記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.

DOI： 10.1038/s41525-024-00394-z

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記述言語：日本語   出版者・発行元：日本レックリングハウゼン病学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy.

DOI： 10.1111/cas.16065

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

DOI： 10.1186/s12903-023-03586-8

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(公社)日本臨床細胞学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

With the rapid expansion of genomic medicine, more citizens are compelled to think about genetics in their daily lives. This study aims to explore appropriate types of educational media and methods to enlighten activities for genetics and hereditary cancer. We presented an 18-min YouTube video on genetics and hereditary cancer to participants at a scientific event, Science Agora 2020, and administered a web questionnaire to investigate their opinions about when and how citizens should start learning about genetics and hereditary cancer. We recruited 133 participants who watched the video, and 26.3% (35/133) responded to the questionnaire. Most of them were evaluated to understand and appreciate the contents of the video. They identified websites, or videos as suitable learning media, irrespective of their sex, age, or profession. They highlighted upper elementary school or junior high school as appropriate educational stages to start learning about genetics and hereditary cancer to facilitate collecting their own genetic information by themselves. Our findings show that educational institutions should provide opportunities to learn about genetics and hereditary cancers, especially for upper elementary school and junior high school students, using learning media, such as videos, depending on their level or demand.

DOI： 10.1007/s12687-023-00663-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Few studies have been conducted on comprehensive genomic profiling (CGP) panels in Japanese patients with thoracic malignancies after completing standard treatment. Consequently, its value in clinical practice remains unclear. METHODS: We conducted a retrospective study of Japanese patients with thoracic malignancies who underwent CGP between June 2019 and November 2022 at our hospital. We evaluated the detection rate of actionable genetic alterations and percentage of patients who received genomically-matched therapy. Furthermore, we examined the value of the CGP panel in patients who underwent multiplex gene-panel testing prior to their initial treatment. This study was performed in accordance with the principles of the Declaration of Helsinki. RESULTS: The study included 56 patients, of whom 47 (83.9%) had actionable genetic alterations and 8 (14.3%) received genomically-matched therapy. Of these, four patients were treated with approved drugs and three patients were treated with investigational agents. In addition, one patient was treated with approved drugs using the patient-directed care system. Of the 17 patients who had multiplex gene-panel testing performed at the start of their initial therapy, two (11.8%) were newly identified by the CGP panel and subsequently received genomically-matched therapy. EGFR L718Q and MET amplification were observed in two of the seven patients with epidermal growth factor receptor-tyrosine kinase inhibitor resistance. CONCLUSIONS: The CGP panel could identify genetic alterations, thereby facilitating genomically-matched therapy, even in patients with thoracic malignancies who could not be identified using multiplex gene-panel testing.

DOI： 10.1016/j.resinv.2023.08.005

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記述言語：英語  

DOI： 10.1111/pin.13377

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02397-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02360-8

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of rare and aggressive ovarian carcinosarcoma with a germline pathogenic BRCA2 variant. A patient with a history of breast cancer who developed an inflammatory ovarian tumor with peritonitis carcinomatosis involving the appendix suffered from cachexia. Following three cycles of weekly paclitaxel and carboplatin chemotherapy, emergency surgery was required owing to sepsis. Bilateral salpingo-oophorectomy, total hysterectomy, appendectomy, and small intestine adhesiolysis were performed. Histologically, the tumor comprised an admixture of carcinomatous and sarcomatous components, with involvement of the appendix, which had caused perforation and abscess formation. The final diagnosis was ovarian carcinosarcoma with a germline pathogenic BRCA2 variant, c.658_659del (p.Val220fs). The patient responded completely to adjuvant chemotherapy. A combination of chemotherapy and surgery might be beneficial to patients with ovarian carcinosarcoma and germline pathogenic BRCA2 variants with a poor general condition. This is the first report of ovarian carcinosarcoma with a germline pathogenic BRCA2 variant that responded favorably to chemotherapy.

DOI： 10.1111/jog.15736

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

DOI： 10.1007/s10147-023-02345-7

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担当区分：筆頭著者   記述言語：日本語  

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記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of \24,000/h for physicians and \2800/h for nonphysicians, mean labor cost was \78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (\3,951,854 vs. \1,687,167 vs. \487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden.

DOI： 10.1111/cas.15833

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記述言語：日本語   出版者・発行元：(公社)日本臨床細胞学会  

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記述言語：日本語   出版者・発行元：(公社)日本臨床細胞学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision-Rapid. Through the PleSSision-Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin-fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision-Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/μL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.

DOI： 10.1111/pin.13318

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

DOI： 10.1002/cncr.34582

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

DOI： 10.1038/s41416-022-02067-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved.

DOI： 10.18926/AMO/64117

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記述言語：日本語   出版者・発行元：(一社)日本臨床薬理学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本臨床検査医学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

J-GLOBAL

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

PubMed

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

医療者間の連携、医療者と患者の連携および患者と家族間の連携はがん診療全般でも必要事項ではあり、がんゲノム医療のもつ特性を考えた連携を構築することが望ましい。わが国のがんゲノム医療の定義で提唱されているとおり、がん未発症者を含むがん発症予防が可能になって初めて国民の確実ながん死低減が可能になる。(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

J-GLOBAL

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

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記述言語：英語  

A hereditary breast and ovarian cancer (HBOC) pedigree was detected via liquid biopsy, and cancer prevention was initiated for the patient's daughter, after receiving a definitive result from BRCA genetic testing. A 48-yearold woman with ovarian cancer was administered precision medicine, which used cell-free DNA from plasma. The results revealed a pathogenic variant of BRCA1 as a presumed germline pathogenic mutation. We confirmed the germline pathological variant BRCA1 c.81-1G> A and suggested treatment with a PARP inhibitor. One of her three children had the variant, was diagnosed as an unaffected pathogenic variant carrier, and was advised to initiate surveillance.

DOI： 10.18926/AMO/63908

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cognitive function progressively declines with advancing age. The aging process can be promoted by obesity and attenuated by exercise. Both conditions affect levels of the chemokine CX3CL1 in peripheral tissues; however, its role in cognitive aging is unknown. In the current study, we administered CX3CL1 into the peritoneal cavity of aged mice to investigate its impact on the aging process. In the peritoneal cavity, CX3CL1 not only reversed the age-associated accumulation of cells expressing the senescence marker p16INK4a but also increased peritoneal phagocytic activity, indicating that CX3CL1 affected the phenotypes of peritoneal cells. In the hippocampus of aged mice, intraperitoneal administration of CX3CL1 increased the number of Type-2 neural stem cells and promoted brain-derived neurotrophic factor (BDNF) expression. This treatment, furthermore, improved novel object recognition memory impaired with advancing age. Intraperitoneal transplantation of peritoneal cells from CX3CL1-treated aged mice improved novel object recognition memory in recipient aged mice. It indicates that peritoneal cells have a critical role in the CX3CL1-induced improvement of recognition memory in aged mice. Vagotomy inhibited the CX3CL1-induced increase in BDNF expression, demonstrating that the vagus nerve is involved in the hippocampal BDNF expression induced by intraperitoneal administration of CX3CL1. Thus, our results demonstrate that a novel connection among the peritoneal cells, the vagus nerve, and the hippocampus can reverse the age-associated decline in recognition memory.

DOI： 10.1007/s11357-022-00579-3

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

がんゲノム医療は「がん患者の腫瘍部および正常部のゲノム情報を用いて治療の最適化・予後予測・発症予防をおこなう医療(未発症者も対象とすることがある。またゲノム以外のマルチオミックス情報も含める)」と定義される(がんゲノム医療推進コンソーシアム懇談会報告書〜国民参加型がんゲノム医療の構築に向けて〜厚生労働省HP平成29年6月27日)。「治療の最適化」についてはがん医療へコンパニオン診断の導入から、2019年6月のがん遺伝子パネル検査の保険収載を契機に、個別化治療に到達する道筋が整備されてきている。一方でがんゲノム医療は定義にあるように「がん未発症者」を含む「がん発症予防」を含む概念である。がん発症高リスクのがん未発症者に対する介入が可能になってはじめて、国民の確実ながん死低減が可能になるといえる。婦人科診療を窓口に個々のゲノム情報に応じて未発症者も既発症者の区別なく対応していき、「治療の最適化・予後予測・発症予防」によって最終的に国民のがん死低減に寄与することが可能になる。(著者抄録)

J-GLOBAL

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記述言語：日本語   出版者・発行元：(有)科学評論社  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

がんゲノム医療の重要性が加速する今日、一般市民が遺伝医療に対するリテラシーを持つことが急務である。本研究では、一般市民のがんゲノム医療啓発を目的として、「遺伝子とがん」をテーマにしたまんが教材を開発した。そして、教材の有用性を評価するため、高校生124名を対象に、教材介入前後の質問紙調査を行った。開発した教材に対し理解のしやすさや有用性の項目で約9割が肯定的回答を示し、がんの原因や遺伝性のがんに関する知識向上が確認された。教材介入による不安感は遺伝性のがんの割合の質問正答率と関連が見られ、正確な知識を持つことが不安感の軽減に繋がると示唆された。遺伝カウンセラーの認知や理解に対しても肯定的評価を得た。本調査から、高校生が遺伝やがんの早期教育の重要性を認識し、知識習得の機会を期待していたことも明らかとなった。教材の開発がリテラシー向上に有用であり、個々の健康管理に繋がることが期待される。(著者抄録)

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In June 2019, the Japanese National Health Insurance (NHI) system introduced coverage for two types of tumor genomic profiling (TGP): FoundationOneⓇ CDx (F1) and OncoGuide™ NCC OncoPanel System (NCCOP). TGP sometimes reveals germline variants that are potentially pathogenic as secondary findings (SFs). We conducted a questionnaire-based survey to find out the operational statuses of F1 and NCCOP at institutions where TGP was performed to elucidate issues related to SFs. Responses were received from 97 of 112 institutions (86.6%). As of May 31, 2020, 88 (90.7%) and 78 (80.4%) institutions started performing F1 and NCCOP, respectively. Since F1 only examines tumor samples, germline confirmatory testing is necessary to determine whether they are actually germline pathogenic variants (GPVs). When physicians are obtaining informed consent all but 2.3% of the patients requested SF disclosure. Conversely, when presumed germline pathogenic variants (PGPVs) were detected, 46.2% were not willing to receive confirmatory tests as they wanted to prioritize cancer treatment over SFs investigation, while only 23.3% underwent confirmatory tests. Problems in cancer genomic medicine reported by clinical genetics departments included short-staffing (n = 10), insufficient interdepartmental cooperation (n = 9), inconsistent understanding of genetics among healthcare professionals (n = 8), and low utilization rate of SFs due to lack of insurance coverage for confirmatory tests and post-test health checkups (n = 8). Solutions include; determining the appropriate timing to confirm patient intent on SF disclosure, covering confirmatory tests for PGPVs by the NHI, and establishing cooperation between the oncology and clinical genetics departments.

DOI： 10.1038/s10038-022-01028-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

DOI： 10.3802/jgo.2022.33.e50

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記述言語：英語  

DOI： 10.1016/j.amjmed.2022.02.042

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gynecologic cancers are more often caused by genetic factors than other cancers. Genetic testing has become a promising avenue for the prevention, prognosis, and treatment of cancers. This review describes molecular features of gynecologic tumors linked to hereditary syndromes, gives an overview of the current state of clinical management, and clarifies the role of gynecology in the treatment of hereditary tumors. Typical hereditary gynecologic tumors include hereditary breast and ovarian cancer, Lynch syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. Multigene panel testing, which analyzes a preselected subset of genes for genetic variants, has recently become the first-choice test because it can provide more accurate risk assessment than a single test. Furthermore, comprehensive genomic cancer profiling enables personalized cancer treatment and aids in germline findings.

DOI： 10.1111/jog.15197

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

DOI： 10.3390/ijms23010523

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

DOI： 10.3390/ijms23010348

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd  

Background: Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation: Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions: Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

DOI： 10.1186/s13053-020-00160-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. CASE PRESENTATION: A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. CONCLUSIONS: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

DOI： 10.1186/s13053-021-00205-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

DOI： 10.1007/s00428-021-03232-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. METHODS: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. RESULTS: Twenty-four patients were included in this study. The median age was 55.5 years (37-80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. CONCLUSIONS: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

DOI： 10.1007/s10147-021-02050-3

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記述言語：日本語   出版者・発行元：(一社)日本臨床検査医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.

