Can Endometrial Cytology Identify Patients Who Would Benefit from Immunotherapy?

INTRODUCTION: Patients with polymerase epsilon (POLE) mutation (POLEmut) subtype, MMR-deficient (MMR-d) subtype as classified by The Cancer Genome Atlas (TCGA), and a high tumor mutation burden (TMB-high) potentially benefit from immunotherapy. However, characteristics of the cytological morphology within these populations remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded tissues was subjected to next-generation sequencing analysis. Genomic mutations related to gynecological cancers, TMB, and microsatellite instability were analyzed and were placed in four TCGA classification types. The following morphological cytological investigations were conducted on endometrial cancer using a liquid-based preparation method, prior to the commencement of initial treatment: (i) cytological backgrounds; (ii) differences between each count of neutrophils and lymphocytes as described below. RESULTS: Insignificant differences in the cytological background patterns of TCGA groups and TMB status were found. Although there was no significant difference in neutrophil count (p = 0.955) in the TCGA groups, POLEmut and MMR-d had significantly higher lymphocyte counts than no specific molecular profile (NSMP) (p = 0.019 and 0.037, respectively); furthermore, p53mut also tended to be significant (p = 0.064). Lymphocyte counts in TMB-high were also significantly greater than TMB-low (p = 0.002). POLEmut showed a positive correlation between TMB levels and lymphocyte counts. For predicting patients with POLEmut plus MMR-d, lymphocyte counts demonstrated a superior diagnostic accuracy of area under the curve (AUC) (0.70, 95% CI: 0.57-0.84), with a cutoff value of 26 high-power field. CONCLUSION: Lymphocyte count using liquid-based cytology for patients with endometrial cancer may predict POLEmut plus MMR-d of TCGA groups and TMB-high in those who can benefit from immunotherapy.

The first report of surgery for gynecological diseases using the hinotori™ surgical robot system.

OBJECTIVE: This study aimed to report the first surgery for gynecological diseases using a new robotic platform, the hinotori™, and validate its feasibility in clinical settings. METHODS: The world's first robot-assisted total hysterectomy for a gynecological ailment was carried out at Kagoshima University Hospital in December 2022 utilizing the hinotori™ surgical robot system. Eleven other patients then underwent comparable procedures. The surgical team was certified to execute the procedure and had undergone official hinotori™ training. RESULTS: Preoperative diagnoses indicated five cases of endometrial cancer, four cases of uterine myoma and one case each of atypical endometrial hyperplasia, uterine adenosarcoma and high-grade cervical intraepithelial neoplasia. Median age and body mass index were 51 (range: 38-70) years and 26.9 (range: 17.3-33.3) kg/m2, respectively. Median roll-in, cockpit and operation times were 15 (range: 10-18), 161 (range: 110-225) and 214 (range: 154-287) min, respectively. The median blood loss was 22 (range: 7-83) mL and conversion to laparotomy was not allowed. Only one patient had postoperative pelvic region infection. The median length of hospital stay was 6 (range: 4-10) days. CONCLUSION: Based on our experience with presented 12 cases, robotic surgery with the hinotori™ is a feasible technique of minimally invasive surgery for gynecological diseases.

Validation of single-photon emission computed tomography with computed tomography and lymphoscintigraphy for sentinel lymph node identification in cervical cancer.

OBJECTIVE: To compare single-photon emission computed tomography with computed tomography (SPECT/CT) and lymphoscintigraphy (LSG) for the detection of sentinel lymph nodes (SLNs) in patients with early-stage cervical cancer. METHODS: This hospital-based, single-center, retrospective study included 128 patients with cervical cancer (aged >18 years) treated between 2014 and 2022. Injection of 99 m Technetium-labeled phytate into the uterine cervix was used to detect pelvic SLNs. SNL identification rates and locations were analyzed for preoperative LSG and SPECT/CT. RESULTS: Median age and body mass index of patients were 40 years (range, 20-78 years) and 21.7 kg/m2 (range, 16-40 kg/m2 ), respectively. There was no significant difference in overall identification rates (identification of at least one SLN) of SLNs between SPECT/CT (91%) and LSG (88%). There was no significant difference in bilateral SLN identification rates between SPECT/CT (66%) and LSG (65%). A total of 219 pelvic SLNs (110 right and 109 left hemipelvis) were identified by SPECT/CT; the most frequent locations were the obturator (122 SLNs, 56%) and external iliac (67 SLNs, 30%). CONCLUSION: SPECT/CT and LSG showed high SLN identification rates in patients with cervical cancer, and there was no significant difference in overall or bilateral SLN identification rates between the two techniques.

