Therapy-related myeloid neoplasms after treatment for ovarian cancer: A retrospective single-center case series.

OBJECTIVE: Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC). METHODS: All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs. RESULTS: Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months. CONCLUSIONS: Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis.

Suppressor-type TERT mutations associated with recurrence in ovarian clear cell carcinoma.

Several cancers harbor "enhancer-type" mutations of the telomerase reverse transcriptase (TERT) promoter for immortalization. Here, we report that 8.6% (8/93) of ovarian clear cell carcinomas (OCCCs) possess the "suppressor-type" TERT promoter mutation. The recurrence rate of OCCCs with "suppressor-type" TERT promoter mutations was 62.5% (5/8) and was significantly higher than that of the "unaffected-type" with no mutation (20.8%, 15/72) or "enhancer-type" TERT promoter mutations (7.7%, 1/13). Our findings show that the acquired suppression of TERT is closely associated with OCCC development and recurrence, indicating the need for further research on telomerase suppression in cancers.

"Welcome to OBGYN World!" A novel recruitment event for medical students organized by the Japan Society of Obstetrics and Gynecology.

"Welcome to OBGYN World!" A novel recruitment event for medical students organized by the Japan Society of Obstetrics and Gynecology. Since 2012, the number of doctors in Japan who specialize in obstetrics and gynecology has shown a decreasing trend. To increase the number of doctors majoring in obstetrics and gynecology, the Japanese Trainees in Obstetrics and Gynecology subcommittee developed a new recruitment event called Welcome to OBGYN World! (WOW!); the aim of this event was to focus on lower grades of medical students. The present report describes the content of WOW! and the results of a post-event questionnaire administered to participating students and tutors. WOW! was held online in order to avoid the risk of Coronavirus Disease 2019 infection for participants. Sixty of the 82 medical schools nationwide (73.2%) participated in this event. Overall, there were 285 participating students, ranging from first to fourth grade in medical school, and 106 tutors were involved to teach material at the event. In the post-event questionnaire survey, 97.6% (248/254) and 100% of the participants stated they now had a high degree of interest in obstetrics and gynecology and found the specialty attractive, respectively. Furthermore, 93.6% (90/94) of the tutors stated that WOW! had helped recruitment activities in their universities. Based on this outcome, members of the Japanese Trainees of Obstetrics and Gynecology subcommittee will now try to increase the number of doctors specializing in obstetrics and gynecology by holding WOW! annually.

Serum FSH as a Useful Marker for the Differential Diagnosis of Ovarian Granulosa Cell Tumors.

Background: We evaluated whether the serum hormone levels are useful in the differential diagnosis of granulosa cell tumors (GCTs), regardless of menopausal status. Methods: Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol, and progesterone were measured preoperatively in all patients (n = 471) who underwent surgery for ovarian tumors at Chiba University Hospital between 2009 and 2021. These were compared in two groups, a GCT group (n = 13) and a group with other histological types (non-GCT) (n = 458). Results: The GCT group had significantly lower serum LH and FSH (p = 0.03 and p < 0.001, respectively) and significantly higher testosterone, estradiol, and progesterone (p < 0.001, p < 0.001, and p = 0.045, respectively) than the non-GCT group. Multivariate analysis revealed that serum FSH and estradiol were significantly associated with GCT (FSH, odds ratio (OR) = 0.0046, 95% confidence interval (CI) = 0.0026−0.22, p = 0.004; estradiol, OR = 0.98, 95% CI = 0.96−0.998, p = 0.046). Receiver-operating characteristic curve analysis for GCTs showed that the area under the curve of serum FSH was 0.99, with a sensitivity of 100% and a specificity of 98%, when the cutoff level was set at 2.0 IU/L. Conclusions: Preoperative serum FSH level is an extremely useful marker for differentiating GCTs from all ovarian tumors.

Validity of the 2014 FIGO Stage IIIA1 Subclassification for Ovarian, Fallopian Tube, and Peritoneal Cancers.

