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

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

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

BACKGROUND: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA. METHODS: Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m2 on days 1 and 29) and S-1 (60 mg/m2/day at level 0 and 80 mg/m2/day at level 1 on days 1-14 and 29-42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively. RESULTS: Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m2/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1-73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred. CONCLUSIONS: Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA. CLINICAL TRIAL INFORMATION: jRCTs031180002.

DOI： 10.1007/s10147-023-02361-7

PubMed

researchmap

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

The involvement of neutrophil extracellular traps (NETs) in cancer metastasis is being clarified, but the relationship between intrahepatic cholangiocarcinoma (iCCA) and NETs remains unclear. The presence of NETs was verified by multiple fluorescence staining in clinically resected specimens of iCCA. Human neutrophils were co-cultured with iCCA cells to observe NET induction and changes in cellular characteristics. Binding of platelets to iCCA cells and its mechanism were also examined, and their effects on NETs were analyzed in vitro and in in vivo mouse models. NETs were present in the tumor periphery of resected iCCAs. NETs promoted the motility and migration ability of iCCA cells in vitro. Although iCCA cells alone had a weak NET-inducing ability, the binding of platelets to iCCA cells via P-selectin promoted NET induction. Based on these results, antiplatelet drugs were applied to these cocultures in vitro and inhibited the binding of platelets to iCCA cells and the induction of NETs. Fluorescently labeled iCCA cells were injected into the spleen of mice, resulting in the formation of liver micrometastases coexisting with platelets and NETs. These mice were treated with dual antiplatelet therapy (DAPT) consisting of aspirin and ticagrelor, which dramatically reduced micrometastases. These results suggest that potent antiplatelet therapy prevents micrometastases of iCCA cells by inhibiting platelet activation and NET production, and it may contribute to a novel therapeutic strategy.

DOI： 10.1016/j.canlet.2023.216260

PubMed

researchmap

Language：English  

Navigation surgery using indocyanine green (ICG) fluorescence imaging has been used in thoracoabdominal surgery, and its usefulness has been reported in many cases. In this study, laparoscopic lateral lymph node dissection was performed using ICG fluorescence imaging in a patient with left femoral spinous cell carcinoma with inguinal and external iliac lymph node metastases. Spinous cell carcinoma is classified as a rare cancer in Japan, and there is a scarcity of evidence for pelvic lymph node dissection, as well as a lack of studies that mention the dissection area. We hypothesized that visualization of lymph nodes and lymph flow using intraoperative ICG fluorescence imaging would indicate the area of dissection and lead to more efficient dissection. In conclusion, intraoperative ICG fluorescence imaging may be useful in this area where there is limited evidence, although there are some limitations.

DOI： 10.1111/ases.13159

PubMed

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：English  

A 70-year-old male with anal pain and fever was diagnosed with rectal cancer perforation and abscess in the right gluteus maximus (GM) muscle. He underwent a transverse colon colostomy followed by preoperative capecitabine+oxaliplatin. Some local control was achieved but a residual abscess was observed in the right GM muscle. To secure circumferential resection margin by tumor reduction, he received chemoradiotherapy as total neoadjuvant therapy (TNT) and underwent laparoscopic abdominoperineal resection, D3 lymph node dissection, combined coccyx resection, and partial resection of the right GM muscle. The skin defect and pelvic dead space were filled with a right lateral vastus lateral great muscle flap. Histopathologically, the resected specimen showed no tumor cells in the primary tumor or lymph nodes, indicating a pathological complete response (pCR). This case suggests that TNT might improve the R0 resection and pCR rates and overall survival.

DOI： 10.18926/AMO/65152

PubMed

researchmap

Language：Japanese   Publisher：(株)へるす出版  

researchmap

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

Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy.

DOI： 10.1038/s41598-023-29397-z

PubMed

researchmap

Language：English  

An annular pancreas is a rare anomaly of the pancreas, defined as pancreatic tissue that totally or partly encircles the duodenum, usually the descending portion. A 76-year-old man who was diagnosed with gastric cancer cT3N0M0 Stage IIB underwent laparoscopic distal gastrectomy with D2 lymph node dissection. Intraoperatively, the dorsal half of the duodenal bulb was seen to be half surrounded by the pancreas, and a non-typical annular pancreas was diagnosed. Because of the risk to the pancreas, it was considered impossible to perform anastomosis by a linear stapler as in the usual laparoscopic procedure. Therefore, we performed laparoscopically assisted distal gastrectomy and Billroth-I reconstruction using a circular stapler, and the surgery was completed without difficulties. His postoperative course was good despite the development of a pancreatic fistula, which was an International Study Group for Pancreas Fistula biochemical leak. Some APs can be diagnosed preoperatively, but the rarer subtypes such as ours are more difficult to visualize on imaging. In gastrectomy, it is both oncologically important and technically challenging to perform lymph node dissection around the pancreas. In this case with an especially proximal pancreas, a circular stapler was considered better suited for gastroduodenal anastomosis and required a broader field than that afforded by laparoscopy. A case of non-typical annular pancreas diagnosed during laparoscopic gastric surgery is described.

DOI： 10.18926/AMO/64368

PubMed

researchmap

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

BACKGROUND AND AIMS: Ulcerative colitis (UC) can develop colitis-associated colorectal neoplasm (CAN). Adenine-to-inosine RNA editing, which is regulated by adenosine deaminase acting on RNA (ADAR), induces the posttranscriptional modification of critical oncogenes, including antizyme inhibitor 1 (AZIN1), leading to colorectal carcinogenesis. Therefore, we hypothesized that ADAR1 might be involved in the development of CAN in UC. METHODS: We systematically analyzed a cohort of 139 UC cases (40 acute phase, 73 remission phase, 26 CAN). The degree of inflammation was evaluated using the Mayo endoscopic score (MES). RESULTS: The type 1 IFN-related inflammation pathway was upregulated in the rectum of active UC, rectum of UC-CAN, and tumor site of UC-CAN patients. ADAR1 expression was upregulated in the entire colon of CAN cases, while it was down-regulated in non-CAN MES0 cases. ADAR1 expression in the rectum predicted the development of CAN better than p53 or β-catenin, with an area under the curve of 0.93. The high expression of ADAR1 and high AZIN1 RNA editing in UC was triggered by type 1 IFN stimulation from UC-specific microbiomes, such as Fusobacterium in vitro analyses. The induction of AZIN1 RNA editing by ADAR1, whose expression is promoted by Fusobacterium, may induce carcinogenesis in UC. CONCLUSIONS: The risk of CAN can be evaluated by assessing ADAR1 expression in the rectum of MES0 UC patients, freeing UC patients from unnecessary colonoscopy and reducing their physical burden. RNA editing may be involved in UC carcinogenesis, and may be used to facilitate the prevention and treatment of CAN in UC.

DOI： 10.1093/ecco-jcc/jjac186

PubMed

researchmap

Language：English  

An 84-year-old female underwent open right hemicolectomy with D3 lymph node dissection for cecal cancer, pathologically identified as pT4aN2M0 Stage IIIc and BRAF mutation-positive. Due to early recurrence of abdominal wall and right lateral lymph nodes, the patient was treated with FOLFOXIRI+Bevacizumab. Imaging after 5 courses of chemotherapy found tumor shrinkage and no new metastases. The patient did not tolerate chemotherapy well, and tumor resection was performed. Microsatellite instability (MSI) testing using multiplex polymerase chain reaction (PCR) fragment analysis revealed MSI-high status. The patient is currently recurrence-free without chemotherapy at 1 year postoperatively. BRAF-mutated colorectal cancer has a poor prognosis, and may require resection of the metastatic or recurrent tumor after comprehensive evaluation.

DOI： 10.18926/AMO/64043

PubMed

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

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

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability-high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX-CRT regimen. CRT can promote proteomic diversity via RNA editing.

DOI： 10.1038/s41598-022-17773-0

PubMed

researchmap

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

researchmap

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

researchmap

Language：English  

An 89-year-old male came to the hospital with a complaint of abdominal distension. Abdominal computed tomography showed wall thickening in the descending colon and marked dilatation of the proximal colon, and lower gastrointestinal endoscopy demonstrated a stenosis in the descending colon. Although a biopsy from the stenotic lesion showed calcified eggs of Schistosoma japonicum with no malignant findings, we suspected malignant involvement, so we performed a descending colectomy with regional lymph node dissection. Pathological examination revealed a moderately differentiated adenocarcinoma. The colon cancer was diagnosed as pT4bN0M0, Stage IIc. The patient's history as a resident of one of the formerly endemic areas of Japan suggests that he may have carried S. japonicum for a long time, and that it may have contributed to carcinogenesis.

DOI： 10.18926/AMO/63748

PubMed

researchmap

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

BACKGROUND: Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC. METHODS: Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC. RESULTS: Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher's exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann-Whitney U test). CONCLUSIONS: FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis.

DOI： 10.1038/s41416-022-01838-y

PubMed

researchmap

Language：English  

A 43-year-old female underwent pelvic magnetic resonance imaging for uterine myoma that incidentally revealed a 4.6 × 2.8 cm soft tissue mass in the anorectal region. Rectal endoscopy showed a submucosal tumor just above the anal canal. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed an anorectal tumor with very high FDG uptake. Aspiration cytology and needle biopsy were inconclusive, and the patient underwent trans-perineal tumor resection. The excised tumor was a 4.6 × 3.5 × 2.7 cm gray-white bifurcated nodular tumor. Light microscopy revealed fenestrated growth of poorly dysmorphic short spindle-shaped cells with eosinophilic sporophytes. Immunohistochemical staining was positive for αSMA and desmin, negative for CD117 (KIT) and S100, and the patient was diagnosed with benign leiomyoma. Tumor cells were also positive for glucose transporter-1 (GLUT1) immunohistochemically. It is important to keep in mind that FDG-PET/CT may show false-positive results even in benign anal leiomyoma for various reasons, including GLUT1 overexpression.

DOI： 10.1093/jscr/rjac101

PubMed

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

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

PURPOSE: Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2. METHODS: GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed. RESULTS: Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p < 0.0001) and less blood loss (290 mL vs 125 mL, p < 0.0001) were observed in PHP-D2, and no pancreatic fistulas were observed in PHP-D2. More lymph nodes of #11p (1 vs 1.5, p = 0.0328) and #12a lymph nodes (0 vs 1, p = 0.0034) were retrieved in PHP-D2, with no significant differences in #8a and #9 lymph nodes. Lymphatic recurrence was significantly less in PHP-D2 (p = 0.0166), and univariate and multivariate analyses showed that non-PHP-D2 was a significant risk factor for lymphatic recurrence (p = 0.0158), although there were no significant differences between non-PHP-D2 and PHP-D2 in 5-year overall survival and 5-year relapse-free survival. CONCLUSION: PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC.

