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PURPOSE To investigate the efficacy and safety of trastuzumab deruxtecan, an antibody-drug conjugate targeting human epidermal growth factor receptor 2 (HER2) with a topoisomerase I inhibitor payload, in patients with uterine carcinosarcoma (UCS) expressing HER2. PATIENTS AND METHODS Patients with recurrent UCS with HER2 immunohistochemistry scores ≥1+ previously treated with chemotherapy were included. Patients were assigned to the HER2-high (immunohistochemistry score ≥2+; n = 22) or low (immunohistochemistry score of 1+; n = 10) groups for primary and exploratory analyses, respectively. Trastuzumab deruxtecan 6.4 or 5.4 mg/kg was administered intravenously once every 3 weeks until unacceptable toxicity or disease progression. Dose modification was based on the updated recommended phase II dose for breast cancer to be 5.4 mg/kg. The primary end point was the objective response rate by central review in the HER2-high group. Secondary end points included the overall response rate (ORR) in the HER2-high group by investigator assessment, ORR in the HER2-low group, progression-free survival (PFS), overall survival (OS), and safety. RESULTS The ORR by central review in the HER2-high and HER2-low groups were 54.5% (95% CI, 32.2 to 75.6) and 70.0% (95% CI, 34.8 to 93.3) and those by investigator assessments were 68.2% and 60.0%, respectively. The median PFS and OS in the HER2-high and HER2-low groups were 6.2 and 13.3 months and 6.7 months and not reached, respectively. Grade ≥ 3 adverse events occurred in 20 patients (61%). Grades 1-2 and 3 pneumonitis/interstitial lung disease occurred in eight (24%) and one (3%) patient, respectively. CONCLUSION Trastuzumab deruxtecan has efficacy in patients with UCS, regardless of HER2 status. The safety profile was generally consistent with that previously reported. Toxicities were manageable with appropriate monitoring and treatment.

New treatments, particularly second-line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody-drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single-arm, open-label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non-Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1-2 prior lines of therapy. In part 1, no dose-limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment-emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non-Japanese patients.

Pan-cancer analysis across The Cancer Genome Atlas has revealed the molecular profiles of major types of carcinomas. High-grade serous carcinomas (HGSCs) have been characterized; however, in ovarian cancer, the profile of carcinoma with minor histopathological changes remains unclear. This study aimed to perform the molecular profiling of rare malignant ovarian tumors, including non-epithelial tumors (NETs; germ cell tumors and sex cord tumors) and clear cell carcinoma (CCC), to determine how they differ from the major HGSCs.Sixty-nine malignant ovarian tumors surgically resected at the Shizuoka Cancer Center between January 2014 and March 2019 were classified based on their histopathological types. The germline and somatic mutations in these carcinomas, including NETs, were determined using next-generation sequencing. Gene expression analysis was performed to investigate the major pathways of drug resistance, which is a characteristic of CCC.NETs harbored copy-neutral loss of heterozygosity, accompanied by a high homologous recombination deficiency score; germline mutations of PALB2 and BARD1 were identified in two patients with NET. In chemoresistant CCC, the epithelial-mesenchymal transition pathway was activated regardless of ABC transporter expression.This study revealed some genomic characteristics of rare malignant ovarian tumors, including NETs and CCC.

This multicenter, open-label, phase II study aimed to evaluate the efficacy and safety of paclitaxel-carboplatin, bevacizumab, and bevacizumab-based maintenance therapy for metastatic, recurrent, and persistent uterine cervical cancer.Patients with measurable diseases that were not adapted to regional therapies, such as surgery or radiotherapy, and were systematic chemotherapy-naïve were eligible. The participants received paclitaxel (175 mg/mSixty-nine patients were analyzed using our protocol. The median paclitaxel- carboplatin therapy duration was six cycles; 40% of patients received bevacizumab maintenance therapy. The median PFS was 11.3 months. The median OS was not reached; the median time to treatment failure was 5.9 months. The ORR was 79.7% [95% confidence interval (CI) 63.8-88.4]; 16 patients (23.2%) showed complete response (CR) and 39 patients (56.5%) showed partial response (PR). The median PFS was 14.3 months (95% CI 7.3-17 months) for the 25 patients who received maintenance therapy and 7.4 months (95% CI 6.1-11 months) for nonrecipients (p = 0.0449). Gastrointestinal perforation/fistulas occurred in four patients (5.6%), all of whom had a history of radiation therapy.Paclitaxel-carboplatin and bevacizumab therapy is an acceptable and tolerable treatment for advanced or recurrent cervical cancer.

Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99 m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4 cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12-16 years, and catch-up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2-3 (CIN2-3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12-15 years (n = 36), 16-18 years (n = 23), 19-22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P .001). This finding was supported by age at first sexual intercourse; among women with CIN2-3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan.

