Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer at a single institution: A retrospective study.

AIM: In this study, we aimed to investigate patient characteristics, efficacy, prognostic factors, and safety of olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer at our institution. METHODS: Patients responding to platinum-based therapy and starting olaparib maintenance therapy for recurrent epithelial ovarian, fallopian tube, or peritoneal cancer at Kurume University Hospital between January 2018 and November 2021 were enrolled in the study. Their data were extracted retrospectively from medical records. RESULTS: In all, 50 patients were included. The median (range) age of the patients, follow-up time, and duration of olaparib maintenance therapy were 62 (39-87) years, 21.6 (2.2-45.9) months, and 7.2 (2-45.9) months, respectively. Among the 29 patients tested for homologous recombination (HR) status, 22 (75.9%) were positive for HR deficiency (HRD), 12 (54.5%) of whom had BRCA-positive tumors. The median progression-free survival was 8.9 months (95% confidence interval: 6.2-12.6), and the median overall survival was 27.1 months (95% confidence interval: 22.5-40.3). Multivariate analysis of prognostic factors revealed that HRD was an independent prognostic factor for both progression-free survival and overall survival. The most common adverse event was nausea (any grade, n = 30, 60%), resulting in drug interruption (n = 23, 46%), dose reduction (n = 17, 34%), and discontinuation of treatment (n = 1, 2%). CONCLUSION: Olaparib maintenance therapy for recurrent platinum-sensitive ovarian cancer at our institution was effective, with acceptable adverse events. HRD was the most significant prognostic factor for patients with recurrent platinum-sensitive ovarian cancer.

Association of Chemotherapy Response Score with Multidrug Resistance 1 and CA125 ELIMination Rate Constant K in Patients with Advanced Ovarian Cancer Treated with Neoadjuvant Chemotherapy.

AIM: The relationship between chemotherapy response score (CRS), a widely used response predictor of neoadjuvant chemotherapy-interval debulking surgery (NAC-IDS), and multidrug resistance 1 (MDR1) and CA125 ELIMination rate constant K (KELIM), is undetermined. We evaluated CRS in advanced ovarian cancer patients undergoing NAC and looked for associations between CRS and MDR1 and CA125 KELIM. Our aim was to predict the therapeutic effect of NAC before interval debulking surgery (IDS) by examining its association with CRS. METHODS: This retrospective cohort study included patients who underwent NAC-IDS (first-line treatment) at Kurume University Hospital, Japan, between 2004 and 2017. CRS association with MDR1 and CA125 KELIM was examined using Cox proportional hazard regression analyses. Survival curves used Kaplan-Meier method, and survival differences between groups used log-rank test. RESULTS: Overall, 55 patients were classified into CRS1 (n=22), CRS2 (n=19), and CRS3 (n=14). The CRS3 group had a significantly better prognosis than the CRS1 or CRS2 group. CRS, age, and IDS status were clinical prognostic factors for ovarian cancer. MDR1 positivity for excision repair cross-complementing group 1, ß-tubulin, and Y-box binding protein-1 occurred in 15, 17, and 11 patients, respectively, but these were not associated with CRS. CA125 KELIM was <0.5 (n=8), 0.5-1.0 (n=30), and ≥ 1.0 (n=17) but not associated with CRS. CONCLUSION: CRS is reconfirmed as a treatment response predictor for NAC-IDS, but its association with drug resistance factors remains unconfirmed.

Comprehensive Molecular Profiling and Clinicopathological Characteristics of Gastric-Type Mucinous Carcinoma of the Uterine Cervix in Japanese Women.