DOI： 10.1007/s00423-022-02437-4

PubMed

researchmap

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

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Plastic and Reconstructive Surgery  

DOI： 10.53045/jprs.2022-0020

researchmap

Publishing type：Research paper (scientific journal)  

Objective: This study aimed to identify factors associated with outlet obstruction and high-output stoma (HOS) after ileostomy creation. Summary of background data: Ileostomy creation is effective in preventing leakage among patients undergoing low anterior resection for rectal cancer. However, major complications such as outlet obstruction and HOS can occur after surgery. Moreover, these complications cannot be prevented. Methods: This retrospective study included 34 patients with rectal cancer who underwent low anterior resection and ileostomy creation at Okayama University Hospital from January 2015 to December 2018. Then, the risk factors associated with outlet obstruction and HOS were analyzed. Results: Of 34 patients, 7 (21%) experienced outlet obstruction. In a multivariate logistic regression analysis, advanced T stage (P ¼ 0.10), ileostomy with a short horizontal diameter (P ¼ 0.01), and thick rectus abdominis (RA) muscle (P ¼ 0.0005) were considered independent risk factors for outlet obstruction. There was a significant correlation between outlet obstruction and HOS (P ¼ 0.03). Meanwhile, the independent risk factors of HOS were advanced T stage (P ¼ 0.03) and thick RA muscle (P ¼ 0.04). Conclusions: Thick RA muscle and advanced T stage were the common risk factors of outlet obstruction and HOS. Therefore, in high-risk patients, these complications can be prevented by choosing an appropriate ileostomy location according to RA muscle thickness and by preventing tubing into the ileostomy.

DOI： 10.9738/INTSURG-D-21-00012.1

Scopus

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

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

BACKGROUND AND AIM: Fusobacterium nucleatum (Fn) is involved in colorectal cancer (CRC) growth and is a biomarker for patient prognosis and management. However, the ecology of Fn in CRC and the distribution of intratumoral Fn are unknown. METHODS: We evaluated Fn and the status of KRAS and BRAF in 200 colorectal neoplasms (118 adenomas and 82 cancers) and 149 matched adjacent normal mucosas. The differentiation status between "surface" and "deep" areas of cancer tissue and matched normal mucosa were analyzed in 46 surgical samples; the Ki-67 index was also evaluated in these samples. RESULTS: Fusobacterium nucleatum presence in the tumor increased according to pathological stage (5.9% [adenoma] to 81.8% [stage III/IV]), while Fn presence in normal mucosa also increased (7.6% [adenoma] to 40.9% [stage III/IV]). The detection rates of Fn on the tumor surface and in deep areas were 45.7% and 32.6%, while that of normal mucosa were 26.1% and 23.9%, respectively. Stage III/IV tumors showed high Fn surface area expression (66.7%). Fn intratumoral heterogeneity (34.8%) was higher than that of KRAS (4.3%; P < 0.001) and BRAF (2.2%; P < 0.001). The Ki-67 index in Fn-positive cases was higher than that in negative cases (93.9% vs 89.0%; P = 0.01). CONCLUSIONS: Fusobacterium nucleatum was strongly present in CRC superficial areas at stage III/IV. The presence of Fn in the deep areas of adjacent normal mucosa also increased. The intratumoral heterogeneity of Fn is important in the use of Fn as a biomarker, as Fn is associated with CRC proliferative capacity.

DOI： 10.1111/jgh.15361

PubMed

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

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

PubMed

researchmap

Language：English  

Targeted therapies for malignant melanoma have improved patients' prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma.

DOI： 10.18926/AMO/61906

PubMed

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

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

PURPOSE: To clarify the usefulness of chemoradiotherapy (CRT) for low rectal cancer, we investigated the current status of CRT in Japan and its short- and long-term outcomes versus surgery alone for low rectal cancer in a large multicenter cohort study. METHODS: Between January 2010 and December 2011, data from 1608 patients with clinical Stage II-III rectal adenocarcinoma were collected from 69 specialized centers. Of these 1608 patients, 923 were diagnosed with clinical stage III low rectal cancer, 838 were enrolled in this study, divided into the surgery-alone group (n = 649) and preoperative CRT group (n = 189), and analyzed. RESULTS: The following parameters were significantly lower in the CRT versus surgery-alone group: blood loss (210 vs. 431.5 mL), postoperative complications (27.5% vs 39.0%), and the incidence of anastomotic leakage (3.7% vs. 8.8%). The 3-year overall survival, relapse-free and local recurrence-free survival rates did not between the two groups to a statistically significant extent (91.2% vs. 87.4%, 68.8% vs. 66.4%, and 88.2% vs. 88.4%, respectively). CONCLUSIONS: The present study revealed the current status of CRT for low rectal cancer in Japan. The results showed that CRT could be safely performed for advanced low rectal cancer in comparison to surgery alone.

DOI： 10.1007/s00595-020-02034-2

PubMed

researchmap

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

Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells.

DOI： 10.1016/j.omto.2020.03.016

PubMed

researchmap

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

researchmap

Language：English  

DOI： 10.1016/j.cgh.2020.02.020

PubMed

researchmap

Language：Japanese   Publisher：日本家族性腫瘍学会  

症例は54歳男性.大量出血を伴う小腸多発GIST(Gastrointestinal stromal tumor)を認めて緊急入院となった.姉が神経線維腫症1型(neurofibromatosis type 1:NF1)と診断されており,患者にもおよそ20個の神経線維腫を疑う腫瘤とcafe au lait斑を6個以上認めたためNF1と診断した.出血コントロール目的に開腹手術を行ったが,GISTはおよそ20個多発しており,大量小腸切除を避けるために10mm以上の腫瘍のみ外科的切除を行い,多発微小腫瘍は経過観察とした不完全切除を選択した.切除標本の病理検査では紡錘形核と好酸性胞体を有する紡錘形細胞が密に錯綜する腫瘍を認め,免疫染色でKIT陽性.核分裂数は5以下/50HPFsであり低悪性度GISTと診断した.NF1に伴うGISTは比較的予後が良いとの報告もあるが,このような多発微小病変については明らかな治療指針がない.今後さらなる症例の集積と検討を要する.(著者抄録)

researchmap

Language：English  

INTRODUCTION: Laparoscopic liver resection of segment seven (LLR-S7) is a technically challenging procedure due to its anatomical location and difficult accessibility. Herein, we present our experience with LLR-S7, and demonstrate a literature review regarding surgical techniques. PRESENTATION OF CASE: A 28-year-old female was diagnosed with rectosigmoid cancer and synchronous liver metastases at the segment three (S3) and S7, which were treated with laparoscopic procedure. After the completely mobilization of the right lobe, the Glissonean pedicle of S7 (G7) was intrahepatically transected. The right hepatic vein was exposed to identify the venous branch of S7 (V7). Finally the liver parenchyma between RHV and dissection line was divided. DISCUSSION: Various laparoscopic approaches for S7 have been reported including the Glissonian approach from the hilum, the intrahepatic Glissonean approach, the caudate lobe first approach, and the lateral approach from intercostal ports. To perform LLR-S7 safely, it is important to understand the advantage of each technique including the trocar placement and approaches to S7 by laparoscopy. CONCLUSION: We present our experience of LLR-S7 for the tumor located at the top of S7, successfully performed with the intrahepatic Glissonean approach. LLR-S7 can be performed safely with advanced laparoscopic techniques and sufficient knowledge on various approaches for S7.

DOI： 10.1016/j.ijscr.2020.06.107

PubMed

researchmap

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

Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC.

DOI： 10.1016/j.canlet.2018.12.009

PubMed

researchmap

Language：Japanese   Publisher：(株)南江堂  

104歳女。排便時出血を主訴とし、排便障害を認めた。心エコーにて左室駆出率は73%で、中等度の大動脈弁逆流を認めた。直腸内視鏡検査にて、下部直腸に半周性の2型腫瘍を認め、生検にて高分化〜中分化管状腺癌と診断した。骨盤MRIでは、下部直腸左壁を中心に壁肥厚を認めた。以上の所見より、直腸癌Rb-P、Type2、T3N0M0H0P0、cStage IIと診断し、腹腔鏡下直腸切断、上方D2リンパ節郭清、S状結腸単孔式人工肛門造設を施行した。摘出標本は、下部直腸から肛門管にかけて5×4cmの半周性の2型腫瘍を認めた。病理組織学的所見は、中分化〜高分化の直腸癌で、郭清リンパ節1個に転移を認めた。術後は、合併症は認めず、術後1年が経過したが、再発は認めなかった。

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00393&link_issn=&doc_id=20190130050017&doc_link_id=issn%3D0016-593X%26volume%3D81%26issue%3D2%26spage%3D177&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0016-593X%26volume%3D81%26issue%3D2%26spage%3D177&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(株)南江堂  

108歳女。右季肋部痛、嘔吐を主訴とした。腹部CTでは、胆嚢は腫大し、造影効果が途絶している部位を認め、周囲脂肪織の上昇と、右側腹部に少量の腹水貯留を認めたため、急性懐疽性胆嚢炎と診断した。術前リスクを評価したところ、予測合併症発生率は52.7%、予測死亡率は3.4%であったことから、術後合併症リスクは高いが、全身麻酔下の手術は可能と判断し、開腹手術を施行した。全身麻酔下に上腹部正中切開で開腹し、胆嚢は壊死性変化および周囲に漿液性の腹水貯留を認めた。胆嚢を減黄後に十分な止血を行いつつ、胆嚢を摘出した。病理組織学的所見にて急性懐疽性胆嚢炎であった。術後は早期リハビリを開始し、廃用予防・嚥下機能維持・喀痰に努め、第8病日にリハビリ病院に転移後、16日目には自宅退院となり、現在は110歳で、デイサービスに通所されている。

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00393&link_issn=&doc_id=20190115080017&doc_link_id=issn%3D0016-593X%26volume%3D81%26issue%3D1%26spage%3D88&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0016-593X%26volume%3D81%26issue%3D1%26spage%3D88&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：The Japanese Society for Familial Tumors  

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder caused by germline variants in the NF1 tumor suppressor gene characterized by multiple caféau lait spots and cutaneous neurofibromas. Therefore, NF1 predisposes patients to benign and malignant tumor development. We report a 54-year-old NF1 male with multiple gastrointestinal stromal tumors (GIST) in the small intestine. We resected a part of the small intestine with larger tumors, but left the part with small tumors to avoid short bowel syndrome. Histological examination revealed spindle cells with eosinophilic cytoplasm. The tumors were positive for KIT on immunopathological examination. They were smaller than 3.5 cm and their mitotic activity was less than 5/50 in high-power fields. We left 17 GIST that were smaller than 10 mm, but no progression has been detected to date. (<250 words)

DOI： 10.18976/jsft.19.2_77

CiNii Article

researchmap

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞はじめに 虫垂goblet cell carcinoid(以下,虫垂GCC)の発生率は0.015%(1.5人/10万人)で,虫垂切除術の0.02〜1.5%に存在すると報告されている.今回われわれは,腸閉塞を繰り返し,大腸内視鏡検査時の生検で診断された虫垂GCCの1例を経験したので,若干の文献的考察を加え報告する.

