Koji Yamanoi

Utilization of genomic signatures to identify high-efficacy candidate drugs for chemorefractory endometrial cancers.

Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High‐grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore, discovery of efficacious new drugs in this setting is required to benefit chemorefractory cases. The 50% growth‐inhibitory (GI50) concentration of 27 clinically relevant drugs was measured in the NCI60 panel of cell lines. Gene expression data were analyzed using Bayesian binary regression, to first generate a response signature for each drug and then to calculate individual susceptibility scores using in vivo endometrial cancer data (GSE2109; http://www.ncbi.nlm.nih.gov/geo) and in vitro data (GSE25458), as well as to identify candidate drugs for chemorefractory cases. Using these candidates, cell proliferation, apoptosis and caspase assays were performed in vitro. The tumor growth‐inhibitory effect of the candidate was also assessed in vivo using nude mice. Through microarray analysis, fludarabine and temsirolimus showed higher susceptibility scores in high‐grade cases compared to cisplatin, doxorubicin and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin‐resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p < 0.001). Fludarabine treatment also enhanced caspase‐3/7 activity in HEC1A relative to HEC50B cells (p < 0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p < 0.05). These results support that identification and use of genomic signatures can lead to identification of new therapeutic candidates that may prove beneficial to chemoresistant cases. Fludarabine may be useful in targeting high‐grade, chemorefractory endometrial cancer.

Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation

Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8+ tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail-expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT.Snail is a transcription factor that induces epithelial-mesenchymal transition. Here the authors show that, in the mesenchymal subtype of ovarian cancer, Snail expression promotes tumorigenesis by inducing immune evasion through CXCR2-ligands-mediated recruitment of myeloid-derived suppressor cells.

Suppression of ABHD2 , identified through a functional genomics screen, causes anoikis resistance, chemoresistance and poor prognosis in ovarian cancer

Anoikis resistance is a hallmark of cancer, and relates to malignant phenotypes, including chemoresistance, cancer stem like phenotypes and dissemination. The aim of this study was to identify key factors contributing to anoikis resistance in ovarian cancer using a functional genomics screen. A library of 81 000 shRNAs targeting 15 000 genes was transduced into OVCA420 cells, followed by incubation in soft agar and colony selection. We found shRNAs directed to ABHD2, ELAC2 and CYB5R3 caused reproducible anoikis resistance. These three genes are deleted in many serous ovarian cancers according to The Cancer Genome Atlas data. Suppression of ABHD2 in OVCA420 cells increased phosphorylated p38 and ERK, platinum resistance, and side population cells (p<0.01, respectively). Conversely, overexpression of ABHD2 decreased resistance to anoikis (p<0.05) and the amount of phosphorylated p38 and ERK in OVCA420 and SKOV3 cells. In clinical serous ovarian cancer specimens, low expression of ABHD2 was associated with platinum resistance and poor prognosis (p<0.05, respectively). In conclusion, we found three novel genes relevant to anoikis resistance in ovarian cancer using a functional genomics screen. Suppression of ABHD2 may promote a malignant phenotype and poor prognosis for women with serous ovarian cancer.

A novel diagnostic criterion for lymph node metastasis in cervical cancer using multi-detector computed tomography

OBJECTIVES The sensitivity of the current 10mm cut-off diameter that is used to diagnose lymph node (LN) metastasis is too low. This is the first study to develop a new criterion to diagnose LN metastasis in a region-by-region manner using multi-detector computed tomography (MDCT). METHODS 1) The short-axis diameter of the LNs in MDCT images from 1-mm slices obtained immediately prior to surgery was compared with the pathological diagnosis in 78 uterine cervical cancer patients undergoing primary surgery. For the region-by-region analysis, we divided para-aortic and pelvic spaces into 13 regions. 2) In 28 cases in which patients received neoadjuvant chemotherapy (NAC) followed by surgery, we compared MDCT images before and after NAC. RESULTS 1) The optimal cut-off in the region-by-region analysis was 5mm, yielding 71% sensitivity and 79% specificity. 2) NAC significantly decreased LN size (p<0.0001). NAC decreased the number of swollen LN regions (>5mm) from 51% (81/158) to 26% (41/158). CONCLUSIONS The new criterion developed using MDCT could be effective for accurately assessing LN status. It also facilitates the assessment of NAC efficacy regarding the eradication of LN metastases.

