal response or better) and non-response. Non-responding (25.5%, vs. response 85.9%, p = 0.002), axillary node-positive (58.4% vs. node negative 100%, p=0.045), and high pretreatment Ki-67 index (41.4% vs. low Ki-67 87.1%, p=0.03) patients were significantly associated with poor 5-year relapse-free survival. Multivariate analysis of relapse-free survival indicated that pathological response was independent. Therefore, pathological response may be a favorable prognostic factor after NAET. (c) 2007 Elsevier Ltd. Alt rights reserved.

DOI： 10.1016/j.breast.2007.02.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Some kinds of breast cancer cell lines, similar to several types of solid tumors, express epidermal growth factor receptor (EGFR). However, gefitinib, an EGFR tyrosine kinase inhibitor, is not effective for all these cell lines. Similarly, taxane is effective for many of the cell lines, although some, such as the multidrug-resistant MCF7/ADR cell line, show taxane-resistance. Here, we examined the growth inhibitory effect of combination treatment with gefitinib and taxane on the breast cancer cell lines MDA-MB-231 (EGFR-positive) and MCF7/ADR (EGFR- and HER2-positive). To estimate the combined effect, a Combination Index was calculated for each cell line. The combination of gefitinib and taxane showed a strong synergistic effect on MCF7/ADR cells, but an in vitro additive-antagonistic effect on MDA-MB-231 cells. Similarly, the combination treatment showed a significantly increased tumor inhibitory effect on MCF7/ADR xenografts, but not on MDA-MB-231 xenografts. Regarding the mechanism of the synergistic effect, Western blotting analysis revealed that taxane activated the EGFR-Akt pathway in MCF7/ADR cells but not in MDA-MB-231. To determine the optimal sequential administration of gefitinib and taxane for MCF7/ADR cells, we used flow cytometry to analyze the cell cycle and apoptosis; finding that taxane treatment followed by gefitinib produced a higher rate of G2 arrest and apoptosis than gefitinib treatment followed by taxane. These results suggest gefitinib overcomes the drug-resistance of these cells, thereby increasing the effects of taxane on MCF7/ADR cells. Further, activation of the EGFR-Akt pathway by taxane is related to this synergistic effect. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22187

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Language：English   Publisher：The Japanese Breast Cancer Society  

Background: We encountered two patients with inflammatory breast carcinoma who developed symptomatic brain metastases after achieving local pathological complete responses (pCR) with neoadjuvant chemotherapy (NAC).<BR>Case presentations: The first patient is a 39-year-old woman (Case 1), who underwent NAC with AC (doxorubicin + cyclophosphamide)followed by weekly paclitaxel. After achieving a clinical CR (cCR), we conducted a modified radical mastectomy. Pathological evaluation confirmed no residual malignant cells within the breast tissue or lymph nodes. However, she developed neurological symptoms from brain metastases one month postoperatively. The second patient is a 44-year-old woman (Case 2). Again, no residual malignant cells were detected within the breast tissue or lymph nodes following NAC, but the patient developed symptomatic brain metastases eight months postoperatively. When primary breast tumors are locally advanced, it may be worthwhile to rule out brain metastases even if pCR is obtained after NAC.

DOI： 10.2325/jbcs.14.420

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Other Link： http://search.jamas.or.jp/link/ui/2008154599

Language：Japanese   Publisher：日本臨床外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 mu M to 36.9 mu M. In combination, gelitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.