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00393&link_issn=&doc_id=20180301200015&doc_link_id=issn%3D0016-593X%26volume%3D80%26issue%3D3%26spage%3D272&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0016-593X%26volume%3D80%26issue%3D3%26spage%3D272&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：西日本泌尿器科学会  

researchmap

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

Sphincter-preserving procedures (SPPs) for surgical treatment of low-lying rectal tumors have advanced considerably. However, their oncological safety for locally advanced low rectal cancer compared with abdominoperineal resection (APR) is contentious. We retrospectively analyzed cohort data of 1500 consecutive patients who underwent elective resection for stage II-III rectal cancer between 2010 and 2011. Patients with tumors 2-5 cm from the anal verge and clinical stage T3-4 were eligible. Primary outcome was 3-year local recurrence rate, and confounding effects were minimized by propensity score matching. The study involved 794 patients (456 SPPs and 338 APR). Before matching, candidates for APR were more likely to have lower and advanced lesions, whereas SPPs were carried out more often following preoperative treatment, by laparoscopic approach, and at institutions with higher case volume. After matching, 398 patients (199 each for SPPs and APR) were included in the analysis sample. Postoperative morbidity was similar between the SPPs and APR groups (38% vs 39%; RR 0.98, 95% CI 0.77-1.27). Margin involvement was present in eight patients in the SPPs group (one and seven at the distal and radial margins, respectively) and in 12 patients in the APR group. No difference in 3-year local recurrence rate was noted between the two groups (11% vs 14%; HR 0.77, 95% CI 0.42-1.41). In this observational study, comparability was ensured by adjusting for possible confounding factors. Our results suggest that SPPs and APR for locally advanced low rectal cancer have demonstrably equivalent oncological local control.

DOI： 10.1002/ags3.12032

PubMed

researchmap

Language：Japanese   Publisher：(一社)高知県医師会  

<目的>当施設の局所進行直腸癌に対する術前化学放射線療法(neoadjuvant chemoradiotherapy;以下、NCRT)の治療成績を明らかにした。<対象と方法>2008年3月から2016年8月までにNCRTを施行した局所進行下部直腸癌34症例の臨床病理学的検討を行った。<結果>年齢中央値57歳、男性27例、女性7例。全例long course RTで50Gy、60Gyがそれぞれ1例、40Gyが24例、45Gyが8例で、併用した化学療法はS-1が23例、UFTが8例、UFT/UZELが3例であった。手術までの待機期間は45日で開腹手術が6例、腹腔鏡手術が28例、術式はAPR/LAR/ISR/TPE/Hartmannが18/9/4/2/1例であった。術後合併症は13例(38.2%)にみられた。進行度はpStage I/II/IIIa/IIIbが7/13/9/3例で、組織学的治療効果判定でGrade2以上の奏効例が16例(47.1%)にみられた。観察期間中央値48ヵ月で局所再発は4例にみられ、5年全生存率は86.6%、3年無再発生存率は68.6%、3年累積局所再発率は17.3%であった。<結語>局所進行直腸癌に対するNCRTは安全に施行可能で、一定の局所制御率がえられた。(著者抄録)

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Gastroenterological Surgery  

Peripheral primitive neuroectodermal tumor (pPNET) is defined as small round cell sarcoma with neuroectodermal differentiation. It tends to arise in extremities, paravertebral lesions and chest wall of adolescents or young adults. This time, we present a rare case of pPNET arising in the stomach. A 68-year-old man visited our hospital with the complaint of anorexia. On endoscopy, a large tumor with ulcerative lesion was detected at cardiac lesion. Histological examination on biopsy material detected small round cells with enlarged round nuclei and scanty cytoplasm. Immunohistochemical staining was performed, but it was difficult to obtain definite diagnosis as for the histological type preoperatively. Total gastrectomy was performed, and immunohistochemical staining on resected specimen revealed that the tumor cells expressed CD99. Besides, EWS-FLI1 fusion transcript was confirmed by reverse transcription-polymerase chain reaction, which led us to the final diagnosis of tumor was pPNET arising in the stomach. The patient died 4 months after the operation due to multiple liver metastasis. Recently, the efficacy of the multidisciplinary treatment for pPNET has been reported. When we encounter a primary gastric tumor consisting of small round tumor cells, pPNET should be included in the differential diagnosis to obtain definite diagnosis before starting the treatment.

DOI： 10.5833/jjgs.2016.0189

Scopus

researchmap

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

We report the case of a patient with advanced rectal cancer who achieved a pathological complete response to preoperative chemoradiotherapy (CRT). A 65-year-old man was diagnosed as having a two-thirds circumferential well- to moderately differentiated tumor (Rb-P, type 2). To control local recurrence, we treated the patient with CRT. Radiotherapy was administered in fractions of 2 Gy/day (total, 40 Gy). Concurrently, S-1 was administered orally at a fixed daily dose of 80 mg/m2 for 20 days. Withdrawal and/or dose reduction of S-1 was not necessary in spite of Grade 1 or 2 toxic effects, including diarrhea and periproctitis, occurring on day 7. Laparoscopic abdominoperineal resection was performed 6 weeks after the final dose of chemotherapy was administered. The histopathological regression grade was Grade 3. No recurrence was detected on enhanced CT more than 5 years after surgery. This case suggests that the regimen was both effective and tolerated, and that preoperative chemoradiotherapy may be effective for tumor suppression to prevent local recurrence.

Scopus

PubMed

researchmap

Language：English  

BACKGROUND: We have revisited prognostic outcomes and recurrence patterns in patients with gastrointestinal stromal tumors (GISTs) who underwent complete surgical resection at a single institution. PATIENTS AND METHODS: Patients who underwent curative surgical treatment were divided into two groups: those with high-risk GISTs (high-risk group) and those with very low-, low-, and intermediate-risk GISTs (lower-risk group). RESULTS: A total of 109 patients who underwent surgery as an initial treatment for GIST were studied. The overall 5- and 10-year survival rates after surgery were 90.3 and 71.1%, respectively. The 5-year survival rate in high-risk group patients was 88.1%, and their overall survival rate did not vary significantly from that of the lower-risk group (5-year survival rate, 91.3%). The recurrence rate in patients with high-risk GISTs gradually increased without reaching a plateau, with a cumulative rate of GIST recurrence of 26.4 and 48.9% at 5 and 10 years after surgical treatment, respectively. CONCLUSIONS: Our data suggest that the repeat surgical management in metastatic GIST is of clinical usefulness whatever the risk and improves survival.

DOI： 10.1159/000445208

PubMed

researchmap

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

Actinomycosis of the ileocecal region, which is a favored site for abdominal actinomycotic infection, is often difficult to diagnose and treat in the presence of any complication. We report a case of ileocecal actinomycosis after chemoradiotherapy for uterine cervical cancer. A 46-year-old woman received chemoradiotherapy for uterine cervical cancer in September 2009. A positron emission tomography-computed tomography (CT) examination in May 2010 showed abnormal fludeoxyglucose accumulation in the pelvic lymph nodes and on the dorsal side of the ascending colon
therefore, we suspected recurrence of uterine cervical cancer. The patient presented at our hospital with a complaint of pain in the right lower abdomen in June 2010. Abdominal CT examination showed a periappendiceal abscess. Blood tests suggested an inflammatory reaction. Because of signs of peritoneal irritation, the patient underwent emergency surgery and ileocecal resection. Histopathological examination indicated actinomycosis. The patient started taking ampicillin orally for 6 months. At the same time, she received anticancer drug therapy for uterine cervical cancer. Actinomycosis did not worsen during cancer treatment. © 2013 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.2012.0166

Scopus

researchmap

Language：Japanese  

A83 -year-old man was admitted to our hospital for the treatment of advanced ascending colon cancer with liver metastases. He had initially undergone an ileocecal resection for ascending colon cancer. Subsequently, we started oral administration of UFT/LV(UFT 400mg/day, LV 75 mg/day, and 4 weeks of therapy followed by a week suspension of treatment). After 3 courses, his tumors responded well to treatment, and CT showed marked regression of liver metastases. After 10 courses, liver metastases had almost disappeared. Two years passed without any adverse events since UFT/LV therapy was started. These findings suggest that UFT/LV therapy is very safe and effective for elderly patients with unresectable colorectal cancer.