Gastric-type mucinous carcinoma (GAS) of the uterine cervix is the most common adenocarcinoma that develops independently of human papillomavirus infection; it is typically diagnosed at an advanced stage and has a poorer prognosis than usual-type endocervical adenocarcinoma. Few studies have examined the molecular profile of GAS, but genetic alterations in TP53 and STK11 have been repeatedly reported. We analyzed the clinicopathological characteristics and molecular profile of GAS. Fresh-frozen tissue specimens and formalin-fixed paraffin-embedded (FFPE) tissues from 13 patients with GAS treated between January 2000 and December 2020 were analyzed. We performed next-generation sequencing on eight fresh-frozen GAS specimens using the Cancer Hotspot Panel v2 (cases 1-8) and the FoundationOne companion diagnostic (F1CDx) assay on six FFPE samples (cases 8-13). Seventy-four genomic alterations were identified in 42 genes. In order of frequency, TP53, ATRX, CDKN2A, KRAS, APC, and STK11 were altered in at least three cases. Targetable genomic alterations were identified in all six patients' specimens analyzed using the F1CDx assay. GAS harbors various genomic alterations associated with sustained activation of signaling pathways or cell cycle regulation in addition to abnormalities in TP53, and precision medicine based on molecular profiling will be necessary to overcome GAS.

N-Myc Downstream Regulated Gene-1 May Play an Important Role in the Prognosis of Ovarian Cancer, in Its Association with Beta-Catenin.

NDRG1 is a nickel- and calcium-inducible gene that plays important roles in the primary growth of malignant tumors, as well as in invasion and metastasis. This study investigated the associations of NDRG1 expression with cell adhesion and other clinicopathological factors in ovarian cancer. The clinical records of 123 women who underwent surgery for ovarian cancer in our institute were reviewed retrospectively. The expression of NDRG1, E-cadherin, and beta-catenin in surgical specimens were evaluated immunohistochemically. The NDRG1 expression level was significantly associated with beta-catenin expression, peritoneal metastasis outside the pelvic cavity, lymph node metastasis, and FIGO stages. The Kaplan-Meier analysis showed a significant association between the NDRG1 expression level and progression-free survival: high NDRG1 expression was related to poor survival. Our results suggest that the increased expression of NDRG1 is associated with cell adhesion and may be a poor prognostic indicator in women with ovarian cancer.

Platinum rechallenge treatment using gemcitabine plus carboplatin with or without bevacizumab for platinum-resistant ovarian cancer.

PURPOSE: Platinum-resistant ovarian cancer (PROC) is usually treated with single-agent chemotherapy. A synergistic effect of gemcitabine and platinum has been reported in PROC. We evaluated the efficacy and safety of gemcitabine and carboplatin with or without bevacizumab (GC ± B) in patients with PROC. METHODS: From April 2014 to April 2018, patients with PROC received gemcitabine on days 1 and 8, and carboplatin on day 1, with or without bevacizumab (Bev) on day 1 every 3 weeks. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and rate of adverse events. RESULTS: In total, 215 cycles were administered to 31 patients, of whom 21 received Bev and the median number of cycle for each patient was 6 (range, 2-19). The median platinum-free interval (PFI) was 4 months. The ORR and DCR were 51.9% and 92.6%, respectively. Median PFS and OS were 7.9 months and 16.1 months, respectively. PFS and OS of patients with 3-6 months PFI were significantly longer than those with PFI < 3 months (median PFS, 9.7 vs. 5.8 months; p < 0.01; median OS, 20.0 vs. 12.1 months; p = 0.03). Grade 3 or 4 hematological toxicities observed included neutropenia (71.0%), leukopenia (54.8%), anemia (51.6%), and thrombocytopenia (25.8%). No other grade 2-4 nonhematological toxicity was observed except for hypertension in one and CBDCA hypersensitivity reaction in two. CONCLUSION: GC ± B may be effective and safe treatment alternative for PROC, especially with PFI of 3-6 months, despite hematological toxicity.

Human papillomavirus genotyping predicts residual/recurrent disease after local treatment for cervical intraepithelial neoplasia better than viral DNA testing.

