A qualitative systematic review of the significance of adjuvant therapy in patients with low-risk endometrial cancer presenting positive peritoneal cytology: a relevant study to the guideline update for endometrial cancer by the Japan society of gynecologic oncology guideline committee.

In association with an update of the Japan Society of Gynecologic Oncology clinical practice guidelines for endometrial cancer in 2023, a systematic review was conducted about the therapeutic benefit of adjuvant therapy on patients with early-stage endometrial carcinoma, who presented positive peritoneal cytology (PPC) without the risk factors for recurrence. The systematic review only included two eligible retrospective studies. Both studies included patients with risk factors for recurrence. A nationwide study in the United States reported that adjuvant chemotherapy was associated with the reduced risk of death among patients with stages I-II endometrial cancer with PPC by multivariate, propensity score-adjusted analysis. Another single-center study in Japan reported no association between adjuvant chemotherapy and relapse-free survival among patients with stage IA endometrial cancer by univariate analysis. This systematic review identified that evidence was limited with conflicting results. Continuous evaluation is warranted to address this clinical question.

A single-institution retrospective exploratory analysis on the effectiveness and safety of lenvatinib plus pembrolizumab for advanced endometrial cancer: insights from ProMisE molecular classification system.

BACKGROUND: The Proactive Molecular Risk Classifier for Endometrial Cancer has identified four risk groups for the prognosis of endometrial cancer. Lenvatinib plus pembrolizumab was recently approved as a second-line treatment for unresectable endometrial cancer, but reports in clinical practice are lacking. The relationship between the efficacy of lenvatinib/pembrolizumab and Proactive Molecular Risk Classifier for Endometrial Cancer classification is unclear. METHODS: This single-centre retrospective study included patients who underwent lenvatinib/pembrolizumab therapy at Iwate Medical University Hospital between January 2022 and March 2023. Formalin-fixed paraffin-embedded specimens obtained from patients before treatment were collected and classified into the mismatch repair-deficient, p53 abnormal and no specific molecular profile subtypes using immunohistochemistry. The response rate, progression-free survival and adverse events were evaluated using electronic medical records. The study was approved by the hospital's ethics committee (approval number: MH2022-093). RESULTS: This study enrolled 20 patients, who underwent a median follow-up of 17.8 months (95% confidence interval: 16.6-18.9). The best overall response rate was 60.0% (36.1-80.9), and the median progression-free survival was 11.6 months (2.9-20.3). The median progression-free survival in the p53 abnormal group (n = 9) was 3.4 months (3.0-3.8); however, progression-free survival did not reach the median (P < 0.001) in the mismatch repair-deficient/no specific molecular profile group (n = 11). Symptomatic immune-related adverse events (except hypothyroidism) occurred in 4/20 (25.0%) patients, and partial responses were observed in all cases. No treatment-related deaths occurred. CONCLUSION: The p53abn group in the Proactive Molecular Risk Classifier for Endometrial Cancer classification has a poor prognosis even after treatment with lenvatinib/pembrolizumab.

Prevalence of germline BRCA1/2 pathogenic variants in Japanese patients treated with castration-resistant prostate cancer and efficacy of CRPC treatment in real-world clinical practice.

OBJECTIVE: The companion diagnosis for olaparib, a poly (ADP-ribose) polymerase inhibitor for prostate cancer, aims to detect BRCA1/2 gene variants. In clinical practice, the frequency of germline BRCA1/2 variants in patients receiving castration-resistant prostate cancer treatment is unknown. We aimed to evaluate the prevalence of germline BRCA1/2 variants and their relationship to prognosis and treatment efficacy in castration-resistant prostate cancer. METHODS: Between June 2021 and 2023, 92 patients receiving castration-resistant prostate cancer treatment were examined for germline BRCA1/2 variants using BRACAnalysis CDx®. Furthermore, the associations between BRCA1/2 pathogenic variants and clinical outcomes were assessed. RESULTS: Of the 92 patients referred for genetic testing, 6 (6.5%) carried germline pathogenic variants in BRCA1/2. The BRCA2 variant was the most frequent (n = 5), followed by BRCA1 variant (n = 1). Among the five variants in BRCA2, the p.Asp427Thrfs*3 variant was identified for the first time in prostate cancer. Overall survival from castration-resistant prostate cancer for patients with BRCA1/2 variants was significantly shorter than for patients without BRCA1/2 variants (P = 0.043). Progression-free survival of androgen receptor signaling inhibitors for patients with BRCA1/2 variants was significantly shorter than for those without (P = 0.003). Progression-free survival of taxane chemotherapy was significantly shorter in patients with BRCA1/2 variants than in those without (P = 0.0149). CONCLUSIONS: In clinical practice, 6.5% of patients treated with castration-resistant prostate cancer carried germline BRCA1/2 pathogenic variants. Japanese castration-resistant prostate cancer patients with germline BRCA1/2 mutants have a poor prognosis and may be less responsive to treatment with androgen receptor signaling inhibitors and taxane-based chemotherapy for castration-resistant prostate cancer.