PubMed

researchmap

Language：English  

Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

DOI： 10.1371/journal.pone.0039292

PubMed

researchmap

Language：English  

BACKGROUND: Intersphincteric resection (IRS) is a surgical technique used to preserve sphincter function, mainly cases of low rectal cancer located less than 5 cm from the anal verge [1, 2]. There have been reports of laparoscopic ISR [3, 4], but discussion of the specific techniques used in this laparoscopic surgical procedure have not been sufficient. For better outcomes of this sophisticated procedure, extreme care must taken to prevent perforation of the rectal wall and to preserve the external sphincter muscle. The most difficult steps for ISR are the circular dissection and separation of the internal sphincter muscle from the external sphincter and puborectalis using the perineal approach. The authors' techniques and the advantages of laparoscopic ISR are shown by a video presentation of three rectal tumor cases. Also, the perioperative outcomes for the patients who underwent laparoscopic ISR with this technique are described. METHODS: From January 2006 to September 2009, laparoscopic ISR with total mesorectal excision was performed for 15 patients (10 men and 5 women). The median age of the patients was 60.5 years. The T categories of the tumor node metastasis (TNM) classification for the rectal cancers were Tis for two patients, T1 for one patient, T2 for four patients, and T3 for eight patients. The median distance from the anal verge to the tumor in this series was 3.7 cm. The Tis cases had large laterally spreading tumors that could not be removed by endoscopic submucosal dissection. The T1 case presented in the video had a small tumor just above the dentate line that had developed in the presence of chronic ulcerative colitis. Because this case required total proctocolectomy and ileal pouch anal anastomosis, local resection was not used (Table 1). Table 1 Patients' clinical characteristics (2006.1-2009.8) No. of patients: 15 Gender (M/F):10/5 Age: years (range): 60.5 (31-75) pT*: Tis (n=2), T1 (n=1), T2 (n=4), T3 (n=8) Distance from anal verge: cm (range): 3.7 (2-5) * Pathological T categories of the tumor node metastagis (TNM) classification CASES: The 68-year-old man in case 1 had a large, laterally spreading rectal tumor. The 61-year-old man in case 2 had rectal cancer, with a tumor located 4 cm from the anal verge. Laparoscopic surgery was performed after neoadjuvant chemoradiotherapy. The 71-year-old woman in case 3 had T1 rectal cancer, with a tumor located just above the dentate line. After dissection of the intersphincteric space, the prolapsing technique was used. METHODS: In the male patients, the rectum with the mesorectum was first dissected to the anal hiatus, initially on the posterior side along the avascular plane. Second, Denonvilliers' fascia was dissected, and the seminal vesicle was exposed. The third step was dissection of the lateral tissues followed by incision of Denonvilliers' fascia with the rectal wall exposure and care taken not to injure the neurovascular bundle (Fig. 1). Along this dissection plane, the puborectalis could be reached and intersphincteric space entered from the lateral side of the rectal wall (Fig. 2). The final step was dissection of the hiatal ligament at the posterior side of the rectum. Nearly circular dissection of the intersphincteric space could be completed. The difficulties associated with the perineal approach were reduced by this abdominal approach, and the tumor could be exteriorized easily. Fig. 1 After incission of the Denonvilliers' fascia at the lateral side of the seminal vesicle puborectalis muscle can be reached at the lateral side of the rectum. Fig. 2 Adhesion line between the puborectalis muscle and rectal wall is enposed. Intersphinecteric space can be entered along this dissection plane at the lateral side of the rectum. RESULTS: The mean duration of surgery was 386 min, and the mean blood loss was 108 ml. The mean postoperative hospital stay was 18 days. The diverting ileostomy was closed at a mean of 7.3 postoperative months. No remarkable perioperative complication was encountered (Table 2). Table 2 Perioperative outcomes (n=15) Duration of surgery: min (range) 386 (319-510) Blood loss: ml (range) 108 (0-180) Postoperative hospital stay: days (range) 18 (11-31) COMPLICATIONS: n (range) Anastomotic leakage 1 Stricture of the anastomosis 1 Pelvic abscess 1 Postoperative period until the stoma closure (months) 7.3 (3-16) CONCLUSION: Laparoscopic ISR enabled reduction of the difficulties associated with the perineal approach. An advantage of laparoscopic ISR is the ability clearly to visualize anatomic structures in the deep pelvic cavity.

DOI： 10.1007/s00464-010-1451-x

PubMed

researchmap

Language：Japanese   Publisher：Japan Surgical Association  

A 60-year-old man was referred to our hospital because of fever and general fatigue.<BR>Gastrointestinal endoscopy was performed, and a 4-cm submucosal tumor was found in the corpus of the stomach. A Gastrointestinal Stromal Tumor (GIST) was thus suspected. In addition, multiple polycystic tumors were found in the right lobes of the liver by CT and MRI. Although liver abscess was suspected from the clinical features and CT/MRI findings, ultrasonography showed solid tumors, and the possibility of liver metastasis from GIST could not be ruled out. Therefore, partial gastrectomy and extended right hepatectomy were performed. On pathological examination, the gastric submucosal tumor was diagnosed as GIST with intermediate risk of aggressive behavior. No malignant findings were observed in the hepatic mass, which was diagnosed as a liver abscess, but the pathogenic bacterium of the abscess could not be identified. Because there are few reports on liver abscess associated with gastric GIST, this case provides valuable information. We report this case herein with the relevant literature.

DOI： 10.3919/jjsa.72.67

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2011107141

Language：Japanese   Publisher：Japan Pancreas Society  

Anaplastic carcinoma of the pancreas is a relatively rare type of invasive ductal carcinoma. When detected, patients usually have huge tumors showing rapid growth and thus have a very poor prognosis. Intraductal papillary-mucinous neoplasm of the pancreas is sometimes accompanied by invasive ductal carcinoma. We herein report a case of anaplastic carcinoma of the pancreas coexisting with intraductal papillary-mucinous carcinoma (IPMC). A 78-year-old woman with acute heart failure and aortic stenosis was admitted to our hospital. Computed tomography accidentally revealed a tumor of the head of the pancreas. She first underwent aortic valve replacement for aortic stenosis, and computed tomography two months later inadvertently revealed a rapidly expanding tumor in the head of the pancreas. We performed subtotal stomach-preserving pancreaticoduodenectomy following diagnosis of the pancreatic carcinoma. The pathological diagnosis was anaplastic carcinoma of the pancreas coexisting with IPMC.<br>

DOI： 10.2958/suizo.25.521

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2010292744

Language：Japanese  

FOLFOX therapy is a commonly used chemotherapeutic regimen against recurrent and unresectable colon cancer. However, its acute neurotoxicity is rare and not well recognized. We herein report a case of mFOLFOX6-induced hyperammonemic encephalopathy in a patient having recurrent colon cancer. A 74-year-old female with a history of sigmoid colon cancer was diagnosed as liver, lung, and peritoneal recurrences by surveillance CT and PET/CT. She was initially treated with modified FOLFOX6 therapy. After completing treatment, she presented with sudden onset of confusion, cognitive disturbances, and repeated seizures. None of the other radiographic examinations and laboratory tests provided an explanation for her symptoms except hyperammonemia. She was treated with branched-chain amino acid solutions and high-volume drip infusion, 6 hours after which the encephalopathy resolved. Clinicians should be aware of the adverse hyperammonemia induced by mFOLFOX6 when patients treated with mFOLFOX6 present with neurological disorders.

PubMed

researchmap

Language：English  

INTRODUCTION: The occurrence of cytomegalovirus colitis is well known in immunosuppressed patients, such as neoplastic patients following chemotherapy, although its exact etiology remains unclear. CASE PRESENTATION: We present a case of cytomegalovirus colitis occurring in a 77-year-old man with vomiting and diarrhea 2 weeks after initial systemic chemotherapy consisting of 5-fluorouracil, leucovorin and irinotecan for a recurrent colorectal cancer. Initial colonoscopy revealed multiple punched-out ulcers in the transverse colon and the diagnosis of cytomegalovirus was based on positive cytomegalovirus antigen detected by indirect enzyme antibody method, although immunohistological examination of tissues biopsied at colonoscopy was negative. The symptoms ceased under ganciclovir and octreotide treatment, and the patient recovered gradually. CONCLUSION: The most probable cause of the cytomegalovirus colitis in this case was impaired immunity following chemotherapy. Cytomegalovirus infection should be included in the differential diagnosis of gastrointestinal disease in colorectal cancer patients after chemotherapy and, when suspected, the clinician should pursue appropriate diagnostic interventions including colonoscopy.

DOI： 10.1186/1752-1947-2-289

PubMed

researchmap

Language：English   Publisher：GEORG THIEME VERLAG KG  

DOI： 10.1055/s-2007-966403

Web of Science

researchmap

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

Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.

PubMed

researchmap

Language：English  

PURPOSE: The tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) and oncolytic viruses have recently been investigated extensively for cancer therapy. However, preclinical and clinical studies have revealed that their clinical application is hampered by either weak anticancer activity or systemic toxicity. We examined whether the weaknesses of the two strategies can be overcome by integrating the TRAIL gene into an oncolytic vector. EXPERIMENTAL DESIGN: We constructed a TRAIL-expressing oncolytic adenovector designated as Ad/TRAIL-E1. The expression of both the TRAIL and viral E1A genes is under the control of a synthetic promoter consisting of sequences from the human telomerase reverse transcriptase promoter and a minimal cytomegalovirus early promoter. The transgene expression, apoptosis induction, viral replication, antitumor activity, and toxicity of Ad/TRAIL-E1 were determined in vitro and in vivo in comparison with control vectors. RESULTS: Ad/TRAIL-E1 elicited enhanced viral replication and/or stronger oncolytic effect in vitro in various human cancer cell lines than a TRAIL-expressing, replication-defective adenovector or an oncolytic adenovector-expressing green fluorescent protein. Intralesional administration of Ad/TRAIL-E1 eliminated all s.c. xenograft tumors established from a human non-small cell lung cancer cell line, H1299, on nu/nu nude mice, resulting in long-term, tumor-free survival. Furthermore, we found no treatment-related toxicity. CONCLUSIONS: Viral replication and antitumor activity of oncolytic adenovirus can be enhanced by the TRAIL gene and Ad/TRAIL-E1 could become a potent therapeutic agent for cancer therapy.

PubMed

researchmap

Language：English  

We report a rare case of esophageal intramural pseudodiverticulosis with esophageal strictures. Barium esophagogram demonstrated multiple flask-shaped diverticula out of the esophageal wall with comprehensive luminal stenosis involving the proximal 8 cm and distal 4 cm of the esophagus. Chest computed tomographic scan demonstrated round wall thickening and several intramural gas collections of the proximal esophagus. Endoscopy revealed a fibrotic stricture and multiple small orifices of pseudodiverticula with mild inflammatory changes. Biopsy specimens showed active chronic inflammatory changes of the mucosa with candidiasis. Dysphagia improved dramatically with esophageal dilation. However, the tiny diverticula did not resolve after treatment.

PubMed

researchmap

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

One of the challenges of oncolytic virotherapy is the inability to easily track or monitor virus activity during treatment. Here we describe the construction and functional characterization of Ad/hTC-GFP-E1, an oncolytic virus whose transgenes GFP and E1A are both under the control of a synthetic promoter (hTC). This promoter consists of sequences from the human telomorase reverse transcriptase promoter and a minimal cytomegalovirus (CMV) early promoter. The tumor-specific expression of E1A and GFP was demonstrated by Western blot and fluorescent microscope analyses, and the tumor-specific cytotoxicity by crystal-violet staining and cell viability assays. Viral replication and tumor cell lysis occured at multiplicities of infection (MOI) as low as 100 viral particles per cell in sensitive cell lines. No overt cytotoxic effect was observed in normal human fibroblasts, even at MOIs over 2000 vp. The presence of oncolytic vector was easily visualized and quantitated in vitro and in vivo, in correlation with viral replication. Intralesional administration of the virus into subcutaneous H1299 (NSCLC) tumor xenografts significantly suppressed tumor growth and provided a survival benefit. Together, these results demonstrate that an hTERT-specific oncolytic adenovirus expressing an hTERT-specific transgene is applicable for cancer therapy.