DOI： 10.1016/j.isci.2021.102963

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.

DOI： 10.1007/s10147-021-02015-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

[Objective] Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair (MMR) genes. Endometrial cancer frequently precedes another LS-associated tumor. This study aimed to clarify the incidence and features of LS in young Japanese endometrial cancer patients.[Methods] Sixty-five patients aged 40 years or younger, who were diagnosed with endometrial cancer, were enrolled in this study. Targeted sequencing of a hereditary colorectal cancer-related gene panel including the MMR genes MLH1, MSH2, MSH6, and PMS2 was conducted on DNA samples extracted from blood cells.[Results] Overall, 6 missense variants (2 in MSH2, 2 in MSH6, and 2 in PMS2), 1 inframe deletion variant in MSH2, 1 splice variant in MSH2, and 1 two-base substitution in the 3' untranslated region in MLH1 were detected in 9 (13.8%) patients. Among these, the splice variant c.1276G > T (p.Ile411_Gly426del16) in MSH2 was annotated as pathogenic, while other variants were of uncertain significance. The patient with the pathogenic variant had a family history of endometrial and colorectal cancer and was diagnosed with endometrial cancer at age 35.[Conclusion] The incidence of LS among Japanese endometrial cancer patients of reproductive age (≤ 40 years) in this study was at least 1.5%; however, 12.3% of patients had variants of uncertain significance in MMR genes.

DOI： 10.1007/s10147-021-01953-5

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記述言語：英語  

Secretory carcinoma of the skin is an extremely rare adnexal tumor, histopathologically identical to homologous lesions in the salivary glands and breast tissue. Although this tumor was previously reported as indolent, we report a case of secretory carcinoma of the skin with metastases and recurrence. The patient, a 31-year-old women, had a subcutaneous mass in the right axilla. The resected specimen contained a circumscribed mass, with proliferating tumor cells that exhibited prominent nucleoli. They exhibited glandular and papillary growth patterns and there were amphophilic secretions in the glands. Immunohistochemically, the tumor cells were positive for mammaglobin and S100. The tumor was surrounded by sweat glands and there was no mammary glandular tissue, suggesting that it was derived from axillary sweat glands. Accordingly, we made a diagnosis of secretory carcinoma of the skin. Four years after the operation, there were metastases in both lungs. The resected specimen revealed a tumor identical to that of the original skin tumor. Next-generation sequencing-based multiplex gene assay performed on the metastatic tissue revealed an ETV6-NTRK3 fusion gene. This is a rare case report of secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs.

DOI： 10.1111/cup.14028

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.

DOI： 10.1007/s10147-021-01881-4

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記述言語：英語  

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.

DOI： 10.3390/ijms22157962

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記述言語：英語  

DOI： 10.1038/s41440-021-00633-1

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

約20年前にCYP11B1/B2キメラ遺伝子を確認しグルココルチコイド反応性アルドステロン症(GRA)と診断された日本人1家系3例(発端者、母、妹)のうち、発端者が出産した5歳と3歳の男児に対し遺伝子検査を行った。その結果、男児2人ともキメラ遺伝子を検出しGRA保因者であることが明らかとなった。また、キメラ遺伝子の交叉部位について検討した結果、2児と発端者は同一のシークエンスで、交叉部位はエクソン3とイントロン5間であった。2児とも高血圧を認めないが低レニン・高アルドステロン症を伴っており、今後、成人期までの慎重な経過観察が必要である。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01160&link_issn=&doc_id=20210811280023&doc_link_id=10.1507%2Fendocrine.97.S.Update_71&url=https%3A%2F%2Fdoi.org%2F10.1507%2Fendocrine.97.S.Update_71&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. CASE REPORT A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. CONCLUSIONS JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

DOI： 10.12659/AJCR.932241

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, two cancer genomic profiling tests have been approved in Japan and implemented in routine clinical practice: the FDA-approved FoundationOne CDx test, and the OncoGuide NCC Oncopanel test. The quality and quantity of DNA significantly affects the sequencing results; therefore, preparing a sufficient amount of high-quality DNA for clinical cancer genomic profiling tests is important. We examined the best practices for the extraction of cancer genomic DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues of pancreatic, lung and colon cancer specimens. We found that the quality of cancer genomic DNA extracted from 10-μm-thick FFPE samples improved significantly, compared with that from 4-μm-thick FFPE samples, suggesting that 10-μm-thick FFPE samples are preferable for clinical cancer genomic profiling tests. For convenience, we created a quick reference table for calculating the required number of FFPE slides.

DOI： 10.1111/pin.13086

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記述言語：日本語   出版者・発行元：西日本泌尿器科学会  

症例は45歳,男性。X-1年9月に肉眼的血尿と右腰痛を主訴に当院を受診し,単純CTで右腎上極に長径5cm大の腫瘤を認めた。腹部造影CTでは動脈相で早期濃染,後期相でwashout patternを伴う内部不整な腫瘤を同部位に認めたが,明らかなリンパ節・他臓器転移を認めなかった。右腎癌cT1bN0M0 Stage Iと診断し,同年10月に腹腔鏡下右腎摘除術を施行した。病理所見は,腫瘍細胞は淡明細胞や好酸性細胞が乳頭状・管状の構造を取り,細胞質に好酸性の核小体および核周囲明庭を認めた。Fumarate hydratase(FH)免疫染色陰性でFH欠損腎細胞癌と診断した。術後2ヵ月で多発骨転移を認め,International Metastatic RCC Database Consortium(IMDC) intermediate riskと判断し,イピリムマブ・ニボルマブ併用療法を開始した。4コース施行後,CT上新規の転移巣や転移巣の増大を認めなかった。遺伝学的検査でFH遺伝子の病的バリアントを認め,腎細胞癌の家族歴と合わせ,遺伝性平滑筋腫症-腎細胞癌症候群(hereditary leiomyomatosis and renal cell carcinoma syndrome;HLRCC)関連腎細胞癌と診断した。現在ニボルマブ単剤投与を継続中で,骨転移増悪や新規遠隔転移は認めていない。(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a <italic>BRCA2</italic> pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic <italic>BRCA2</italic> variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.

DOI： 10.1007/s13691-020-00449-9

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その他リンク： http://link.springer.com/article/10.1007/s13691-020-00449-9/fulltext.html

担当区分：責任著者   記述言語：日本語   出版者・発行元：(株)診断と治療社  

遺伝性乳がん卵巣がん症候群(HBOC)やLynch症候群を代表とする遺伝性腫瘍は婦人科腫瘍とのかかわりが深い。特にごく最近では2019年のBRCA1/2遺伝学的検査のコンパニオン診断とがんゲノム医療の保険診療化、そして2020年4月のHBOC診療の一部保険診療化に伴い、産婦人科医にとって遺伝性腫瘍の知識は不可欠なものとなっている。個々の遺伝情報を知ることは、がん治療および予防の観点から有用性が高い。(著者抄録)

J-GLOBAL

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00525&link_issn=&doc_id=20201221170010&doc_link_id=%2Fae4sanke%2F2021%2F008801%2F011%2F0065-0072%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2021%2F008801%2F011%2F0065-0072%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests.

DOI： 10.3390/ijms21249504

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGERNATURE  

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.

DOI： 10.1038/s10038-020-0802-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. METHODS: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. RESULTS: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. CONCLUSIONS: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

DOI： 10.1093/jjco/hyaa173

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in < 3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs.

DOI： 10.1038/s41598-020-69488-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

DOI： 10.1007/s10147-019-01610-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. METHODS: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. RESULTS: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. CONCLUSION: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

DOI： 10.1007/s10147-019-01498-8

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記述言語：日本語   出版者・発行元：日本家族性腫瘍学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

DOI： 10.1038/s41598-020-58066-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive form of malignant mesothelioma. Sufficient biological tools for studying the functional characteristics of this cancer have not been developed. Therefore, in this study, a novel human cancer cell line, KOG-1, was established from ascites fluids isolated from a 39-year-old Japanese woman with pemetrexed-resistant MPeM. Cells were dendritic or linear immediately after thawing, showed a jigsaw puzzle-like and spindle arrangement during growth, and formed monolayers without contact inhibition in two-dimensional (2D) culture. The population doubling time was 13.7 h. Karyotypic and molecular genetic analyses showed that chromosome numbers ranged from 62 to 142, with a peak of 73 with complicated copy number alterations. No germline BAP1 pathogenic variant was detected. Cells expressed various tumor markers of mesothelioma, such as calretinin, podoplanin, and Wilms tumor 1 (WT-1). Drug sensitivity and resistance testing with a set of 36 drugs using 2D and three-dimensional (3D) culture models demonstrated that KOG-1 cells showed high and low sensitivity to pemetrexed under 2D and 3D culture conditions, respectively, whereas control ovarian cancer cell lines showed low sensitivity to pemetrexed under both culture conditions. This newly established cell line will be a valuable biological resource to expand the feasibility of functional studies as well as drug testing for potential therapeutic purposes in MPeM.

DOI： 10.1007/s13577-019-00286-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

DOI： 10.1038/s41523-020-0163-1

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1248/yakushi.19-00217-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Poor quality of biological samples will result in an inaccurate analysis of next-generation sequencing (NGS). Therefore, methods to accurately evaluate sample integrity are needed. Among methods for evaluating RNA quality, the RNA integrity number equivalent (RINe) is widely used, whereas the DV200, which evaluates the percentage of fragments of >200 nucleotides, is also used as a quality assessment standard. In this study, we compared the RINe and DV200 RNA quality indexes to determine the most suitable RNA index for the NGS analysis. Seventy-one RNA samples were extracted from formalin-fixed paraffin-embedded tissue samples (n = 30), fresh-frozen samples (n = 25), or cell lines (n = 16). After assessing RNA quality using the RINe and DV200, we prepared two kinds of stranded mRNA sequencing libraries. Finally, we calculated the correlation between each RNA quality index and the amount of library product (1st PCR product per input RNA). The DV200 measure showed stronger correlation with the amount of library product than the RINe (R2 = 0.8208 for the DV200 versus 0.6927 for the RINe). Receiver operating characteristic curve analyses revealed that the DV200 was the better marker for predicting efficient library production than the RINe using a threshold of >10 ng/ng for the amount of the 1st PCR product per input RNA (cutoff value for the RINe and DV200, 2.3 and 66.1%; area under the curve, 0.99 and 0.91; sensitivity, 82% and 92%; and specificity, 93% and 100%, respectively). Our results indicate that NGS libraries prepared using RNA samples with the DV200 value > 66.1% exhibit greater sensitivity and specificity than those prepared with the RINe values > 2.3. These findings suggest that the DV200 is superior to the RINe, especially for low-quality RNA, because it is a more consistent assessment of the amount of the 1st NGS library product per input.

DOI： 10.1155/2020/9349132

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13053-020-00160-z

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その他リンク： http://link.springer.com/article/10.1186/s13053-020-00160-z/fulltext.html

記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The present study was performed to clarify the significance of DNA methylation alterations during endometrial carcinogenesis. Genome-wide DNA methylation analysis and targeted sequencing of tumor-related genes were performed using the Infinium MethylationEPIC BeadChip and the Ion AmpliSeq Cancer Hotspot Panel v2, respectively, for 31 samples of normal control endometrial tissue from patients without endometrial cancer and 81 samples of endometrial cancer tissue. Principal component analysis revealed that tumor samples had a DNA methylation profile distinct from that of control samples. Gene Ontology enrichment analysis revealed significant differences of DNA methylation at 1034 CpG sites between early-onset endometrioid endometrial cancer (EE) tissue (patients aged ≤40 years) and late-onset endometrioid endometrial cancer (LE) tissue, which were accumulated among 'transcriptional factors'. Mutations of the CTNNB1 gene or DNA methylation alterations of genes participating in Wnt signaling were frequent in EEs, whereas genetic and epigenetic alterations of fibroblast growth factor signaling genes were observed in LEs. Unsupervised hierarchical clustering grouped EE samples in Cluster EA (n = 22) and samples in Cluster EB (n = 12). Clinicopathologically less aggressive tumors tended to be accumulated in Cluster EB, and DNA methylation levels of 18 genes including HOXA9, HOXD10 and SOX11 were associated with differences in such aggressiveness between the two clusters. We identified 11 marker CpG sites that discriminated EB samples from EA samples with 100% sensitivity and specificity. These data indicate that genetically and epigenetically different pathways may participate in the development of EEs and LEs, and that DNA methylation profiling may help predict tumors that are less aggressive and amenable to fertility preservation treatment.