Homologous recombination inquiry through ovarian malignancy investigations: JGOG3025 Study.

The Cancer Genome Atlas (TCGA) network has clarified that ~50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next-generation sequencing for 51 targeted genes (including 29 HR-associated genes) in 701 ovarian cancers (298 high-grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low-grade serous cases, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55-0.94) and 0.57 (95% CI, 0.38-0.86) for PFS and OS, respectively, compared with those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR-associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR-associated gene in ovarian cancer.

Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study.

BACKGROUND: This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC). METHODS: In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes "HRDness signature". We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction. RESULTS: High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation. CONCLUSIONS: The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.

Ovarian serous borderline tumors with recurrent or extraovarian lesions: a Japanese, retrospective, multi-institutional, population-based study.

BACKGROUND: Ovarian serous borderline tumors (SBT) are typically unilateral and are primarily treated using hysterectomy and bilateral salpingooophorectomy (SO). However, most young patients prefer fertility-sparing surgeries (FSS) with tumorectomy or unilateral SO. Micropapillary morphology and invasive implants have been designated as histopathological risk indicators for recurrence or metastasis, but their clinical impact remains controversial because of limitations like diagnostic inconsistency and incomplete surgical staging. METHODS: A nationwide multi-institutional population-based retrospective surveillance was conducted with a thorough central pathology review to reveal the clinical features of SBT. Of 313 SBT patients enrolled in the Japanese Society of Clinical Oncology's Surveillance of Gynecologic Rare Tumors, 289 patient records were reviewed for clinical outcomes. The glass slides of patients at stage II-IV or with recurrence or death were re-evaluated by three gynecological pathologists. RESULT: The 10-year overall and progression-free survival (PFS) rates were 98.6% and 92.3%. The median recurrence period was 40 months and 77.0% was observed in the contralateral ovary within 60 months. Patients aged ≤ 35 years underwent FSS more frequently and relapsed more (p < .001). A clinic-pathological analysis revealed diagnosis during pregnancy, FSS, and treatment at non-university institutes as well as advanced stage and large diameter were independent risk factors of recurrence. Among patients having pathologically confirmed SBTs, PFS was not influenced by the presence of micropapillary pattern or invasive implants. CONCLUSION: The recurrence rate was lower in this cohort than previous reports, but the clinical impacts of incomplete resection and misclassification of the tumor were still significant on the treatment of SBT.

Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor.

Cervical cancer is one of the most common cancers in women. The development of new therapies with immune checkpoint inhibitors (ICIs) is being investigated for cervical cancer; however, their efficacy is not currently sufficient. Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. In this report, the therapeutic potential of a triple-mutated oncolytic herpes virus (T-01) with an ICI for human papillomavirus (HPV)-related cervical cancer was evaluated using a bilateral syngeneic murine model. The efficacy of intratumoral (i.t.) administration with T-01 and subcutaneous (s.c.) administration of anti-programmed cell death ligand 1 (PD-L1) antibody (Ab) was equivalent to that of anti-PD-L1 Ab alone on the T-01-injected side. Moreover, combination therapy had no significant antitumor effect compared to monotherapy on the T-01-non-injected side. Combination therapy significantly increased the number of tumor specific T cells in the tumor. While T-01 could not be isolated from tumors receiving combination therapy, it could be isolated following T-01 monotherapy. Furthermore, T-01 had a cytotoxic effect on stimulated T cells. These results suggest that T-01 and anti-PD-L1 Ab partially counteract and therefore concomitant administration should be considered with caution.

Immunosuppressive tumor microenvironment in uterine serous carcinoma via CCL7 signal with myeloid-derived suppressor cells.

