Usage of nivolumab and ipilimumab for recurrent or advanced malignant vaginal melanoma: a two-case series.

Immune checkpoint inhibitors help treat malignant melanoma, but show limited use in treating malignant vaginal melanoma, an aggressive, rare gynecological malignancy. We identified two patients treated with ipilimumab and nivolumab for vaginal melanoma; both were immunonegative for programmed cell death-ligand 1 and wild-type BRAF. Case 1, a 56-year-old female who underwent radical surgery for stage 1 malignant vaginal melanoma, experienced recurrence 15 months postoperatively. She briefly responded to ipilimumab and nivolumab combination therapy before showing disease progression. Tumor shrinkage occurred with nivolumab and local radiotherapy and, 45 months postoperatively, she survives with the melanoma. Case 2, a 50-year-old female, presented with a 4-cm blackish polypoid vaginal tumor with metastatic pelvic lymph nodes. She received ipilimumab and nivolumab combination therapy for stage III unresectable malignant vaginal melanoma. The vaginal tumor shrank after the third course of treatment, and the lymphadenopathy disappeared. The patient underwent radical surgery and is currently disease-free, using nivolumab for maintenance therapy. Both patients had immune-related adverse events coinciding with periods of high therapeutic efficacy of immune checkpoint inhibitors. Neoadjuvant therapy with immune checkpoint inhibitors and radiotherapy for immune checkpoint inhibitor resensitization may effectively treat advanced or recurrent vaginal melanoma.

Immunohistochemical and molecular analysis of an α-fetoprotein-producing cervical adenocarcinoma with clear cell morphology.

Adenocarcinomas with clear cell morphology may be associated with elevated serum alpha-fetoprotein levels in various organs. We report the case of an alpha-fetoprotein-producing cervical adenocarcinoma with clear cell morphology and compare it immunohistochemically, molecularly, and virologically with cervical clear cell carcinoma, gastric-type mucinous carcinoma, and ovarian clear cell carcinoma. A 51-year-old Japanese woman was initially diagnosed with cervical clear cell carcinoma. The tumor was resistant to standard surgery, radiotherapy, and chemotherapy. Serum carcinoembryonic antigen and alpha-fetoprotein were elevated. The tumor was immunohistochemically positive for alpha-fetoprotein, human chorionic gonadotropin, cytokeratin 20, spalt-like transcription factor 4, glypican 3, MUC6, and HIK1083. Gene panel testing revealed CCNE1 amplification, CDKN2A loss, and TP53 R282W. We compared the present case with 120 ovarian clear cell carcinoma cases using a tissue microarray. Only one case (0.8%) showed very limited immunohistochemical positivity for alpha-fetoprotein. Of the 54 cases in which serum carcinoembryonic antigen was measured, only one (1.9%) was elevated (19.9 ng/mL). We diagnosed the case as alpha-fetoprotein-producing cervical gastric-type mucinous carcinoma with enteroblastic differentiation. In conclusion, alpha-fetoprotein-producing cervical adenocarcinoma is a rare but aggressive tumor. Clinicians and pathologists should be aware of this unfamiliar tumor, its diagnostic clues, prognostic markers, and treatment strategies.

Vulvar neuroendocrine carcinoma that is independent of merkel cell polyomavirus and human papillomavirus suggests endometrial cancer recurrence: a case report.

BACKGROUND: Vulvar neuroendocrine carcinomas with small cell morphology need an appropriate differential diagnosis with respect to primary Merkel cell carcinomas, primary small cell neuroendocrine carcinomas, and secondary/metastatic carcinomas. Herein, we report a woman with a history of endometrial carcinoma led to neuroendocrine vulvar carcinoma. CASE PRESENTATION: An 82-y-old woman with right vulvar swelling was transferred to our hospital. Computed tomography scan showed a 75 mm irregular mass in her right vulva. Three years ago, she had been diagnosed with endometrial endometrioid carcinoma stage IA and had undergone surgery. Vulvar biopsy revealed neuroendocrine carcinomas with small cell morphology. Immunohistochemical staining showed that the vulvar tumor was positive for CD56 and chromogranin A, but negative for Merkel cell polyomavirus and cytokeratin 20. Incidentally, her endometrial carcinoma was also positive for CD56 and chromogranin A. Human papillomavirus DNA typing analysis of vulvar tumor was negative. Hence, the vulvar tumor seemed to be a recurrence of the endometrial cancer rather than a primary vulvar neuroendocrine carcinoma. The patient died of the disease within a month. CONCLUSION: We report a case of vulvar neuroendocrine carcinoma that is independent of Merkel cell polyomavirus and human papillomavirus, thereby suggesting a recurrence of endometrial cancer. Immunohistochemical and virological analyses helped in the differential diagnosis of the neuroendocrine carcinoma.