BACKGROUND/AIM: The 2014 International Federation of Gynecology and Obstetrics (FIGO) classification subdivides patients with stage IIIA1 ovarian, fallopian tube, and peritoneal cancers by the greatest dimension of metastatic lymph node without supporting evidence. This study aimed to assess the validity of this subdivision. PATIENTS AND METHODS: A retrospective single-institution cohort study was performed in patients with ovarian, fallopian tube, or peritoneal cancer from 2009 to 2020. We compared outcomes between patients diagnosed with IIIA1(i) (metastasis ≤10 mm in the greatest dimension) and IIIA1(ii) (metastasis >10 mm in the greatest dimension). RESULTS: Of the 895 patients, 46 (5.1%) were classified as stage IIIA1, 20 as IIIA1(i), and 26 as IIIA1(ii). In stage IIIA1(ii), there were significantly more cases of serous carcinoma (p<0.001), and the number of positive nodes and lymph node ratio were significantly higher than those in stage IIIA1(i) (p=0.001, p=0.002). Five-year progression-free survival was 68.7% in patients with stage IIIA1(i) cancer and 58.1% in those with stage IIIA1(ii) (p=0.58). Five-year overall survival was 83.1% in patients with stage IIIA1(i) cancer and 80.2% in those with stage IIIA1(ii) (p=0.44). Among other patient characteristics and pathologic findings, there were no prognostic factors for patients with stage IIIA1 cancer. CONCLUSION: In this retrospective cohort study, further classification of FIGO stage IIIA1 cancer was not significantly associated with patient outcomes.

Highly Aggressive Surgery Benefits in Patients With Advanced Ovarian Cancer.

BACKGROUND/AIM: We investigated whether highly aggressive surgery has survival and perioperative complication benefit in patients with advanced ovarian cancer. PATIENTS AND METHODS: This retrospective study included 209 patients with stage III/IV ovarian cancer who underwent aggressive surgery [surgical complexity score (SCS) ≥8] between January 2008 and December 2018. Patients were categorized into the SCS 8-12 (less aggressive surgery, 83 patients) and SCS ≥13 (highly aggressive surgery, 126 patients) groups. Survival outcomes and perioperative complications between the groups were compared. Patient suitability for primary debulking surgery or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) was based on the evaluation of performance status, tumor load, and ascites. If patients were suitable for NACT/IDS, the residual tumor margins were marked at the initial laparotomy. The previously marked lesions were removed during IDS, even in patients with macroscopic tumor resolution. RESULTS: Prevalence rates of stage IV disease, poor performance status, presence of omental cake, peritoneal cancer index ≥15, and IDS performed were significantly higher in the highly aggressive surgery group than in the less aggressive surgery group. The median progression-free survival (PFS) and overall survival (OS) were not significantly different between the groups (PFS, 32 and 31 months, respectively; p=0.622; OS, 99 and 75 months, respectively; p=0.390). The incidence of severe perioperative complications was not significantly different between the less aggressive group (4.8%) and the highly aggressive surgery group (6.4%) (p=0.767). CONCLUSION: Highly aggressive surgery with appropriate selection regardless of the timing of cytoreduction benefits patients with advanced ovarian cancer.

Influence of Estradiol-Producing Ovarian Tumors on the Maturation Index of Cervical Cytology in Postmenopausal Women.