Efficacy and prognosis of robotic surgery with sentinel node navigation surgery in endometrial cancer.

OBJECTIVE: This study aimed to validate the surgical and oncologic outcomes of robotic surgery with sentinel node navigation surgery (SNNS) in endometrial cancer. METHODS: This study included 130 patients with endometrial cancer, who underwent robotic surgery, including hysterectomy, bilateral salpingo-oophorectomy, and pelvic SNNS at the Department of Obstetrics and Gynecology of Kagoshima University Hospital. Pelvic sentinel lymph nodes (SLNs) were identified using the uterine cervix 99m Technetium-labeled phytate and indocyanine green injections. Surgery-related and survival outcomes were also evaluated. RESULTS: The median operative and console times and volume of blood loss were 204 (range: 101-555) minutes, 152 (range: 70-453) minutes, and 20 (range: 2-620) mL, respectively. The bilateral and unilateral pelvic SLN detection rates were 90.0% (117/130) and 5.4% (7/130), respectively, and the identification rate (the rate at which at least one SLN could be identified on either side) was 95% (124/130). Lower extremity lymphedema occurred in only 1 patient (0.8%), and no pelvic lymphocele occurred. Recurrence occurred in 3 patients (2.3%), and the recurrence site was the abdominal cavity, with dissemination in 2 patients and vaginal stump in one. The 3-year recurrence-free survival and 3-year overall survival rates were 97.1% and 98.9%, respectively. CONCLUSION: Robotic surgery with SNNS for endometrial cancer showed a high SLN identification rate, low occurrence rates of lower extremity lymphedema and pelvic lymphocele, and excellent oncologic outcomes.

Cytopathological features associated with POLE mutation in endometrial cancer.

OBJECTIVE: For patients with endometrial cancer, the POLE (polymerase epsilon) mutation (POLEmut)-subtype, one of four molecular-analysis-based categories in the Cancer Genome Atlas (TCGA), has the best prognosis. The following histological characteristics are typically observed in endometroid carcinoma cases with the POLEmut-subtype: (1) the presence of tumour giant cells, (2) numerous tumour-infiltrating lymphocytes (TILs) and/or peri-tumoral lymphocytes, and (3) a high grade. However, in the context of cytology, the morphological characteristics of this subtype remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues was subjected to next-generation sequencing analysis and categorised according to the TCGA classifications. Genomic mutation, tumour mutation burden (TMB), and microsatellite instability were also assessed. Cytological specimens of resected uteri obtained using the Papanicolaou method were histologically separated into three types. RESULTS: Seven out of 112 patients (6%) with endometrial cancer were diagnosed with the POLEmut-subtype between January 2019 and August 2021. Tumour giant cells were observed in three cases (43%) on histology and cytology. TIL and/or peritumoral lymphocytes with inflammatory cells were detected in five cases (71%) on histology and three cases (43%) on cytology. Cases in which these three characteristics were observed on both cytology and histology may have belonged to the POLEmut-subtype. There were no cases in which these characteristics were absent on histology but present on cytology. TMB tended to be higher in cases when the three characteristics were observed in both cytological and histological findings. CONCLUSIONS: Preoperative endometrial cytology highlighted the characteristics of the POLEmut-subtype in the histological analysis of resected uterine specimens and has the potential to play an important role in treatment decisions.

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial.

BACKGROUND: The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. METHODS: Patients with previously untreated stage III-IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. RESULTS: Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18-1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. CONCLUSIONS: Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

Metastatic Leiomyoma Following Menopause: A Case Report and Review of Literature.