Promising therapeutic targets of endometriosis obtained from microRNA studies.

Endometriosis is a benign tumor that affect 6-10% women of reproductive age. To date, it is suggested that the aberrant microRNA (miRNA) expressions play important roles in the pathogenesis of endometriosis. Reviewing the literature, we found nine overexpressed miRNAs, which were thoroughly investigated in the context of endometriotic tissues and cells. Most of the overexpressed miRNAs induced endometriosis-specific characteristics including inhibition of apoptosis and decidualization, upregulation of fibrogenesis, invasion, migration, cell proliferation, attachment to extracellular matrix, inflammation, and angiogenesis in the endometriotic cells. Then, we found that the downstream target molecules of these miRNAs, such as early growth response protein-1, extracellular signal-regulated kinase, matrix metallopeptidase 1, signal transducer and activator of transcription 3, cyclooxygenase-2, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, and vascular endothelial growth factor-A are promising for the therapeutic targets of endometriosis. Recent findings suggest that complex molecular mechanisms leading to development and progression of endometriosis by miRNAs may exist in endometriosis. The meticulous balance between tumorigenic miRNAs and tumoristatic miRNAs may destine the natural course and response to the surgical, medical, and hormonal treatments of this disease. Further investigations into endometriosis-associated miRNAs may elucidate the pathogenesis of endometriosis and help to develop novel therapeutics.

Role of repressed microRNAs in endometriosis.

Endometriosis is a common, estrogen-dependent benign tumor that affect 3-10% women of reproductive age, and is characterized by the ectopic growth of endometrial tissue, which is found primarily in the rectovaginal septum, ovaries, and pelvic peritoneum. To date, accumulating evidence suggests that various epigenetic aberrations, including the expression of aberrant microRNAs (miRNAs), play definite roles in the pathogenesis of endometriosis. This review summarizes the recent findings on the aberrantly repressed miRNAs, as well as their potential roles regarding the pathogenesis of endometriosis.

The inhibitory effect of AMP-activated protein kinase (AMPK) on chemokine and prostaglandin production in human endometrial stromal cells.

BACKGROUND: To investigate the role of adenosine monophosphate (AMP)-activated protein kinase (AMPK) on the production of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, prostaglandin E2 and F2α induced by IL-1ß in endometrial stromal cells (ESCs) following treatment with 5-aminoimidazole-4- carboxamide ribonucleoside (AICAR). METHODS: Endometrial specimens were obtained and cultured. We examined the effects of IL-1ß, IL-1 ra and AICAR on the production of IL-8, MCP-1, PGE2 and PGF2α in human ESCs. The phosphorylations of AMPK, IκB, 4EBP-1, p70S6K and S6 ribosomal protein were analyzed by Western immunoblotting. RESULTS: Following stimulation by IL-1ß, the production of IL-8, MCP-1, PGE2 and PGF2α showed significant increases, and these increases were suppressed by AICAR. The expression of cyclooxygenase-2 (COX-2) induced by IL-1ß and suppressed by AICAR. The phosphorylation of IκB, 4EBP-1, p70S6K and S6 ribosomal protein were inhibited via an AMPK-dependent signal transduction. CONCLUSIONS: The production of IL-8, MCP-1, PGE2 and PGF2α induced by IL-1ß in ESCs were involved in the negative regulatory mechanisms of AMPK. The substances that activate AMPK may be promising agents for the treatment of pathological problems such as dysmenorrhea.

Correlation of World Health Organization 2010 Classification for Gastroenteropancreatic Neuroendocrine Neoplasms with the Prognosis of Ovarian Neuroendocrine Neoplasms: Kansai Clinical Oncology Group-Protocol Review Committee/Intergroup Study.

BACKGROUND: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis. METHODS: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS). RESULTS: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01). CONCLUSION: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors.