ObjectiveWe aimed to identify pathways for potential therapeutic targets by conducting molecular profiling of endometrial carcinomas in patients with poor prognosis.MethodsThe classification of endometrial carcinomas has undergone a paradigm shift with the advent of next generation sequencing based molecular profiling. Although this emerging classification reflects poor prognosis in patients with endometrial carcinoma, knowledge of affected biological pathways is still lacking. In this study, 85 patients with endometrial carcinomas at the Shizuoka Cancer Center were evaluated from January 2014 to March 2019 and classified based on The Cancer Genome Atlas subgroups. The accumulation of germline and somatic mutations was determined using next generation sequencing. Gene expression profiling was used to determine the effect of TP53 inactivation on the recurrence of endometrial carcinoma. Additionally, the biological pathways associated with TP53 inactivation were estimated by pathway analysis based on gene expression.ResultsBased on The Cancer Genome Atlas classification, the ratio of polymerase-epsilon to copy number-high subgroups and the frequency of PTEN and TP53 mutations differed in patients, and mutations of ARHGAP35 observed in normal endometrium were accumulated in the polymerase-epsilon and microsatellite instability subgroups. We revealed that copy number-high reflects TP53 inactivation in endometrial carcinomas, and that TP53-inactive tumors with or without TP53 mutations have poor prognosis. Furthermore, overexpression of aurora kinase A and activation of oxidative phosphorylation were found in TP53-inactivated endometrial carcinomas, suggesting that the PI3K/mTOR and autophagy pathways are potential drug targets.ConclusionOur analysis revealed a relationship between pathways involved in oxidative phosphorylation and poor prognosis and provides insight into potential drug targets.

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48–2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83–1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.

Uterine carcinosarcoma (UCS) is an uncommon and highly aggressive tumor. There is no HER2 testing protocol for UCS despite the development of HER2 antibody conjugates. We aimed to elucidate histopathological HER2 expression details in UCS, to compare HER2 scores between ASCO/CAP criteria for gastric and breast cancer, and to propose requirements for HER2 testing for UCS. Eighty-nine specimens from 84 patients with metastatic/recurrent UCS were prospectively collected from May 2018 to July 2020. We performed HER2 immunohistochemistry (IHC) for 89 specimens and FISH for 44 specimens. HER2 expression details and HER2 score were evaluated according to the latest ASCO/CAP criteria for gastric (2016) and breast cancer (2018). HER2 IHC scores according to the gastric cancer criteria were 0 in 31 cases (35%), 1+ in 26 (29%), 2+ in 22 (25%), and 3+ in 10 cases (11%) of the 89 specimens. A lateral/basolateral membranous staining pattern was observed in 28/32 (88%) specimens with HER2 scores of 2+/3+. HER2 intratumoral heterogeneity was identified in 28/32 (88%) of the specimens with HER2 scores of 2+/3+. The overall concordance rate of HER2 score was 70% between the gastric and breast criteria. FISH revealed HER2 gene amplification in 10/44 (23%) specimens containing only lateral/basolateral membranous staining pattern. Based on the histopathological features of HER2 expression in UCS, a scoring system that accepts lateral/basolateral staining patterns should be applied. Furthermore, we proposed specific requirements for UCS testing, including specimen selection, scoring system, and calculating the proportion of HER2-positive cells.

This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important.

Background: Tumor mutation burden (TMB) is the total exonic mutation count per megabase of tumor DNA. Recent advances in precision medicine occasionally detect Lynch syndrome (LS) by germline sequencing for mismatch-repair (g.MMR) genes but not using TMB. The current study analyzes the utility of TMB in detecting LS. Methods: Whole-exome sequencing (ion-semiconductor sequencing) was performed for somatic and germline DNA from 2,501 various cancer patients to detect TMB and g.MMR sequencing. MMR IHC was conducted when high TMB (≥10) was detected in LS-related cancers with an additional condition of wild-type BRAF in colorectal cancers. Target sequencing and multiplex ligation-dependent probe amplification (MLPA) were further performed for g.MMR genes in MMR-deficient cancers (TMB-based g.MMR target sequencing). We compared universal sequencing and TMB-based target sequencing in their sensitivity for detecting LS. Results: LS was detected in 16 (0.6%) of the 2,501 patients: 1.1% (9/826) of colorectal cancer patients, 16.2% (6/37) of endometrial cancer patients, and 14.3% (1/7) of small intestine cancer patients. TMB-based g.MMR target sequencing (81.3%) showed superior sensitivity for detecting LS than universal g.MMR sequencing (56.3%; P = 0.127) but missed 3 LS patients (1 with a low-TMB cancer, 1 with a BRAF-mutant colorectal cancer, and 1 with an MMR-proficient cancer). Ion-semiconductor sequencing could detect single-nucleotide substitutions but not large deletions. POL-mutated cancers showed extremely high TMBs (48.4–749.2). Conclusions: g.MMR target sequencing, combined with TMB, somatic BRAF mutation, and MMR IHC is an effective strategy for detecting LS. Impact: TMB can be a biomarker for detecting LS in precision medicine.