DOI： 10.1038/sj.cgt.7700944

Web of Science

researchmap

Language：English  

Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies. However, the molecular mechanisms by which bortezomib causes apoptosis selectively in cancer cells still remain unclear. Ras signaling is involved in multiple cellular processes, including cell cycle progression, differentiation, and apoptosis, and can either promote or inhibit apoptosis depending on the type of apoptotic stimuli and the cell model. Here, we investigated the role of K-ras signaling in bortezomib-induced apoptosis. We found that K-ras-transformed cells were more susceptible to bortezomib-induced apoptosis than were nontransformed cells and that bortezomib-induced apoptosis was mainly caspase dependent in K-ras-transformed cells. We also found that mammalian sterile20-like kinase 1 (MST1) was activated by bortezomib in K-ras-transformed cells and K-ras-mutated cancer cells. Treatment of K-ras-transformed cells with bortezomib resulted in translocation of MST1 from cytoplasm into the nucleus and an increase of phosphorylated histone H2B and histone H2AX. Moreover, pretreatment with leptomycin B, an inhibitor of the nuclear export signal receptor, dramatically enhanced bortezomib-mediated MST1 activation, phosphorylation of histones H2B and H2AX, and apoptosis induction in K-ras-transformed cells. Knockdown of MST1 expression by small interfering RNA diminished bortezomib-induced apoptosis or caspase-3 activation. Our data suggested that bortezomib may be useful for treatment of K-ras-mutated cancer cells, and MST1 is one of the mediators for bortezomib-induced apoptosis in K-ras-transformed cells.

PubMed

researchmap

Language：English  

BACKGROUND: Current treatments for prostate cancer are effective in many patients with locally advanced disease, but many of these patients eventually have recurrence. It is therefore important to develop alternative therapeutic agents with improved efficacy and tolerability. We recently identified a synthetic thiazolidin compound, 5-(2,4-dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidione (DBPT), that induces apoptosis in human colon cancer cells, independent of p53 and P-glycoprotein status. Here, we investigated the antitumor properties and mechanisms of action of this compound in human prostate cancer cell lines. METHODS: The effect of DBPT on cell-cycle progression and apoptosis in LNCaP and DU145 cells was examined by flow cytometry and Western blotting. The effect of DBPT on pro-angiogenic molecules was analyzed by Western blotting and by an enzyme-linked immunosorbent assay. RESULTS: DBPT inhibited the growth of LNCaP and DU145 cells with 50% inhibitory concentrations ranging from 1.6 to 5.9 microM. Treating LNCaP and DU145 cells with DBPT led to a time-dependent cell-cycle arrest in the G(2)/M phase and increased levels of G(2)/M checkpoint proteins, such as cyclin B1, cdc25C, phosphorylated histone H(3), and MPM-2. DBPT induced the phosphorylation of Bcl-xL and Bim, and induced apoptosis, as evidenced by cleavage of caspase and poly (ADP-ribose) polymerase. DBPT also effectively induced apoptosis in Bcl-2-overexpressing DU145 cells. Furthermore, DBPT decreased hypoxia-inducible factor 1 alpha and vascular endothelial growth factor expression in LNCaP cells under both normoxia and hypoxia. CONCLUSIONS: DBPT can suppress proliferation, induce apoptosis, and down regulate pro-angiogenic molecules in prostate cancer cells, and might be useful in treating prostate cancer.

PubMed

researchmap

Language：English  

Small-molecule inhibitors of cyclin-dependent kinases (CDKs) are known to induce cell cycle arrest and apoptosis in certain cancer cells. In order to evaluate the antitumor activity of one such inhibitor, GW8510, against human lung cancers, we analyzed the effects of GW8510 on six nonsmall cell lung cancer (NSCLC) cell lines (A549, H1299, H460, H226, H358 and H322) and normal human fibroblast (NHFB). We treated the cells with GW8510 at concentrations of 0-10 microM, and found that it suppressed cell growth in vitro in all the lung cancer cells but not in NHFB. Subsequent study showed that GW8510 induced apoptosis and cell cycle arrest in the A549, H1299 and H460 cells in a time- and dose-dependent manner. Western blot analysis showed that GW8510 downregulated the expression of X-linked inhibitor of apoptosis (XIAP) but had no detectable effect on the expression of Bax, Bak, or Bcl2. GW8510 also downregulated XIAP mRNA level, suggesting that downregulation of XIAP expression occurs at the transcriptional level. Moreover, ectopic XIAP expression diminished growth inhibition and apoptosis induction by GW8510. Importantly, GW8510 was not capable of inducing apoptosis of NHFB cells. These results suggest that GW8510 might provide a treatment strategy for human NSCLC and XIAP is an important target for GW8510-induced apoptosis of NSCLC cells that occurs through inhibition of XIAP mRNA transcription.

PubMed

researchmap

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

Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) gene therapy and oncolytic adenovirotherapy have been investigated extensively in xenografic human tumor models established in immunocompromised nude mice. However, the effects of these therapies on syngeneic murine tumors in immunocompetent settings were not well documented. We hypothesized that TRAIL gene therapy used with an oncolytic adenovirus would overcome the weaknesses of the two therapies used individually. In this study, we evaluated the antitumor effects of an oncolytic adenovirus, Delta24, in both human and murine breast cancer cell lines. We also analyzed the effects of TRAIL gene therapy combined with oncolytic virotherapy in these cancer cells. Our results showed that Delta24 can replicate and help the E1-deleted adenovector replicate in murine cancer cells. We also found that these two therapies combined had greater antitumor activity than either one alone in both human and murine breast cancer cells lines and in the syngeneic breast cancer models established in immunocompetent mice. Moreover, Delta24 virotherapy alone and combined with TRAIL gene therapy dramatically reduced the spontaneous liver metastasis that originated in the subcutaneous 4T1 tumor established in Balb/c mice. These findings provide important considerations in the development and preclinical assessments of oncolytic virotherapy.

DOI： 10.1038/sj.cgt.7700863

Web of Science

researchmap

Language：English  

Although gemcitabine is a potent therapeutic agent in the treatment of human non-small cell lung cancer (NSCLC), resistance to gemcitabine is common. In this study, we investigated the molecular mechanisms involved in acquired gemcitabine resistance against NSCLC cells. Gemcitabine-resistant NSCLC H1299 cells (H1299/GR) were selected by long-term exposure of parental H1299 cells to gemcitabine. The median inhibitory concentrations of gemcitabine in H1299 and H1299/GR cells were 19.4 and 233.1 nM, respectively. Gemcitabine induced activation of c-Jun NH2-terminal kinase (JNK) in parental H1299 cells but not in H1299/GR cells after 48 h. Blocking JNK activation by pretreatment with SP600125, a specific JNK inhibitor, or by transfection with dominant-negative JNK vectors abrogated gemcitabine-induced apoptosis in parental H1299 cells as evidenced by interruption of caspase activation. Transient transfection with a JNKK2-JNK1 plasmid expressing constitutive JNK1 partially restored the effect of gemcitabine in H1299/GR cells. Our results indicate that gemcitabine-induced apoptosis in human NSCLC H1299 cells requires activation of the JNK signaling pathway. Attenuated JNK activation may contribute to development of acquired gemcitabine resistance in cancer cells.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIRKHAUSER VERLAG AG  

We recently identified two thiazolidin compounds, 5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone (MMPT) and 5-(2,4-dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidin (DBPT), that inhibit the growth of human non-small-cell lung and colon cancer cells independent of P-glycoprotein and p53 status. Here we further investigated the mechanism by which these thiazolidin compounds mediate their anticancer effects. Treatment of cancer cells with MMPT and DBPT led to a time-dependent accumulation of cells arrested in the G2/M phase with modulation of the expression of proteins such as cyclin B1, cdc25C, and phosphorylated histone H3. Moreover, treatment with MMPT and DBPT increased M-phase arrest with abnormal spindle formation. DBPT-mediated G2/M phase arrest and phosphorylation of cdc25C and histone H3 were abrogated when JNK activation was blocked either with SP600125, a specific JNK inhibitor, or a dominant-negative JNK1 gene. Moreover, DBPT-mediated microtubule disruption was also blocked by SP600125 treatment. Our results demonstrate that thiazolidin compounds can effectively induce G2/M arrest in cancer cells and that this G2/M arrest requires JNK activation.

DOI： 10.1007/s00018-005-5365-z

Web of Science

researchmap

Language：English  

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at G0-G1 phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients.

PubMed

researchmap

Language：English  

Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear. To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib. The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in IkappaBalpha levels or in NFkappaB functionality were found after treatment with bortezomib. Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction. Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis.

PubMed

researchmap

Language：English  

Development of new therapeutic agents for colon cancer is highly desirable. To this end, we screened a chemical library for new anticancer agents and identified a synthetic compound, 5-(2,4-dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidin (DBPT), which kills cancer cells more effectively than it kills normal human fibroblasts. The molecular mechanism of the antitumor action of DBPT was further analyzed in three human colorectal cancer cell lines. DBPT effectively inhibited the growth of colorectal cancer cells, independent of p53 and P-glycoprotein status, whereas normal fibroblasts were unaffected at the same IC50. Over time, DLD-1 cancer cells treated with DBPT underwent apoptosis. The general caspase inhibitor benzyloxycarbonyl-valine-alanine-aspartate-fluoromethylketone partially blocked DBPT-induced apoptosis in a dose-dependent manner. DBPT-induced apoptosis, including cytochrome c release and caspase activation, was abrogated when c-Jun NH2-terminal kinase (JNK) activation was blocked with either a specific JNK inhibitor or a dominant-negative JNK1 gene. However, constitutive JNK activation alone did not replicate the effects of DBPT in DLD-1 cells, and excessive JNK activation by adenovirus encoding MKK7 had little influence on DBPT-induced apoptosis. Our results suggested that DBPT induces apoptosis in colorectal cancer cell lines through caspase-dependent and caspase-independent pathways and that JNK activation was crucial for DBPT-induced apoptosis. DBPT and its analogues might be useful as anticancer agents.

PubMed

researchmap

Language：English  

To develop new anticancer agents that are effective for treatment of chemoresistant tumors, we screened a chemical library for compounds that can effectively kill both paclitaxel-sensitive lung cancer cell H460 and P-glycoprotein-overexpressing paclitaxel-resistant cell H460/TaxR. A synthetic compound, MMPT (5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone), was identified to induce cytotoxic effects in both H460 and H460/TaxR cells but not in normal fibroblasts. MMPT effectively inhibited the growth of several human lung cancer cell lines in a dose-dependent manner, with 50% inhibitory concentrations ranging from 4.9 to 8.0 microM. The inhibitory effect on cancer cells is independent of the status of p53 and P-glycoprotein. Moreover, MMPT had no obvious toxic effects on normal human fibroblasts and mesenchymal stem cells at the 50% inhibitory concentration for lung cancer cell lines. Treating lung cancer cells with MMPT-induced apoptosis with caspase-3, -8, -9, and poly(ADP-ribose) polymerase cleavage and cytochrome c release from mitochondria. MMPT-induced apoptosis was abrogated when c-Jun N-terminal kinase (JNK) activation was blocked with a specific JNK inhibitor, SP600125. Furthermore, in vivo administration of MMPT suppressed human H460 xenograft tumor growth in nude mice. Our results suggest that MMPT may induce tumor-selective cell killing in both P-glycoprotein-negative and -positive cancer cells and could be a new anticancer agent for treatment of refractory tumors.