Pathological processes and pretreatment cytologic diagnosis of neuroendocrine carcinoma of the endometrium: addendum report of the Kansai Clinical Oncology Group/Intergroup study in Japan.

A previous retrospective study of a neuroendocrine carcinoma of the endometrium including 42 cases employed a central pathologic review to ensure the reliability of the findings. However, the pathological processes were not described in detail. In this study, we further analyzed these processes and the results of pretreatment endometrial cytology of neuroendocrine carcinoma. Of the 65 patients from 18 institutions registered in the study, 42 (64.6%) were diagnosed with neuroendocrine carcinoma of the endometrium based on the central pathological review. Thirteen of the 23 excluded cases conflicted from their original diagnoses: 5 (38.5%) were diagnosed with endometrioid adenocarcinoma, 5 (38.5%) with undifferentiated carcinoma, and 3 (23.1%) with carcinosarcoma. Immunohistochemical staining led to a change in diagnosis for 8 (61.5%) of the 13 cases. Pretreatment endometrial cytology was examined in 38 (90.5%) cases; 34 (89.5%) of these 38 cases were found, or suspected, to be positive. To ensure the selection of appropriate therapy and keeping patients correctly informed, it is important to distinguish neuroendocrine carcinoma from other similar histologic types. Endometrial cytology may help in the early detection of this disease.

hsa-miR-100-5p, an overexpressed miRNA in human ovarian endometriotic stromal cells, promotes invasion through attenuation of SMARCD1 expression.

BACKGROUND: A number of microRNAs are aberrantly expressed in endometriosis and are involved in its pathogenesis. Our previous study demonstrated that has-miR-100-5p expression is enhanced in human endometriotic cyst stromal cells (ECSCs). The present study aimed to elucidate the roles of has-miR-100-5p in the pathogenesis of endometriosis. METHODS: Normal endometrial stromal cells (NESCs) were isolated from normal eutopic endometrium without endometriosis. Using hsa-miR-100-5p-transfected NESCs, we evaluated the effect of hsa-miR-100-5p on the invasiveness of these cells by Transwell invasion assay and in-vitro wound repair assay. We also investigated the downstream signal pathways of hsa-miR-100-5p by microarray analysis and Ingenuity pathways analysis. RESULTS: hsa-miR-100-5p transfection enhanced the invasion and motility of NESCs. After hsa-miR-100-5p transfection, mRNA expression of SWItch/sucrose non-fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1) was significantly attenuated. Whereas, the expression of matrix metallopeptidase 1 (MMP1) mRNA and active MMP1 protein levels was upregulated. CONCLUSION: We found that SMARCD1/MMP-1 is a downstream pathway of hsa-miR-100-5p. hsa-miR-100-5p transfection enhanced the motility of NESCs by inhibiting SMARCD1 expression and MMP1 activation. These findings suggest that enhanced hsa-miR-100-5p expression in endometriosis is involved in promoting the acquisition of endometriosis-specific characteristics during endometriosis development. Our present findings on the roles of hsa-miR-100-5p may thus contribute to understand the epigenetic mechanisms involved in the pathogenesis of endometriosis.

ATM expression is attenuated by promoter hypermethylation in human ovarian endometriotic stromal cells.

A number of genes involved in the pathogenesis of endometriosis are silenced by the hypermethylation of their promoter regions. We assessed the effect and mechanism of the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) (10 µM) on the cell cycle in human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) by flow cytometry. The DNA methylation status of G2/M checkpoint regulators were investigated by methylation-specific PCR. The expression of ataxia telangiectasia mutated (ATM) and the effect of 5-aza-dC on its expression were also evaluated by quantitative RT-PCR and western blotting analysis. 5-aza-dC treatment resulted in the cell cycle arrest of ECSCs at the G2/M phase. In contrast, 5-aza-dC did not affect the cell cycle of NESCs. The promoter region of the ATM gene was hypermethylated in ECSCs, but not in NESCs. ATM mRNA expression was attenuated in ECSCs compared to that in NESCs. Further, 5-aza-dC was found to restore ATM expression in ECSCs by its promoter demethylation. Our findings indicate that ATM promoter hypermethylation occurs in endometriosis, and that ATM silencing is involved in tumorigenesis during this disease; moreover, selective DNA demethylating agents and molecular target drugs against ATM silencing are promising for the treatment of endometriosis.