Uterine leiomyomas commonly reduce naturally after menopause. We report a rare case of metastasizing leiomyoma that grew after surgical menopause. A 68-year-old woman suffered from pelvic and lung masses without clinical symptoms. Nineteen years ago, she underwent a total hysterectomy and bilateral adnexectomy for multiple uterine myomas and bilateral endometriotic cysts. She has since been regularly prescribed conjugated estrogens. Surgery was scheduled in order to rule out malignancy; abdominal masses resection and thoracoscopic left partial pulmonary resection (S3, S4, S10) were performed. The histological diagnosis was leiomyoma in both abdominal and lung masses, and there was no evidence of gene mutations, which suggested that leiomyosarcoma was indicated. This case may indicate that hormone replacement was augmented via derived nutrient vessels after a surgical ovarian absence.

Comparison of radio-isotope method with 99m technetium and near-infrared fluorescent imaging with indocyanine green for sentinel lymph node detection in endometrial cancer.

BACKGROUND: We aimed to compare the detection rate of pelvic sentinel lymph node between the radio-isotope with 99m technetium (99mTc)-labeled phytate and near-infrared fluorescent imaging with indocyanine green in patients with endometrial cancer. METHODS: This study included 122 patients who had undergone sentinel lymph node mapping using 99mTc and indocyanine green. In the radio-isotope method, sentinel lymph nodes were detected using uterine cervix 99mTc injections the day before surgery. Following injection, the number and locations of the sentinel lymph nodes were evaluated by lymphoscintigraphy. In addition, indocyanine green was injected into the cervix immediately before surgery. RESULTS: The overall pelvic sentinel lymph node detection rate (at least one pelvic sentinel lymph node detected) was not significantly different between 99mTc (95.9% [117/122]) and indocyanine green (94.3% [115/122]). Similarly, the bilateral sentinel lymph node detection rate was not significantly different between 99mTc (87.7% [107/122]) and indocyanine green (79.5% [97/122]). More than two sentinel lymph nodes per unilateral pelvic lymph node were found in 12.3% (15/122) and 27% (33/122) of cases with 99mTc and indocyanine green, respectively, in the right pelvic side, and 11.5% (14/122) and 32.8% (40/122) of cases with 99mTc and indocyanine green, respectively, in the left pelvic side. indocyanine green showed that there were significantly more than two sentinel lymph nodes in either the left or right pelvic sentinel lymph nodes (P < 0.0001). There was a significant difference in the mean number of total pelvic sentinel lymph nodes between 99mTc (2.2) and indocyanine green (2.5) (P = 0.028) methods. CONCLUSION: Although indocyanine green is useful for sentinel lymph node identification, we believe it is better to use it in combination with 99mTc until the surgeon is accustomed to it.

The importance of choosing the right strategy to treat small cell carcinoma of the cervix: a comparative analysis of treatments.

BACKGROUND: Standard treatments for small cell carcinoma of the cervix (SCCC) have not been established. In this study, we aimed to estimate the optimal treatment strategy for SCCC. METHODS: This was a multicenter retrospective study. Medical records of patients with pathologically proven SCCC treated between 2003 and 2016 were retrospectively analyzed. Overall survival (OS) was plotted using the Kaplan-Meier method. Log-rank tests and Cox regression analysis were used to assess the differences in survival according to stage, treatment strategy, and chemotherapy regimen. RESULTS: Data of 78 patients were collected, and after excluding patients without immunohistopathological staining, 65 patients were evaluated. The median age of the included patients was 47 (range: 24-83) years. The numbers of patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 stages I-IIA, IIB-IVA, IVB were 23 (35%), 34 (52%), and 8 (12%), respectively. Of 53 patients who had undergone chemotherapy, 35 and 18 received SCCC and non-SCCC regimens as their first-line chemotherapy regimen, respectively. The 5-year OS for all patients was 49%, while for patients with FIGO stages I-IIA, IIB-IVA, IVB, it was 60, 50, and 0%, respectively. The 5-year OS rates for patients who underwent treatment with SCCC versus non-SCCC regimens were 59 and 13% (p < 0.01), respectively. This trend was pronounced in locally advanced stages. Multivariate analysis showed that FIGO IVB at initial diagnosis was a significant prognostic factor in all patients. Among the 53 patients who received chemotherapy, the SCCC regimen was associated with significantly better 5-year OS in both the uni- and multivariate analyses. CONCLUSION: Our results suggest that the application of an SCCC regimen such as EP or IP as first-line chemotherapy for patients with locally advanced SCCC may play a key role in OS. These findings need to be validated in future nationwide, prospective clinical studies.