Many reports demonstrate that a high tumor mutation burden (TMB-H) is closely associated with good prognosis of cancer. However, specific studies investigating the association of various TMB statuses with overall survival in patients with solid tumors are scarce.In the present study, we investigated the association of TMB status with overall survival in 5,072 patients with cancer from the HOPE project and clarified the specific mechanism responsible for the good prognosis of the TMB-H group. All tumors were classified into one of four groups based on TMB: ultralow (UL), low (L), intermediate (I) and high (H).The TMB-H group had a better prognosis than the TMB-I and TMB-L groups, but not than the TMB-UL group. Analyzing the expression of 293 immune response-associated genes, 17 genes were up-regulated in the TMB-H group compared to the TMB-I and TNB-L groups, and two genes [CD274 and interferon-γ (IFNG)] were identified as good prognostic factors. Analysis of immune cell populations inside tumors demonstrated that the frequencies of exhausted CD8One possible mechanism for the good prognosis of the TMB-UL group compared to the TMB-H group might be that the TMB-UL group features a balance between immunosuppression and immunostimulation.

Venous thromboembolism (VTE) is a serious complication of ovarian cancer. However, the mechanism of thrombus formation in ovarian cancer has not been sufficiently clarified. We aimed to examine the pathogenic mechanism of thromboembolism in patients with ovarian tumors before surgery using the activated protein C sensitive ratio (APC-sr) and endogenous thrombin potential (ETP) measurements in plasma. The incidence of thromboembolism in patients with ovarian tumors was determined. APC-sr and ETP were measured from plasma samples obtained from ovarian tumor patients before surgery at our hospital. There were 60 enrolled patients. Thrombosis was found in 10 patients, of which 9 had ovarian cancer and 1 had borderline malignancy. The incidence of thromboembolism was significantly higher in cases of ovarian cancer than in cases of benign and borderline tumors (p

Project High-tech Omics-based Patient Evaluation (HOPE), which used whole-exome sequencing and gene expression profiling, was launched in 2014. A total of ~2,000 patients were enrolled until March 2016, and the survival time was observed up to July 2019. In our previous study, a tumor microenvironment immune type classification based on the expression levels of the programmed death-ligand 1 (PD-L1) and CD8B genes was performed based on four types: A, adaptive immune resistance; B, intrinsic induction; C, immunological ignorance; and D, tolerance. Type A (PD-L1+ and CD8B+) exhibited upregulated features of T helper 1 antitumor responses. In the present study, survival time analysis at 5 years revealed that patients in type A had a better prognosis than those in other categories [5 year survival rate (%); A (80.5) vs. B (73.9), C (73.4) and D (72.6), P=0.0005]. Based on the expression data of 293 immune response-associated genes, 62 specific genes were upregulated in the type A group. Among these genes, 18 specific genes, such as activated effector T-cell markers (CD8/CD40LG/GZMB), effector memory T-cell markers (PD-1/CD27/ICOS), chemokine markers (CXCL9/CXCL10) and activated dendritic cell markers (CD80/CD274/SLAMF1), were significantly associated with a good prognosis using overall survival time analysis. Finally, multivariate Cox proportional hazard regression analyses of overall survival demonstrated that four genes (GZMB, HAVCR2, CXCL9 and CD40LG) were independent prognostic markers, and GZMB, CXCL9 and CD40LG may contribute to the survival benefit of patients in the immune type A group.

A 62-year-old Japanese woman developed numbness of the extremities and megaloblastic anemia. She had undergone total abdominal hysterectomy, whole-pelvis radiation therapy and chemotherapy for gynecological cancer 10 years before. Chronic abdominal pain, diarrhea and intermittent small-bowel obstruction had afflicted her for a long time. We diagnosed her with vitamin B12 deficiency anemia and polyneuropathy due to chronic radiation enteritis causing malabsorption. Vitamin B12 injections improved her numbness and anemia. The early diagnosis and treatment of deficiency of vitamin B12 are important. Physicians should regularly measure vitamin B12 levels and supplement vitamin B12 as needed in patients with chronic radiation enteritis.

5513 Background: MORAb-202 is an antibody-drug conjugate consisting of farletuzumab (an antibody that binds to folate receptor alpha [FRα]) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin-B–cleavable linker. The dose-escalation part of this phase 1 study confirmed antitumor activity in pts with ovarian cancer (Shimizu 2021, CCR); based on efficacy and safety, MORAb-202 0.9 mg/kg and 1.2 mg/kg Q3W were chosen as doses for the expansion part of this study in pts with PROC. Methods: The primary objective for the expansion part of this phase 1 study conducted in Japan was to define the safety and tolerability of MORAb-202. Secondary objectives included PK characterization and efficacy assessment (best overall response, objective response rate, progression-free survival, and overall survival). Eligible pts included those who had received ≤2 regimens of chemotherapy after diagnosis of PROC, had measurable disease per RECIST v1.1, and an ECOG PS of ≤1. Pts (except those with high grade serous histology) in the expansion phase were required to be FRα positive. The expansion phase began at the 0.9 mg/kg dose (Cohort 1); Cohort 2 (1.2 mg/kg) was initiated after safety assessment of Cohort 1 was completed. Tumor responses were assessed per RECIST v1.1 by investigator. Results: Twenty-four pts were treated in Cohort 1 and 21 pts were treated in Cohort 2. Grade ≥3 TEAEs occurred in 33.3% of pts in Cohort 1 and 28.6% of pts in Cohort 2. The most common TEAE was interstitial lung disease (ILD)/pneumonitis at both dose levels (Cohort 1: 37.5% [n=9; 8 with grade 1, 1 with grade 2]; Cohort 2: 66.7% [n=14; 6 with grade 1, 7 with grade 2, 1 with grade 3]). Other common TEAEs of any grade were nausea (25.0%; 33.3%), pyrexia (33.3%; 42.9%), malaise (16.7%; 28.6%), and headache (12.5%; 47.6%), in Cohorts 1 and 2, respectively. ORR was 25.0% and 52.4% in Cohorts 1 and 2, respectively (Table). Antitumor activity was observed across FRα-expression levels (