DOI： 10.1093/carcin/bgz046

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記述言語：日本語   出版者・発行元：(株)文光堂  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Six years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the third revised edition was published in 2017. The 2017 Guidelines includes 10 additional clinical questions (CQ), which brings the total to 95 CQ (12 on infectious disease, 28 on oncology and benign tumors, 27 on endocrinology and infertility and 28 on healthcare for women). Currently a consensus has been reached on the Guidelines and therefore the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding recommendation level (A, B, C) is indicated.

DOI： 10.1111/jog.13831

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

がん診療のエンドポイントは"がん死の低減"であるが、女性においては集学的治療やリスク低減手術によって女性ホルモンの欠落をきたし、quality of life(QOL)低下を余儀なくされるケースがある。近年のがんゲノム医療の急速な進展は、実地臨床においてがん薬物療法の標的となる遺伝子病的バリアント(変異)のみならず、遺伝性腫瘍の原因となる生殖細胞系列バリアントも明らかにしてきている。2人に1人ががんに罹患するという今日、医療人はがんの"診断・予防・治療"のみならず、女性ヘルスケアについてもシームレスに行う体制を構築する必要がある。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00060&link_issn=&doc_id=20190408030015&doc_link_id=%2Faa7ayuma%2F2019%2F026901%2F016%2F0085-0088%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2019%2F026901%2F016%2F0085-0088%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(株)診断と治療社  

＜POINT!＞◆遺伝性腫瘍関連遺伝子の病的バリアント保持者に対して、がん一次予防として化学予防が選択肢とされることがある。◆BRCA1/2病的バリアント保持者に対する現時点で提唱されている確実ながん予防法はリスク低減卵管卵巣摘出術(RRSO)である。◆低用量経口避妊薬は卵巣癌予防効果があり、RRSOを選択しないBRCA1/2病的バリアント保持者に対しては卵巣癌一次予防法の選択肢となり得る。(著者抄録)

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞遺伝性腫瘍診療のエンドポイントは「がん死の低減」であり,遺伝性腫瘍の病的バリアント(変異)を同定することで,がん予防策を構築することを目指す。婦人科領域における遺伝性腫瘍としては遺伝性乳癌卵巣癌症候群(HBOC),リンチ症候群などが代表である。近年はがん診療のなかで生殖細胞系列病的バリアントが同定される機会が多くなってきている。婦人科癌ではほかのがん種と比較しても生殖細胞系列病的バリアントが潜在している頻度が高いことから,遺伝性腫瘍診療において産婦人科が担う役割は大きい。さらに,病的バリアント同定後のがん治療やがん予防のサーベイランスを施行する立場としても産婦人科実地臨床は重要な立場にある。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00535&link_issn=&doc_id=20190228020012&doc_link_id=10.18888%2Fsp.0000000762&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fsp.0000000762&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01750&link_issn=&doc_id=20190215160001&doc_link_id=issn%3D0289-5803%26volume%3D37%26issue%3D2%26spage%3D9&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0289-5803%26volume%3D37%26issue%3D2%26spage%3D9&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

DOI： 10.1007/978-981-13-1519-0_19

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with MSH2 mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of MSH2 (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This MSH2 mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC.

DOI： 10.3892/mco.2018.1723

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

遺伝性乳癌卵巣癌(hereditary breast cancer ovarian cancer syndrome、HBOC)は、BRCA1またはBRCA2(BRCA1/2)の生殖細胞系列病的変異(バクアント)が原因であり、家系内に乳癌・卵巣癌・卵管癌・腹膜癌などが好発し、BRCA1/2遺伝子変異保持者では70歳までに卵巣癌発症例が40%以上であると報告されている。BRCA1/2遺伝子変異保持者に対するマネージメントとして、リスク低減卵管卵巣摘出術(risk reduction salpingo-oophorectomy、RRSO)は卵巣癌や卵管癌の発症リスクを減少させ、全死亡率を低下することも報告されているが、閉経前の両側卵巣摘出術は医原性の卵巣欠落症状を惹起するため、その管理が重要である。本検討では、当院でRRSOを施行した8症例を対象に、RRSO後の諸症状より女性QOLについて後方視的に検討した。8例のうち6例で乳癌の既往があった。術後に薬物治療を必要とする卵巣欠落症状を呈した症例は3例で漢方治療を行っていた。またRRSO後早期に脂質異常症を発症した例もあった。BRCA1/2遺伝子変異保持者に対するRRSOは本邦の実臨床に導入されてきているが、RRSO実施例では短期的には卵巣欠落症状、長期的には脂質異常症や骨粗鬆症などを発症してQOL低下をもたらす可能性が高い。海外の各種ガイドラインでは術後卵巣欠落症状に対するホルモン補充療法(HRT)が提唱されているものの、乳癌既往例などではHRTが禁忌な例が存在し、症例には漢方療法が有効である。RRSO後はがんサーベイランスとともに、女性医学の観点から将来的なQOLに関係する項目を経時的に追跡することが重要である。(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本医師会  

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（研究会，シンポジウム資料等）  

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記述言語：英語   掲載種別：研究論文（研究会，シンポジウム資料等）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18632/oncotarget.25712

PubMed

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記述言語：日本語   出版者・発行元：(一社)東京産科婦人科学会  

ベバシズマブは婦人科がんにおいて日常的に用いられる分子標的薬となっているが、特有の有害事象により投与継続が困難となるケースを経験する。そこで本研究ではベバシズマブ投与中止の原因となった重篤な有害事象と臨床的背景を明らかにすることを目的とした。ベバシズマブ併用化学療法を2013年12月から開始した上皮性卵巣癌、卵管癌、腹膜癌(以下卵巣癌)48例および2017年1月から開始した子宮頸癌12例の計60例について後方視的に有害事象とその発現時期を検討した。卵巣癌は初発投与19例、再発投与29例の計48例、子宮頸癌は初発投与1例、再発投与11例の計12例を組み入れた。卵巣癌の年齢中央値は54歳(37〜76歳)、ベバシズマブ投与サイクル数中央値は15回(1〜68回)であった。子宮頸癌の年齢中央値は50歳(33〜68歳)、ベバシズマブ投与サイクル数中央値は5.5回(1〜10回)であった。卵巣癌48例中有害事象による投与中止例は4例あり、内訳は高度蛋白尿・ネフローゼ2例(4.2%)、腸炎1例(2.08%)、血栓塞栓症1例(2.08%)であった。子宮頸癌12例中有害事象による投与中止例は3例あり、全例血栓塞栓症(25%)であった。血液毒性、高血圧による投与中止例は認めず、出血および消化管穿孔、瘻孔は認めなかった。有害事象の発現時期について高度蛋白尿・ネフローゼは17、23サイクル終了時、血栓塞栓症はそれぞれ1、1、2、8サイクル終了時に認めた。高度蛋白尿・ネフローゼは投与数を重ねてから出現し、血栓塞栓症は投与開始後早期に認めた。検討した症例数は少ないものの、子宮頸癌では卵巣癌に比較して血栓塞栓症を多く認める可能性が示唆され、今後症例の蓄積が必要である。(著者抄録)

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞遺伝性腫瘍における臨床目標の1つが,「病的バリアント保持者※(遺伝子変異保持者)に対するがん死低減」である。遺伝性腫瘍に対するリスク低減手術はわが国においても実施施設では着実に実地臨床に導入されている。本稿においては,リスク低減卵管卵巣摘出術の効果およびその対象となる遺伝性腫瘍の概要を中心に,実際の手術手技のポイントについて述べる。その実施にあたっては,オカルト癌の可能性を念頭に病理学的に詳細な検討を行うことや,遺伝診療部門との堅実な連携体制を構築し,十分な遺伝カウンセリングを行うなど,他診療科との体制整備が必要である。※アメリカ臨床遺伝学会(ACMG)ガイドラインの表記に従い,最近では,「変異(mutation)」の代わりに「バリアント(variant)」が使われるようになってきている。もともと変異という言葉に否定的な響きがあり,また定義そのものがあいまいで混乱をきたすということを理由に,最近はこうした表現をやめ,代わりにバリアント(多様体)という言葉を使うことが推奨されており,本稿ではバリアントという表記に統一する。

J-GLOBAL

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00535&link_issn=&doc_id=20180525020017&doc_link_id=10.18888%2Fsp.0000000437&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fsp.0000000437&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

遺伝性乳がんに関連するさまざまな原因遺伝子が同定されてきた。中でも遺伝性乳癌卵巣癌症候群(HBOC)の原因遺伝子であるBRCA1/2遺伝子の関連は25%を占める。遺伝性乳がんに関わる疾患として、臨床的に重要視されつつあるHBOCを中心に、Li Fraumeni症候群、Cowden病について解説した。また、Multi-gene panel検査、NCCNガイドラインを参照にしたマネジメントについて述べた。さらに、主治医が理解しておくべき遺伝学的検査の特徴、結果による治療戦略、家族への影響について触れた。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J06305&link_issn=&doc_id=20180620100003&doc_link_id=%2Fai1whitc%2F2018%2F000601%2F003%2F0015-0022%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1whitc%2F2018%2F000601%2F003%2F0015-0022%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：産婦人科漢方研究会  

遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer syndrome:HBOC)は、BRCA1またはBRCA2(BRCA1/2)の生殖細胞系列変異(病的バリアント)が原因であり、家系内に乳癌や卵巣癌(卵管癌・腹膜癌含む)などが好発する。BRCA1/2遺伝子変異保持者では70歳までに卵巣癌発症例が40%以上であり、現時点ではリスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy:RRSO)が卵巣癌発症リスクを減少させ全死亡率の低下を可能とすることから、最も確実な癌予防法とされている。しかしながら閉経前のRRSOは医原性の卵巣欠落症状を惹起するため、その術後の管理が重要である。本検討では当院でRRSOを施行した症例における術後の女性QOL管理について検討した。2008年から2016年までに当院にてRRSOを施行した8例を調査対象として、RRSO後の卵巣欠落症状の有無・血清脂質・骨密度検査について検討した。特に卵巣欠落症状に対する漢方薬を含めた介入につき後方視的に検討した。8例のうち7例が継続的に当院女性健康維持外来に受診をしており、7例全例(100%)で介入を施行されていた。術後に薬物治療を必要とする卵巣欠落症状を呈したのは5例(71%)で、いずれも術後に漢方治療を行っていた。なお6例で乳癌の既往があった。BRCA1/2遺伝子変異保持者に対するRRSOはわが国の実臨床に導入されてきているが、RRSO実施例では短期的には卵巣欠落症状、長期的には脂質異常症や骨粗鬆症などを発症してQOL低下をもたらす可能性が高い。海外の各種ガイドラインでは術後卵巣欠落症状に対するホルモン補充療法(HRT)が提唱されているものの、乳癌既往例などET療法が困難な例が存在し、症例によっては漢方療法が有効であると考えられた。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KOREAN SOC GYNECOLOGY ONCOLOGY & COLPOSCOPY  

Objective: Reports on the repeated administration of medroxyprogesterone acetate (MPA) for intrauterine recurrence after fertility-preserving therapy for atypical endometrial hyperplasia (AEH) and early grade 1 endometrioid carcinoma (G1) are lacking. We aimed to clarify the outcomes of repeated MPA therapy in cases of intrauterine recurrence after fertility-preserving therapy with MPA against AEH/early G1.Methods: Patients with AEH or stage IA well-differentiated endometrioid carcinoma without myometrial invasion who underwent first-line MPA therapy for primary lesions or intrauterine recurrence were divided into initial treatment and repeated treatment groups (162 and 82 patients, respectively). Oral MPA administration (400-600 mg/day) was continued until pathological tumor disappearance. Data regarding clinicopathological factors, adverse events, and outcomes following the initial and repeated hormonal treatments were extracted from medical records and analyzed.Results: Complete response rates in the initial and repeated treatment groups were 98.5% and 96.4%, respectively, among patients with AEH, and were 90.7% and 98.1%, respectively, among patients with G1. In the initial treatment group, 5-year recurrence-free survival (RFS) rates were 53.7% and 33.2% among patients with AEH and G1, respectively. In the repeated treatment group, RFS rates were 14.0% and 11.2% among patients with AEH and G1, respectively. Among patients with AEH, the pregnancy rate tended to be lower in the repeated treatment group than in the initial treatment group (11.1% vs. 29.2%; p=0.107), while no significant group difference was observed among patients with G1 (20.8% vs. 22.7%).Conclusion: Repeated treatment is sufficiently effective for intrauterine recurrence after hormonal therapy for AEH/early G1.