PubMed

researchmap

Language：English  

Proteasome inhibitors can resensitize cells that are resistant to tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly(ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated resensitization of TRAIL.

PubMed

researchmap

Language：English  

The tumor-selective cytotoxic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) makes TRAIL an attractive candidate as an anticancer agent. However, resistance to TRAIL poses a challenge in anticancer therapy with TRAIL. Therefore, characterizing the mechanisms of resistance and developing strategies to overcome the resistance are important steps toward successful TRAIL-mediated cancer therapy. In this study, we investigated mechanisms of acquired TRAIL resistance in a colon cancer DLD1 cell line. Compared with the TRAIL-susceptible DLD1 cell line, TRAIL-resistant DLD1/TRAIL-R cells have a low level of caspase-8 protein, but not its mRNA. Suppression of caspase-8 expression by siRNA in parental DLD1 cells led to TRAIL resistance. Restoration of caspase-8 protein expression by stable transfection rendered the DLD1/TRAIL-R cell line fully sensitive to TRAIL protein, suggesting that the low level of caspase-8 protein expression might be the culprit in TRAIL resistance in DLD1/TRAIL-R cells. Sequencing analysis of the caspase-8 coding region revealed a missense mutation that is present in both TRAIL-sensitive and TRAIL-resistant DLD1 cells. Subsequent study showed that the degradation of caspase-8 protein was accelerated in DLD1/TRAIL-R cells compared to parental DLD1 cells. Thus, accelerated degradation of caspase-8 protein is one of the mechanisms that lead to TRAIL resistance.

PubMed

researchmap

Language：English  

AIM: Because of a major resistance to chemotherapy, prognosis of hepatocellular carcinoma (HCC) is still poor. New treatments are required and gene therapy may be an option. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in multiple malignant tumors, and using adenoviral vectors has shown a targeted tumor-specific therapy. However, repeated administration of adenoviral vectors can lead to cell resistance, which may be caused by the initial coxsackie-adenovirus receptor (CAR). One technique to overcome resistance is the use of modified adenoviral vectors containing an Arg-Gly-Asp (RGD) sequence. In this study we constructed an adenoviral vector (designated Ad/TRAIL-F/RGD) with RGD-modified fibers, expressing the TRAIL gene from the human telomerase reverse transcriptase (hTERT) promoter, and evaluated its antitumor activity in HCC cell lines. METHODS: To investigate the effects of Ad/TRAIL-F/RGD in human HCC cell lines Hep G2 and Hep 3b, cells were infected with Ad/CMV-GFP (vector control), Ad/gTRAIL (positive control), and Ad/TRAIL-F/RGD. Phosphate-buffered saline (PBS) was used as control. Cell viability was determined by proliferation assay (XTT), and apoptosis induction by fluorescence activated cell sorting (FACS). RESULTS: Cells treated with Ad/TRAIL-F/RGD and Ad/gTRAIL showed a significantly reduced cell viability in comparison to PBS and Ad/CMV-GFP treatment in both cell lines. Whereas, treatment with PBS and Ad/CMV-GFP had no cell-killing effect. The reduced cell viability was caused by induction of apoptosis as shown by FACS analysis. The amount of apoptotic cells was similar after incubation with Ad/gTRAIL and Ad/TRAIL-F/RGD. CONCLUSION: The new RGD modified vector Ad/TRAIL-F/RGD could become a potent therapeutic agent for the treatment of HCC, adenovirus resistant tumors, and CAR low or negative cancer cells.

PubMed

researchmap

Language：English  

We previously found that a change in the balance between mitochondrial pro- and anti-apoptotic proteins caused by ectopic expression of the Bax gene led to increased induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To investigate whether a similar effect can be elicited by down-regulating Bcl-X(L), an anti-apoptotic protein, we tested the effects of a small interfering RNA (siRNA) specific for Bcl-X(L) in TRAIL-resistant cells. The down-regulation of Bcl-X(L) by siRNA inhibited cell proliferation and sensitized TRAIL-induced apoptosis in human cancer cells with both acquired and intrinsic TRAIL resistance. Combining the Bcl-X(L) siRNA with TRAIL protein treatment resulted in an increase in the percentage of apoptotic cells and increased cleavage of caspase-8, caspase-9, caspase-3 and PARP. Furthermore, the release of cytochrome c but not Smac from mitochondria was induced by Bcl-X(L) siRNA alone, and this release was dramatically amplified by combining the Bcl-X(L) siRNA and TRAIL protein treatment. Together, our data suggest that simultaneous triggering of the death receptor and mitochondrial apoptotic pathways leads to enhanced induction of apoptosis, which makes it potentially useful for the treatment of resistant cancers.

PubMed

researchmap

Language：English  

5-Fluorouracil (5-FU) is commonly used to treat human colon cancers but resistance to this compound is frequently observed in clinics. To characterize mechanisms of resistance to 5-FU and to develop new strategies for overcoming it, we established two cell lines that were resistant to 5-FU but not other chemotherapeutic agents from parental 5-FU-sensitive cell lines. Western blot analysis revealed that these resistant cells overexpressed the proteins Bcl-XL, Bcl-Xs, and Bik, and further data showed that the cells were resistant to 5-FU-induced DNA damage and cell cycle disorder. However, in parental cells, enforced expression of Bcl-XL protein provided only limited protection from 5-FU-induced apoptosis and overexpression of Bcl-XL protein did not affect 5-FU-induced DNA damage or cell cycle changes; these findings suggested that overexpression of Bcl-XL protein was not the major contributor to 5-FU resistance in any of our cells lines. Even so, knockdown of Bcl-XL protein expression by Bcl-XL-specific small interfering RNA could inhibit proliferation more effectively in 5-FU-resistant cells than in 5-FU-sensitive cells, and the combination of Bcl-XL-specific small interfering RNA and 5-FU had additive effect on the inhibition of 5-FU-resistant cells. These results suggest that down-regulation of Bcl-XL protein expression might provide a new treatment strategy for human 5-FU-resistant colon cancer therapy.

PubMed

researchmap

Language：English  

Local and locoregional administration of adenovectors expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been demonstrated to be useful in treating established tumors in animals. Moreover, expression of the TRAIL gene from the human telomerase reverse transcriptase (hTERT) promoter can be used to prevent possible liver toxicity of the TRAIL gene. However, it remains unknown whether systemic administration of the TRAIL-expressing adenovector can be used for cancer therapy. Here, we showed that a combination of TRAIL gene therapy and gemcitabine, the first-line chemotheraphy agent for pancreatic cancer, had a synergistic effect on the induction of apoptosis in human pancreatic cancer cell lines in vitro. Systemic administration of an adenovector that contains an insertion of integrin-binding motif argine-glycine-aspartate (RGD) in the HI loop of the adenoviral fiber protein and expresses the human TRAIL gene from the hTERT promoter (designated Ad/TRAIL-F/RGD) suppressed the growth of human pancreatic tumor cells inoculated in the liver of nu/nu nude mice. Furthermore, Ad/TRAIL-F/RGD in combination with gemcitabine suppressed the tumor growth of pancreatic cancer in the liver more than did treatments consisting of each agent alone. No obvious liver toxicity was detected in any of the treatment groups. Our results suggest that TRAIL gene therapy in combination with gemcitabine might be a useful therapeutic approach for treating metastatic pancreatic cancers.

PubMed

researchmap

Language：English  

Currently available methods for detection of tumors in vivo such as X-ray, computed tomography, and ultrasonography are noninvasive and have been well studied; the images, however, are not specific for tumors. Direct optical imaging of tumor cells in vivo that can clearly distinguish them from surrounding normal tissues may be clinically useful. Here, we describe a new approach to visualizing tumors whose fluorescence can be detected using tumor-specific replication-competent adenovirus (OBP-301, Telomelysin) in combination with Ad-GFP, a replication-deficient adenovirus expressing green fluorescent protein (GFP). Human telomerase reverse transcriptase is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. We constructed an adenovirus 5 vector in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site and showed that OBP-301 replicated efficiently in human cancer cells, but not in normal cells such as human fibroblasts. When the human lung and colon cancer cell lines were infected with Ad-GFP at a low multiplicity of infection, GFP expression could not be detected under a fluorescence microscope; in the presence of OBP-301, however, Ad-GFP replicated in these tumor cells and showed strong green signals. In contrast, coinfection with OBP-301 and Ad-GFP did not show any signals in normal cells such as fibroblasts and vascular endothelial cells. We also found that established subcutaneous tumors could be visualized after intratumoral injection of OBP-301 and Ad-GFP. A549 human lung tumors and SW620 human colon tumors transplanted into BALB/c nu/nu mice were intratumorally injected with 8 x 10(5) plaque-forming units of Ad-GFP in combination with 8 x 10(6) plaque-forming units of OBP-301. Within 3 days of treatment, the fluorescence of the expressed GFP became visible by a three-chip color cooled charged-coupled device camera in these tumors, whereas intratumoral injection of Ad-GFP alone could not induce GFP fluorescence. Moreover, intrathoracic administration of Ad-GFP and OBP-301 could visualize disseminated A549 tumor nodules in mice after intrathoracic implantation. Our results indicate that intratumoral or intrathoracic injection of Ad-GFP in combination with OBP-301 might be a useful diagnostic method that provides a foundation for future clinical application.

PubMed

researchmap

Language：English  

We recently found that a small molecule 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) could induce apoptosis and downregulate Bcl-XL expression in various cancer cells. Here, we found that 2,3-DCPE suppressed the proliferation of Bcl-XL-overexpressing cancer cells without inducing apoptosis. Subsequently, we found that 2,3-DCPE could induce S-phase arrest and upregulate p21 but not p27 at a time- and dose-dependent but p53-dispensable manner in DLD-1 human colon cancer cells. Activation of ERK was also detected after treatment with 2,3-DCPE. Moreover, p21 induction was dramatically attenuated by ERK inhibitors PD98059 and U0126. Induction of p21 and S-phase arrest and corresponding activation of ERK were also observed in ATM-defective cells, suggesting that 2,3-DCPE-induced these events were ATM-dispensable. Furthermore, ERK inhibitors dramatically attenuated 2,3-DCPE-induced S-phase arrest. Together, our data indicate that ERK activation correlated with the 2,3-DCPE-mediated induction of p21 expression and S-phase arrest. This finding may have implication for cancer therapy.

