Histopathological subtyping of high- grade serous ovarian cancer using whole slide imaging

Chiho Miyagawa,Hidekatsu Nakai,Tomoyuki Otani,Ryusuke Murakami,Shiki Takamura,Hisamitsu Takaya,Kosuke Murakami,Masaki Mandai,Noriomi Matsumura 대한부인종양학회 2023 Journal of Gynecologic Oncology Vol.34 No.4

Objective: We have established 4 histopathologic subtyping of high-grade serous ovarian cancer (HGSOC) and reported that the mesenchymal transition (MT) type has a worse prognosis than the other subtypes. In this study, we modified the histopathologic subtyping algorithm to achieve high interobserver agreement in whole slide imaging (WSI) and to characterize the tumor biology of MT type for treatment individualization. Methods: Four observers performed histopathological subtyping using WSI of HGSOC in The Cancer Genome Atlas data. As a validation set, cases from Kindai and Kyoto Universities were independently evaluated by the 4 observers to determine concordance rates. In addition, genes highly expressed in MT type were examined by gene ontology term analysis. Immunohistochemistry was also performed to validate the pathway analysis. Results: After algorithm modification, the kappa coefficient, which indicates interobserver agreement, was greater than 0.5 (moderate agreement) for the 4 classifications and greater than 0.7 (substantial agreement) for the 2 classifications (MT vs. non-MT). Gene expression analysis showed that gene ontology terms related to angiogenesis and immune response were enriched in the genes highly expressed in the MT type. CD31 positive microvessel density was higher in the MT type compared to the non-MT type, and tumor groups with high infiltration of CD8/CD103 positive immune cells were observed in the MT type. Conclusion: We developed an algorithm for reproducible histopathologic subtyping classification of HGSOC using WSI. The results of this study may be useful for treatment individualization of HGSOC, including angiogenesis inhibitors and immunotherapy.

Groin lymph node detection and sentinel lymph node biopsy in vulvar cancer

Chieko Sakae,Ken Yamaguchi,Noriomi Matsumura,Hidekatsu Nakai,Yumiko Yoshioka,Eiji Kondoh,Junzo Hamanishi,Kaoru Abiko,Masafumi Koshiyama,Tsukasa Baba,Aki Kido,Masaki Mandai,Ikuo Konishi 대한부인종양학회 2016 Journal of Gynecologic Oncology Vol.27 No.6

Objective: To identify suitable diagnostic tools and evaluate the efficacy of sentinel lymphnode (SLN) biopsy for inguinal lymph node metastasis in vulvar cancer. Methods: Data from 41 patients with vulvar cancer were evaluated retrospectively, includingmagnetic resonance imaging (MRI) measurements, SLN biopsy status, groin lymph nodemetastasis, and prognosis. Results: SLN biopsy was conducted in 12 patients who had stage I to III disease. Groinlymphadenectomy was omitted in five of the nine patients with negative SLNs. All SLNnegativepatients who did not undergo groin lymphadenectomy showed no evidence ofdisease after treatment. On MRI, the long and short diameters of the inguinal node weresignificantly longer in metastasis-positive cases, compared with negative cases, in 25 patientswhose nodes were evaluated pathologically (long diameter, 12.8 mm vs. 8.8 mm, p=0.025;short diameter, 9.2 mm vs. 6.7 mm, p=0.041). The threshold of >10.0 mm for the longaxis gave a sensitivity, specificity, positive predictive value, and negative predictive value of87.5%, 70.6%, 58.3%, and 92.3%, respectively, using a binary classification test. Decisiontree analysis revealed a sensitivity, specificity, and accuracy of 87.5%, 70.6%, and 76.0%,respectively, with the threshold of >10.0 mm for the long axis on MRI. The criteria of >10.0mm for the long axis on MRI predicted an advanced stage and poorer prognosis using avalidation set of 15 cases (p=0.028). Conclusion: Minimally invasive surgery after preoperative evaluation on MRI and SLN biopsyis a feasible strategy for patients with vulvar cancer.

Adult granulosa cell tumors of the ovary: a retrospective study of 30 cases with respect to the expression of steroid synthesis enzymes

Sachiko Kitamura,Kaoru Abiko,Noriomi Matsumura,Hidekatsu Nakai,Yumiko Akimoto,Hirotoshi Tanimoto,Ikuo Konishi 대한부인종양학회 2017 Journal of Gynecologic Oncology Vol.28 No.4

Objective: Some, but not all, granulosa cell tumors are characterized by estrogen production. This study was designed to determine whether there are clinical or pathological variations ingranulosa cell tumors in relation to the expression of sex steroid synthesis enzymes. Methods: Clinical symptoms, serum hormonal values, and histology of 30 granulosacell tumor patients who underwent surgery between 2002 and 2014 were retrospectivelyreviewed. Results: Most patients presented with abnormal genital bleeding including abnormalmenstrual cycles. Eight of 16 patients older than 50 years had endometrial hyperplasia andone had endometrial cancer. Serum 17β-estradiol (E2) levels tended to be higher in patientsover 50 years of age (p=0.081). Serum follicle-stimulating hormone (FSH) levels were low inall patients irrespective of serum E2 levels. Magnetic resonance imaging revealed a thickerendometrium in older as compared to younger patients (p<0.05). Tumor cells in the majorityof cases were positive for inhibin α and P450 aromatase, irrespective of age and serum E2levels. P450 17α-hydroxylase (P450c17) expression varied among cases. P450c17 was stronglypositive in luteinized tumor cells and weakly positive in theca cells and fibroblasts. High E2levels were associated with P450c17-positive cells in the tumor (p<0.05). Conclusion: The expression of hormone-synthesizing enzymes divides granulosa celltumors into 2 distinct types; tumors with P450c17-positive cells show elevated serum E2 andrelated clinical symptoms, while tumors without these cells show symptoms related to FSHsuppression by inhibin.

