[A Case of Myelodysplastic Syndrome Developed during Chemotherapy for Postoperative Recurrent Ovarian Cancer That Progressed to Acute Myeloid Leukemia].

Recent developments in chemotherapy for gynecologic malignancies have improved treatment results in patients and promoted long-term survival. However, various adverse events caused by long-term chemotherapy are still being observed. Here, we report a case of myelodysplastic syndrome that developed during chemotherapy for recurrent ovarian cancer and progressed to acute myeloid leukemia. However, chemotherapy for ovarian cancer was continued while maintaining the quality of life under certain conditions, such as maintenance of platelet levels in collaboration with a hematologist. A 69- year-old woman(gravida 3, para 2)was diagnosed with stage ⅢC ovarian cancer in our department. After 6 cycles of preoperative chemotherapy with paclitaxel plus carboplatin plus bevacizumab(TC plus Bev), we performed a simple abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, sigmoid colon resection, and low anterior resection. Postoperatively, 3 cycles of TC plus Bev and 6 cycles of Bev monotherapy were completed for stage ⅢC ovarian cancer (ypT3cNXM0, high-grade serous carcinoma). However, the cancer recurred, and the patient received 3 cycles of gemcitabine plus Bev and 3 cycles of doxorubicin plus Bev. Precursor cells and prolonged neutropenia were observed, and myelodysplastic syndrome was diagnosed. One month later, the condition progressed to acute myeloid leukemia. The patient's neutrophil count recovered spontaneously, and subsequently, 7 cycles of weekly paclitaxel plus Bev therapy were completed along with symptomatic treatment. Unfortunately, she died of septic shock against the background of acute myeloid leukemia. It is important to monitor the appearance of blasts for early detection of therapy-related myelodysplastic syndromes occurring during chemotherapy, as in the case in this report. Additionally, it is important to maintain platelet count and continue chemotherapy for the primary disease.

Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy. METHODS: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m2) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0-2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1-4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24-120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676. FINDINGS: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75-83] of 354 patients in the olanzapine group and 231 (66% [61-71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group. INTERPRETATION: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy. FUNDING: Japan Agency for Medical Research and Development.

The mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin than to conventional taxane and carboplatin chemotherapy in high grade serous ovarian carcinoma: A survey of Japanese Gynecologic Oncology Group study (JGOG3016A1).

OBJECTIVE: Recently, we established new histopathological subtypes of high-grade serous ovarian cancer (HGSOC) that include the mesenchymal transition (MT) type, the immune reactive (IR) type, the solid and proliferative (SP) type and the papillo-glandular (PG) type. Furthermore, we identified that the mesenchymal transcriptome subtype might be sensitive to taxane. We investigated whether these different histopathological subtypes of HGSOC require individualized chemotherapy for optimal treatment. METHODS: We conducted the Japanese Gynecologic Oncology Group (JGOG) 3016A1 study, wherein we collected hematoxylin and eosin slides (total n = 201) and performed a histopathological analysis of patients with HGSOC registered in the JGOG3016 study, which compared the efficacy of conventional paclitaxel and carboplatin (TC) and dose-dense TC (ddTC). We analyzed the differences in progression-free survival (PFS) and overall survival (OS) among the four histopathological subtypes. We then compared the PFS between the TC group and the ddTC group for each histopathological subtype. RESULTS: There were significant differences in both PFS and OS among the four histopathological subtypes (p = 0.001 and p < 0.001, respectively). Overall, the MT subtype had the shortest PFS (median 1.4 y) and OS (median 3.6 y). In addition, the MT subtype had a longer PFS in the ddTC group (median 1.8 y) than in the TC group (median 1.2 y) (p = 0.01). Conversely, the other types had no significant difference in PFS when the two regimens were compared. CONCLUSIONS: The MT type of HGSOC is sensitive to taxane; therefore, the ddTC regimen is recommended for this histopathological subtype.

[Transvaginal ultrasound-guided core needle biopsy for residual potentially malignant ovarian tumors in cases with severe peritoneal adhesion and frozen pelvis requiring polysurgery].

A multiparous woman in her 40s had advanced peritoneal adhesions and frozen pelvis from 3 previous surgeries. Endometrial ovarian cysts also remained. After the last surgery, imaging showed cysts with a septum and enhanced moieties in the Douglas pouch. Highly invasive surgery was anticipated, and the patient underwent a transvaginal ultrasound-guided core needle biopsy(TVCNB, 16-gauge needle)with full awareness of the risks involved. The histopathological diagnosis was adenocarcinoma. We inserted a ureteral stent and performed an S-shaped colon resection and standard ovarian cancer surgery after preoperative chemotherapy. TVCNB in this case was less invasive and easier to perform than other exploratory procedures, and has a low risk of iatrogenic intraperitoneal dissemination even if the tumor is malignant. Chemotherapy can be administered before surgery if malignancy is detected. In summary, TVCNB is a useful alternative method for conducting exploratory operations.

Clinicopathological features and programmed death-ligand 1 immunohistochemical expression in a multicenter cohort of uterine and ovarian melanomas: a retrospective study in Japan (KCOG-G1701s).