Large-cell neuroendocrine carcinoma arising in the endometrium: A case report

Large-cell neuroendocrine carcinoma (LCNEC) of the endometrium is an extremely rare, high-grade malignant tumor. We herein report a case of a rapidly growing LCNEC arising in the endometrium. A 52-year-old woman was referred to Toyooka Hospital (Tooyoka, Japan) due to genital bleeding in February 2016. There had been no abnormalities on a regular gynecological and physical examination 3 months prior to the consultation. Imaging (computed tomography and magnetic resonance imaging) and a pelvic examination revealed a tumor sized 16.9×8.4×7.8 mm occupying the intrauterine cavity and extending into the vaginal cavity. Multiple metastatic pelvic and paraaortic lymph nodes were also identified. Continuous bleeding from the tumor was observed, and a blood examination revealed anemia, which was likely due to that bleeding. Biopsy of the tumor was performed, and large atypical cells were identified. The tumor cells were negative for cytokeratin AE1/AE3 and chromogranin A, but positive for CD56 and synaptophysin. There was also an abundance of Ki-67-positive cells in the tumor, altogether suggesting that the tumor was an LCNEC. The patient succumbed to the disease 36 days after the first consultation. Based on the findings of the present case and previously published cases, LCNECs arising in the endometrium may progress rapidly and are associated with an unfavourable outcome. LCNEC should be included in the differential diagnosis in cases of rapidly growing tumors of the uterine corpus.

Gliomatosis peritonei with 18F-fluorodeoxyglucose accumulation and contrast enhancement secondary to immature teratoma: A case report

Gliomatosis peritonei (GP) is a rare condition characterized by mature glial tissue implants widespread in the peritoneum, which is occasionally followed by treatment for immature teratoma (IM). The present study reported a case of GP with fluorodeoxyglucose (FDG) accumulation and contrast enhancement followed by treatment for IM. A 30-year-old female, 2-gravida and 0-para, underwent laparotomy with hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy followed by four cycles of chemotherapy with bleomycin, etoposide, and cisplatin for IM (Grade 2) of stage IIIC. At the 6-month follow-up, computed tomography (CT) revealed a 1-cm mass with contrast enhancement on splenic flexure. Positron-emission tomography (PET)/CT revealed intense FDG accumulation at the same site. Although α-fetoprotein, which was elevated preoperatively, remained normal, she was diagnosed with IM recurrence. The patient underwent three cycles of chemotherapy with paclitaxel, ifosfamide, and cisplatin, but the size, the degree of contrast enhancement and FDG accumulation of the mass did not change after chemotherapy. A diagnostic laparoscopy was performed. which revealed multiple small peritoneal implants, including a 1-cm mass at the splenic flexure. The 1-cm mass was dissected at the splenic flexure and some other implants. Mature well-differentiated glial tissue with non-atypia was identified in all tissue, and a diagnosis of GP was made. The patient is currently undergoing regular follow-up. Few reports are available regarding FDG-PET/CT imaging of GP. GP should be considered as the differential diagnosis of FDG-avid mass followed by IM therapy. A laparoscopic diagnosis is useful to obtain an accurate diagnosis of GP.

A Case of Pelvic Abscess Caused by Edwardsiella tarda followed by Laparoscopic Resection of a Hematoma Derived from Caesarean Section

Edwardsiella tarda (E. tarda) infections are rare and can be fatal. We report a case of an E. tarda abscess which developed in the hematoma originally derived from a caesarean section. A 24-year-old gravida 1 woman was admitted to our hospital with a complaint of abdominal pain. Approximately one month before her admission, pelvic hematoma had developed derived from caesarean section. Followed by the failure of conservative management, she underwent laparoscopic surgery to remove the hematoma 6 days before her admission. On computed tomography examination, we found that the abscess with a diameter of 9 cm was located in the right pelvic space. We punctured the abscess and identified E. tarda in the abscess. We continued administering antibiotics, but her symptoms, including fever and abdominal pain, became worse, and the abscess enlarged. We performed laparotomy drainage and ileocecal resection on the 10th posthospitalization day. After drainage surgery, the patients condition improved gradually, and the patient was discharged uneventfully. There are no reports in patients of E. tarda infection during the perinatal period. E. tarda infection can be a life-threatening illness even in immunocompetent patients. In the case of E. tarda infection, intensive care and surgical procedures should be considered.