Phase II study of adjuvant chemotherapy with paclitaxel and nedaplatin for uterine cervical cancer with lymph node metastasis.

The purpose of this phase II trial was to assess the efficacy and toxicity of paclitaxel and nedaplatin (TN) as the initial postoperative adjuvant chemotherapy for uterine cervical cancer with lymph node metastases (LNM). Patients with FIGO stage IB1-IIA2 squamous cell carcinoma of the uterine cervix were enrolled. Histological confirmation of LNM was mandatory. Intravenous paclitaxel at 175 mg/m2 and nedaplatin at 80 mg/m2 were administered every 28-day cycle, of which there were 5 cycles after radical hysterectomy. Sixty-two patients were enrolled in the study from November 2011 to July 2015. Their median age was 48.5 years (range 28-64). The median tumor diameter was 37 mm (5-64). Overall, 30 patients (48.4%) had 1 metastatic lymph node, 11 (17.7%) had 2, 3 (4.8%) had 3, 5 (8.1%) had 4, and 13 (21.0%) had 5 or more. With a median follow-up of 45.7 months (range 23.4-69.5), the 2-year relapse-free survival and 2-year overall survival rates were 79.0% (90% CI, 69.0%-86.2%) and 93.5% (95% CI, 83.7%-97.5%), respectively. Almost all adverse events were relatively mild. Grade 3-4 adverse events (NCI-CTC ver. 4.0) that occurred in 5% or more of patients were neutropenia (60.7%) and infection (6.6%). The proportion of patients who completed 5 cycles of treatment was 90.3%. Postoperative adjuvant chemotherapy with TN for cervical cancer with LNM was demonstrated to be an effective and feasible treatment. A phase III trial is warranted to compare this with concurrent chemoradiotherapy.

Ruptured external iliac artery pseudoaneurysm following surgery for ovarian cancer: A case report and literature review.

Ruptured pseudoaneurysm following pelvic surgery is a rare and fatal complication. Because of its rarity, existing evidence is limited to a small case series. A 60-year-old woman underwent staging laparotomy, including pelvic and para-aortic lymphadenectomy, for ovarian cancer. On the 11th day, the patient developed a sudden lumbar pain and loss of consciousness, which resulted in a state of shock. She was diagnosed as having a pelvic abscess and ruptured external iliac artery pseudoaneurysm. We performed ligation of the external iliac artery to restrain hemorrhage and femoro-femoral artery bypass to prevent infection, which saved the patient's life. Our study had two findings. First, this is the first reported case of ruptured external iliac artery pseudoaneurysm following surgery for ovarian cancer. Second, treatment of ruptured pseudoaneurysm requires rapid hemostasis, prevention of infection, and revascularization.

Expression of angiogenic factors in sclerosing stromal tumours of the ovary.

Sclerosing stromal tumours (SSTs) are rare benign tumours and are generally observed in individuals in their teens to 20 s. Many cases are suspected as malignant tumours pre-operatively, owing to their high vascularity on diagnostic imaging. Herein, we aimed to evaluate the expressions of various angiogenic factors in SSTs. The expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF) were examined by immunohistochemical staining. Upon immunohistochemistry, overexpressions of VEGF, bFGF, and HGF in the ovarian stroma were observed in SSTs. In the normal ovary, the expressions were strong around the vessels and weak in the stroma of the ovary, while a Sertoli-Leydig cell tumour showed weak staining with VEGF, locally strong staining with bFGF and negative staining with HGF. This is the first report about angiogenic factors such as bFGF, and HGF in SST. Impact statement What is already known on this subject? Sclerosing stromal tumour (SST) is a rare benign tumour with high vascularity. The high vascularity of SSTs are reported to be related to the overexpression of vascular endothelial growth factor (VEGF). But there is no study on the expressions of other angiogenic factors in SST. What do the results this study add? In the immunohistochemical analysis, VEGF, bFGF and HGF were found to be widely stained in SSTs. This results suggest the possibility that the high vascularity seen on diagnostic imaging, and the many small vessels observed microscopically may be related to the expressions of VEGF, bFGF and HGF in SSTs. What are the implications of these findings for clinical practice and/or further research? Our results suggest the possibility that the combined expression pattern of VEGF, bFGF, and HGF may be used as marker of SSTs.

Arcyriaflavin a, a cyclin D1-cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis.