The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option.

The post-progression survival of patients with recurrent or persistent ovarian clear cell carcinoma: results from a randomized phase III study in JGOG3017/GCIG.

OBJECTIVE: In this study we sought to investigate the clinical factors that affect post-progression survival (PPS) in patients with recurrent or persistent clear cell carcinoma (CCC). We utilized the JGOG3017/Gynecological Cancer InterGroup data to compare paclitaxel plus carboplatin (TC) and irinotecan plus cisplatin (CPT-P) in the treatment of stages I to IV CCC. METHODS: We enrolled 166 patients with recurrent or persistent CCC and assessed the impact of variables, including platinum sensitivity, treatment arm, crossover chemotherapy, primary stage, residual tumor at primary surgery, performance status, ethnicity, and tumor reduction surgery at recurrence on the median of PPS in patients with recurrent or persistent CCC. RESULTS: A total of 77 patients received TC, and 89 patients received CPT-P. The median PPS for patients with platinum-resistant disease was 10.9 months, compared with 18.8 months for patients with platinum-sensitive disease (hazard ratio [HR]=1.88; 95% confidence interval [CI]=1.30-2.72; log-rank p<0.001). In the multivariate analysis, the platinum sensitivity (resistant vs. sensitivity; HR=1.60; p=0.027) and primary stage (p=0.009) were identified as independent predictors of prognosis factors for PPS in recurrent or persistent CCC. CONCLUSIONS: Our findings revealed that platinum sensitivity and primary stage are clinical factors that significantly affect PPS in patients with recurrent or persistent CCC as well as other histologic subtypes of ovarian cancer. PPS in patients with recurrent CCC should establish the basis for future clinical trials in this population.

[A case of complex endometrial hyperplasia with atypia treated by microwave endometrial ablation].

Complex endometrial hyperplasia with atypia (CEHA) often precedes an endometrial carcinoma. A nulli-gradiva woman at high risk due to various complications underwent microwave endometrial ablation (MEA) at a frequency of 2.45 GHz for treatment of CEHA as an alternative to hysterectomy. The endometrium near the internal orifice was conserved to avoid hematometra. Endometrial biopsy specimen from the neighborhood of the internal orifice did not show any signs of endometrial hyperplasia postoperatively. Two years after the operation, endometrial biopsy revealed recurrence. The second MEA was performed. MRI one month after the second operation revealed that the uterine lining was completely replaced by avascular area without signs of regrowing endometrium or endocevix. Eighteen months have passed without recurrence.

Using a vortex mixer for testicular sperm collection.

OBJECTIVE: To evaluate 2 methods of processing testicular tissue for the retrieval of viable sperm from men with nonobstructive azoospermia. STUDY DESIGN: Fresh testicular tissue was obtained from nonobstructive azoospermia patients using a biopsy needle. The specimens were divided into 2 fractions. All specimens were minced and immersed in human tubal fluid (HTF). The first fraction was filtered through a nylon filter and incubated for 3 hours. The supernatant was centrifuged, resuspended in HTF and analyzed. The second fraction was immediately vortexed for 5 minutes and filtered through a nylon filter. The supernatant was centrifuged, resuspended in HTF and analyzed. RESULTS: Spermatozoa were obtained in 13 of 24 cases (54.2%) using the vortex method and in 5 of 24 cases (20.8%) with the nylon filter method. CONCLUSION: The vortex mixing method may be a better option than the conventional method for processing testicular tissue for sperm collection.

Promotion of human blastocyst formation by red cell hemolysate.

Recently, blastocyst transfer has been increasingly performed to improve the implantation rate achieved by in vitro fertilization and embryo transfer. This has created the need for new culture methods to improve in vitro blastulation. Culture with erythrocyte hemolysate promotes the development of early mouse embryos due to an antioxidant effect. The present study investigated whether erythrocyte hemolysate could also promote blastulation of human embryos. Eighty surplus embryos were obtained from 15 patients who gave informed consent. These embryos were cultured for 2 to 7 days after oocyte retrieval in medium with or without erythrocyte hemolysate. Blastocyst formation was observed in 53% and 28% of the embryos grown in hemolysate-supplemented and control cultures, respectively. The blastulation rate was significantly higher in hemolysate-supplemented culture than in control group (p = 0.02). These results suggest that culture medium supplemented with erythrocyte hemolysate may promote the blastulation of human embryos.

Expression and distribution of cyclooxygenase-2 in human ovary during follicular development.

Prostaglandins play important roles for oocyte maturation and follicular rupture. Cyclooxygenase-2 (COX-2), an inducible isoform of a prostaglandin metabolic enzyme, is essential for the timed production of prostaglandins in the ovary. The aim of the present study is to examine expression and distribution of COX-2 in human ovarian follicles at each of the maturation stages. Immunohistochemical staining shows that COX-2 is expressed in the granulosa cell layer of secondary and developing follicles, but is not detected in primary and Graafian follicles. Western blotting analysis revealed the existence of COX-2 in periovulatory follicular fluid at a mean concentration of 5.6 +/- 0.6 ng/ml. COX-2 might begin to be produced at the secondary follicle stage, and once a follicle reaches the Graafian follicle stage, the production of this enzyme is stopped. After exposure to luteinizing hormone (LH) surge, follicles might resume production of COX-2, and this is secreted into the follicular fluid.