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA).

PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BACKGROUND: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT). METHODS: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared. RESULTS: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort. CONCLUSION: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.

Efficacy of 5-aminolevulinic acid and LED photodynamic therapy in cervical intraepithelial neoplasia: A clinical trial.

BACKGROUND: 5-Aminolaevulinic acid (5ALA) is a precursor of the strong sensitizer protoporphyrin IX (PpIX) in the heme synthesis pathway. We conducted aclinical trial designed to evaluate the efficacy and safety of 5ALA photodynamic therapy (PDT) using a light-emitting diode (LED) in patients with cervical intraepithelial neoplasia (CIN). METHODS: Data for 51 CIN patients who underwent 5ALA-PDT between 2012 and 2017 were prospectively analysed. After a 20 % 5ALA jelly formulation was topically applied to the cervix, the region was irradiated with red light at approximately 633 nm to excite PpIX for treatment. We estimated outcomes by cytology, pathology, and human papilloma virus (HPV) testing after PDT. RESULTS: Patients underwent two PDT sessions at one-week intervals during outpatient treatment and achieved favourable results without photosensitivity and severe adverse events. Over a long follow-up period, 96.1 % of all patients showed some positive effects, including approximately 70 % with a complete response (CR), 10 % with a partial response, and 15 % with downgrades. The HPV clearance rate in patients with CR was 79.4 %. Recurrence occurred in five patients who mostly remained HPV-positive after PDT. CONCLUSIONS: Based on our study, topical 5ALA-PDT using an LED light source potentially represents a safe treatment for CIN on an outpatient basis.

Development of the Daily Time Management Scale for Use by Working People with Type 2 Diabetes.

AIM: The purpose of this study was to develop a scale to assess daily time management capabilities among working patients with diabetes and to test this scale's reliability and validity. METHODS: A self-administered questionnaire survey was conducted among 277 diabetes outpatients, and data from 220 participants (mean age = 54.3 ± 10.2 years, 76.8% male) were analyzed. Questionnaire items were selected through exploratory factor analysis. During the process of developing the questionnaire, opinions were solicited from experts on education for patients with diabetes, and Cronbach's α was calculated as a coefficient of reliability. Correlations with the Instrument of Diabetes Self-Care Agency (IDSCA) were examined and confirmatory factor analysis was performed to check for validity. RESULTS: Adequacy of a 4-factor, 16-item scale was confirmed. Cronbach's α coefficient was ≥.7 for the entire scale and for the subscale items. There was a significant correlation between total IDSCA scores and various factors (r = .280-.469). However, there was no correlation between the "adjustment of life rhythms" and parts of the IDSCA subscale. CONCLUSION: Although some aspects warrant further investigation, the developed scale provides a reliable and valid means of assessing daily time management capabilities among working patients with diabetes, and can thus be applied to help diabetes patients to manage their daily lives.

Analysis of the relapse patterns and risk factors of endometrial cancer following postoperative adjuvant chemotherapy in a phase III randomized clinical trial.