PubMed

researchmap

Language：English  

An adenoviral vector with RGD-modified fibers and expressing the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene from the human telomerase reverse transcriptase (hTERT) promoter (designated Ad/TRAIL-F/RGD) was constructed, and its antitumor activity was evaluated in vitro and in vivo. An in vitro study showed that treatment with Ad/TRAIL-F/RGD elicited a high rate of apoptosis in human pancreatic and colon cancer cell lines that were either susceptible or resistant to conventional adenovectors. In vivo study showed that direct administration of Ad/TRAIL-F/RGD to an orthotopic implantation tumor model established in the pancreatic tails of nu/nu mice significantly suppressed tumor growth: tumors in the animals treated with Ad/TRAIL-F/RGD were approximately eight times smaller than those in animals treated with a control vector. We also evaluated hTERT promoter activity and the effect of Ad/TRAIL-F/RGD on mesenchymal stem cells. Our results showed that transgene expression from the hTERT promoter in human bone marrow mesenchymal stem cells was minimal. No adverse effect was observed in mesenchymal stem cells treated with Ad/TRAIL-F/RGD. Together, our results suggest that Ad/TRAIL-F/RGD could become a potent therapeutic agent for the management of pancreatic cancer.

PubMed

researchmap

Language：English  

We recently found that repeated application of adenovectors expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or recombinant TRAIL proteins to TRAIL-susceptible cancer cells resulted in selection and expansion of TRAIL-resistant cells. Overcoming this acquired resistance to TRAIL is desirable for TRAIL-mediated cancer therapy. Here we demonstrate that several chemotherapeutic agents, including 5-fluorouracil (5-FU) and mitomycin, and calpain inhibitor I, an NFkappaB inhibitor, can overcome acquired resistance to TRAIL in DLD1 colon cancer cells. The combination of TRAIL (approved gene symbol TNFSF10) gene therapy and 5-FU enhanced tumor suppression in vivo in nude mice bearing subcutaneous tumors established from TRAIL-resistant colon cancer cells. Whereas treatment with the combination of TRAIL and 5-FU or mitomycin led to enhanced activation of caspase-3, the combination of TRAIL and calpain inhibitor I resulted in enhanced activation of both caspase-8 and caspase-3. Moreover, mitomycin, but not 5-FU or calpain inhibitor I, induced overexpression of the BAX gene, which was correlated with enhanced TRAIL-induced cell killing in TRAIL-resistant DLD1 cells. Together, these results suggest that acquired resistance to TRAIL can be overcome by different mechanisms and that combinations of TRAIL gene therapy and chemotherapy may be a useful approach for cancer treatment.

PubMed

researchmap

Language：English  

Activation of MAP kinases is involved in various cellular processes, including immunoregulation, inflammation, cell growth, cell differentiation, and cell death. To investigate the role of p38 MAP kinase activation in the signaling pathway of TRAIL-mediated apoptosis, we compared TRAIL-mediated MAP kinase activation in TRAIL-susceptible human colon cancer cell line DLD1 and TRAIL-resistant DLD1/TRAIL-R cells. TRAIL-mediated activation of ERK occurred in both cell lines. In contrast, both DLD1 and DLD1/TRAIL-R cells showed no obvious JNK activation after treatment with TRAIL. Interestingly, TRAIL-mediated activation of p38 MAP kinases was observed in DLD1 cells but not in DLD1/TRAIL-R cells. However, activation of p38 MAP kinases was observed in both DLD1 and DLD1/TRAIL-R cells after treatment with anisomycin. Furthermore, inhibiting activated p38 MAP kinases with known inhibitors or with an adenovector expressing dominant negative p38alpha did not block TRAIL-mediated cell death in DLD1 cells. Moreover, activation of p38 MAP kinases by adenovectors expressing constitutive MKK3 or MKK6 (Ad/MKK3bE or Ad/MKK6bE) did not induce cell death in either DLD1 or DLD1/TRAIL-R cell lines. Our results suggest that activation of p38 MAP kinases does not play a major role in TRAIL-mediated apoptosis in DLD1 cells and that lack of TRAIL-mediated p38 MAP kinase activation may not be the mechanism of TRAIL-resistance in DLD1/TRAIL-R cells.

PubMed

researchmap

Language：English  

In a search for new anticancer agents, we identified that 2[[3-(2,3-dichlorophenoxy) propyl]amino]ethanol (2,3-DCPE) induced apoptosis more effectively in various cancer cells than in normal human fibroblasts. We further evaluated the cell-killing effects of this compound in vitro in several human cancer cell lines and normal human fibroblasts. A cell viability assay showed that IC(50)s for human colon cancer cell lines LoVo and DLD-1, for human lung cancer cell lines H1299 and A549, and for normal human fibroblasts were 0.89, 1.95, 2.24, 2.69, and 12.6 micro M, respectively. Subsequent studies revealed that 2,3-DCPE could cause cleavage of caspase-8, caspase-3, caspase-9, and poly(ADP-ribose) polymerase and release of cytochrome c in cancer cells but not in normal human fibroblasts. Our data also showed that 2,3-DCPE attenuated the protein level of Bcl-XL and that apoptosis induction by 2,3-DCPE could be blocked by enforced overexpression of Bcl-XL. Our results suggest that 2,3-DCPE might be a potential new anticancer agent.

PubMed

researchmap

Language：English  

PURPOSE: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells. EXPERIMENTAL DESIGN: We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo. RESULTS: TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated. CONCLUSIONS: Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.

PubMed

researchmap

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

Background: Gene transfer to the esophageal epithelium holds the potential for the therapy of malignant as well as premalignant lesions in the upper gastrointestinal tract. Replication-deficient recombinant adenoviruses represent an efficient means of introducing genes in vivo into cells in a variety of organs. The majority of in vivo studies utilize direct submucosal injection for delivery of the viral vectors into the locoregional area of the gut
transferring genes into epithelial cells, however, is difficult because viruses are retained in the subepithelial space. To establish the efficient method for gene transfer into the epithelial cells, we have developed a multiluminal spray catheter that can be passed through the accessory channel of an endoscope, and we have evaluated the feasibility of fibrin glues as a vehicle of recombinant adenoviruses in a porcine model. Methods: The fibrinogen solution and the thrombion solution containing an E1/E3 deleted recombinant adenovirus expressing the bacterial lacZ gene (Ad-lacZ) were endoscopically sprayed on the porcine esophagus through the catheter attached to the dual-barrel syringe. Twenty-four hours after gene delivery, β -galactosidase activity of the esophagus was determined under the microscope following X-gal staining. Results: The fibrin glue could be locally sprayed on the porcine esophagus by using the multichannel catheter through the endoscope. Attachment of the fibrin glue comtining Ad-lacZ caused strong β-galactosidase staining on epithelial cells in the mucosal surface, but not in the basal cell layer. Conclusion: Endoscopic local delivery of recombinant adenoviruses in aerosolized fibrin glues through a multiluminal catheter could provide an optimal technique for gene transfer into epithelial cells in the mucosal surfece, which may have important implications for the treatment of human esophageal premalignant diseases.

DOI： 10.1007/s00464-003-8146-5

Scopus

PubMed

researchmap

Language：English  

The biological effects of retinoic acid (RA) are mediated by nuclear retinoic acid receptors (RARs) that function as ligand-activated transcriptional factors. The response of human cancer cells to RA is known to be associated with the expression of RARbeta. Recent studies have demonstrated that the loss of RARbeta expression is involved in the development of a variety of human malignancies. We show that recombinant adenovirus-mediated p21(sdi1) gene transfer enhances RARbeta mRNA expression as well as protein expression and induces the sensitivity to all-trans RA (ATRA) in human cancer cells. Semi-quantitative reverse transcription-polymerase chain reaction analysis demonstrated that infection with adenovirus carrying human p21(sdi1) gene (Ad5CMV-p21), which encodes a cyclin-dependent kinase inhibitor, induced RARbeta mRNA and protein expression in H1299 human non-small cell lung cancer cells and DLD-1 human colorectal cancer cells. We also found that exogenous introduction of the p21(sdi1) gene transcriptionally activated the upstream promoter function of the RARbeta gene. Treatment with 1 microM of ATRA showed no significant inhibitory effects on the growth of H1299 and DLD-1 cells; after Ad5CMV-p21 infection, however, cells underwent apoptosis with ATRA treatment at the same concentration, suggesting that p21(sdi1) gene transfer sensitized H1299 and DLD-1 cells, presumably, through RARbeta upregulation. We also demonstrated the efficacy of intratumoral injection of Ad5CMV-p21 in combination with systemic administration of ATRA in a nude mice xenograft model. Our results indicate that recombinant adenovirus-mediated p21(sdi1) gene transfer could be potentially useful for the local induction of RA sensitivity in human premalignant and malignant lesions lacking appropriate RARbeta expression.

PubMed

researchmap

Language：English  

The tumor suppressor p53 gene product is an essential component of the cytotoxic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We previously demonstrated that adenovirus-mediated wild-type p53 gene transfer could enhance the cytotoxic actions of chemotherapeutic drugs both in vitro and in vivo; however, the molecular mechanism of this chemosensitization is still unclear. Cyclin D1 is a major regulator of the progression of cells into the proliferative stage of the cell cycle. Here we show that infection with an adenovirus vector expressing the wild-type p53 gene (Ad-p53) caused an increase in cyclin D1 protein levels in human colorectal cancer cell lines DLD-1 and SW620; treatment with the anti-cancer drug adriamycin, however, down-regulated their cyclin D1 protein expression in a dose-dependent manner. The suppression of cyclin D1 expression following adriamycin treatment could be blocked by simultaneous Ad-p53 infection. Furthermore, DLD-1 and SW620 cells transfected with the cyclin D1 expression construct displayed increased sensitivity to adriamycin compared to that of the vector-transfected control. Our results suggest that ectopic wild-type p53 gene transfer results in increased cyclin D1 expression and, consequently, sensitizes human colorectal cancer cells to chemotherapeutic agents.

PubMed

researchmap

Language：Japanese   Publisher：Japan Surgical Association  

The authors describe a case of large endometrial polyp possibly due to tamoxifen (TAM) regimen associated with Paget's disease of the right breast in a postoperative woman with left breast cancer. A 71-year-old woman was admitted to the hospital because of nipple eczema. She had been administered TAM for two years after the previous operation for left breast cancer. As she was diagnosed as having Paget's disease of the contralateral breast by a biopsied specimen, a right mastectomy was performed. Furthermore, a large endometrial polyp 4.0cm in maximum diameter was detected and it was extirpated. Though TAM is widely used as an adjuvant hormone therapy for breast cancer, two years or more prolonged TAM treatment causes proliferative endometrial lesions due to its partial estrogenic action. On the other hand, significant reductions in the incidence rate of contralateral breast cancer have been observed. ER of Paget's cells revealed negative by an immunohistochemical study in this case. Gynecological examination is necessary for the patients administered TAM in spite of the cumulative dose and duration of the regimen.