Serous carcinoma of the uterus (USC) is a pathological subtype of high-grade endometrial cancers, with no effective treatment for advanced cases. Since such refractory tumors frequently harbor antitumor immune tolerance, many immunotherapies have been investigated for various malignant tumors using immuno-competent animal models mimicking their local immunities. In this study, we established an orthotopic mouse model of high-grade endometrial cancer and evaluated the local tumor immunity to explore the efficacy of immunotherapies against USC. A multivariate analysis of 62 human USC cases revealed that the tumor-infiltrating cell status, few CD8+ cells and abundant myeloid-derived suppressor cells (MDSCs), was an independent prognostic factor (P < 0.005). A murine endometrial cancer cell (mECC) was obtained from C57BL/6 mice via endometrium-specific deletion of Pten and Tp53, and another high-grade cell (HPmECC) was established by further overexpressing Myc in mECCs. HPmECCs exhibited higher capacities of migration and anchorage-independent proliferation than mECCs (P < 0.01, P < 0.0001), and when both types of cells were inoculated into the uterus of C57BL/6 mice, the prognosis of mice bearing HPmECC-derived tumors was significantly poorer (P < 0.001). Histopathological analysis of HPmECC orthotopic tumors showed serous carcinoma-like features with prominent tumor infiltration of MDSCs (P < 0.05), and anti-Gr-1 antibody treatment significantly prolonged the prognosis of HPmECC-derived tumor-bearing mice (P < 0.05). High CCL7 expression was observed in human USC and HPmECC, and MDSCs migration was promoted in a CCL7 concentration-dependent manner. These results indicate that antitumor immunity is suppressed in USC due to increased number of tumor-infiltrating MDSCs via CCL signal.

Prevalence of common aneuploidy in twin pregnancies.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04-0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Sentinel node navigation surgery in cervical cancer: a systematic review and metaanalysis.

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.

Comparison of treatment outcomes between first-line chemotherapy with or without bevacizumab for advanced ovarian, fallopian tube, and primary peritoneal cancer (Tohoku gynecologic cancer unit: TGCU-RS001 study).

BACKGROUND: Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit. PATIENTS AND METHODS: The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events. RESULTS: The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P < 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P < 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P < 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group. CONCLUSION: Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.

The efficacy of a third-generation oncolytic herpes simplex viral therapy for an HPV-related uterine cervical cancer model.

PURPOSE: Cervical cancer is the fourth most common cancer in women and the seventh most common of all human cancers. Development of new treatments is mandatory to improve the outcome of this disease. Replication-selective oncolytic herpes simplex viruses (HSVs) have emerged as a new platform for cancer therapy. The therapeutic potential of a triple-mutated oncolytic HSV (T-01) for human papillomavirus (HPV)-related cervical cancer was evaluated with immunodeficient and immune-complete models. METHODS: (1) The in vitro efficacy of T-01 on human cervical cancer cell lines, TC-1, HeLa, CaSki, and SKG IIIa was evaluated. (2) The in vivo efficacy of T-01 was examined in human HeLa xenograft and TC-1 syngeneic models of human cervical cancer. After flank tumors reached 5 mm in diameter, the first intratumoral (i.t.) administration of T-01 was performed. Intratumoral administration of T-01 was performed with a 5 day interval a total of 6 times. RESULTS: In the in vitro study, T-01 was highly cytotoxic for all cell lines (48 h after infection with T-01 at 1 × 105 PFU, T-01 killing HeLa: 67.5%, Caski: 62.8%, SKG IIIa: 43.2%). Furthermore, in the human HeLa xenograft and TC-1 syngeneic models, T-01 resulted in a significant reduction of tumor growth. In addition, tumor-bearing mice treated with T-01 showed significantly increased numbers of CD8 + T-cells precursors than the control mice (p = 0.03). CONCLUSIONS: These results demonstrate that T-01 has cytotoxic efficacy and inhibited against HPV-related cervical cancer cells. These findings indicate that T-01 has therapeutic potential for HPV-related cervical cancer.

Survey of the clinical practice pattern of using sentinel lymph node biopsy in patients with gynecological cancers in Japan: the Japan Society of Gynecologic Oncology study.

BACKGROUND: Sentinel lymph node (SN) biopsy is essential for evaluating survival and minimal treatment-related morbidity associated with cervical, endometrial, and vulvar cancer in Japan. As such, our aim in this study was to evaluate the current practice pattern of using SN biopsy for cervical, endometrial, and vulvar cancer in Japan. METHODS: We deployed a 47-question survey on the use of SN biopsy for gynecological cancers to 216 gynecological oncology training facilities. The survey included information on the use of SN biopsy for uterine (cervical and endometrial) and vulvar cancers; details on the type, timing, and concentration of tracers used; surgical approach used for SN biopsy; method of biopsy and pathological examination; and facilities' experience with clinical research on SN biopsy. RESULTS: The response rate was 84% (181/216), with 40 facilities (22%) having experience in SN biopsy for gynecological cancers, 34 (85%) for uterine cancers, and 15 (37%) for vulvar cancers. Radioisotope, indocyanine green (ICG), and blue dyes were available for the detection of uterine cancers in 21 (52%), 25 (62%), and 19 (48%) facilities and for vulvar cancers in 9 (22%), 3 (7%), and 11 (27%) facilities, respectively. Thirty-four facilities (85%) used intraoperative frozen section procedure for diagnosis when possible, with 24 (71%) of these facilities using 2-mm specimen cuts. Diagnosis included pathological examination (85%), immunostaining (57%), and one-step nucleic acid amplification (5%). CONCLUSION: Increasing research evidence, providing insurance coverage for radioisotope tracers, and increasing the availability of training are expected to increase the use of SN biopsy in Japan.