Combination of Aprepitant, Azasetron, and Dexamethasone as Antiemetic Prophylaxis in Women with Gynecologic Cancers Receiving Paclitaxel/Carboplatin Therapy

Background The aim of this study was to evaluate the antiemetic effect of aprepitant and to determine how to provide triple combination therapy (aprepitant/azasetron/dexamethasone) to women receiving paclitaxel/carboplatin moderately emetogenic chemotherapy (MEC). Material/Methods The current study was a prospective study of 163 women with gynecologic cancers. We compared the digestive symptoms scores (nausea, vomiting, appetite loss, and dietary intake) of 37 women with ovarian cancers before and after aprepitant administration. We also compared these symptoms in women who underwent 193 cycles of triple combination therapy with symptoms of women who underwent 226 cycles of double combination therapy. For triple combination therapy, azasetron, dexamethasone (reduced dose: 40% of 20 mg), and aprepitant (125 mg) were administered on Day 1, followed by only aprepitant (80 mg) administration on Days 2 and Day 3. Results In 37 women with ovarian cancer, three symptoms, nausea, appetite loss, and dietary intake, were significantly improved by primarily adding aprepitant to double combination therapy in the delayed phase of MEC. Upon comparing their digestive symptoms in all cycles, however, these three symptoms were not significantly different in the delayed phase. Furthermore, all four symptoms in all cycles were worse following triple combination therapy than following double combination therapy in the acute phase (p<0.02). The control of digestive symptoms was generally insufficient without the administration of dexamethasone. Conclusions Primary aprepitant as an addition to MEC demonstrated efficacy in improving digestive symptoms in the delayed phase. However, its effect may decrease with repeated use. To improve the antiemetic effect, the dose reduction of dexamethasone should be restricted on Day 1 and dexamethasone should be used throughout the delayed phase as well.

A case of preoperatively-predicted extragonadal mature cystic teratoma in the pouch of Douglas resected via laparoscopic surgery.

Mature cystic teratomas derived from extragonadal lesions are rare. We report a case of extragonadal mature cystic teratoma (EMCT) in the pouch of Douglas (POD), which was predicted preoperatively and successfully resected by performing laparoscoic surgery. A 35-year-old woman was incidentally diagnosed with a mass measuring 6 cm in diameter in the right pelvis on ultrasonographic examination. Magnetic resonance imaging (MRI) findings were suggestive of mature cystic teratoma. Both normal ovaries were found adjacent to the mass. We considered the possibility of EMCT, and performed laparoscopic surgery. Intraoperatively, the cyst was found in the POD and both ovaries appeared normal. There were violin string-like adhesions between the cyst wall and the back of the uterus, right ovary, and serosa of the rectum. We dissected the adhesions with the rectum with the help of a gastroenterological surgeon, and dissected the other adhesions easily ourselves. The patient had an uneventful postoperative course and was discharged on the fourth post-operative day. Pathological examination of the resected mass revealed the mass to be EMCT. Only approximately 20 cases of EMCTs in POD have been reported till date. There are several hypotheses to explain their etiopathogenesis. We hypothesize that auto-amputation could be the mechanism that resulted in EMCT in this case. Though EMCTs are rare, we should consider performing detailed preoperative evaluations with EMCT as a differential diagnosis. Subsequently, we can plan an appropriate surgical approach beforehand, and perform laparoscopic

Clinical efficacy of neoadjuvant chemotherapy with irinotecan (CPT-11) and nedaplatin followed by radical hysterectomy for locally advanced cervical cancer

Objective To investigate the clinical efficacy of neoadjuvant chemotherapy (NAC) with irinotecan (CPT-11) and nedaplatin (NED) followed by radical hysterectomy. Methods Patients with locally advanced cervical cancer (stage Ib2–IIb) were treated with NAC followed by surgery, primary surgery or primary radiotherapy. NAC was usually performed using transuterine arterial chemotherapy (TUAC) or intravenous CPT-11/NED. Survival rates were analysed in the three treatment groups; response rates and adverse events associated with NAC, TUAC and CPT-11/NED were compared, along with previously reported adverse events of chemoradiotherapy. Results A total of 165 patients with cervical cancer were recruited. Of these, 70 were treated with NAC followed by surgery (48 with CPT-11/NED, 18 with TUAC and four with other types of chemotherapy), 73 were treated with primary surgery and 22 with primary radiotherapy (including chemoradiotherapy). There were no significant differences in progression-free survival or overall survival rates between the three treatment groups. The response rates for the NAC regimen of CPT-11/NED and TUAC were high (75% and 78%, respectively). The frequency of severe thrombocytopenia was lower in patients receiving CPT-11/NED compared with TUAC, and the incidence of severe anaemia, vomiting and cystitis was lower in patients receiving CPT-11/NED compared with chemoradiotherapy. Conclusions The use of CPT-11/NED as a NAC regimen shows favourable activity, with lower toxicity compared with NAC using TUAC or chemoradiotherapy, for the treatment of locally advanced cervical cancer.