DOI： 10.3919/jjsa.61.2605

CiNii Article

researchmap

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

researchmap

Language：Japanese   Publisher：(公社)日本皮膚科学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)日本腹部救急医学会  

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：GID(性同一性障害)学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：克誠堂出版(株)  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.SABCS18-4330

Web of Science

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2017363151

Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：日本臨床外科学会  

DOI： 10.3919/jjsa.77.730

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2017010186

Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：日本臨床外科学会  

DOI： 10.3919/jjsa.75.S723

researchmap

Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(一社)日本大腸肛門病学会  

researchmap

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

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2012122184

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2012059133

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

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

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

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：(社)高知市医師会  

平成17年3月から平成20年7月までに高知医療センター消化器外科で行った食道癌手術症例81例を検討した。平均年齢67歳、男性70例、女性11例。全症例の進行度はStage 0が9例、Stage Iが16例、Stage IIが21例、Stage IIIが26例、Stage IVaが9例であった。全症例の生存率(他病死を含む)は1年80%、2年68%であった。術後合併症として、呼吸器合併症6例(7%)、反回神経麻痺3例(4%)、吻合部狭窄5例(6%)、縫合不全13例(16%)を認めた。(著者抄録)

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese  

DOI： 10.4044/joma.120.13

J-GLOBAL

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2008008049

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：日本肺癌学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：岡山医学会  

CiNii Article

CiNii Books

researchmap

Other Link： http://ousar.lib.okayama-u.ac.jp/13365

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：(株)南江堂  

過去12年間に筆者らの施設で手術された食道癌177例中,食道表在癌51例(男47例・女4例,年齢45〜83歳・平均61.4歳)を対象に臨床病理学的に検討した.深達度はm1(上皮内癌)10例,m2(粘膜固有層癌)4例,m3(粘膜筋板浸潤癌)9例,粘膜下層癌(sm癌)のsm1が7例,sm2が8例,sm3が13例であった.深達度と内視鏡的病型分類との関係では,0-IIbはいずれもm1,m2で,0-IIa,0-IIcはm1〜sm3まで幅広く認めたが,0-I,0-III, 0-IIa+IIcはいずれもsm癌であった.深達度と脈管侵襲・リンパ節転移では,m1・m2では脈管侵襲[ly(+)]・リンパ節転移[n(+)]共に認められなかったが,m3ではly(+)11.1%,n(+)11.1%に認めた.sm1ではly(+)28.6%,n(+)14.3%に認められ,sm2ではly(+)50.0%,血管侵襲[v(+)]12.5%,n(+)25.0%に認められ,sm3ではly(+)84.6%,v(+)61.5%,n(+)38.5%に認められた.累積生存率は,1年で96.1%,5年で74.7%であり,深達度が進むほど予後不良であった

researchmap

Language：Japanese   Publisher：(社)高知市医師会  

症例は34歳男,68歳女,41歳男で,全て十二指腸第2部に発生し,摘出標本の主腫瘍最大径は各々14.0cm,8.4cm,11.0cmであった.術式は1例は膵頭十二指腸切除,他の2例は幽門輪温存膵頭十二指腸切除を施行した.予後は各々6年9ヵ月目に肝転移で死亡,3年3ヵ月目に肝転移で死亡,9ヵ月現在生存中である

researchmap

Language：Japanese   Publisher：(社)高知市医師会  

33歳女,主訴は発熱,近医にて治療を受けたが,肝機能障害を指摘され,平成9年11月25日近医入院となった.汎血球減少症が同時に見られ,症状は一時軽快したが,再び,肝機能障害が悪化したため,当院紹介入院となった.入院時検査所見では白血球1200/mm3,Hb.9.2g/dl,血小板12.2×103/mm3と低下,T-Bil 12.2mg/dl,D-Bil 8.5mg/dl,GOT 782IU/l,GPT 229IU/l,ALP 3662IU/l,γ-GTP 770IU/l,LDH 10386IU/lと上昇していた.その臨床経過よりHPSが考えられ,血漿交換,ステロイド療法等を行ったが,DIC,呼吸不全に陥り,急速に全身状態が悪化し,発症後,28日目に死亡した

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

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

肝内胆管癌に対する手術施行24症例を対象に,肉眼型と予後因子について検討を行った.肝内結石・総胆管結石合併は20.8%,CEA陽性が38.1%,CA19-9陽性が86.4%に認められた.手術症例の1年生存率は55.3%,5年生存率は22.1%と不良であった.日本肝癌研究会にて報告された肝内胆管癌の肉眼分類(案)(1994年)に基づいて腫瘤形成型,胆管浸潤型,胆管内発育型に分類した.累積生存率の比較を行ったところ,腫瘤形成型(9例)と胆管浸潤型(11例)はそれぞれ予後は悪く,両者間には有意差は認められなかったが,胆管内発育型(4例)は予後良好で全例生存中であった.原発性肝癌取扱い規約(第3版,1992年)に基づいて予後因子を検討した.リンパ節転移,漿膜浸潤,門脈腫瘍塞栓において有意差が認められ,予後不良因子であった

DOI： 10.3919/jjsa.60.1751

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2000016546

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：(一社)日本移植学会  

DSGは慢性期の拒絶反応,特にlate acute rejection,acute on chronic rejectionに対して有効であるが,副作用,特に骨髄抑制に対して十分に注意を払う必要がある

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：(社)高知市医師会  

CiNii Article

researchmap

Language：Japanese   Publisher：金原出版(株)  

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：高知県立中央病院  

68歳男性.下痢便を主訴として入院.注腸及び大腸内視鏡検査で肛門より8cmの部位に中心部に潰瘍を伴う隆起性病変(2型病変)を認めた.胸部X線で右胸心,腹部CTで内臓転移を認めた.直腸低前方切除術及びリンパ節郭清を行った.7.0×4.0cmの腫瘍で高分化型腺癌で,直腸傍リンパ節(No251)に転移を認めた

CiNii Article

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.5

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese  

researchmap

Event date： 2021.3

Language：English  

researchmap

Event date： 2021.3

Language：Japanese  

researchmap

Event date： 2021.3

Language：Japanese  

researchmap

Event date： 2021.3

Language：Japanese  

researchmap

Event date： 2021.2

Language：Japanese  

researchmap

Event date： 2021

Language：Japanese  

上皮間葉転換(EMT)可視化プローベを用い、間葉型大腸癌がhybrid E/Mで最も化学療法抵抗性であるかをイメージングによって明らかにするとともに、時間的にEMTマーカーを追跡した。Vimentinプロモーター下に赤色蛍光タンパク遺伝子(rfp)がドライブさせるEMT可視化プローベを作成した。大腸癌細胞株HCT116、RKOにEMT可視化プローベを導入した。大腸癌の代表的な抗癌剤5-FU、オキサリプラチン(L-OHP)、シスプラチン(CDDP)、イリノテカン(CPT-11)を曝露させた。その結果、RKOではL-OHP、CDDP、5-FUの順で赤色を呈するEMTを起こし、HCT116では5-FU、L-OHP、CDDPの順でEMTを起こした。また、時間軸では化学療法後48時間するとEMTを起こし赤色になったが、化学療法終了後48時間経過するとEMTを起こし無色に戻った。化学療法施行前にEMT阻害剤で前治療しておくと、化学療法に曝露しても赤色にならず(EMTは阻害され)、さらに化学療法への感受性も増加していた。

researchmap

Event date： 2020.12

Language：Japanese  

researchmap

Event date： 2020.12

Language：Japanese  

researchmap

Event date： 2020.12

Language：Japanese  

researchmap

Event date： 2020.12

Language：Japanese  

researchmap

Event date： 2020.10

Language：English  

researchmap

Event date： 2020.10

Language：English  

researchmap

Event date： 2020.10

Language：English  

researchmap

Event date： 2020.9

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.7

Language：Japanese  

researchmap

Event date： 2020.6

Language：Japanese  

researchmap

Event date： 2020.3

Language：English  

researchmap

Event date： 2020.2

Language：Japanese  

症例は54歳男性.大量出血を伴う小腸多発GIST(Gastrointestinal stromal tumor)を認めて緊急入院となった.姉が神経線維腫症1型(neurofibromatosis type 1:NF1)と診断されており,患者にもおよそ20個の神経線維腫を疑う腫瘤とcafe au lait斑を6個以上認めたためNF1と診断した.出血コントロール目的に開腹手術を行ったが,GISTはおよそ20個多発しており,大量小腸切除を避けるために10mm以上の腫瘍のみ外科的切除を行い,多発微小腫瘍は経過観察とした不完全切除を選択した.切除標本の病理検査では紡錘形核と好酸性胞体を有する紡錘形細胞が密に錯綜する腫瘍を認め,免疫染色でKIT陽性.核分裂数は5以下/50HPFsであり低悪性度GISTと診断した.NF1に伴うGISTは比較的予後が良いとの報告もあるが,このような多発微小病変については明らかな治療指針がない.今後さらなる症例の集積と検討を要する.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J03931&link_issn=&doc_id=20200310200005&doc_link_id=10.18976%2Fjsft.19.2_77&url=https%3A%2F%2Fdoi.org%2F10.18976%2Fjsft.19.2_77&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Event date： 2019.12

Language：Japanese  

researchmap

Event date： 2019.12

Language：Japanese  

researchmap

Event date： 2019.12

Language：Japanese  

researchmap

Event date： 2019.12

Language：Japanese  

researchmap

Event date： 2019.11

Language：Japanese  

researchmap

Event date： 2019.9

Language：English  

researchmap

Event date： 2019.7

Language：Japanese  

researchmap

Event date： 2019.7

Language：Japanese  

researchmap

Event date： 2019.7

Language：Japanese  

researchmap

Event date： 2019.5

Language：Japanese  

researchmap

Event date： 2019.5

Language：Japanese  

researchmap

Event date： 2019.4

Language：Japanese  

researchmap

Event date： 2019.3

Language：Japanese  

researchmap

Event date： 2019.1

Language：Japanese  

researchmap

Event date： 2019.1

Language：Japanese  

researchmap

Event date： 2018.12

Language：Japanese  

researchmap

Event date： 2018.12

Language：Japanese  

researchmap

Event date： 2018.12

Language：Japanese  

researchmap

Event date： 2018.12

Language：Japanese  

researchmap

Event date： 2018.12

Language：Japanese  

researchmap

Event date： 2018.12

Language：Japanese  

researchmap

Event date： 2018.10

Language：Japanese  

researchmap

Event date： 2018.9

Language：Japanese  

researchmap

Event date： 2018.9

Language：Japanese  

researchmap

Event date： 2018.9

Language：Japanese  

researchmap

Event date： 2018.7

Language：Japanese  

researchmap

Event date： 2018.7

Language：Japanese  

researchmap

Event date： 2018.7

Language：Japanese  

researchmap

Event date： 2018.7

Language：Japanese  

researchmap

Event date： 2018.7

Language：Japanese  

researchmap