DOI： 10.18926/AMO/30755

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：B M J PUBLISHING GROUP  

Aims: To evaluate the expression of common biological markers and the epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation (DCMDs).
Materials/methods: Thirty DCMDs were clinicopathologically and immunohistochemically analysed and compared with 36 control cases of high grade conventional invasive ductal carcinoma (IDC).
Results: EGFR, HER2/neu, oestrogen receptor, progesterone receptor, and p53 expression was seen in 21, one, three, four, and 20 of the 30 DCMDs, compared with eight, nine, 18, 17, and five of the 36 conventional IDCs (p &lt; 0.05), respectively. In 16 of the 30 DCMDs, metastases were found in the brain, lung, bone, and liver, within a maximum of 47 months (mean, 13.9) after initial surgery, whereas only four of the 36 conventional IDCs metastasised to the lung and bone within a maximum of 27 months (mean, 18.0) after initial surgery (p = 0.0001). There was a significant difference in disease free survival between DCMD and conventional IDC (p = 0.001). EGFR was frequently overexpressed in DCMD compared with conventional IDC, whereas the expression of HER2/neu and hormone receptors was lower in DCMD. Fluorescent in situ hybridisation revealed that the mean EGFR to chromosome 7 centromere (CEP7) ratio of the 24 DCMD cases available for evaluation was 1.03, and EGFR gene amplification was not detected in the 21 DCMD cases with EGFR overexpression.
Conclusion: Immunohistochemistry for myoepithelial markers and EGFR is useful for the accurate diagnosis and molecular target treatment of high grade DCMD.

DOI： 10.1136/jcp.2005.026096

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Advances in the therapeutic agents used for neoadjuvant chemotherapy (NAC) have recently achieved higher response rates and induced a greater number of pathologic complete responses (pCR) than ever before. The aim of this study is the diagnosis of pCR after NAC by diagnostic imaging of clinical complete response (cCR) patients. This study included 35 breast cancer patients who demonstrated cCR after receiving NAC with a combination of anthracycline and taxane from May 1998 to August 2003. Surgical treatment included breast-conserving therapy followed by radiotherapy or mastectomy. The identity of post-NAC lesions as either a complete response (CR) or partial response (PR) were made by mammography, ultrasonography, and contrast-enhanced computed tomography (CT). Among the 35 patients, 11 achieved pCR, including the disappearance of both invasive and intraductal components. Of the patients achieving pCR, eight were defined as CR and three were determined to be PR by CT There was a significant relationship between the pCR and the determination of CR by CT The determination of CR by ultrasonography was indicative of the disappearance of pathologic invasive components. While mammography appeared to reflect the observed histologic results, we did not observe any statistical differences. A subset of cases exhibited discrepancies between the imaging and pathologic results, likely due to the replacement of destroyed tumor cells by fibrosis and granulomatous tissue. The evaluation of CR by CT was significantly indicative of pCR. The positive predictive value, however, was not large enough to avoid surgical treatment. Further studies will be needed to establish a diagnosis of pCR.

DOI： 10.1111/j.1075-122X.2005.00003.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

High expression of epidermal growth factor receptor (EGFR) is thought to be correlated with cell proliferation, invasion, metastasis, resistance to chemoradiotherapy, and poor prognosis in Various kinds of human cancers. Blockade of EGFR signal transduction can be a promising strategy for cancer therapy. Approximately 40-70% of esophageal squamous cell carcinomas (ESCCs) show high expression of EGFR. In this study, we examined the antitumor effect of gefitinib, an EGFR tyrosine kinase inhibitor, against ESCC cells in vitro and in vivo. In three ESCC cell lines (TE8, T.T and T.Tn), cell proliferation had been inhibited in a dose-dependent manner and IC(50) Values (respectively, 8.49, 18.9 and 17.3 mu M). Gefitinib inhibited EGF-induced autophosphorylation of EGFR and its downstream signaling pathways, Ras/Raf/MAPK and PI3K/Akt, and caused G(1) arrest of cell cycle and apoptosis confirmed with flow cytometry. We examined the effect of gefitinib on nude mice bearing established TE8 and T.T xenografts. Gefitimb (100 or 200 mg/kg once-daily, p.o.) showed antitumor activity in a dose-dependent manner, resulting in a significantly improved survival of treated mice as compared with untreated mice. Immunohistochemical examination of the harvested tumor was performed to examine the status of phosphorylated EGFR, PCNA, Factor VIII and apoptosis. We found inhibition of EGFR phosphorylation, cell cycle arrest (by PCNA staining), decrease of microvessel density (Factor VIII) and induction of apoptosis by TUNEL staining. In conclusion, our findings demonstrate that gefitinib is effective for growth inhibition of ESCC cell lines in vitro and in vivo and suggest that gefitinib may be one of the new therapeutic options for ESSC. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2004.12.025