3090 Background: MORAb-202 is an ADC consisting of farletuzumab (an antibody that binds to FRα) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin B-cleavable linker. A phase 1 dose-escalation and expansion study in patients with advanced solid tumors evaluated MORAb-202 doses ranging from 0.3 mg/kg to 1.2 mg/kg IV every 3 weeks (Shimizu 2021, CCR). The dose-expansion part included starting doses of 0.9 mg/kg and 1.2 mg/kg in an ovarian cancer (OC) cohort. Objective response rates (ORR) by investigator per RECIST v1.1 and rates of all-grade interstitial lung disease (ILD), an adverse event of interest, were lower at the 0.9 mg/kg dose vs the 1.2 mg/kg dose. To support dose optimization for clinical benefit while reducing the risk of ILD, a MORAb-202 PPK model was developed to characterize the pharmacokinetics and to obtain model-predicted exposure measures. Methods: Exposure was predicted for different dosing scenarios: flat dosing, bodyweight (BW)-based dosing with or without a dose cap, adjusted ideal BW dosing, and body surface area (BSA)-based dosing. E-R analyses for efficacy (ie, ORR) and safety (ie, ILD by expert review) were conducted using logistic-regression analysis. Simulations (N = 1000) were performed using a BW distribution from a previous phase 3 farletuzumab study in OC (Vergote 2016, JCO) to predict the probability of ORR and ILD in patients treated with MORAb-202. Results: MORAb-202 exposures were dose proportional, and the pharmacokinetics were described by a 2-compartment model with zero-order IV infusion and first-order elimination. Patients with higher BW had less-than-proportional increases in clearance (allometric exponent [AE] 0.571) and distribution volume (AE 0.524). MORAb-202 demonstrated a positive exposure (based on area under the curve [AUC]) dependence to ORR and ILD. The probability of achieving a tumor response was higher with higher AUC (odds ratio [OR] for an AUC unit change of 1000 µg•h/mL: 1.73 [95% CI 1.06–3.11]). The probability of an ILD event was higher with higher AUC (OR for an AUC unit change of 1000 µg•h/mL: 3.50 [95% CI 1.89–7.81]). Simulations across BW ranges (34.2–144 kg) indicated that BSA-based dosing (33 mg/m2), compared with BW-based dosing (0.9 mg/kg), yielded similar predicted median (90% prediction interval) rates for ORR (33.7% [19.3–62.2] vs 37.9% [20.6–67.5]) and all-grade ILD (46.8% [18.2–88.2] vs 55.1% [20.7–91.9]). However, BSA-based dosing is predicted to reduce ILD in the highest BW quartile (> 80–144 kg) by approximately 35% compared with BW-based dosing. Conclusions: Based on this assessment, BSA-based dosing is predicted to lower the exposure-dependent ILD risk in patients with higher BW and is being further evaluated in ongoing clinical studies. Clinical trial information: NCT03386942.

The fifth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was published in 2020. The guidelines contain 6 chapters-namely, (1) overview of the guidelines; (2) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (4) borderline epithelial tumors of the ovary; (5) malignant germ cell tumors of the ovary; and (6) malignant sex cord-stromal tumors. Furthermore, the guidelines comprise 5 algorithms-namely, (1) initial treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (2) treatment for recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) initial treatment for borderline epithelial ovarian tumor; (4) treatment for malignant germ cell tumor; and (5) treatment for sex cord-stromal tumor. Major changes in the new edition include the following: (1) revision of the title to "guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer"; (2) involvement of patients and general (male/female) participants in addition to physicians, pharmacists, and nurses; (3) clinical questions (CQs) in the PICO format; (4) change in the expression of grades of recommendation and level of evidence in accordance with the GRADE system; (5) introduction of the idea of a body of evidence; (6) categorization of references according to research design; (7) performance of systematic reviews and meta-analysis for three CQs; and (8) voting for each CQ/recommendation and description of the consensus.

Background Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC. Methods Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared. Results A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II–IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125. Conclusions High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.