AIM: Type-specific persistent infection (TSPI) of human papillomavirus (HPV) is reportedly associated with a high risk of residual/recurrent disease after local treatment for cervical intraepithelial neoplasia (CIN). This study aimed to evaluate whether HPV genotyping is more accurate in detecting residual/recurrent disease than HPV DNA testing and identify which HPV genotype can predict a high risk of residual/recurrent disease. METHODS: We retrospectively reviewed patient outcomes and results of HPV DNA testing and genotyping at 6-12 months after local treatment for CIN2/3 for 439 women. We investigated residual/recurrent disease occurrence according to the TSPI and new infections. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) of the two testing methods for predicting residual/recurrent diseases were also evaluated. RESULTS: Eighty-five (19.4%) patients were positive for HPV DNA testing after treatment, of which 74 (87.1%) had TSPI. Residual/recurrent disease was identified in 34 (7.7%) patients, of which 30 were positive for HPV DNA testing and had TSPI of HPV16, 18, 31, 33, 52, and 58 (six HPV genotypes). The sensitivity and NPV of HPV DNA testing and TSPI were equal at 88.2% and 98.9%, respectively. The specificity and PPV of TSPI were higher than those of HPV DNA testing (89.1% vs. 86.4%, 40.5% vs. 35.2%, respectively). Furthermore, the TSPI of the six HPV genotypes further improved specificity (90.6%) and PPV (44.1%) with the same sensitivity and NPV. CONCLUSION: HPV genotyping is more useful than HPV DNA testing for determining TSPI, especially of the six HPV genotypes.

Carcinomatous meningitis from recurrent glassy cell carcinoma of the uterine cervix-A case report.

Carcinomatous meningitis presents with a variety of neurological symptoms and has a poor prognosis. We encountered a case of carcinomatous meningitis from cervical cancer. A 30-year-old patient was diagnosed with cervical cancer (glassy cell carcinoma), stage IIB. She underwent radical hysterectomy and chemoradiotherapy. Nine months later, the disease recurred with iliac lymph node and right lung metastases. The patient received chemotherapy; however, after seven cycles, the lung lesions increased. The patient responded to supportive care; nevertheless, symptoms including headaches developed and were followed by diplopia. A contrast-enhanced magnetic resonance image of the head confirmed the diagnosis of carcinomatous meningitis. She was transferred to the palliative care unit and died approximately 1 week later. Carcinomatous meningitis has a poor prognosis and is difficult to treat; however, early diagnosis may provide meaningful time to patients. Therefore, attention must be paid to meningeal irritation and neurological symptoms.

Correlation of World Health Organization 2010 Classification for Gastroenteropancreatic Neuroendocrine Neoplasms with the Prognosis of Ovarian Neuroendocrine Neoplasms: Kansai Clinical Oncology Group-Protocol Review Committee/Intergroup Study.

BACKGROUND: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis. METHODS: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS). RESULTS: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01). CONCLUSION: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors.

Clinicopathologic features, treatment, prognosis and prognostic factors of neuroendocrine carcinoma of the endometrium: a retrospective analysis of 42 cases from the Kansai Clinical Oncology Group/Intergroup study in Japan.

OBJECTIVE: We conducted a retrospective, multi-institutional, collaborative study to accumulate cases of neuroendocrine carcinoma of the endometrium, to clarify its clinicopathologic features, treatment, prognosis and prognostic factors to collate findings to establish future individualized treatment regimens. To our knowledge, this is the largest case study and the first study to statistically analyze the prognosis of this disease. METHODS: At medical institutions participating in the Kansai Clinical Oncology Group/Intergroup, cases diagnosed at a central pathologic review as neuroendocrine carcinoma of the endometrium between 1995 and 2014 were enrolled. We retrospectively analyzed the clinicopathologic features, treatment, prognosis and prognostic factors of this disease. RESULTS: A total of 65 cases were registered from 18 medical institutions in Japan. Of these, 42 (64.6%) cases were diagnosed as neuroendocrine carcinoma of the endometrium based on the central pathological review and thus included in the study. Advanced International Federation of Gynecology and Obstetrics stages (stage III and IV) and pure type small cell neuroendocrine carcinoma cases had a significantly worse prognosis. Upon multivariate analysis, only histologic subtypes and surgery were significant prognostic factors. Pure type cases had a significantly worse prognosis compared to mixed type cases and complete surgery cases had a significantly better prognosis compared to cases with no or incomplete surgery. CONCLUSION: Our findings suggest that complete surgery improves the prognosis of neuroendocrine carcinoma of the endometrium. Even among cases with advanced disease stages, if complete surgery is expected to be achieved, clinicians should consider curative surgery to improve the prognosis of neuroendocrine carcinoma of the endometrium.