DOI： 10.3802/jgo.2018.29.e21

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Scopus

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記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

がん診療のエンドポイントは生存率(survival)の向上であるが、がん治療にともなうQOLも重要な課題である。近年の婦人科がん罹患数の増加と集学的治療法の進歩は、将来における婦人科がんサーバイバー(がん生存者)の増加を意味しており、女性がんサバイバーのQOLに対して系統的に早期介入する体制を確立することは喫緊の課題である。さらに近年はがん罹患者のみならず、がん高危険群に対する予防的治療も現実のものとなってきている。遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer:HBOC)の原因遺伝子であるBRCA1またはBRCA2(BRCA1/2)遺伝子の病的バリアント(遺伝子変異)保持者に対するリスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy:RRSO)は、国内の実施臨床に確実に導入されてきている。しかしながらRRSOは閉経前に施行することが多いため、短期的には卵巣欠落症状、皮膚・泌尿器症状など、長期的には脂質異常症や骨粗鬆症の高危険群となる。さらに最近は「生活習慣病としてのがん」という観点から、女性医学と腫瘍学のクロストークが注目を浴びつつある。このような背景のもと、我々は質の高い臨床データ、家系員情報をともなった婦人科疾患バイオバンク試料をもとに、リスクの層別化に基づいた個別化がん予防戦略を構築し、最終的に女性のQOLの臨床に還元する臨床と研究を行ってきた。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance.

DOI： 10.1111/cas.13469

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hereditary colorectal cancer accounts for less than 5% of all colorectal cancer cases. Some of the unique characteristics that are commonly encountered in cases of hereditary colorectal cancer include early age at onset, synchronous/metachronous occurrence of the cancer, and association with multiple cancers in other organs, necessitating different management from sporadic colorectal cancer. While the diagnosis of familial adenomatous polyposis might be easy because usually 100 or more adenomas that develop in the colonic mucosa are in this condition, Lynch syndrome, which is the most commonly associated disease with hereditary colorectal cancer, is often missed in daily medical practice because of its relatively poorly defined clinical characteristics. In addition, the disease concept and diagnostic criteria for Lynch syndrome, which was once called hereditary non-polyposis colorectal cancer, have changed over time with continual research, thereby possibly creating confusion in clinical practice. Under these circumstances, the JSCCR Guideline Committee has developed the "JSCCR Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (HCRC)," to allow delivery of appropriate medical care in daily practice to patients with familial adenomatous polyposis, Lynch syndrome, or other related diseases. The JSCCR Guidelines 2016 for HCRC were prepared by consensus reached among members of the JSCCR Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR Guidelines 2016 for HCRC.

DOI： 10.23922/jarc.2017-028

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Results: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Conclusion: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

DOI： 10.1200/PO.18.00091

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(in press)  

Pathogenic germline BRCA1, BRCA2 (BRCA1/2), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1), 8 (3.5%; BRCA2), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D), 2 (0.9%; ATM), 1 (0.4%; MRE11A), 1 (FANCC), and 1 (GABRA6). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2. Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

DOI： 10.18632/oncotarget.22733

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) is currently one of the preferred treatment options for advanced ovarian, fallopian tube or peritoneal cancer. This study was conducted to evaluate the clinical efficacy and safety of dose-dense paclitaxel plus carboplatin therapy (ddTC therapy) as NAC for these cancers.A retrospective study was conducted in 25 patients with Stage III/IV ovarian, fallopian tube or peritoneal cancer who received ddTC therapy as NAC. For ddTC therapy, paclitaxel (80 mg/m(2)) was administered intravenously on Days 1, 8 and 15 and carboplatin (AUC 6.0 mg/ml x min) was administered intravenously on Day 1 every 3 weeks. IDS was performed after three cycles of ddTC therapy, and ddTC therapy was also continued after surgery.With ddTC therapy as NAC, the response rate was 92% and disease progression did not occur in any patient. Grade 4 hematologic toxicity and >= Grade 3 non-hematologic toxicity both occurred in 8% of the patients, but no patient discontinued NAC because of adverse events. When IDS was performed, the complete surgery rate was 64% and the optimal surgery rate was 96%. >= Grade 3 perioperative complications occurred in 16% of the patients, but there were no perioperative deaths. Median overall survival was 35.7 months and median progression-free survival was 17.7 months.This study showed that ddTC therapy was considerably effective and tolerable as NAC. The complete surgery rate was high with IDS, and perioperative complications were acceptable.

DOI： 10.1093/jjco/hyx118

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective Sentinel nodes (SNs) have been observed in several reports from Japan and overseas in cases with endometrial cancer; however, no consensus has been reached regarding the types of tracers or the method of their injection. A combination of the radioisotope (RI) and dye method is considered to be desirable. We assessed SN mapping using either dye or near-infrared fluorescence imaging to clarify a suitable method in cases of endometrial cancer.Methods Patients were enrolled from 92 patients diagnosed with endometrial cancer and having no extrauterine metastasis by the preoperative imaging between 2009 and 2014 at our institution. To identify the SNs, we performed 3 methods using either dye or fluorescence solutions in conjunction with a RI method. In the dye method, we injected indocyanine green in the uterine subserosa, visually identifying SNs as stained green. In the fluorescence method, a dilute indocyanine green solution (0.5 mg, fluorescence A or 0.25 mg, fluorescence B, each per 10 mL of solvent) was injected and the SN identified by the HyperEye Medical System.Results The SN detection rates were 100%, 100%, and 96% using dye and fluorescence A or B solution, respectively. Pelvic SNs were detected by the 3 methods in 98%, 100%, and 96% of cases and para-aortic SNs in 65%, 88%, and 74%, respectively. Fluorescence A solution was somewhat better than dye in detecting para-aortic SNs, although not significantly so (P = 0.07). The sensitivity and negative predictive values for detecting SNs with metastases with the dye method were 92% and 98% compared with 100% and 100%, respectively, for both fluorescence solutions.Conclusions Although both dye and fluorescence methods performed well, no method perfectly identified para-aortic SNs. The concomitant use of the RI method is required to detect para-aortic SNs.

DOI： 10.1097/IGC.0000000000000997

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記述言語：日本語   出版者・発行元：(株)東京医学社  

がんは遺伝因子と環境因子の双方が関与して発症するが、卵巣癌の約10〜15%は遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer;HBOC)の原因遺伝子であるBRCA1もしくはBRCA2(BRCA1/2)の生殖細胞系列変異に基づく。BRCA1/2変異保持者は卵巣癌のリスクが高く、がん予防策を講じる必要がある。もっとも確実なリスク低減策はリスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy;RRSO)であり、発癌リスクを80%減らすことができる。BRCA1/2変異のある癌に対しては合成致死作用によりPARP阻害薬が奏効する。PARP阻害薬のコンパニオン診断としてBRCA1/2遺伝子検査が行われるようになり、precision medicineの先駆けとしてゲノム医療の実用化が始まっている。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J03723&link_issn=&doc_id=20170807200010&doc_link_id=%2Faq9seijd%2F2017%2F004707%2F010%2F0861-0866%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faq9seijd%2F2017%2F004707%2F010%2F0861-0866%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：金原出版(株)  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00535&link_issn=&doc_id=20170626230016&doc_link_id=10.18888%2FJ00535.2017268170&url=https%3A%2F%2Fdoi.org%2F10.18888%2FJ00535.2017268170&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A patient's medical history and familial cancer history are important information for assessing the risk of hereditary cancer. We have generated a self-administered questionnaire for patients with gynecologic cancer. This pilot study analyzed the usefulness of this questionnaire and the rates of patients that meet the Society of Gynecologic Oncology criteria in ovarian cancer and endometrial cancer patients. Method: Ovarian or endometrial cancer patients were recruited for this study. After informed consent was obtained, participants completed the questionnaire. Genetic risks were assessed from the data of each patient's questionnaire by Society of Gynecologic Oncology guideline. Clinical and pathological findings were compared between the genetic risk groups. Results: A total of 105 patients were identified with ovarian cancer and 56 patients with endometrial cancer eligible for this study. According to the Society of Gynecologic Oncology guideline, of the 105 ovarian cancer patients, 25 patients (23%) had a 20-25% risk and three patients (2.9%) had a 5-10% risk of hereditary breast and ovarian cancer syndrome. A further 22 patients (21%) had a 5-10% risk of Lynch syndrome. Two patients (1.9%) met the Amsterdam criteria II. Of 56 endometrial cancer patients, 24 patients (42.9%) had a 5-10% risk of Lynch syndrome. The endometrial cancer patients with genetic risk of Lynch syndrome were younger (mean age: 47.79) at diagnosis compared to patients without a genetic risk of Lynch syndrome (mean age: 57.91). Conclusions: In this study, we were able to show that the newly designed questionnaire is a useful tool for evaluating cancer family history along with Society of Gynecologic Oncology criteria or Amsterdam criteria II. When considering the risk of Lynch syndrome for a patient with ovarian cancer, it is important to collect a second and third relative's family history.

DOI： 10.1093/jjco/hyx019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

This study shows that the newly designed self-administered questionnaire is a useful tool to assess the risk of hereditary cancer for patients with gynecologic cancer.A patient's medical history and familial cancer history are important information for assessing the risk of hereditary cancer. We have generated a self-administered questionnaire for patients with gynecologic cancer. This pilot study analyzed the usefulness of this questionnaire and the rates of patients that meet the Society of Gynecologic Oncology criteria in ovarian cancer and endometrial cancer patients.
Ovarian or endometrial cancer patients were recruited for this study. After informed consent was obtained, participants completed the questionnaire. Genetic risks were assessed from the data of each patient's questionnaire by Society of Gynecologic Oncology guideline. Clinical and pathological findings were compared between the genetic risk groups.
A total of 105 patients were identified with ovarian cancer and 56 patients with endometrial cancer eligible for this study. According to the Society of Gynecologic Oncology guideline, of the 105 ovarian cancer patients, 25 patients (23%) had a 20-25% risk and three patients (2.9%) had a 5-10% risk of hereditary breast and ovarian cancer syndrome. A further 22 patients (21%) had a 5-10% risk of Lynch syndrome. Two patients (1.9%) met the Amsterdam criteria II. Of 56 endometrial cancer patients, 24 patients (42.9%) had a 5-10% risk of Lynch syndrome. The endometrial cancer patients with genetic risk of Lynch syndrome were younger (mean age: 47.79) at diagnosis compared to patients without a genetic risk of Lynch syndrome (mean age: 57.91).
In this study, we were able to show that the newly designed questionnaire is a useful tool for evaluating cancer family history along with Society of Gynecologic Oncology criteria or Amsterdam criteria II. When considering the risk of Lynch syndrome for a patient with ovarian cancer, it is important to collect a second and third relative's family history.

DOI： 10.1093/jjco/hyx037

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

DOI： 10.1111/jog.13202

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

We investigated whether UGT1A1 polymorphisms are associated with the prognosis of ovarian cancer patients treated with irinotecan. UGT1A1 genotypes were analyzed in 11 stage I ovarian clear cell carcinoma patients who received irinotecan as first-line therapy. Progression-free survival, overall survival and adverse events were also assessed for each genotype. Three patients harbored UGT1A1*1/*6 while another three harbored UGT1A1*1/*28. Two patients with a wildtype genotype experienced recurrence and one died, whereas no recurrence or death was observed in patients with heterozygous genotypes. Adverse events tended to be more severe in patients with UGT1A1*6 and *28, although progression-free survival and overall survival rates tended to be better than in wild-type; the differences were not significant. We conclude that UGT1A1 polymorphisms have the potential to be a prognostic marker of irinotecan treatment.