BACKGROUND: We previously showed that microRNA-503 (miR-503) transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1. This finding prompted us to evaluate the potential therapeutic effects of cyclin D1 inhibitors in endometriotic cells. This study aimed to determine whether arcyriaflavin A, a representative inhibitor of cyclin D1-cyclin-dependent kinase 4 (CDK4), is beneficial in the treatment of endometriosis. METHODS: ECSCs were isolated from the ovarian endometriotic tissues of 32 women. The effects of arcyriaflavin A on cell viability and proliferation, vascular endothelial growth factor A expression, apoptosis, and cell cycle progression were evaluated using a modified methylthiazoletetrazolium assay, enzyme-linked immunosorbent assay (ELISA), Caspase-Glo® 3/7 assay, and flow cytometry. RESULTS: Arcyriaflavin A significantly inhibited cell viability, proliferation, and angiogenesis of ECSCs as assessed using the 5-bromo-2-deoxyuridine (BrdU) and methylthiazoletetrazolium bromide (MTT) assays, and vascular endothelial growth factor (VEGF) ELISA. Arcyriaflavin A induced apoptosis as shown in the Caspase-Glo® 3/7 assay and cell death detection ELISA whilethe cell cycle was arrested at the G0/G1 phase. CONCLUSION: The findings indicate that cyclin D1-CDK4 inhibitors may be promising candidates for the treatment of endometriosis. This is the first study to demonstrate the potential usefulness of arcyriaflavin A as a therapeutic agent for endometriosis. Further studies of the effects of cyclin D1-CDK4 inhibitors on endometriosis may provide useful information on pathogenesis and treatment.

Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Müllerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402).

BACKGROUND: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)). METHODS: We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed. RESULTS: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS. CONCLUSIONS: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.

miR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells.

STUDY QUESTION: Is the micro-RNA (miRNA) miR-503, downregulated in endometriotic cyst stromal cells (ECSCs) and does this affect the cell cycle, cell proliferation, angiogenesis and contractility of these cells? SUMMARY ANSWER: miR-503 expression is downregulated in ECSCs by DNA hypermethylation and this contributes to their proliferation, resistance to apoptosis, extracellular matrix (ECM) contractility and angiogenesis through effects on cyclin D1, B-cell lymphoma/leukemia (Bcl)-2, Ras homology A  and vascular endothelial growth factor A (VEGF-A). WHAT IS KNOWN ALREADY: A variety of miRNAs are demonstrated to involve in the pathogenesis of endometriosis. miR-503 is a miRNA with tumor-suppressor functions, whose expression is suppressed in ECSCs. STUDY DESIGN, SIZE, DURATION: We isolated ECSCs and normal endometrial stromal cells (NESCs) from ovarian endometriotic tissues (n = 32) and eutopic endometrial tissues without endometriosis (n = 8), respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We investigated the functions of miR-503 by using miR-503-transfected ECSCs and the DNA methylation status of miR-503 gene in ECSCs and NESCs by combined bisulfite restriction analysis. MAIN RESULTS AND THE ROLE OF CHANCE: In ECSCs, miR-503 is downregulated by the DNA hypermethylation of its gene. The transfection of miR-503 into ECSCs resulted in the inhibition of cell proliferation and induction of cell-cycle arrest at G0/G1 phase through the suppression of cyclin D1, the induction of apoptosis through Bcl-2 suppression, the inhibition of VEGF-A production and the attenuation of ECM contractility via the suppression of Rho/Rho-associated coiled-coil-forming protein kinase-pathways. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: The present experiments were carried out only with the stromal component of endometriosis and eutopic endometrium. The experiments with the eutopic endometrial stromal cells from women with endometriosis are not performed. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that epigenetically repressed miR-503 in ECSCs is involved in the acquisition of endometriosis-specific cellular functions. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 26861335 to K.K. and no. 23592407 to H.N.) and the Kanzawa Medical Research Foundation (to K.K.). There are no conflicts of interest to declare.

Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial.