Introduction/Background Standard therapy for recurrent endometrial cancer is chemotherapy. There is less conclusive evidence about surgical treatment of recurrent endometrial cancer. We investigated outcomes after surgical treatment for recurrent endometrial cancer at our hospital and verified its effectiveness. Methodology We reviewed the medical records retrospectively for patients who underwent surgical treatment for primary recurrent endometrial cancer between September 2002 and March 2016. We evaluated clinicopathological characteristics, time to recurrence, age at the time of surgical treatment for recurrence, the site of recurrence, residual tumor and postoperative therapy of recurrent surgery, progression-free survival (PFS) and overall survival (OS). Results 18 patients were evaluated. The median follow-up was 28.9 months (12.7–134.2). Median age was 65.5 (48–78) years old. The site of recurrence were lung 7, peritoneal dissemination 7, and lymph nodes 5. 14 of 18 patients had underwent macroscopic complete tumor resection. Median PFS was 18.1 months (0.9–134.2) and median OS was 119.1 months (31.1–189.2).Prognostic factors for surgical treatment of PFS were lung metastases (HR 0.18 [95% CI: 0.042–0.77], P Conclusion Surgical treatment of recurrent endometrial cancer may be effective for patients who had longer time to recurrence and underwent macroscopic complete tumor resection. Disclosure Nothing to disclose.

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.

This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics, and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg twice daily on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3+3 design to determine dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose-limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea, and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in 5 patients, was partial in 4 and complete in 1 (objective response rate 100%). Response could not be assessed in 4 patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg twice daily. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer. This article is protected by copyright. All rights reserved.

The treatment for most patients with early-stage cervical cancer involves radical hysterectomy and pelvic lymph node dissection, and indications for postoperative adjuvant therapy have been determined by evaluating the prognostic risk factors for recurrence in each case. The aim of this review is to raise and discuss the various issues that have not yet been resolved regarding the prognostic risk factors and postoperative adjuvant therapy. Several clinicopathological factors, such as tumor size, lymphovascular space involvement, deep stromal invasion, parametrial involvement and lymph node metastasis, have been identified to have prognostic significance in early-stage cervical cancer. However, this remains controversial because there is suggested to be substantial heterogeneity among patients after radical hysterectomy and lymphadenectomy and it would be difficult to define the risk groups clearly. This indicates the need to develop more convenient and accurate criteria to define risk groups. According to the currently available evidence, patients in the high-risk group should receive adjuvant concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) and fluolouracil. However, CCRT with CDDP administered weekly (CCRT-P) has instead been applied in a clinical context worldwide. Whether CCRT-P has a survival benefit compared with radiotherapy (RT) alone is unknown because no randomized phase III trials have been performed for patients in the high-risk group after radical surgery. Patients with high-risk factors have a high incidence of distant metastasis, for whom systemic chemotherapy might be a key to improving overall survival. The pivotal study that investigated the role of RT alone for patients with intermediate-risk factors after hysterectomy is the GOG092 trial. This trial showed a 47% reduction in the risk of recurrence after RT compared with no further treatment (NFT). However, the improvement in overall survival with RT did not reach statistical significance, while patients allocated to the RT group did experience an increase in severe toxicities compared with the NFT group. This could be why many physicians are reluctant to treat patients with this approach, although guidelines recommend RT for patients with intermediate-risk factors. With regard to toxicities, postoperative RT would be problematic because the organs in the pelvis targeted by RT have already been damaged by radical surgery. To reduce the toxicities, intensity-modulated radiotherapy would best be used worldwide. Further improvement in adjuvant therapy will come from enhanced definition of prognostic risk factors, better patient selection, and refinements in both local and systematic therapies.

Objective High-grade neuroendocrine carcinoma of uterine cervix (HGNCUC) has been recognized as a highly malignant tumor. Therapeutic strategy specific to neuroendocrine (NE) tumors needs to be considered, but some cases wouldn't allow simple final diagnoses. Insulinoma-associated protein 1 (INSM1), which is a zinc-finger transcription factor related to NE differentiation, is frequently expressed in NE tumors. We investigated the association between INSM1 and HGNCUC, and the possibility of INSM1 as a useful NE marker. Methods Thirty-seven cases of formalin-fixed and paraffin-embedded HGNCUCs were evaluated immunohistochemically for conventional NE markers and INSM1. We also surveyed polymerase chain reactions and examined the frequency and the genotype of human papillomavirus (HPV) infections. Results In HGNCUC, chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) were expressed in 86%, 86% and 68%, respectively. In addition, INSM1 was detected in 95%. Positivity for INSM1 was clearly evaluated histologically, because the intensity of nuclear staining on positive cells was high and nonspecific reactions were minimal. In uni- and multivariate analyses of prognostic factors on stage I and II surgical cases, the association between INSM1 expression and prognosis was insignificant. We confirmed 72% of 29 examined cases had high risk HPV infections (type 16, 14%; type 18, 86%). Conclusions This study has clarified that INSM1 is closely related to the development of HGNCUC, and a useful new NE marker in conducting its correct and rapid diagnosis.