INTRODUCTION: The aim of the study was to evaluate the influence of estradiol-producing ovarian tumors, including surface epithelial-stromal tumors, on the cervical cytology of postmenopausal women. METHODS: This case-controlled study included 160 postmenopausal women who underwent a gynecological surgery between January 2009 and December 2016. The relationship between serum estradiol levels and the maturation index of cervical cytology was examined. Patients with ovarian tumors and a high estradiol level (≥28 pg/mL) constituted the estradiol-producing ovarian tumor group (30 women, including 23 with surface epithelial-stromal tumors). The maturation index of this group was compared with that of the control group (130 women with normal estradiol levels [<28 pg/mL] with either ovarian tumors or uterine tumors). RESULTS: For all patients, the serum estradiol levels were significantly correlated with the maturation index (p < 0.001, r = 0.65). The maturation index of the estradiol-producing ovarian tumor group was significantly higher than that of the control group (0.67 ± 0.21 vs. 0.075 ± 0.16, p < 0.001). The area under the receiver operating characteristic curve for the maturation index was 0.94. The best maturation index cut-off level for estradiol-producing ovarian tumors was 0.20. Using this cut-off, the sensitivity and specificity were 94% and 82%, respectively. CONCLUSION: Estradiol-producing ovarian tumors influence cervical epithelial maturation in postmenopausal women. An increased maturation index may trigger the early detection of asymptomatic ovarian tumors.

Bevacizumab-based Salvage Chemotherapy Improves Survival Outcomes for Patients With Brain Metastasis from Ovarian Cancer.

BACKGROUND/AIM: Brain metastases from ovarian cancer remain rare and the appropriate treatment is unknown. We investigated survival outcomes following salvage chemotherapy before and after bevacizumab approval to evaluate the efficacy of bevacizumab in patients with brain metastasis from ovarian cancer. PATIENTS AND METHODS: We investigated 23 consecutive patients with brain metastasis from ovarian cancer at our hospital between 2001 and 2020. Bevacizumab was administered for treating ovarian cancer after approval in Japan in November 2013. Survival after brain metastasis was compared between 9 patients treated before bevacizumab approval (2000-2013) and 14 patients treated after approval (2014-2020). Seven patients treated in the latter period received bevacizumab-salvage chemotherapy for brain metastasis. RESULTS: Median survival in all patients was 9.1 months [95% confidence interval (CI)=4.2-33.5]. In addition, patients treated during the latter period presented better survival outcomes than those treated in the former period (former, 2.9 months vs latter, 33.5 months, log-rank test, p=0.015; Wilcoxon test, p=0.009). Multivariate analysis revealed that bevacizumab addition (p=0.020), interval to brain metastasis (p=0.005), number of brain lesions (p=0.001), number of recurrences (p=0.001), and platinum sensitivity (p=0.028) were independently associated with survival in all cohorts. CONCLUSION: Bevacizumab-based salvage chemotherapy may improve survival outcomes in patients with brain metastasis.

Predictors of postoperative pancreatic fistula after splenectomy with or without distal pancreatectomy performed as a component of cytoreductive surgery for advanced ovarian cancer.

OBJECTIVE: Splenectomy with or without distal pancreatectomy is occasionally performed during cytoreductive surgery for advanced ovarian cancer. We investigated pre-, intra-, postoperative risk factors and predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in patients who underwent cytoreductive surgery for advanced ovarian cancer. METHODS: We investigated 165 consecutive patients with ovarian, fallopian tube, and peritoneal carcinoma categorized as stage III/IV disease, who underwent splenectomy with or without distal pancreatectomy as a component of cytoreductive surgery performed as initial treatment at Chiba University Hospital. Patient characteristics, clinical factors, and surgical outcomes were compared between those with and without CR-POPF. RESULTS: CR-POPF occurred in 20 patients (12%). There were no significant intergroup differences in the characteristics between patients with CR-POPF and patients without CR-POPF except for operative time, intraoperative blood loss, amylase (AMY) levels in drain fluid on postoperative day (POD)1 and POD3, and pancreatic stump thickness. Multivariate analysis showed that the POD3 drain fluid AMY level was the only significant risk factor and predictor of CR-POPF in patients who underwent cytoreductive surgery for advanced ovarian cancer. The receiver operating characteristic curve of the POD3 drain fluid AMY level, which predicted development of CR-POPF showed an area under the curve of 0.77, and the optimal cut-off value of AMY was 808 U/L. A pancreatic fistula did not occur in patients with POD3 drain fluid AMY levels <130 U/L. CONCLUSION: The POD3 drain fluid AMY level can be early diagnostic predictor CR-POPF after splenectomy with or without distal pancreatectomy for advanced ovarian cancer.