PURPOSE: Olanzapine is effective in chemotherapy-induced nausea and vomiting (CINV). In patients receiving highly emetogenic chemotherapy (HEC), its efficacy was reported as rescue therapy for breakthrough emesis refractory to triplet therapy (palonosetron, aprepitant, and dexamethasone). However, its preventive effects with triplet therapy for CINV are unknown. This study aimed to investigate efficacy and safety of preventive use of olanzapine with triplet therapy for CINV of HEC. METHODS: This study is a prospective multicenter study conducted by Kansai Clinical Oncology Group. Forty chemo-naïve gynecological cancer patients receiving HEC with cisplatin (≥50 mg/m(2)) were enrolled. Oral olanzapine (5 mg) was administered with triplet therapy a day prior to cisplatin administration and on days 1-5. The primary endpoint was complete response (no vomiting and no rescue) rate for the overall phase (0-120 h post-chemotherapy). Secondary endpoints were complete response rate for acute phase (0-24 h post-chemotherapy) and delayed phase (24-120 h post-chemotherapy) and complete control (no vomiting, no rescue, and no significant nausea) rate and total control (no vomiting, no rescue, and no nausea) rate for each phase. These endpoints were evaluated during the first cycle of chemotherapy. RESULTS: Complete response rates for acute, delayed, and overall phases were 97.5, 95.0, and 92.5 %, respectively. Complete control rates were 92.5, 87.5, and 82.5 %, respectively. Total control rates were 87.5, 67.5, and 67.5 %, respectively. There were no grade 3 or 4 adverse events. CONCLUSIONS: Preventive use of olanzapine combined with triplet therapy gives better results than those from previously reported studies of triplet therapy.

Intravenous leiomyomatosis treated with radical hysterectomy and adjuvant aromatase inhibitor therapy.

Intravenous leiomyomatosis (IVL), a rare disease that is histologically benign but clinically aggressive, is characterized by the intraluminal growth of benign leiomyoma in the intrauterine and systemic veins. Preoperative diagnosis of IVL is difficult, because the symptoms of early stage IVL are similar to those of uterine leiomyoma. The efficacy of adjuvant hormone therapy after surgical resection of IVL remains unclear. Herein is described a case of IVL that was diagnosed preoperatively, in which successful total resection of the tumor was achieved by radical hysterectomy. The patient, a 50-year-old premenopausal Japanese woman, also underwent aromatase inhibitor treatment and was free of disease at 36 months after surgery. Contrast-enhanced computed tomography is suggested as the best assessment for identifying and diagnosing IVL. Radical hysterectomy can be considered a successful therapy for total resection. Aromatase inhibitor treatment may be effective, especially when the patient has not yet entered menopause.

Combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium: A case report and survey of related literature.

Primary large-cell neuroendocrine carcinoma of the endometrium is extremely rare and has a poor prognosis. This report describes a case of combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium diagnosed as stage IIIA. The patient underwent surgery and chemotherapy and has been well with no evidence of disease for 20 months. The optimal treatment for this rare tumor has not been established. Considering its rarity and variability, it is difficult to establish an evidence-based therapeutic regimen.

Wisteria floribunda agglutinin-binding glycan expression is decreased in endometriomata.

BACKGROUND: Glycosylation is one of the most common post-translational modifications of eukaryotic proteins and is known to undergo dynamic changes in a wide range of biological processes. To date, however, the glycan expression profiles in endometriosis are largely unknown. The objective of the study was to identify the panel of glycans that were aberrantly expressed in endometriosis, a hormone-dependent disease. METHODS: The glycan expression profiles in primary cultured human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were determined by lectin microarray analysis. Distribution of Wisteria floribunda agglutinin (WFA)-binding glycans in ovarian endometriotic cysts and eutopic proliferative phase endometrium were assessed by lectin histochemistry. The expressions of N-acetylgalactosaminyl transferases that synthesize WFA-binding glycans were evaluated in ECSCs and NESCs. RESULTS: We found that the levels of WFA-binding glycans were decreased in ECSCs. Lectin histochemistry revealed that WFA-binding glycans were decreased only in the stromal components of the ovarian endometriotic cysts, but not in the epithelial components, compared to the eutopic proliferative phase endometrium. The expressions of N-acetylgalactosaminyl transferases that synthesize WFA-binding glycans were downregulated in ECSCs. CONCLUSIONS: Utilizing lectin microarray analysis and lectin histochemistry, we found that WFA-binding glycans were decreased in endometriosis. The synthetic enzymes of WFA-binding glycans were significantly downregulated in ECSCs. It is suggested that reduced expression of N-glycans with WFA-binding properties on ECSCs is a novel characteristics of endometriosis.