Quality indicators for cervical cancer care in Japan

Tomone Watanabe,Mikio Mikami,Hidetaka Katabuchi,Shingo Kato,Masanori Kaneuchi,Masahiro Takahashi,Hidekatsu Nakai,Satoru Nagase,Hitoshi Niikura,Masaki Mandai,Yasuyuki Hirashima,Hiroyuki Yanai,Wataru Ya 대한부인종양학회 2018 Journal of Gynecologic Oncology Vol.29 No.6

Objective: Choice of hysterectomy and adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrioid endometrial cancer (EEC) is still controversial. Aims of this study were to evaluate survival benefits and adverse effects of different hysterectomies with or without adjuvant radiotherapy (RT), and to identify prognostic factors. Methods: The patients at 14 member hospitals of the Taiwanese Gynecologic Oncology Group from 1992 to 2013 were retrospectively investigated. Patients were divided into simple hysterectomy (SH) alone, SH with RT, radical hysterectomy (RH) alone, and RH with RT groups. Endpoints were recurrence-free survival (RFS), overall survival (OS), disease-specific survival (DSS), adverse effects and prognostic factors for survival. Results: Total of 246 patients were enrolled. The 5-year RFS, OS, DSS and recurrence rates for the entire cohort were 89.5%, 94.3%, 96.2% and 10.2%, respectively. Patients receiving RH had more adverse effects including blood loss (p<0.001), recurrent urinary tract infections (p=0.013), and leg lymphedema (p=0.038). Age over 50-year (HR=9.2; 95% confidence interval [CI], 1.2–70.9) and grade 3 histology (HR=7.28; 95% CI, 1.45–36.6) were independent predictors of OS. Grade 3 histology was an independent predictor of RFS (HR=5.13; 95% CI, 1.38–19.1) and DSS (HR=5.97; 95% CI, 1.06–58.7). Patients receiving adjuvant RT had lower locoregional recurrence (p=0.046), but no impact on survival. Conclusion: Different treatment modalities yield similar survival outcomes. Patients receiving SH with RT had lower locoregional recurrent with acceptable morbidity. Age and tumor grading remained significant predictors for survival among patients with FIGO 2009 stage II EEC. 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.

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer

Kazuhiro Takehara,Takashi Matsumoto,Junzo Hamanishi,Kosei Hasegawa,Motoki Matsuura,Kiyonori Miura,Shoji Nagao,Hidekatsu Nakai,Naotake Tanaka,Hideki Tokunaga,Kimio Ushijima,Hidemichi Watari,Yoshihito Y 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.2

Objective: The primary objective of this study was to evaluate the safety of niraparib 300 mg/dayin Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting. Methods: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients withplatinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30days after initial niraparib administration) was justified by the incidences of a global pivotalphase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematologicaladverse event of niraparib. The overall safety analysis examined other treatment-emergentadverse events (TEAEs). Results: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8–79.1)kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib300 mg/day but this decreased in subsequent cycles (mean±standard deviation doseintensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. Noprogression-free or overall survival events occurred; only 1 of 4 response-evaluable patientshad a post-baseline tumor assessment (stable disease). Conclusion: The incidence of grade 3 or 4 thrombocytopenia-related events in Japaneseovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall,the safety profile was acceptable and consistent with the known safety profile and previousexperience with niraparib. Trial Registration: ClinicalTrials.gov Identifier: NCT03759587

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer

Aikou Okamoto,Eiji Kondo,Toshiaki Nakamura,Satoshi Yanagida,Junzo Hamanishi,Kenichi Harano,Kosei Hasegawa,Takeshi Hirasawa,Kensuke Hori,Shinichi Komiyama,Motoki Matsuura,Hidekatsu Nakai,Hiroko Nakamur 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.2

Objective: To evaluate the efficacy and safety of niraparib in Japanese women with heavilypretreated ovarian cancer. Methods: This Phase 2 open-label, single-arm study enrolled Japanese women withhomologous recombination deficiency-positive relapsed, high-grade serous ovarian,fallopian tube, or primary peritoneal cancer who had completed 3–4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-daycycles until objective progressive disease, unacceptable toxicity, consent withdrawal ordiscontinuation. The primary endpoint, objective response rate (ORR), was assessed bythe investigator using RECIST version 1.1. Safety evaluations included the incidence oftreatment-emergent adverse events (TEAEs), including serious TEAEs. Results: Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS)was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Diseasecontrol rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) wereanemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leadingto discontinuation of niraparib whereas reductions or interruptions were reported in 14(70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily)corresponded to a relative dose intensity of 67.6%. Conclusion: Efficacy and safety of niraparib in heavily pretreated Japanese women wascomparable to that seen in an equivalent population of non-Japanese women. No new safetysignals were identified.Trial Registration: ClinicalTrials.gov Identifier: NCT03759600