Background Somatic PTEN mutation occurs in a proportion of ovarian endometrioid carcinomas. However, these cancers have seldom been reported in diseases associated with germline PTEN variants, such as Cowden syndrome (CS). Case presentation The present case was a 39-year-old woman with a left ovarian carcinoma who demonstrated a germline splice variant of PTEN (c.1026 + 1G > T) following genome-wide whole exome sequencing of her germline DNA. Histology of her resected tumor revealed endometrioid carcinoma of the same type as a right ovarian cancer resected eight years previously. These tumors showed null immunostaining for PTEN. She was genetically diagnosed with CS. Despite her clinical examinations had demonstrated several characteristic findings of CS, including mammary fibroma, esophageal and skin papilloma, colonic hamartoma, uterine myoma, and lipoma, the clinicians could not approach this diagnosis. Conclusion Ovarian endometrioid carcinoma is generally thought to develop from endometrial tissue menstruated from the uterus and implanted on the ovary. To date, ovarian cancers have not been listed as CS-related cancers; however, ovarian endometrioid cancer can have a potential association with CS in endometriosis cases.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

To compare the efficacy, safety, and tolerability profiles of pegylated liposomal doxorubicin and carboplatin (PLDC) with those of gemcitabine and carboplatin (GC) for the treatment of patients with platinum-sensitive recurrent ovarian cancer. Ovarian cancer patients with recurrence > 6 months after first-line platinum and taxane-based therapies were randomly assigned to PLDC [pegylated liposomal doxorubicin 30 mg/m2 plus carboplatin area under the curve (AUC) 5 mg/mL/min on day 1] every 4 weeks or GC (gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 4 mg/mL/min on day 1) every 3 weeks for at least 6 cycles. The primary endpoint was progression-free survival, and overall response rate, overall survival, toxicity, and dose administration were secondary endpoints. One-hundred patients (49 PLDC; 51 GC) were randomly assigned. Over a median follow-up of 24 months, the median progression-free survival was 12.0 months (95% CI 9.2–15.0) for PLDC and 9.8 months (8.9–12.3) for GC [HR 0.69 (0.455–1.047)] with a difference of 2.2 months. The response rate was 57.1% (41.0–72.3) for PLDC and 56.4% (39.6–72.2) for GC. No obvious differences in toxicity (G3/4) were noted between arms. The median relative dose intensity of planned dose per week was 88.9% for pegylated liposomal doxorubicin and 53.1% for gemcitabine (p

Modified radical hysterectomy (MRH) is thought to be equivalent to class II (Piver classification) or type B (Querleu classification) radical hysterectomy (RH) and identical to the original method of the Wertheim operation. MRH is a method of hysterectomy defined as being intermediate between simple hysterectomy and RH and enabling almost full preservation of the pelvic splanchnic nerves and hypogastric plexus. This surgical procedure entails the cutting of the anterior leaf, not the posterior one, of the vesicouterine ligament of the uterus. The ureter is mobilized laterally, part of the parametrial tissue is transected at the level of the ureteral tunnel, and at least 10 mm of the vaginal wall from the uterine cervix is removed. The indication of MRH (with pelvic lymphadenectomy) in cervical cancer is International Federation of Gynecology and Obstetrics stage IA1 with lymphovascular space invasion or stage IA2. MRH is associated with a very low (≤1%) rate of significant postoperative complications, and compared with RH, it reduces the rate of adverse effects on the urinary tract, such as fistula formation and severe voiding dysfunction. The mortality rate for those undergoing this procedure is 0.4–0.5%. The possibility of MRH for low-risk FIGO stage IB1 patients has been considered, and clinical trials are ongoing.

e18077 Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinomas (CCC) from borderline ovarian tumors (BD) and non-CCC epithelial ovarian cancers (EOC). We examined the prediction performances of TFPI2, including high specificity, for preoperative diagnosis of CCC in multi-center settings. Methods: We collected serum samples obtained preoperatively from patients with ovarian masses who needed surgical treatment to confirm pathological diagnoses in five hospitals in Japan. The diagnostic powers of serum levels of TFPI2 (cutoff value 270 pg/mL) and CA125 (cutoff value 35 U/mL) to discriminate CCC from BD, non-CCC-EOC, and benign lesions were compared. Results: A total of 351 patients (77 ovarian benign lesions, 65 BD and 209 EOC including 69 CCC) were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean±SD, 508.2±812.0 pg/mL) than in patients with benign lesions (154.7±46.5), BD (181±95.5) and non-CCC EOC (265.4±289.1). TFPI2 had a high diagnostic specificity to CCC (sensitivity and specificity: 43.5% and 79.5%, respectively). The sensitivity of TFPI2 was improved to 71.1% when combined with CA125, and it was increased in Stage II–IV CCC (66.7%) compared with Stage I CCC (33.3%). In patients with benign endometriotic cysts (BEM), no patient was positive for TFPI2 but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating Stage II–IV CCC from BD and non-CCC EOC patients (AUC 0.815 for TFPI2 versus 0.505 for CA125) or from BEM (AUC 0.957 for TFPI2 versus 0.748 for CA125). Conclusions: High specificity of TFPI2 for the preoperative detection of CCC was re-verified with the defined cutoff level of TFPI2 in practice. TFPI2 and CA125 may have a substantial contribution to the precise prediction of intractable CCC. [Table: see text]

Lambert-Eaton myasthenic syndrome (LEMS) is most commonly associated with small cell lung carcinoma, while it is rarely associated with gynecological and breast carcinoma. We herein report a case of LEMS associated with synchronous double cancer, which was a combination of small cell carcinoma of the cervix and breast carcinoma. The early diagnosis and treatment of LEMS are important for achieving a good outcome. The possibility of accompanying paraneoplastic neurological syndrome must be sufficiently considered in gynecology and breast cancer patients. To our knowledge, this is the first report of LEMS associated with synchronous double cancer.