DOI： 10.1093/jjco/hyw163

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

DOI： 10.1111/jog.13202

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記述言語：日本語   出版者・発行元：更年期と加齢のヘルスケア学会((NPO)更年期と加齢のヘルスケア)  

遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer syndrome:HBOC)はBRCA1またはBRCA2遺伝子(BRCA1/2)の生殖細胞系列変異によるもので、BRCA1遺伝子変異保持者女性の卵巣癌発症リスクは39〜46%、BRCA2遺伝子変異保持者女性では12〜27%であると報告されている。HBOCは常染色体優性遺伝性疾患であり、血縁者にその関連疾患が多発することから、家族歴の聴取が発見の端緒となる。BRCA1/2変異保持者に対しては、がん発症リスクを理解した上で適切な対策を講じる必要がある。腫瘍遺伝学の臨床におけるエンドポイントは「遺伝子変異保持者におけるがん死の低減」である。その目的のため遺伝子変異保持者に対してはがん予防策をとることが必要となる。がん一次予防法としてはリスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy:RRSO)、リスク低減乳房切除術(risk-reducing mastectomy:RRM)、経口避妊薬による卵巣癌予防およびタモキシフェンによる乳癌予防などが挙げられる。そのなかでもRRSOは卵巣癌発症のリスク低減効果のみならず、乳癌発症リスク、さらには卵巣癌や乳癌による死亡率のみならず全死亡も低減すると報告されており、現時点でBRCA1/2遺伝子変異保持者に対する最も効果が高いがん一次予防法である。BRCA1/2遺伝子変異保持者に対するRRSOは本邦の実臨床に導入されてきている。しかしながらRRSOは閉経前に施行されることが多く、術後短期的には卵巣欠落症状、長期的には脂質異常症や骨粗鬆症などを発症してQOL低下をもたらす可能性が高い。海外の各種ガイドラインでは術後卵巣欠落症状に対するホルモン補充療法(ET療法)が提唱されているものの、乳癌既往例などET療法が困難な例が存在し、そのような場合は漢方療法が有効な場合がある。RRSO施行後は乳癌や腹膜癌などの発生についての「がんサーベイランス」とともに、女性ヘルスケアの観点からも経時的に追跡することが重要である。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)東京産科婦人科学会  

当科において手術前禁忌薬である経口女性ホルモン製剤(OC・LEP)を内服している患者に、術前休薬の指示がされなかったために発生したインシデント事例について、後方視的に検討した。2015年1月から12月に、当院で入院のうえ手術を施行した1,250例のうち、OC・LEPを内服していた症例は17例であり、そのうち3例は術前に内服中止の指示がされず、手術延期となった。院内における対策として医療者への教育強化、医師への注意喚起、看護師・薬剤師によるダブルチェックなどのチェック機構強化を図った。その結果、当科においては手術前禁忌薬に関する同様のインシデント発生を防ぐことが可能となった。防御システムを多重化すること、医療者の認識を高めることが、インシデント発生を防止するために重要であると考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本遺伝性腫瘍学会  

本邦における家族性腫瘍の遺伝カウンセリング体制は近年急速に整備されつつあるが,その多くは大学病院やセンター病院といった大規模病院である.今回我々は,地域がん診療連携拠点病院における家族性腫瘍相談外来開設の経験をもとに,一般市中病院での遺伝カウンセリング体制の課題などについて当院での現状を紹介し,考察する.依頼元の内訳は乳腺外科からの受診相談が約30%にのぼり,さらに遺伝学的検査の内訳で見ると43%が乳癌の術前依頼であり,受診動機として癌罹患者の術式選択が大きな要因になっていることが示唆された.また,受診された遺伝子変異保持者および血縁者を対象にハイリスク外来を同時に開設し,心理的支援とサーベイランスを継続している.今後もクライエントのために,一般市中病院の立場で家族性腫瘍に関する正しい情報提供およびサーベイランスや,診断後の治療を含む実地診療との密な協力体制の構築を目標に,よりクライエント中心型のカウンセリング体制の整備が必要と考える.(著者抄録)

DOI： 10.18976/jsft.16.2_38

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J03931&link_issn=&doc_id=20170714280003&doc_link_id=%2Fcg3kazok%2F2016%2F001602%2F003%2F0038-0043%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcg3kazok%2F2016%2F001602%2F003%2F0038-0043%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(株)診断と治療社  

近年、遺伝性乳癌卵巣癌症候群の原因遺伝子であるBRCA1またはBRCA2(BRCA1/2)遺伝子の遺伝学的検査が実地臨床に導入されてきている。今後はがん治療や予防の領域においてはBRCA1/2遺伝子のステータスに応じて、PARP(poly ADP ribose polymerase)阻害薬を用いた個別化治療法や、リスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy:RRSO)などの個別化予防法が実用化されることは確実である。そこで、BRCA1/2遺伝子変異保持者女性に対するHRTは女性医学、臨床腫瘍学、臨床遺伝学知見に基づいた統合的対応が必要である。(著者抄録)

J-GLOBAL

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00525&link_issn=&doc_id=20171124130011&doc_link_id=%2Fae4sanke%2F2017%2F008412%2F012%2F1468-1471%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2017%2F008412%2F012%2F1468-1471%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/nature20171

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)-1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

DOI： 10.3390/genes7100086

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

Trousseau症候群は悪性腫瘍に伴う血液凝固線溶異常により血栓塞栓症を生じる病態であり、進行例が多く予後不良である。当科でも2006〜2014年に5例の脳梗塞を発症したTrousseau症候群を経験した。年齢の中央値は63歳(54〜69歳)で、合併悪性腫瘍は子宮体癌2例、卵巣癌2例、子宮頸癌1例であり、組織型は類内膜腺癌2例、漿液性腺癌2例、扁平上皮癌1例であった。4例は進行再発癌、1例は早期癌であった。病態はいずれも多発脳梗塞によるものであり、脳出血の症例はなかった。感染性心内膜炎との鑑別に難渋した進行再発例の1例を除く全症例でヘパリンナトリウムによる抗凝固療法を開始したが、手術不能な進行再発癌の4例は原疾患の治療が奏効せず、発症後約2ヵ月以内に死亡した。手術で腫瘍を完全摘出できた早期の卵巣癌の1例は予後良好であり、手術可能な症例では原疾患の摘除により予後改善の可能性があることが示唆された。(著者抄録)

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Lippincott Williams and Wilkins  

OBJECTIVE: The aim of the study was to clarify the prevalence and severity rates of symptoms and investigate whether symptoms varied in relation to body mass index (BMI). METHODS: The study group composed of 1,969 women, aged 40 to 60 years, who presented at our department from 1993 through 2014. The participation rate was 98%. The presence or absence of symptoms was evaluated by having the participants complete the Keio Questionnaire, a self-administered questionnaire. To allow the results to be compared according to ovarian function, serum levels of follicle-stimulating hormone and estradiol were measured. Participants were classified into three groups according to BMI: underweight, normal weight, and overweight. Symptoms were also compared among these subgroups. RESULTS: The most common symptom was general fatigue. Vasomotor symptoms differed significantly between pre- and postmenopause status. When symptoms were analyzed according to BMI, the severity rates of the following symptoms were significantly higher in the overweight group than in the normal weight and underweight groups: hot flushes, sweats, joint pain, numbness, and incontinence. On the contrary, the underweight group had significantly higher severities of cold constitution, nervousness, and wrinkled skin than did the other groups. In addition, an increase in BMI was associated with an increased severity of vasomotor symptoms. CONCLUSIONS: The prevalence and severities of shoulder stiffness, considered a characteristic symptom in Japanese women, were high. Increased BMI was shown to be associated with a higher severity of vasomotor symptoms, joint pain, nervousness, and urinary symptoms.

DOI： 10.1097/GME.0000000000000660

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective:The aim of the study was to clarify the prevalence and severity rates of symptoms and investigate whether symptoms varied in relation to body mass index (BMI).Methods:The study group composed of 1,969 women, aged 40 to 60 years, who presented at our department from 1993 through 2014. The participation rate was 98%. The presence or absence of symptoms was evaluated by having the participants complete the Keio Questionnaire, a self-administered questionnaire. To allow the results to be compared according to ovarian function, serum levels of follicle-stimulating hormone and estradiol were measured. Participants were classified into three groups according to BMI: underweight, normal weight, and overweight. Symptoms were also compared among these subgroups.Results:The most common symptom was general fatigue. Vasomotor symptoms differed significantly between pre- and postmenopause status. When symptoms were analyzed according to BMI, the severity rates of the following symptoms were significantly higher in the overweight group than in the normal weight and underweight groups: hot flushes, sweats, joint pain, numbness, and incontinence. On the contrary, the underweight group had significantly higher severities of cold constitution, nervousness, and wrinkled skin than did the other groups. In addition, an increase in BMI was associated with an increased severity of vasomotor symptoms.Conclusions:The prevalence and severities of shoulder stiffness, considered a characteristic symptom in Japanese women, were high. Increased BMI was shown to be associated with a higher severity of vasomotor symptoms, joint pain, nervousness, and urinary symptoms.

DOI： 10.1097/GME.0000000000000660

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT INST ANTICANCER RESEARCH  

AIM: There is poor evidence regarding effective treatment for recurrent endometrial cancer. We treated patients with recurrent endometrial cancer with docetaxel-cisplatin (DP) therapy as second-line or third-line chemotherapy. We aimed to evaluate the feasibility and efficacy of DP therapy for patients with recurrent endometrial cancer. PATIENT AND METHODS: We included 26 patients diagnosed with recurrent endometrial cancer, who underwent DP chemotherapy at our Institution. Docetaxel at 70 mg/m(2)and cisplatin at 60 mg/m(2)were administered by intravenous injection every 3 weeks. We retrospectively analyzed the clinicopathological factors associated with the response rate (RR) and prognosis. We also analyzed the adverse effects of DP therapy. RESULTS: Median follow-up was 33.8 months and the median number of therapy cycles was six. Grade 3 or 4 adverse effects included leukopenia (66%), neutropenia (81%), anemia (9%), diarrhea (12%), general fatigue (12%), liver dysfunction (4%), peripheral neuropathy (4%), and hyponatremia (4%). RR was 58% and the median progression-free survival (PFS) was 7.5 months. The group with a treatment-free interval of 6 months or more tended to have better PFS than that with less than 6 months (p=0.01). The group with a platinum-free interval of 6 months or more had significantly better PFS than that with less than 6 months (p=0.09). Although the history of taxane usage was not relevant to prognosis, a taxane-free interval of 12 months or more was associated with a tendency for better PFS (p=0.06). CONCLUSION: DP therapy was fully feasible and demonstrated efficacy for patients with recurrent endometrial cancer.

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記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

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記述言語：日本語   出版者・発行元：更年期と加齢のヘルスケア学会((NPO)更年期と加齢のヘルスケア)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

BACKGROUND: Patients hoping to preserve their fertility receive conservative treatment with high-dose medroxyprogesterone acetate (MPA) for well-differentiated endometrioid adenocarcinoma (EC) or atypical endometrial hyperplasia (AEH) . Such treatment generally involves frequent intrauterine operations, including dilation and curettage (D&C) and endometrial biopsy (EMB), which could result in endometritis, endometrial thinning, or intrauterine adhesion. In turn, any of these outcomes could adversely affect implantation and pregnancy development. The current study thus aimed to identify factors that might affect pregnancy following conservative treatment by MPA. METHODS: We compared a pregnancy group (45 patients) with a non-pregnancy group (53 patients) of MPA-treated patients to evaluate the factors affecting clinical pregnancy establishment. We undertook a multivariate logistic regression analysis based on factors shown by univariate analysis to be significantly different between the groups. Univariate analysis identified number of D&C, endometrial thickness, duration of MPA administration, age of pregnancy permission (the age at which a patient was first allowed to attempt pregnancy after disappearance of the lesion), period of disappearance of lesions, and recurrence as independent variables. RESULTS: The odds ratios (95 % confidence interval) of multivariate analysis for disease recurrence, endometrial thickness during ovulation, and age of pregnancy permission were 0.283 (0.102-0.785), 1.677 (1.251-2.248), and 0.889 (0.792-0.998), respectively. There was no significant difference in the other independent variables between groups. CONCLUSIONS: We identified three factors considered to affect pregnancy establishment following conservative treatment with MPA: recurrence, endometrial thickness during ovulation, and the age of the pregnancy permission. Introduction of infertility treatment including assisted reproductive technology (ART) soon after achieving tumor disappearance by MPA would therefore be beneficial for patients with disease recurrence, thin endometrium, or a higher age of pregnancy permission.