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Background: Expression of epidermal growth factor receptor (EGFR) by human breast cancer tissues is associated with poor clinical response. The EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839), is a leading example of a molecular targeted agent, and has an anti-proliferative effect on various cancer cells. But the details of the anti-cancer effect and mechanism have not been elucidated. We studied the anti-cancer effect of gefitinib in breast cancer cell lines and the intracellular pathway downstream of EGFR associated with cell migration. Methods: In this study, we analysed the anti-proliferative and anti-migratory effect of gefitinib in EGFR (+) breast cancer cell lines by WST-1 analysis and chemotaxis chamber analysis. We analyzed several intracellular phosphorylated pathways which are activated by mitogen activated kinases (extracellular signal-regulated protein kinase 1 and 2: MEK), phosphatidylinositol 3'-kinase (PI3K) and phpspholipase C (PLC), by blocking those pathways using inhibitors of each kinase, and also investigated the effects on the phosphorylation of myosin light chain (MLC). Results: Gefitinib inhibited proliferation in most of these cell lines. MDA-MB231 was shown to be resistant. Furthermore, proliferation of MDA-MB231 cells was not affected by EGF stimulation, but migration of MDA-MB231 cells was significantly inhibited. PI3K and PLC inhibitors blocked EGF-stimulated cell migration and MLC phosphorylation, but the MEK inhibitor did not influence cell migration. Conclusions: Gefitinib has an anti-migratory effect on MDA-MB231 that results in an anti-proliferative effect. PI3K and PLC are important for the migration of MDA-MB231 cells, and gefitinib may inhibit migration by blocking these signalling pathways.

DOI： 10.1007/BF02968044

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

Purpose. The clinical benefits acquired by introducing hexakis-2-methoxyisobutylisonitrile (MIBI), the reliability of MIBI, and the adequacy of applying less invasive surgeries based on MIBI imaging were retrospectively investigated.
Methods. The surgical results before introducing Tc-99m-MIBI scintigraphy (MIBI) in 10 patients with primary hyperparathyroidism were compared with those after introducing MIBI in 22 patients.
Results. Surgical failure occurred in two patients (20.0%) before introducing MIBI, and in one (4.5%) after introducing MIBI, thus suggesting that the surgical results improved after introducing MIBI. This was because the diagnosis of ectopic adenoma improved with MIBI. Less invasive surgeries were performed in two patients before introducing MIBI, and in 13 patients after introducing MIBI. Consequently, the operation time decreased significantly. The sensitivity of MIBI,. ultrasonography, and computed tomography to adenoma was 100%, 72.2%, and 57.1%, respectively, thus indicating MIBI to have the highest sensitivity. The positive predictive value of MIBI was 85.7%, and all false-positive results were caused by nodular lesions of the thyroid gland. However, the preoperative differentiation of false-positive results could be successfully performed by combining MIBI with neck ultrasonography.
Conclusion. The sensitivity of MIBI to adenoma was thus found to be highly satisfactory. As a result, it might be possible to perform less invasive surgeries based on MIBI imaging without any decrease in the surgical results.

DOI： 10.1007/s00595-003-2687-z

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(株)篠原出版新社  

原発性乳癌手術症例309例を対象に,Epidermal Growth Factor Receptor(EGFRの発現とホルモンレセプター,予後の関連について比較検討した.その結果,平均観察期間74.6ヵ月で,EGFR(+)を認めた症例は121例(39.2%)であった.EGFR(+)群は閉経前症例,Stage進行例が有意に多かった.EGFRはホルモンレセプターの発現と有意な逆相関を示し,EGFR(+)ER(-)群は有意に5年健存,生存率が不良で,EGFR(-)PgR(+)群では有意に予後良好であった.なお,補助療法とEGRFの発現からみた生存曲線では,内分泌療法,化学療法ともEGRF(+)と(-)群の間の生存率に有意差はみられなかった.以上より,EGFRは予後予測因子の指標として重要であると思われた