Objective We aimed to propose a set of quality indicators (QIs) based on the clinical guidelines for cervical cancer treatment published by The Japan Society of Gynecologic Oncology, and to assess adherence to standard-of-care as an index of the quality of care for cervical cancer in Japan. Methods A panel of clinical experts devised the QIs using a modified Delphi method. Adherence to each QI was evaluated using data from a hospital-based cancer registry of patients diagnosed in 2013, and linked with insurance claims data, between October 1, 2012, and December 31, 2014. All patients who received first-line treatment at the participating facility were included. The QI scores were communicated to participating hospitals, and additional data about the reasons for non-adherence were collected. Results In total, 297 hospitals participated, and the care provided to 15,163 cervical cancer patients was examined using 10 measurable QIs. The adherence rate ranged from 50.0% for 'cystoscope or proctoscope for stage IVA' to 98.8% for 'chemotherapy using platinum for stage IVB'. Despite the variation in care, hospitals reported clinically valid reasons for more than half of the non-adherent cases. Clinically valid reasons accounted for 75%, 90.9%, 73.4%, 44.5%, and 88.1% of presented non-adherent cases respectively. Conclusion Our study revealed variations in pattern of care as well as an adherence to standards-of-care across Japan. Further assessment of the causes of variation and non-adherence can help identify areas where improvements are needed in patient care.

Background This open-label phase III trial evaluated efficacy and safety of S-1 plus cisplatin vs. cisplatin alone as first-line chemotherapy in patients with stage IVB, recurrent, or persistent cervical cancer. Methods Patients were randomised (1:1) to S-1 plus cisplatin (study group) or cisplatin alone (control group). In each cycle, cisplatin 50 mg/m2 was administered on Day 1 in both groups. S-1 was administered orally at 80–120 mg daily on Days 1–14 of a 21-day cycle in the study group. The primary endpoint was overall survival (OS). Results A total of 375 patients were enrolled, of whom 364 (188, study group; 176, control group) received treatment. Median OS was 21.9 and 19.5 months in the study and control groups, respectively (log-rank P = 0.125; hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.67–1.05). Median progression-free survival (PFS) was 7.3 and 4.9 months in the study and control groups, respectively (HR 0.62, 95% CI 0.48–0.80, P

Aim The aim of this retrospective study was to analyze data for patients with stage IB–IIB uterine cervical cancer who were treated with concurrent chemoradiotherapy with fluorouracil (5-FU) and cisplatin (CCRT-FP) as postoperative adjuvant therapy and to re-examine these issues and further treatment. Methods Patients with high risk for recurrence underwent CCRT-FP as postoperative adjuvant therapy. A total of 73 patients who met these criteria were included in this study. Data related to survival, toxicity, and treatment feasibility were analyzed, and the question of whether there were differences in survival and toxicity according to the number of dissected lymph nodes at surgery was evaluated. Results Median patient age was 45 years (range, 24–67 years). Two-thirds of patients had squamous cell histologic type, 41 patients (56.2%) had parametrial invasion, and 60 patients (82.2%) had lymph node metastases. Estimated 4-year progression-free survival, overall survival, and local control rates were 71.8%, 84.1%, and 88.5%, respectively. Sixteen patients (21.9%) had grade 3–4 neutropenia and one of them died of septic shock. Non-hematological toxicities were also common: 13 (17.8%) experienced grade 3–4 nausea, and nine (12.3%) experienced grade 3–4 diarrhea. Ileus occurred in 17 patients (23.3%), and seven of them (9.6%) were not yet cured. One patient experienced gastrointestinal perforation. Conclusions CCRT-FP in the postoperative setting resulted in good survival outcome but toxicity remained problematic. Development of appropriate treatment for patients with high-risk prognostic factors after radical hysterectomy and lymphadenectomy is required.