A phase II trial of irinotecan in patients with advanced or recurrent endometrial cancer and correlation with biomarker analysis.

OBJECTIVE: Chemotherapy for advanced or recurrent endometrial cancer requires further development. Irinotecan hydrochloride (CPT-11) suppresses tumor growth in several endometrial cancer strains. The present study evaluated the anti-tumor activity and toxicity of CPT-11 in patients with advanced or recurrent endometrial cancer. METHODS: Enrolled patients had advanced endometrial cancer with measurable lesions and received 2 pretreatment regimens. A 90-minute intravenous infusion of CPT-11 (100 mg/m2) was given on days 1, 8, and 15 of a 4-week cycle, aiming for an effect with ≤2 cycles. Treatment was continued until the primary disease worsened or severe toxicity occurred. The primary endpoint was response rate, and the secondary endpoints were progression-free survival, overall survival, and adverse events. Antitumor effect and adverse events were evaluated according to RECIST version 1.1 and NCI-CTC AE version 3.0, respectively. RESULTS: Twenty-two patients were registered (11 endometrioid carcinomas and 11 serous carcinomas). The median duration of the treatment-free interval (TFI) was 7.5 months, and the median number of administered cycles per patient was 4. Response rate was 36.4% (complete response: 1 patient, partial response: 7 patients). Clinical benefit rate, including stable disease, was 77.3%. Median progression-free and overall survival was 4.4 and 18.4 months, respectively. Observed adverse events included grade 4 hematotoxicity (neutropenia and thrombocytopenia), and grade 2 or 3 non-hematotoxicity (diarrhea). All adverse events were manageable. Biomarker predictors of therapeutic effectiveness were not observed. CONCLUSION: As a single agent, CPT-11 has anti-tumor activity for advanced or recurrent endometrial cancer and has manageable adverse events.

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

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 b.i.d. 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 five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. 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.

Clinical Utility of Endometrial Cell Block Cytology in Postmenopausal Women.

OBJECTIVE: To investigate the diagnostic utility of endometrial (EM) cell block (CB) cytology for the detection of intrauterine malignancy in postmenopausal women. METHODS: We reviewed the medical records of 104 postmenopausal women between January 2012 and November 2014. We reviewed symptoms upon admission, body mass index, parity, transvaginal ultrasonographic findings, and histopathological results based on CB and conventional cytology. RESULTS: The mean age was 62.6 (range 48-95) years. The mean menopausal age was 50.8 years and the mean duration of menopause was 12.0 years. The sensitivity of CB and conventional cytology was 82.3% (29/35) and 85.7% (30/35) and the specificity was 98.6% (68/69) and 94.2% (65/69), respectively. The sensitivity and specificity of CB cytology combined with conventional cytology were 82.3% (29/35) and 94.2% (65/69), respectively. The predictive values for EM hyperplasia and type-II carcinoma were 100 and 85.7%, respectively. CONCLUSION: CB cytology provides specimens for examination in a single outpatient session. Additionally, immunohistochemical staining can provide useful information for histological diagnosis. A combination of CB and conventional cytology can improve the diagnostic accuracy of EM lesions and may be a valid method for screening in postmenopausal women.

Enhancement of humoral and cell mediated immune response to HPV16 L1-derived peptides subsequent to vaccination with prophylactic bivalent HPV L1 virus-like particle vaccine in healthy females.