Surgical Techniques and Outcomes of Colorectal Anastomosis after Left Hemicolectomy with Low Anterior Rectal Resection for Advanced Ovarian Cancer.

Extended colon resection is often performed in advanced ovarian cancer. Restoring intestinal continuity and avoiding stoma creation improve patients' quality of life postoperatively. We tried to minimize the number of anastomoses, restore intestinal continuity, and avoid stoma creation for 295 patients with stage III/IV ovarian cancer who underwent low anterior rectal resection (LAR) with or without colon resection during cytoreductive surgery. When the remaining colon could not reach the rectal stump after left hemicolectomy with LAR, we used the following techniques for tension-free anastomosis: right colonic transposition, retro-ileal anastomosis through an ileal mesenteric defect, or an additional colic artery division. Rates of stoma creation and rectal anastomotic were 3% (9/295) and 6.6% (19/286), respectively. Among 21 patients in whom the remaining colon did not reach the rectal stump after left hemicolectomy with LAR, 20 underwent tension-free anastomosis, including eight, six, and six patients undergoing right colonic transposition, retro-ileal anastomosis through an ileal mesenteric defect, and an additional colic artery division, respectively. Colorectal anastomosis is feasible for patients with extended colonic resection. Low anastomotic leakage and stoma rates can be achieved with careful attention to colonic mobilization and tension-free anastomosis.

Bevacizumab in First-Line Chemotherapy Improves Progression-Free Survival for Advanced Ovarian Clear Cell Carcinoma.

(1) Background: We investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab (Bev) for ovarian cancer in Japan to evaluate the efficacy of Bev for advanced clear cell carcinoma (CCC). (2) Methods: We investigated 28 consecutive patients diagnosed with CCC (stages III/IV) at our hospital between 2008 and 2018. Bev was administered for treatment of advanced CCC after approval in Japan in November 2013. Progression-free survival (PFS) was compared between 10 patients treated before Bev approval (2008-2013, Bev- group) and 18 patients treated after Bev approval (2014-2018, Bev+ group) for first-line chemotherapy. (3) Results: No intergroup difference was observed in patient characteristics. The rate of completeness of resection was higher in the Bev - group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev + group received ≥ 21 cycles of Bev. The median PFS increased from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), Bev administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for PFS. (4) Conclusions: Bev incorporated into first-line chemotherapy might improve PFS in patients with advanced CCC. We hope that our findings will be confirmed in adequate clinical trials.

Introduction of rectosigmoid colectomy improves survival outcomes in early-stage ovarian cancer patients.

BACKGROUND: To investigate whether rectosigmoid colectomy can improve the prognosis of patients with early-stage ovarian cancer when the ovarian tumor adheres to the rectum. METHODS: We retrospectively studied 210 consecutive patients with stage I/II ovarian cancer treated between 2000 and 2016. The surgical strategy differed between the periods 2000-2007 and 2008-2016 with respect to adhesion between the ovarian tumor and rectum. In the former period, ovarian tumor was exfoliated from the rectum. Only when the residual tumor was apparently observed on the rectal surface after salpingo-oophorectomy with hysterectomy, it was subsequently removed by colorectal surgeons performing rectosigmoid colectomy. In the latter period, the ovarian tumor was resected en bloc with the rectum by performing rectosigmoid colectomy. We compared the progression-free survival (PFS) between the two treatment periods. RESULTS: Rectosigmoid colectomy was performed more frequently in the latter period than in the former period (43 patients, 31% vs. 6 patients, 8%, p < 0.001). There was no significant difference in complete resection rate between the two periods (97% in the former period, 99% in the latter period, p = 0.278). However, the 5-year PFS rate was significantly higher in the latter period than in the former period (86.0% vs. 74.4%, log-rank test, p = 0.034). Multivariate Cox proportional-hazards regression analysis indicated that disease stage (hazard ratio [HR], 2.87, 95% confidence interval [CI] 1.14-7.34) and treatment period (HR 0.32, 95% CI 0.14-0.73) were independent risk factors for recurrence. CONCLUSIONS: Rectosigmoid colectomy could improve the prognosis of patients with early-stage ovarian cancer when the ovarian tumor adheres to the rectum.