OBJECTIVE: This study was to analyze patterns and risk factors of relapse after postoperative adjuvant chemotherapy for endometrial cancer. METHODS: Among patients enrolled in a randomized phase III trial (JGOG2043) investigating the efficacy of adjuvant chemotherapy for endometrial cancer at a high risk of progression, the recurrent patients were studied. Clinical information were collected, and correlation between relapse-related factors and clinicopathological factors were analyzed. RESULTS: Among 193 patients analyzed, 50% had local relapse and 63% had distant relapse. Local relapse involved regional lymph nodes in 30%, while distant relapse involved the abdominal cavity in 42%. Imaging was used to confirm relapse in 83%, and the median disease-free interval (DFI) was 11.5 months. Factors showing a significant correlation with DFI ≤12 months were residual tumor at surgery (p < 0.01), Grade 3 histology (p < 0.01), and lymph node metastasis (p = 0.03). In contrast, treatment with paclitaxel and carboplatin showed a significant correlation with DFI >12 months (p = 0.04). The median post-relapse overall survival (RS) was 23.9 months. In multivariate analysis, CA125 ≥ 100 U/mL prior to relapse (p < 0.01), distant metastasis (p < 0.01), DFI ≤ 12 months (p = 0.02), and not performing para-aortic lymphadenectomy (p = 0.01) were independently related to poor RS. CONCLUSIONS: Relapse of endometrial cancer following adjuvant chemotherapy often occurs by 1 year after treatment, with common relapse sites of the abdominal cavity and regional lymph nodes. Among treatment-related factors, RS was correlated with DFI and para-aortic lymphadenectomy.

Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

Epidemiological overview of metastatic ovarian carcinoma: long-term experience of TOTSG database.

Malignant ovarian neoplasm is one of the most lethal malignancies among cancers of the female reproductive system. Occasionally, these tumors originate from non-ovarian organs as metastatic lesions since the ovary is a frequent metastatic target of many cancers. However, there limited clinical information on metastatic ovarian carcinoma (MOC) and its hallmarks are unknown. During the period of 1986-2015, 4,284 patients with malignant ovarian neoplasm were identified using the Tokai Ovarian Tumor Study Group (TOTSG) database. Of these, excluding borderline malignant tumor, 3,478 patients with malignant ovarian cancer were extracted. The pathological slides were evaluated under central pathological review. Among them, a total of 143 (4.1%) patients with MOC were identified. The median age of patients with MOC was 54 (29-82) years. The most and second most frequent original tumors were colorectal (43%, N=62) and gastric (29%, N=42) carcinoma, respectively. The rates of carcinoma of the appendix, breast, and pancreas were 8, 6, and 4%, respectively. This is the one of the largest studies clarifying the rates of MOC among malignant ovarian neoplasms. Although the rate is low, we should keep in mind that MOC, particularly from colorectal and gastric cancer should be considered when encountering clinical practice of ovarian cancer.

Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial.

IMPORTANCE: The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. OBJECTIVE: To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. INTERVENTIONS: Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. RESULTS: Among 788 eligible patients, the median (SD) age was 59 (22-74) years; 263 patients were assigned to doxorubicin plus cisplatin treatment, 263 patients to docetaxel plus cisplatin treatment, and 262 patients to paclitaxel plus carboplatin treatment. The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. CONCLUSIONS AND RELEVANCE: There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. TRIAL REGISTRATION: UMIN-CTR identifier: UMIN000000522.

Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium.

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.

Net Survival of Elderly Patients with Gynecological Cancer Aged Over 75 Years in 2006-2008

Background: The number of elderly patients with gynecological cancer in Japan is increasing in line with the aging of society. However, little has been reported on the survival of elderly patients aged 75 or older with gynecological cancer in Japan. Methods: To clarify survival in women aged 75 years or older with gynecological cancer, we analyzed data of 4,089 gynecological cancer cases (cervical cancer, 1,309 cases; endometrial cancer, 1,319 cases; and ovarian cancer, 1,461 cases) in patients aged 75 or older from 21 population-based cancer registries in Japan, diagnosed in 2006-2008. We calculated the net survival (NS) of younger (75-79 years old), older (80-84 years old) and the oldest age group (85-99 years old). We also calculated NS stratified by extent of disease and histological type. Results: Five-year NS of cervical cancer patients was 54.5% in the younger age group, 40.8% in the older age group and 28.2% in the oldest age group. Five-year NS of endometrial cancer patients was 64.5%, 51.6% and 39.0% in the younger, older and oldest age groups, respectively. Five-year NS of ovarian cancer was 34.7%, 18.8% and 8.3%, respectively. Conclusion: We estimated NS in elderly patients aged 75 years or older with gynecological cancers in Japan using data from population-based cancer registries.