In vitro effect of dehydroepiandrosterone sulfate on steroid receptors, aromatase, cyclooxygenase-2 expression, and steroid hormone production in preovulatory human granulosa cells.

OBJECTIVE: To examine the effect of a low concentration of DHEAS on the expression of the androgen receptor, estrogen receptor alpha and beta, progesterone receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2 in human preovulatory granulosa cells, and to measure their production of steroid hormones (estrone, estradiol, progesterone, androstenedione, and testosterone). DESIGN: Analysis of cultured primary human preovulatory granulosa cells by real-time reverse-transcriptase polymerase chain reaction and assays of hormone production. SETTING: Osaka City University Postgraduate School of Medicine. INTERVENTION(S): Preovulatory granulosa cells were collected from follicular fluid obtained from patients undergoing transvaginal oocyte retrieval with ultrasound guidance. The cells were cultured in the absence or presence of a low concentration of DHEAS. Real-time reverse-transcriptase polymerase chain reaction was performed to quantify the RNA expression of the investigated genes, and steroid hormone (estrone, estradiol, progesterone, androstenedione, and testosterone) levels were measured in the culture medium. MAIN OUTCOME MEASURE(S): Changes in [1] the levels of mRNAs encoding androgen receptor, estrogen receptor alpha, estrogen receptor beta, progesterone receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2; and [2] the levels of steroid hormones (estrone, estradiol, progesterone, androstenedione, and testosterone) in the culture medium. RESULT(S): Treatment of granulosa cells with 20 ng/mL DHEAS increased the expression of androgen receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2, reduced the expression of estrogen receptor beta, and increased estrone and estradiol levels, but had no effect on progesterone, androstenedione, or testosterone levels. CONCLUSION(S): DHEAS may be an essential trigger of ovulation.

Insulin-lowering agents inhibit synthesis of testosterone in ovaries of DHEA-induced PCOS rats.

BACKGROUND: Insulin-lowering agents are reported to be useful in treating polycystic ovary syndrome (PCOS) anovulation. It has been suggested that lower insulin levels secondarily affect ovarian tissue, although the direct mechanism of action has not yet been verified. Here we investigated if these agents directly affect the ovary. METHODS: Thirty female Wister rats were studied. Six control rats were injected subcutaneously with 0.2 ml sesame oil, while 24 rats used as PCOS models were injected subcutaneously with dehydroepiandrosterone (DHEA) and divided into four groups. Six rats were injected with only DHEA, while the remaining 18 rats received metformin, pioglitazone or troglitazone. The ovaries were immunohistochemically stained with anti- testosterone and anti-17beta-HSD antibodies, and then evaluated for morphological changes. RESULTS: In the DHEA administration group, the number of atretic follicles significantly increased compared to that of control rats. The insulin-lowering agents did not improve the multicystic appearance. Serum testosterone concentrations significantly increased with DHEA administration, but the increase was inhibited by oral administration of insulin-lowering agents. Testosterone deposits in ovarian tissue were also reduced by feeding rats insulin-lowering agents. CONCLUSION: Insulin-lowering agents affected ovarian tissue by inhibiting testosterone biosynthesis in vivo.

Vascular endothelial growth factor concentrations in follicular fluid obtained from IVF-ET patients: a comparison of hMG, clomiphene citrate, and natural cycle.

PURPOSE: Evaluation of vascular endothelial growth factor (VEGF) concentrations of follicular fluid (FF) in accordance with an ovarian stimulation protocol and ovarian response. METHODS: The subjects of this study were 38 patients undergoing IVF-ET in our hospital. They were divided into three groups according to ovarian stimulation protocols; Group 1: hMG cycles (n = 19), Group 2: clomiphene citrate cycles (n = 10), Group 3: natural cycles (n = 9). They reclassified into three groups according to the number of oocytes harvested. VEGF concentration was measured in FF, employing ELISAs. RESULTS: Group 1 shows lower VEGF concentrations in FF than Group 2 or Group 3. Excluding high responders from Group 1, no difference was found among these three groups. As for the reclassified groups, group of highest number of oocytes havested showed lowest VEGF concentrations in FF. CONCLUSIONS: VEGF concentrations in FF might negatively correlate with the number of follicles, irrespective of the ovulation induction protocol.

Asymptomatic pelvic Castleman disease in an infertile woman: case report.

Castleman disease is defined as angiofollicular benign lymph node hyperplasia usually found in the mediastinum. Pelvic lymph node involvement is very rare. We now report a case of asymptomatic intrapelvic Castleman disease found by chance in an infertile woman. Transvaginal ultrasonography is very useful in diagnosing the disease. After 7 years of follow-up, the patient is free from recurrence.