Prevention of chemotherapy-induced nausea and vomiting (CINV) is crucial for maintaining the quality of life of cancer patients. Female patients have been underrepresented in previous clinical studies of aprepitant or palonosetron. We performed a prospective multicenter study to investigate the efficacy and safety of triple therapy comprising these two agents and dexamethasone in female cancer patients receiving chemotherapy that included cisplatin (≥ 50 mg/m(2)).Aprepitant was administered at a dose of 125 mg before chemotherapy on day 1 and at 80 mg on days 2 and 3. Palonosetron (0.75 mg) was given before chemotherapy on day 1. Dexamethasone was administered at a dose of 9.9 mg before chemotherapy on day 1 and at 6.6 mg on days 2-4. The primary endpoint was the the proportion of patients with a complete response (CR no vomiting and no use of rescue medication) throughout the overall period (0-120 h post-chemotherapy).Ninety-six women (median age 55 years) were enrolled. The overall CR rate was 54.2 %. CR was obtained during the acute phase (0-24 h post-chemotherapy) and the delayed phase (24-120 h post-chemotherapy) in 87.5 and 56.3 % of the patients, respectively. The most common adverse reactions were constipation and fatigue (reported by three patients each).Exhibition of a favorable overall CR rate over existing two-drug combinations suggests that the triple therapy regimen used in the present study is effective and tolerable in patients with gynecological malignancies receiving cisplatin-based chemotherapy. Female patients may have a higher risk of developing CINV.

OBJECTIVE The purpose of this study was to assess whether peritoneal cytology has prognostic significance in uterine cervical cancer. METHODS Peritoneal cytology was obtained in 228 patients with carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics [FIGO] stages IB1-IIB) between October 2002 and August 2010. All patients were negative for intraperitoneal disease at the time of their radical hysterectomy. The pathological features and clinical prognosis of cases of positive peritoneal cytology were examined retrospectively. RESULTS Peritoneal cytology was positive in 9 patients (3.9%). Of these patients, 3/139 (2.2%) had squamous cell carcinoma and 6/89 (6.7%) had adenocarcinoma or adenosquamous carcinoma. One of the 3 patients with squamous cell carcinoma who had positive cytology had a recurrence at the vaginal stump 21 months after radical hysterectomy. All of the 6 patients with adenocarcinoma or adenosquamous carcinoma had disease recurrence during the follow-up period: 3 with peritoneal dissemination and 2 with lymph node metastases. There were significant differences in recurrence-free survival and overall survival between the peritoneal cytology-negative and cytology-positive groups (log-rank p

Pelvic lymphocyst infection is a rare complication after lymphadenectomy for malignant gynecologic tumors. Although medical therapy is a useful addition to surgical drainage, the appropriate antibiotic regimen is unknown because few studies have examined the causative organisms. The purpose of this case series was to identify the micro-organisms infecting pelvic lymphocysts.This was a single-center, retrospective, case-series review conducted at a tertiary-care cancer center between October 2002 and March 2013. The participants included all patients who experienced their first pelvic lymphocyst infection after undergoing pelvic lymphadenectomy for cervical, endometrial, or ovarian cancer and exhibited positive lymphocyst fluid culture. Computed tomography- or sonography-guided percutaneous aspiration procedures were performed to obtain lymphocyst fluid for culture.During the study period, 878 patients underwent lymphadenectomy for gynecologic malignant tumors, and 13 developed a pelvic lymphocyst infection documented microbiologically. Cultures identified Staphylococcus aureus (three patients), S. epidermidis (one patient), Streptococcus agalactiae (three patients), Enterococcus (two patients), Escherichia coli (one patient), and anaerobic bacteria (three patients). They were all monomicrobial infections.Our study and other smaller ones suggest that lymphocyst infections following pelvic lymphadenectomy for malignant gynecologic tumors usually are monomicrobial and caused by gram-positive cocci, including Staphylococcus, Streptococcus, and Enterococcus, and anaerobes such as Bacteroides fragilis. These bacteria should be considered when selecting empiric antibiotic therapy.

Objectives This is a multicenter, collaborative study to accumulate cases of small cell carcinoma of the uterine cervix (SmCC), to clarify its clinical and clinicopathologic features and prognosis, and to obtain findings to establish future individualized treatment. Methods At medical centers participating in the Kansai Clinical Oncology Group/Intergroup, patients diagnosed with SmCC between 1997 and 2007 were enrolled. Clinicopathologic features and prognosis were retrospectively evaluated in patients with SmCC diagnosed at a central pathologic review. Results A total of 71 patients were registered at 25 medical centers in Japan. Of these, 52 patients (73%) were diagnosed with SmCC based on a pathological review. These 52 patients diagnosed with SmCC were analyzed. The median follow-up period was 57months. The 4-year progression-free survival (PFS) was: IB1, 59%; IB2, 68%; IIB, 13%; and IIIB, 17%. The 4-year overall survival (OS) was: IB1, 63%; IB2, 67%; IIB, 30%; IIIB, 29%; and IVB, 25%. For postoperative adjuvant therapy, postoperative chemotherapy (a platinum drug in all cases) was compared to non-chemotherapy. The 4-year PFS was 65% and 14%, and the 4-year OS was 65% and 29%. PFS was significantly better (p=0.002), and the OS tended to be better (p=0.073) in the group with postoperative chemotherapy. Conclusion Even in patients with early stage SmCC, the prognosis is poor. However, in early stage patients, by adding postoperative chemotherapy, the prognosis may improve. Currently, various treatment protocols are used at each medical center, but in the future, a standardized treatment protocol for SmCC will hopefully be established.