Safety and Efficacy of Weekly Paclitaxel and Cisplatin Chemotherapy for Ovarian Cancer Patients with Hypersensitivity to Carboplatin.

BACKGROUND: This study aimed to evaluate the safety and efficacy of weekly paclitaxel and cisplatin chemotherapy (wTP) in patients with ovarian cancer who developed carboplatin hypersensitivity reaction (HSR). METHODS: We retrospectively investigated 86 patients with ovarian, fallopian tube, and peritoneal carcinoma who developed carboplatin HSR during previous chemotherapy (carboplatin and paclitaxel) at our institution between 2011 and 2019. After premedication was administered, paclitaxel was administered over 1 h, followed by cisplatin over 1 h (paclitaxel 80 mg/m2; cisplatin 25 mg/m2; 1, 8, 15 day/4 weeks). We investigated the incidence of patients who successfully received wTP for at least one cycle, treatments compliance, progression-free survival (PFS), and overall survival (OS). RESULTS: The median number of wTP administration cycles was 4 (Interquartile Range IQR, 3-7), 71 patients (83%) successfully received wTP, and 15 patients (17%) developed cisplatin HSR. The efficacy of treatment was as follows: 55 (64%) patients completed the scheduled wTP, 9 (10%) patients discontinued due to HSR to cisplatin within 6 cycles, 1 (1%) patient discontinued due to renal toxicity (grade 2) at the 6th cycle, and 21 (24%) patients discontinued due to progressive disease within 6 cycles. The median PFS and OS after administration of wTP were 10.9 months (95% CI: 7.7-17.7) and 25.9 months (95% CI: 19.0-50.2), respectively. CONCLUSIONS: wTP was safe and well-tolerated in patients who developed carboplatin HSR.

Tailored-dose chemotherapy with gemcitabine and irinotecan in patients with platinum-refractory/resistant ovarian or primary peritoneal cancer: a phase II trial.

OBJECTIVE: We investigated the efficacy and toxicity of tailored-dose chemotherapy with gemcitabine and irinotecan for platinum-refractory/resistant ovarian or primary peritoneal cancer. METHODS: We enrolled patients with ovarian or primary peritoneal cancer who received ≥2 previous chemotherapeutic regimens but developed progressive disease during platinum-based chemotherapy or within 6 months post-treatment. All patients received gemcitabine (500 mg/m²) and irinotecan (50 mg/m²) on days 1 and 8 every 21 days at the starting dose. The dose was increased or decreased by 4 levels in subsequent cycles based on hematological or non-hematological toxicities observed. The primary endpoint was progression-free survival (PFS), and secondary endpoints were disease control rate (DCR), overall survival (OS), and adverse events. RESULTS: We investigated 25 patients who received 267 cycles (median 8 cycles/patient) between October 2008 and May 2011. Tailored-dose gemcitabine was administered up to the 5th cycle as follows: 1,000 mg/m² in 1 (4%), 750 mg/m² in 16 (64%), 500 mg/m² in 6 (24%), and 250 mg/m² in 2 patients (8%). The median PFS and OS were 6.2 months (95% confidence interval [CI]=2.7-10.7) and 16.8 months (95% CI=9.4-30.7), respectively. The DCR was 76%, and PFS was >6 months in 12 of 25 patients (48%). Grade 3 hematological toxicities included leukopenia (9.4%), neutropenia (11.2%), anemia (9.8%), and thrombocytopenia (1.1%). Grade 3/4 non-hematological toxicities did not occur except for fatigue in one patient. CONCLUSIONS: Tailored-dose chemotherapy with gemcitabine and irinotecan was effective and well tolerated in patients with platinum-refractory/resistant ovarian or primary peritoneal cancer. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier: UMIN000004449.