DOI： 10.1186/s12958-015-0136-7

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

基礎研究、トランスレーショナルリサーチ、臨床研究の連携と推進にはバイオリソース、すなわち研究に用いる生物資源が必要であり、バイオバンクがその橋渡し機能を担う。バイオバンクの役割は、単に試料を採取・保管するのみならず、臨床情報、ゲノム解析情報、画像情報をはじめとした重層オミクスのビックデータを扱うことにより、医歯学、保健、基礎生命科学の発展や創薬開発研究のハブ機能にある。がんをはじめとした難治性疾患の個別化治療の実現ためにバイオバンクは不可欠であり、各国とも国をあげてその整備に取り組んでいる。ヒト試料のバンキングは人類が希求する難治性疾患の画期的な診断法・治療法・予防法の開発、さらには知財形成や創薬研究における研究基盤となるため、率先して取り組むべき課題である。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00525&link_issn=&doc_id=20160108220002&doc_link_id=%2Fae4sanke%2F2016%2F008301%2F003%2F0013-0019%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2016%2F008301%2F003%2F0013-0019%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(公社)日本医師会  

J-GLOBAL

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

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記述言語：日本語   出版者・発行元：(一社)東京産科婦人科学会  

重複癌は2つ以上の臓器または組織に異なる種類の癌腫が発生するものであり、子宮体部および卵巣に同時発生する例もしばしば経験される。臨床的には一方の癌による転移との鑑別に苦慮することも少なくないが、両者では臨床的な取扱いや経過が異なるため、その鑑別は重要である。そこで、2002年から2015年に当院において経験した子宮体部・卵巣同時発生重複癌40症例の臨床病理学的背景を検討した。臨床的には診断時の平均年齢は48.5歳と比較的若年者が多く、病理学的には高分化、早期の症例が多数を占め、組織型は子宮体部・卵巣ともに類内膜腺癌が最も多かった。類内膜腺癌重複癌の症例では85.1%で子宮内膜症の併存を認めた。(著者抄録)

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記述言語：日本語   出版者・発行元：金原出版(株)  

DOI： 10.18888/J00535.2016290595

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00535&link_issn=&doc_id=20160704080001&doc_link_id=10.18888%2FJ00535.2016290595&url=https%3A%2F%2Fdoi.org%2F10.18888%2FJ00535.2016290595&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a STK11 splicing variant comprising a 131-bp insertion that is derived from intron 1, which has previously been reported to possess potent pathogenicity. The same variant was detected in a Peutz-Jeghers syndrome patient harboring a genomic deletion in the vicinity of exon 1 of the STK11 gene, which indicated that this variant was derived from the wild-type allele. We also found the same variant in other normal subjects. This variant corresponds to the predicted transcript variant of STK11 (XM_011528209), which is derived from the genomic sequence of Chr19 (NT_011295.12). Therefore, we concluded that the splicing variant was not pathogenic.

DOI： 10.1038/hgv.2016.2

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1254/fpj.146.296

PubMed

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer.
Methods The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8(+) T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses.
Results The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (&lt;10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression.
Conclusions The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

DOI： 10.1097/IGC.0000000000000482

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

High expression of SQSTM1/p62 (p62) protein, which functions as a hub of oncogenic signaling pathways, has been detected in several human cancers. However, the clinicopathological and functional contribution of p62 expression is largely unknown in endometrial cancers (ECs). In this study, we assessed the expression status of p62 in primary ECs (n = 194) by immunohistochemistry and analyzed its clinical significance. Although p62 was expressed in the cytoplasm and/or nucleus in primary ECs, we observed that an expression subtype, high expression of cytoplasmic p62 but low expression of nuclear p62 (cytoplasm(High)/nucleus(Low)), significantly correlated with nonendometrioid types (P = 0.002), high grade (P < 0.001), deep myometrial invasion (P = 0.025), vascular invasion (P = 0.012), and poor prognosis (P < 0.001), and may be an independent prognostic marker of ECs (P = 0.011). Furthermore, RNA interference-mediated inhibition of p62 expression in the HEC-1A EC cell line led to the reduction of invasiveness and resistance to oxidative stress in vitro, as well as the suppression of in vivo tumor growth in an orthotopic mouse model of ECs. High expression of cytoplasmic p62 is a novel prognostic biomarker of ECs, and excess p62 expression may functionally contribute to the acquirement of malignant phenotypes in EC cells.

DOI： 10.1016/j.ajpath.2015.05.008

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer. METHODS: The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8 T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses. RESULTS: The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression. CONCLUSIONS: The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

DOI： 10.1097/IGC.0000000000000482

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Termedia Publishing House Ltd.  

INTRODUCTION: Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life. MATERIAL AND METHODS: This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. RESULTS: No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations. CONCLUSIONS: These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

DOI： 10.5114/pm.2015.54339

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記述言語：日本語   出版者・発行元：(一社)日本遺伝性腫瘍学会  

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記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

【目的】当科「健康維持外来」では、2007年5月より初診時の血液検査項目に、甲状腺刺激ホルモン(TSH)と遊離サイロキシン(fT4)の2項目を甲状腺機能のスクリーニングのために加えている。今回我々は、当外来初診患者に認められた甲状腺機能異常について、潜在性甲状腺機能異常も含めて検証したので報告する。【対象と方法】2007年5月より2014年4月末までの7年間に当外来を受診した初診患者537例(平均年齢51.7歳)に施行した血清TSHおよびfT4の値から、各症例の甲状腺機能を評価した。そしてこれらの測定値が当院で規定されている基準範囲を逸脱している症例については、当外来初診後の甲状腺機能に関する診療経過等について、外来診療録より追跡調査を行った。【結果】(1)症例全体としては、甲状腺機能および血清脂質はいずれも基準範囲であり、体格因子に関しても同様であった。(2)537例中499例(92.9%)は、TSH値とfT4値いずれもが基準範囲であった。甲状腺機能低下症と臨床診断された症例が1例(0.2%)、甲状腺の機能亢進状態であった症例は6例(1.1%)認められた。(3)潜在性甲状腺機能亢進症と診断された症例は、537例中4例(0.7%)に認められた。(4)潜在性甲状腺機能低下症と診断された症例は、537例中23例(4.4%)に認められ、2項目ともに基準範囲であった症例以外では最も多かった。(5)基準範囲例と潜在性甲状腺機能低下症例の2群間では、年齢・体格因子・血清脂質に有意差を認めなかった。【考察】当外来受診患者の9割以上の症例で甲状腺機能は正常であったが、潜在性甲状腺機能低下症例が少なからず存在することが判明し、その罹患率はわが国における人間ドック受診者を対象とした報告に匹敵するものであった。従って、主に更年期女性を対象としている当外来において甲状腺機能のスクリーニング検査を行うことは、有用であると考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Risk-reducing surgery (RRS) is defined as a prophylactic approach with removal of organs at high risk of developing cancer, which is performed in cases without lesions or absence of clinically significant lesions. Hereditary gynecological cancers for which RRS is performed include hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. For HBOC, RRS in the United States (US) is recommended for women with mutations in the breast cancer susceptibility (BRCA)1 and BRCA2 genes and bilateral salpingo-oophorectomy (BSO) is generally performed. This procedure may reduce the risk of breast, ovarian, Fallopian tube and primary peritoneal cancer, although ovarian deficiency symptoms occur postoperatively. For Lynch syndrome, RRS in the US is considered for postmenopausal women or for women who do not desire to bear children and BSO and hysterectomy are usually performed. This approach may reduce the risk of endometrial and ovarian cancer, although ovarian deficiency symptoms also occur. For RRS, there are several issues that must be addressed to reduce the risk of cancer development in patients with HBOC or Lynch syndrome. To the best of our knowledge, this is the first review to discuss RRS with a focus on hereditary gynecological cancer.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective: Synchronous primary endometrial and ovarian cancers have been an important topic in clinical medicine because it is sometimes difficult to distinguish whether there are 2 primary tumors or a single primary tumor and an associated metastasis. In addition, although these tumors are recommended for either immunohistochemistry for DNA mismatch repair (MMR) proteins or a microsatellite instability test in the Bethesda guidelines as Lynch syndrome-associated cancers, few studies have completed these analyses. In this study, we characterized the clinicopathologic features and the expression pattern of MMR proteins in synchronous primary endometrial and ovarian cancers.
Methods: Clinicopathologic features and the expression pattern of MMR proteins (MLH1, MSH2, and MSH6) were characterized and analyzed in 32 synchronous primary endometrial and ovarian cancers.
Results: Most synchronous cancers are endometrioid type (endometrioid/endometrioid) (n = 24, 75%), grade 1 (n = 19, 59.4%), and diagnosed as stage I (n = 15, 46.9%) in both endometrium and ovary. It is worth mentioning that 75% of the patients (n = 24) had endometriosis, which was more common (n = 21, 87.5%) in endometrioid/endometrioid cancers, whereas only 3 cases (37.5%) were of different histology (P = 0.018). Loss of expression of at least 1 MMR protein was observed in 17 (53.1%) of the endometrial tumors and in 10 (31.3%) of ovarian tumors. Only 4 cases (12.5%) that had specific MMR protein loss showed the same type of loss for both endometrial and ovarian tumors, in which 3 of the cases were losses in MLH1. One case showed concordant MSH6 protein loss, although the cases did not meet the Amsterdam criteria II.
Conclusions: These results suggest that most synchronous primary endometrial ovarian cancers are not hereditary cancers caused by germ line mutations but rather sporadic cancers.

DOI： 10.1097/IGC.0000000000000377

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: Synchronous primary endometrial and ovarian cancers have been an important topic in clinical medicine because it is sometimes difficult to distinguish whether there are 2 primary tumors or a single primary tumor and an associated metastasis. In addition, although these tumors are recommended for either immunohistochemistry for DNA mismatch repair (MMR) proteins or a microsatellite instability test in the Bethesda guidelines as Lynch syndrome-associated cancers, few studies have completed these analyses. In this study, we characterized the clinicopathologic features and the expression pattern of MMR proteins in synchronous primary endometrial and ovarian cancers. METHODS: Clinicopathologic features and the expression pattern of MMR proteins (MLH1, MSH2, and MSH6) were characterized and analyzed in 32 synchronous primary endometrial and ovarian cancers. RESULTS: Most synchronous cancers are endometrioid type (endometrioid/endometrioid) (n = 24, 75%), grade 1 (n = 19, 59.4%), and diagnosed as stage I (n = 15, 46.9%) in both endometrium and ovary. It is worth mentioning that 75% of the patients (n = 24) had endometriosis, which was more common (n = 21, 87.5%) in endometrioid/endometrioid cancers, whereas only 3 cases (37.5%) were of different histology (P = 0.018). Loss of expression of at least 1 MMR protein was observed in 17 (53.1%) of the endometrial tumors and in 10 (31.3%) of ovarian tumors. Only 4 cases (12.5%) that had specific MMR protein loss showed the same type of loss for both endometrial and ovarian tumors, in which 3 of the cases were losses in MLH1. One case showed concordant MSH6 protein loss, although the cases did not meet the Amsterdam criteria II. CONCLUSIONS: These results suggest that most synchronous primary endometrial ovarian cancers are not hereditary cancers caused by germ line mutations but rather sporadic cancers.

DOI： 10.1097/IGC.0000000000000377

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記述言語：日本語   出版者・発行元：金原出版(株)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

We previously reported an association between dyslipidemia and endometrial cancers. Osteoporosis is also reported to relate with some cancers. A common etiologic event has been proposed between dyslipidemia and osteoporosis. However, the pattern of interrelationships among dyslipidemia, osteoporosis and endometrial cancer is not well understood. To improve the quality of life of endometrial cancer survivors, these relationships should be determined. This study included 179 Japanese menopausal women who underwent bilateral salpingo-oophorectomy, including 114 women with incident endometrial cancer and 65 without endometrial cancer. The women were categorized according to dyslipidemia status. Bone mineral density was measured and compared between groups. Osteoporosis was statistically more frequent in women with hypertriglyceridemia who did not have endometrial cancer. In contrast, osteoporosis was statistically less frequent in women with hypertriglyceridemia who had endometrial cancer. In this cross-sectional study in a Japanese population, osteoporosis was associated with hypertriglyceridemia in post-menopausal women without endometrial cancer, but was less frequent in endometrial cancer survivors with hypertriglyceridemia.