A Novel Direct Approach to the Deep Uterine Vein in Laparoscopic Radical Hysterectomy.

STUDY OBJECTIVE: To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy. DESIGN: Demonstration of the laparoscopic technique with narrated video footage. SETTING: Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein. INTERVENTIONS: Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures. CONCLUSION: Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed.

Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition.

Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer.

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

Comparison of Postoperative Adjuvant Chemotherapy and Concurrent Chemoradiotherapy for FIGO2018 Stage IIIC1 Cervical Cancer: A Retrospective Study.

Background and Objectives: In October 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised its classification of advanced stages of cervical cancer. The main points of the classification are as follows: stage IIIC is newly established; pelvic lymph node metastasis is stage IIIC1; and para-aortic lymph node metastasis is stage IIIC2. Currently, in Japan, radical hysterectomy is performed in advanced stages IA2 to IIB of FIGO2014, and concurrent chemoradiotherapy (CCRT) is recommended for patients with positive lymph nodes. However, the efficacy of CCRT is not always satisfactory. The aim of this study was to compare postoperative adjuvant chemotherapy (CT) and postoperative CCRT in stage IIIC1 patients. Materials and Methods: Of the 40 patients who had undergone a radical hysterectomy at Iwate Medical University between January 2011 and December 2016 and were pathologically diagnosed as having positive pelvic lymph nodes, 21 patients in the adjuvant CT group and 19 patients in the postoperative CCRT group were compared. Results: The 5 year survival rates were 77.9% in the CT group and 74.7% in the CCRT group, with no significant difference. There was no significant difference in overall survival or progression-free survival between the two groups. There was no significant difference between CT and CCRT in postoperative adjuvant therapy in the new classification IIIC1 stage. Conclusions: The results of the prospective Japanese Gynecologic Oncology Group (JGOG) 1082 study are pending, but the present results suggest that CT may be a treatment option in rural areas where radiotherapy facilities are limited.

Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment.

BACKGROUND: The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy. METHODS: The frequencies of immune cell populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. The expression profiles of both the proteins and genes in the resistant tumours were analysed. The impact of granulocyte-monocyte colony-stimulating factor (GM-CSF) expression on myeloid-derived suppressor cell (MDSC) function in the resistant tumours was evaluated. RESULTS: We found a marked increase and reduction in the number of Gr-1 + MDSCs and CD8 + lymphocytes in the resistant tumour, and the MDSCs preferentially infiltrated the hypoxic region. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. GM-CSF promoted migration and differentiation of MDSCs, which inhibited the CD8 + lymphocyte proliferation. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case. CONCLUSIONS: The anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers.

UGT1A1 polymorphism has a prognostic effect in patients with stage IB or II uterine cervical cancer and one or no metastatic pelvic nodes receiving irinotecan chemotherapy: a retrospective study.

BACKGROUND: Uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) is a predictive biomarker for the side-effects of irinotecan chemotherapy, which reduces the volume of tumors harboring UGT1A1 polymorphisms. We aimed to determine whether UGT1A1 polymorphisms can predict progression-free survival in patients with local cervical cancer treated with irinotecan chemotherapy. METHODS: We retrospectively analyzed the data of 51 patients with cervical cancer treated at a single institution between 2010 and 2015. All patients were diagnosed with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IB1, IB2, IIA, or IIB squamous cell carcinoma, underwent radical hysterectomy, and received irinotecan chemotherapy as neoadjuvant and/or adjuvant treatment. All patients were examined for irinotecan side effects using UGT1A1 tests. Conditional inference tree and survival analyses were performed considering the FIGO stage, age, the UGT1A1 status, and the number of metastatic lymph nodes to determine primary factors associated with progression-free survival. RESULTS: The tree-structured survival model determined high recurrence-risk factors related to progression-free survival. The most relevant factor was ≥2 metastatic lymph nodes (p = 0.004). The second most relevant factor was UGT1A1 genotype (p = 0.024). Among patients with ≤1 metastatic lymph node, those with UGT1A1 polymorphisms benefited from irinotecan chemotherapy and demonstrated significantly longer progression-free survival (p = 0.020) than those with wild-type UGT1A1. CONCLUSIONS: Irinotecan chemotherapy might be beneficial in patients with cervical cancer, UGT1A1 polymorphisms, and ≤ 1 metastatic lymph nodes.