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Language：Japanese   Publisher：Japan Surgical Association  

A 56-year-old woman who had a choroidal metastasis from breast cancer is reported. She had undergone a breast conserving operation with radiotherapy for left breast cancer in 1996. Lymph node metastasis in 1996, local recurrence in 1997 and multiple liver metastases in 2001 were found and she received chemotherapy. She was referred to the hospital because of blurring of vision in her left eye. Serous retinal detachment and flat tumor 1.3cm in diameter were found in her left eye fundus. She was diagnosed as having metastatic choroidal carcinoma. We recommended radiotherapy so as to improve her quality of life, but she rejected. Since patients with breast cancer have turned out to survive for a long time with recent multimodal treatment, patients who experience choroidal metastasis from breast cancer will increase.

DOI： 10.3919/jjsa.64.1082

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：The Japanese Association for Chest Surgery  

Malignant melanoma often presents skin, lymph node, lung, liver metastases and results in a poor prognosis. Some reports of later ecurrence of chroidal malignant melanoma (beyond 10 years) now exist in the literature. We report a case of metastatic melanoma of the lung 24 years after initial treatment. A 65-year-old man was admitted because of an abnormal shadow on the chest X-ray. He had a past history of left eye extraction for choroidal malignant melanoma 24 years earlier. Chest CT revealed a solitary tumor (20mm in diameter) in left 55 lung. Percutaneous needle aspirationcytology was done, and cytologic examination of a specimen of lung tissue revealed metastatic malignant melanoma. Left upper lobectomy was perfomed. Pathological examination revealed metastases in interlobar lymph nodes. He was alive with no signs of recurrence at 8 months after the lung operation. Patients with a history of malignant melanoma have a risk of recurrence even 10 years after initial treatment. Therefore, they have to be followed up for a long time, and resection of a solitary metastatic tumor can obtain long-term survival.

DOI： 10.2995/jacsurg.16.5_635

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Language：Japanese   Publisher：日本臨床外科学会  

80歳男.腹痛,嘔吐を主訴とした.受診時,腹部全体に圧痛を認めたが,腹膜刺激症状はなかった.腹部X線,CTでニボー,腹水を認め,イレウスと診断した.イレウス管留置による保存的治療を行ったが,症状の改善を認めず,発症後4日目に手術を施行した.開腹すると,S状結腸間膜右葉に10cmに異常裂孔を開口部とするヘルニア嚢を認めた.そのヘルニア内容物はTreitz靱帯から10cmの部位より160cmの小腸であり,それに続く肛門側の小腸が捻転して壊死に陥っていた.壊死腸管は70cmであり,壊死腸管を含む120cmの小腸切除と裂孔部の閉鎖を行って手術を終了し,術後22日目に退院となった.S状結腸間膜内ヘルニアとして,本例は本邦13例目であった.腹部外傷や開腹手術の既往歴がなく,イレウスで発症した症例では,内ヘルニアによる絞扼性イレウスを念頭に置き,早期診断と治療を考慮すべきである

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Language：Japanese   Publisher：シュプリンガー・ジャパン(株)  

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64歳男.上腹部痛を主訴とした.CT検査で脾動脈瘤を認めたため緊急手術を行った.術中所見から動脈瘤破裂と診断し,脾動脈を含む動脈瘤の近位で結紮・切離したあと,動脈瘤を含む膵尾部脾合併切除を施行した.術後,血清アミラーゼの軽度上昇を認めたが保存的に軽快し,術後28日目に退院となった

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：三豊総合病院  

66歳男.特発性食道破裂術後の難治性瘻孔に対して治癒した1例.内視鏡下フィブリン糊注入やレーザー焼灼似て瘻孔が閉鎖しなかった症例でも胸腔ドレーンと栄養管理の継続によって瘻孔の閉塞が期待できる.特にcavityに対するCTガイド下胸腔ドレナージは極めて有用である

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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J-GLOBAL

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J-GLOBAL

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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J-GLOBAL

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