Currently prophylactic HPV16/18 L1 virus-like particle (VLP) vaccines are employed with great success for the prevention of HPV infection. However, limited information is available regarding the immune responses against human papillomavirus (HPV) 16/18 L1 subsequent to HPV16/18 L1 VLP vaccination, primarily due to the lack of widely used assays for immune monitoring. The aim of the present study was to identify HPV16 L1-derived B and T cell epitopes for monitoring the immune responses after HPV16/18 L1 VLP vaccination in healthy females. The levels of immunoglobulin G (IgG), IgE, IgA and IgM reactive to HPV16 L1-derived peptides were measured by multiplex bead suspension assay. Following detailed B cell epitope mapping, T cell responses specific to HPV16 L1-derived peptides were evaluated by an IFN-γ ELISPOT assay. The levels of IgG, IgM and IgA reactive to 20-mer peptides (PTPSGSMVTSDAQIFNKPYW) at positions 293-312 and 300-319 of HPV16 L1 were significantly increased in the plasma after 2, 7, and 12 months after first vaccination. Detailed epitope mapping identified the amino acid sequence (TSDAQIFNKP) at position 301-310 of HPV16 L1 as an immunogenic B cell epitope. In addition, T cell responses to an HLA-A2- and HLA-A24-restricted epitope (QIFNKPYWL) at position 305-313 of HPV16 L1 were increased following immunization, suggesting that the HPV16/18 L1-VLP vaccination as able to induce specific immune responses in T and B cells simultaneously. The identified B and T cell epitopes may be useful as a biomarker for monitoring the immune responses subsequent to HPV16/18 L1 VLP vaccination. Thus, the present study may provide novel information to improve the understanding of the immune responses to HPV16 L1.

Identification of appropriate cone length to avoid positive cone margin in high grade cervical intraepithelial neoplasia.

OBJECTIVE: To identify key factors for predicting positive cone margin and appropriate cone length. METHODS: We retrospectively reviewed the margin status of patients who received conization with high grade cervical intraepithelial neoplasia, along with other factors such as patient age, parity, preoperative cytology, size of disease, type of transformation zone, and cone length from patient records. Cut-off value of cone length was analyzed in women younger than 40 years old because we design conization with minimum length especially for women who wish for future pregnancy. Cut-off value of cone length was defined as length corresponds to estimated probability of positive cone margin equal to 0.1 by logistic regression analysis with variables selected by stepwise methods. RESULTS: Among 300 patients, 75 patients had positive cone margin. Multivariable analysis revealed that squamous cell carcinoma at preoperative cytology (p=0.001), 2 or more quadrant disease (p=0.011), and shorter cone length (p<0.001) were risk factors for positive cone margin. Stepwise methods identified cone length and size of lesion as important variables. With this condition, cut-off value of cone length was estimated as 15 mm in single quadrant disease and 20 mm in 2 or more quadrant disease, respectively. CONCLUSION: We identified the independent risk factors of positive cone margin and identified the cut-off value of cone length to avoid positive cone margin in women younger than 40 years old. Conization should be performed not only according to colposcopic findings including type of transformation zone but size of disease and cone length.

Epithelial borderline ovarian tumor: Diagnosis and treatment strategy.

Epithelial borderline ovarian tumors (BOT) are distinctive from benign tumors and carcinoma. They occur in younger women more often than carcinoma, and there is some difficulty making correct diagnosis of BOT. Two subtypes of BOT, serous and mucinous borderline tumor have different characteristics and very different clinical behavior. Serous borderline tumor (SBT) with micropapillary pattern shows more incidence of extra ovarian disease and often coexists with invasive implant. SBT with micropapillary pattern in advanced stage has showed a worse prognosis than typical SBT. Huge mucinous borderline tumors have histologic heterogeneity, and the accuracy of frozen section diagnosis is relatively low. Extensive sampling is required to reach a correct pathological diagnosis. Mucinous adenoma (intestinal type) also runs the risk of recurrence after cystectomy, or intraoperative rupture of cyst. Laparoscopic procedure for BOT has not increased the risk of recurrence. Fertility preserving procedures are generally accepted, except in advanced stage SBT with invasive implants. Only cystectomy shows a significant risk of recurrence. Re-staging surgery and full staging surgery is not necessary for all BOT. We should not attempt to treat them uniformly, by the single diagnosis of "borderline tumor". It depends on histologic type. Close communication with the pathologist is necessary to gain more detail and ask more pathological samples in order to make the optimal treatment strategy for each individual patients.