DOI： 10.1093/jjco/hyu164

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

We previously reported an association between dyslipidemia and endometrial cancers. Osteoporosis is also reported to relate with some cancers. A common etiologic event has been proposed between dyslipidemia and osteoporosis. However, the pattern of interrelationships among dyslipidemia, osteoporosis and endometrial cancer is not well understood. To improve the quality of life of endometrial cancer survivors, these relationships should be determined. This study included 179 Japanese menopausal women who underwent bilateral salpingo-oophorectomy, including 114 women with incident endometrial cancer and 65 without endometrial cancer. The women were categorized according to dyslipidemia status. Bone mineral density was measured and compared between groups. Osteoporosis was statistically more frequent in women with hypertriglyceridemia who did not have endometrial cancer. In contrast, osteoporosis was statistically less frequent in women with hypertriglyceridemia who had endometrial cancer. In this cross-sectional study in a Japanese population, osteoporosis was associated with hypertriglyceridemia in post-menopausal women without endometrial cancer, but was less frequent in endometrial cancer survivors with hypertriglyceridemia.

DOI： 10.1093/jjco/hyu164

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TERMEDIA PUBLISHING HOUSE LTD  

Introduction: Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life.Material and methods: This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated.Results: No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations.Conclusions: These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

DOI： 10.5114/pm.2015.54339

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Scopus

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)メジカルビュー社  

J-GLOBAL

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

遺伝性乳癌卵巣癌(HBOC)の原因遺伝子であるBRCA1またはBRCA2(BRCA1/2)の遺伝子変異保持者(mutant carrier)に対する有効な卵巣癌スクリーニング法は確立されていない。BRCA1/2遺伝子変異保持者に対してリスク低減卵管卵巣摘出術(RRSO)を実施することにより卵巣癌や卵管癌の発症リスクが低減することは確実である。また卵巣癌や乳癌による死亡率を低減することもほぼ確実とされている。RRSOの検体からはoccult cancerが見つかることもあるため病理医との連携が重要である。RRSO施行後は腹膜癌の発症リスクが残るため引き続きサーベイランスが必要であるとともに、卵巣摘出に伴うエストロゲン欠落症状にも対応する。(著者抄録)

J-GLOBAL

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00525&link_issn=&doc_id=20150603110007&doc_link_id=%2Fae4sanke%2F2015%2F008206%2F008%2F0639-0643%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2015%2F008206%2F008%2F0639-0643%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajpath.2015.05.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AIM: One of the important risk factors for recurrence of endometrial cancer is lymph node metastasis. The regional lymph nodes are pelvic lymph nodes (PLN) and para-aortic lymph nodes (PAN). PAN metastasis was often detected in the cases with PLN metastasis. However, PAN metastasis not associated with PLN metastasis was identified in a few cases. We focused on nine cases with PAN metastasis and without PLN metastasis. MATERIAL AND METHODS: The subjects of this study were 260 cases that were diagnosed with endometrial cancer. The initial treatments were surgery, including pelvic and para-aortic lymphadenectomy. Nine of these cases had PAN metastasis but did not have PLN metastasis. We retrospectively analyzed the clinicopathological factors and prognosis in cases with PLN-PAN+ cases. RESULTS: A total of 91 (35%) cases were identified as positive for either PLN or PAN. PAN metastases were detected in 62.6% of the cases that had some regional lymph node metastases and 3.5% of all cases were PLN- and PAN+. In all PLN-PAN+ cases, PAN swelling was not detected by preoperative chest-abdominal computed tomography scan. There were no clear trends among risk factors of regional lymph node metastasis. The 5-year progression-free survival was 87.1% for PLN-PAN- cases, 67.5% for PLN+PAN- cases, 44.4% for PLN-PAN+ cases, and 33.2% for PLN+PAN+ cases. CONCLUSION: During diagnosis and treatment for endometrial cancer, PLN-PAN+ cases should also be considered because the prognosis in PLN-PAN+ cases tended to be lower than that in PLN-PAN- cases and PLN+PAN- cases.

DOI： 10.1111/jog.12399

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Aim One of the important risk factors for recurrence of endometrial cancer is lymph node metastasis. The regional lymph nodes are pelvic lymph nodes (PLN) and para-aortic lymph nodes (PAN). PAN metastasis was often detected in the cases with PLN metastasis. However, PAN metastasis not associated with PLN metastasis was identified in a few cases. We focused on nine cases with PAN metastasis and without PLN metastasis. Material and Methods The subjects of this study were 260 cases that were diagnosed with endometrial cancer. The initial treatments were surgery, including pelvic and para-aortic lymphadenectomy. Nine of these cases had PAN metastasis but did not have PLN metastasis. We retrospectively analyzed the clinicopathological factors and prognosis in cases with PLN-PAN+ cases. Results A total of 91 (35%) cases were identified as positive for either PLN or PAN. PAN metastases were detected in 62.6% of the cases that had some regional lymph node metastases and 3.5% of all cases were PLN- and PAN+. In all PLN-PAN+ cases, PAN swelling was not detected by preoperative chest-abdominal computed tomography scan. There were no clear trends among risk factors of regional lymph node metastasis. The 5-year progression-free survival was 87.1% for PLN-PAN- cases, 67.5% for PLN+PAN- cases, 44.4% for PLN-PAN+ cases, and 33.2% for PLN+PAN+ cases. Conclusion During diagnosis and treatment for endometrial cancer, PLN-PAN+ cases should also be considered because the prognosis in PLN-PAN+ cases tended to be lower than that in PLN-PAN- cases and PLN+PAN- cases.

DOI： 10.1111/jog.12399

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FUTURE MEDICINE LTD  

Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma.

DOI： 10.2217/FON.13.180

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FUTURE MEDICINE LTD  

Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma.

DOI： 10.2217/fon.13.180

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer.
One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer.
Nine of 102 (8.8) families were regarded as having hereditary breastovarian cancer syndrome, two families (2.0) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case.
Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

DOI： 10.1093/jjco/hyt171

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

BACKGROUND: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer. METHODS: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer. RESULTS: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case. CONCLUSIONS: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

DOI： 10.1093/jjco/hyt171

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PubMed

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記述言語：日本語   出版者・発行元：金原出版(株)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY  

High expression of SQSTM1/p62 (p62) protein, which functions as a hub for various cellular signaling pathways, has been detected in several human cancers. However, the clinicopathological impact of high p62 expression is largely unknown in epithelial ovarian cancer (EOC). Here, the expression level of p62 in primary EOCs (n=266) was assessed by immunohistochemistry, and its clinical significance was analyzed. Univariate and multivariate analyses were used to determine the impact of p62 expression on overall survival. p62 was expressed in the cytoplasm (Cyto) and/or nucleus (Nuc) in primary E0Cs, and an expression subtype (Cyto(High)/Nuc(Low)), showing high expression in the cytoplasm but low expression in the nucleus, was significantly correlated with serous carcinoma (P&lt;0.001), advanced stage (P=0.005), presence of residual tumor (P&lt;0.001), and low overall survival rate (P=0.013). Furthermore, in serous carcinomas (n=107), the p62 Cyto(High)/Nuc(Low) subtype was significantly correlated with low overall survival rate (P=0.019) as an independent factor (P=0.044). Thus, our findings suggest that high expression of cytoplasmic p62 may be a novel prognostic biomarker in EOC, particularly in serous carcinoma.

DOI： 10.1267/ahc.14048

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.

DOI： 10.1038/jhg.2013.105

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers
however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients. © 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13.

DOI： 10.1038/jhg.2013.105

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers
however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients. © 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13.

DOI： 10.1038/jhg.2013.105

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

DOI： 10.3892/ol.2013.1527

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

DOI： 10.3892/ol.2013.1527

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PubMed

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記述言語：英語   出版者・発行元：SPANDIDOS PUBL LTD  

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

DOI： 10.3892/ol.2013.1527

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

OBJECTIVE: Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic. METHODS: This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed. RESULTS: Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls. CONCLUSIONS: Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors.

DOI： 10.1093/jjco/hyt125

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Objective: Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic.
Methods: This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed.
Results: Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls.
Conclusions: Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors.

DOI： 10.1093/jjco/hyt125

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2012.45.3019

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2012.45.3019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2012.45.3019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue-or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary.
Methodology/Principal Findings: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model.
Conclusions/Significance: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

DOI： 10.1371/journal.pone.0071480

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

&lt;p&gt;The Wnt/β-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated β-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/β-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of β-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that β-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that β-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that β-catenin regulates Foxa2 expression,

DOI： 10.1038/onc.2012.376

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/onc.2012.376

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

BACKGROUND: Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan. METHODS: We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008. RESULTS: The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan. CONCLUSIONS: Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

DOI： 10.1093/jjco/hyt036

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan.
We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008.
The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan.
Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

DOI： 10.1093/jjco/hyt036

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記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Cancer stroma is thought to play an important role in tumor behavior, including invasion or metastasis and response to therapy. Cancer stroma is generally thought either to be non-neoplastic cells, including tissue-marrow or bone-marrow-derived fibroblasts, or to originate in epithelial mesenchymal transition of cancer cells. In this study, we evaluated the status of the p53 gene in both the cancer cells and the cancer stroma in epithelial ovarian cancer (EOC) to elucidate the origin of the stroma. Samples from 16 EOC patients were included in this study. Tumor cells and adjacent nontumor stromal cells were microdissected and DNA was extracted separately. We analyzed p53 sequences (exons 5-8) of both cancer and stromal tissues in all cases. Furthermore, we examined p53 protein expression in all cases. Mutations in p53 were detected in 9 of the 16 EOCs: in 8 of these cases, the mutations were detected only in cancer cells. In 1 case, the same mutation (R248Q) was detected in both cancer and stromal tissues, and p53 protein expression was detected in both the cancer cells and the cancer stroma. Most cancer stroma in EOC is thought to originate from non-neoplastic cells, but some parts of the cancer stroma might originate from cancer cells.

DOI： 10.1097/PGP.0b013e3182518533

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PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

J-GLOBAL

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00525&link_issn=&doc_id=20131030050008&doc_link_id=%2Fae4sanke%2F2013%2F008011%2F009%2F1465-1472%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2013%2F008011%2F009%2F1465-1472%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本女性医学学会  

【目的】めまいは、古くはKuppermanの閉経期指数にも取り上げられているが、その真の原因が同定出来ないケースも少なくなく、更年期障害の一症状として治療するとしても、その対応に苦慮するケースが少なくない。今回我々は、当科「健康維持外来」受診者に認められためまいの現状について検証を行ったので報告する。【対象と方法】2007年10月より2010年9月末までの3年間に、当外来を受診した初診患者443例の初診時の40症状から成る「健康維持外来調査票」の記入結果を検証した。各症状について、症状なし、(症状)弱、中、強の4段階で評価していくが、今回はめまいに関して「中」ないし「強」と回答した64例を抽出し、これら全症例の初診後の臨床経過について外来診療録より追跡調査を行った。【結果】(1)めまいに対して、443例中48例(10.8%)が「中」、16例(3.6%)が「強」と回答した。(2)当外来受診後、12例が耳鼻咽喉科に、4例が神経内科に、3例が精神神経科に診療依頼を行った。精神神経科を受診した3例は、めまい自体も精神症状由来のものと判断されたが、それ以外の16例のうちめまいに対する明らかな病名診断を得たのは、耳鼻咽喉科に依頼した2例(良性発作性頭位めまい症)に過ぎなかった。(3)依頼した診療科でめまいの治療を行った5例を除く59例中38例は、元々自覚的には気になるめまいを認めず、11例はその後の外来受診時には、めまいは完全に消失していた。(4)「めまい」を含めた各症状の程度を点数化した上で、「めまい」を従属変数、他の39項目を独立した変数として重回帰分析を行った結果、有意差(p<0.05)をもって関連が深い症状は、「動悸」および「吐き気」のみであった。【考察】更年期周辺女性に認められるめまいの(真の)病態解明に当たっては、耳鼻咽喉科医や神経内科医などとの綿密な病診連携が必要であると考える。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本遺伝性腫瘍学会  

子宮体癌は子宮体部や底部から発生することが一般的であるが,まれに体部下部から頸部上部,つまりlower uterine segment(LUS)もしくは峡部と呼ばれる領域から発生する子宮体癌が存在する.子宮峡部から発生する子宮体癌(以降,子宮峡部癌)は子宮体癌全体の3〜3.5%とまれであり,これまで小規模の報告しか存在しない.近年,子宮峡部癌が遺伝性腫瘍であるLynch症候群との関連があると報告され注目されている.一般的な子宮体癌でのLynch症候群の頻度は1〜2%といわれているが,米国の報告によると子宮峡部癌のうち29%がLynch症候群とされ,高頻度にMSH2の変異が存在するとしている.今後わが国をはじめ,より大規模な調査において子宮峡部癌の臨床病理学的特徴やLynch症候群との関連についてさらに検討する必要がある.(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J03931&link_issn=&doc_id=20130830390001&doc_link_id=%2Fcg3kazok%2F2013%2F001301%2F001%2F0001-0005%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcg3kazok%2F2013%2F001301%2F001%2F0001-0005%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：金原出版(株)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

BACKGROUND: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary. METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model. CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

DOI： 10.1371/journal.pone.0071480

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mds492

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) had cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

DOI： 10.3892/or.2012.2008

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) :lad cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

DOI： 10.3892/or.2012.2008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mds492

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

&lt;p&gt;Aim: This study compared the efficiency of Blood-direct InvaderPlus® with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials &amp; methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A16,27,28,60, VKORC1 -1639G&gt;A, VKORC1 1173T&gt;C and CYP2C92 and3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms. © 2012 Future Medicine Ltd.&lt;/p&gt;

DOI： 10.2217/pme.12.71

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FUTURE MEDICINE LTD  

Aim: This study compared the efficiency of Blood-direct InvaderPlus (R) with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials & methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A1*6, *2Z *28, *60, VKORC1 -1639G&gt;A, VKORC1 1173T&gt;C and CYP2C9 *2 and *3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms.

DOI： 10.2217/PME.12.71

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

&lt;p&gt;Aim: This study compared the efficiency of Blood-direct InvaderPlus® with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials &amp; methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A16,27,28,60, VKORC1 -1639G&gt;A, VKORC1 1173T&gt;C and CYP2C92 and3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms. © 2012 Future Medicine Ltd.&lt;/p&gt;

DOI： 10.2217/PME.12.71

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

2008年12月〜2011年4月に当外来を初診した26〜85歳の女性252名を対象に、大腿骨近位部骨密度(F-BMD)と腰椎骨密度(L-BMD)との相関性について検討した。その結果、YAM値表記(%)によるF-BMD値とL-BMD値との間に5%超の差を認めた人が168名(67%)おり、このうちF-BMD値のほうが高い人が34名(全体の13%)、L-BMDのほうが高い人134名(53%)であった。L-BMD値から「原発性骨粗鬆症診断基準(2000年度改訂版)」に従い診断したところ、骨粗鬆症が5名(2%)、骨量減少が25名(10%)、骨量正常が222名(88%)となった。F-BMD値から同様に診断したところ、骨粗鬆症が19名(8%)、骨量減少35名(14%)、骨量正常198名(79%)となり、L-BMD値から診断した結果との一致率をみると、骨量正常群では95%の人が一致したが、骨粗鬆症群では16%、骨量減少群では29%しか一致しなかった。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J03021&link_issn=&doc_id=20120815130024&doc_link_id=%2Fai6ostoe%2F2012%2F002003%2F025%2F0489-0491%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai6ostoe%2F2012%2F002003%2F025%2F0489-0491%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

PubMed

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P &lt; 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and a-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC. (c) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/gcc.21916

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P &lt; 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and a-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC. (c) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/gcc.21916

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Elsevier Inc.  

DOI： 10.1016/B978-0-12-388415-2.00023-8

Scopus

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective: Host antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8(+) cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients.
Methods: The study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4(+) FOXP3(+) cells were identified as Tregs in this study. The numbers of CD8(+) cells, CD4(+) cells, and Tregs as well as the Treg/CD8(+) and Treg/CD4(+) ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis.
Results: Of the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8(+) and CD4(+) cell counts, Treg count, and Treg/CD8(+) and Treg/CD4(+) ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8(+) ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8(+) ratios (P &lt; 0.05).
Conclusions: The Treg count and Treg/CD8(+) ratio may be new prognostic factors for endometrial cancer.

DOI： 10.1097/IGC.0b013e31822c271f

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective: Host antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8(+) cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients.Methods: The study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4(+) FOXP3(+) cells were identified as Tregs in this study. The numbers of CD8(+) cells, CD4(+) cells, and Tregs as well as the Treg/CD8(+) and Treg/CD4(+) ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis.Results: Of the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8(+) and CD4(+) cell counts, Treg count, and Treg/CD8(+) and Treg/CD4(+) ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8(+) ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8(+) ratios (P < 0.05).Conclusions: The Treg count and Treg/CD8(+) ratio may be new prognostic factors for endometrial cancer.

DOI： 10.1097/IGC.0b013e31822c271f

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: Host antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8 cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients. METHODS: The study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4FOXP3 cells were identified as Tregs in this study. The numbers of CD8 cells, CD4 cells, and Tregs as well as the Treg/CD8 and Treg/CD4 ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis. RESULTS: Of the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8 and CD4 cell counts, Treg count, and Treg/CD8 and Treg/CD4 ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8 ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8 ratios (P < 0.05). CONCLUSIONS: The Treg count and Treg/CD8 ratio may be new prognostic factors for endometrial cancer.

DOI： 10.1097/IGC.0b013e31822c271f

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of A EH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P&lt;0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.1131

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of AEH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P<0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.1131

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endometrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of A EH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P&lt;0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.1131

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer.

DOI： 10.1158/0008-5472.CAN-11-0364

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450-62. (C) 2011 AACR.

DOI： 10.1158/0008-5472.CAN-11-0364

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記述言語：日本語   出版者・発行元：(株)永井書店  

妊産婦に対する薬物治療に関しては、妊娠4ヵ月末までは胎児への催奇形性に、5ヵ月以降は胎児の機能的発育への影響に留意しなければならない。可能ならば妊娠が判明した時点で、向精神薬による治療の中止もしくは減量が望ましいが、薬物治療の継続が必要な場合は、患者自身に薬物治療の必要性を十分に理解してもらうよう努めるとともに、どの週数であっても胎児への影響が出来る限り少ない薬剤を単剤から投与することが肝要である。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00534&link_issn=&doc_id=20111007170016&doc_link_id=%2Faf2sftye%2F2011%2F010304%2F016%2F0417-0421%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faf2sftye%2F2011%2F010304%2F016%2F0417-0421%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450-62. (C) 2011 AACR.

DOI： 10.1158/0008-5472.CAN-11-0364

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00525&link_issn=&doc_id=20110825150005&doc_link_id=%2Fae4sanke%2F2011%2F007809%2F006%2F1064-1068%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2011%2F007809%2F006%2F1064-1068%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：金原出版(株)  

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記述言語：日本語   出版者・発行元：(株)南江堂  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J03022&link_issn=&doc_id=20110927270002&doc_link_id=issn%3D1342-0569%26volume%3D16%26issue%3D6%26spage%3D631&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D1342-0569%26volume%3D16%26issue%3D6%26spage%3D631&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(一社)東京産科婦人科学会  

Lynch症候群(Lynch syndrome:hereditary non-polyposis colon cancer,HNPCC)は常染色体優性遺伝の遺伝性腫瘍症候群であり、70歳までに子宮体癌を発症するリスクが一般集団では2.7%であるのに対し、Lynch症候群では20%〜60%と報告されている。我々は、詳細な家族歴の聴取によりLynch症候群家系を疑い、遺伝子検査を経て早期治療が可能となった1例を経験した。症例は46歳未経妊未経産、不正性器出血および遺伝性腫瘍に関する精査を希望し当院を受診した。家族歴の聴取によりLynch症候群が疑われたため遺伝子検査を施行し、原因遺伝子の一つであるMLH1に変異が認められた。その後複数回の子宮内膜検査により子宮内膜異型増殖症を認めたため、拡大子宮全摘出術および両側付属器摘出術を施行した。当該例では遺伝子検査ののちに適切なサーベイランスを行うことで前がん病変の段階で縮小手術を施行したことにより結果的に手術による侵襲を最小限にし、術後合併症やQOL低下を防ぐことが可能であった。現在も外来で定期的にフォローアップを行っており、再発なく経過している。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本遺伝性腫瘍学会  

婦人科領域においても遺伝性腫瘍が存在する.遺伝性乳癌卵巣癌(hereditary breast and ovarian cancer:HBOC)にともなう卵巣癌ではBRCA1またはBRCA2(BRCA1/2)がその責任遺伝子として知られており,BRCA1の変異遺伝子を有する場合,70歳までに卵巣癌発症の確率が40%との報告もある.またLynch症候群家系に子宮体癌が高率に発生することが知られており,近年ではその診断基準に子宮体癌も組み入れられるようになった.さらにPeutz-Jeghers症候群例において子宮頸部腺癌(悪性腺腫)を合併することが以前より知られている.ところで卵巣はがん検診の対象臓器となっておらず,悪性の場合は自覚症状発現時に病変がすでに進行していることが多い.また卵巣腫瘍は多くの場合術前に良悪性の診断をすることが困難である.そこでBRCA1/2遺伝子変異保持例に対しては適切なサーベイランスの手法が存在しないことから,がん一次予防法としてリスク低減卵管卵巣摘出術(Risk-Reducing Salpingo-Oophorectomy:RRSO)が現在のところ最も確実性の高い卵巣癌予防策であるとみなされている.しかしながらRRSO施行後には急速なエストロゲンによる卵巣欠落症状を来すことがあり,さらに長期的には脂質異常症や骨粗鬆症の高危険群となるため,適切な管理が必要である.慶應義塾大学病院産婦人科では女性のトータルヘルスケアを目的とした女性健康維持外来を開設して女性の卵巣機能低下にともなう諸症状を多角的に検証している.さらに遺伝性腫瘍の遺伝子変異保持例は常に異時性発症癌や重複癌発症の不安と共存していかなくてはならず,卵巣機能低下に対する対策と並行して,心理的不安の解消を含めたQOL低下防止策が必要である.卵巣癌BRCA1/2遺伝子変異保持例に対してPARP阻害薬であるOlaparib投与が考慮されており,治験が進められている.(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J03931&link_issn=&doc_id=20110630470004&doc_link_id=%2Fcg3kazok%2F2011%2F001102%2F005%2F0048-0051%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcg3kazok%2F2011%2F001102%2F005%2F0048-0051%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Narrow band imaging (NBI) for detection of blood vessels and microstructures on the mucosal surface is used in gastrointestinal endoscopy since it can improve qualitative diagnosis and detection of lesion. However, there are no studies on flexible hysteroscopy using NBI. We performed flexible hysteroscopy with NBI for outpatients to investigate the sensitivity and specificity of endoscopic diagnosis of malignant endometrial lesions. Of patients who attended our hospital for suspected lesions in the uterine cavity between April 2009 and May 2010, 104 subjects underwent hysteroscopy with NBI, in addition to white light. Using the pathological diagnosis as the gold-standard, we evaluated the sensitivity and specificity of NBI hysteroscopy for detecting atypical endometrial hyperplasia (AEH) or carcinoma. The results were also compared with historical data (n=209) for conventional hysteroscopy using white light only in 2008. The sensitivities were 97.2% [95% confidence interval (95% CI): 90.3-99.7%] and 82.6% (95% CI: 74.4-89.0%) for NBI hysteroscopy and conventional hysteroscopy, respectively. The 95% CIs for the two methods did not overlap and the sensitivity of lesion detection was higher with NBI hysteroscopy. Specificities were comparable, 90.6% (95% CI: 75.0-98.0%) and 85.1% (95% CI: 76.3-91.6%) between the methods. NBI hysteroscopy has increased sensitivity for detection of atypical endometrial hyperplasia (AEH) or carcinoma. A comparison with historical data suggested that NBI may be useful for diagnosis of malignant endometrial lesions. As far as we are aware, this is the first evaluation of flexible hysteroscopy with NBI for diagnosis of malignant endometrial lesions.

DOI： 10.3892/ijo.2011.903

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