Objective: Chemoresistant-epithelial ovarian cancer (EOC) has a poor prognosis, prompting the search for new therapeutic drugs. The diphenylbutylpiperidine (DPBP) class of antipsychotic drugs used in schizophrenia has shown anticancer effects. This study aimed to investigate the preclinical efficacy of penfluridol, fluspirilene, and pimozide (DPBP) using in vitro and in vivo models of EOC.
Methods: Human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with penfluridol, fluspirilene, and pimozide, and cell proliferation, apoptosis, and migration were assessed. The preclinical efficacy of DPBP was also investigated using in vivo mouse models, including cell lines and patient-derived xenografts (PDX) of EOC.
Results: DPBP drugs significantly decreased cell proliferation in chemosensitive (A2780, HeyA8, and SKOV3ip1) and chemoresistant (A2780-CP20, HeyA8-MDR, and SKOV3-TR) cell lines. Among these drugs, penfluridol exerted a relatively stronger cytotoxic effect on all cell lines. Penfluridol significantly increased apoptosis and inhibited migration of EOC cells. In the cell line xenograft mouse model with HeyA8, the penfluridol group showed significantly decreased tumor weight compared with the control group. In the paclitaxel-resistant model with HeyA8-MDR, the penfluridol group had significantly decreased tumor weight compared with the paclitaxel or control groups. Penfluridol exerted anticancer effects on the PDX model.
Conclusion: Penfluridol exerted significant anticancer effects on EOC cells and xenograft models, including PDX. Thus, penfluridol therapy, as a drug repurposing strategy, might be a potential therapeutic for EOCs.
Objective: Prevention of subsequent primary cancer (SPC) is crucial for cancer survivors, particularly those who developed the disease during childhood, adolescence, and young adulthood (CAYA). The aim of this study was to assess the current status of SPC prevention among female CAYA cancer survivors.
Methods: A survey regarding long-term health issues after cancer treatment was conducted using questionnaires that targeted women aged ≥20 years who had developed cancer before the age of 40 years. The survey assessed various health issues, and this paper focuses on the items related to the respondents' perceptions and attitudes toward SPC prevention.
Results: A total of 1,026 respondents were analyzed. Over 60% of respondents were aware of SPC and the need for screening. The percentages of respondents who underwent regular SPC screening were 68.3%, 68.4%, 49.7%, 58.6%, and 57.0% for cervical, breast, lung, and gastric cancers, respectively. After adjusting for age, type of first cancer, and current follow-up, we found that receiving recommendations for SPC screening was the most critical factor in SPC screening uptake (odds ratio=3.836; 95% confidence interval=2.281-6.451; p<0.001 by logistic regression analysis). However, only 40.4% of the respondents received recommendations for SPC screening from their physicians.
Conclusion: Despite good awareness of SPC prevention, the uptake rate for cancer screening among cancer survivors was inadequate, indicating that preventive measures for SPC should be promoted. Because recommendations from others strongly influence SPC screening uptake, healthcare professionals should have accurate knowledge and provide guidance regarding SPC prevention.
Objective: Signal transducer and activator of transcription 3 (STAT3) plays key roles in regulating cancer cell proliferation, survival, and metastasis. We aimed to determine the effects of YHO-1701, an oral STAT3 inhibitor, in ovarian cancer (OC).
Methods: We evaluated the impact of YHO-1701 on cell growth in patient-derived cells (PDCs) and OC cell lines using standard cell proliferation assays. Spheroid models derived from PDCs were assessed using three-dimensional (3D) cell viability assays. Antitumor activity was performed in SKOV3 xenograft mice treated orally administrated YHO-1701 with 20 mg/kg. Changes in STAT3 signaling were analyzed by western blotting. The molecular mechanisms of STAT3 inhibition were investigated by sequencing RNA and analyzing pathways in the SKOV3 using a small interfering RNA targeting STAT3 (STAT3 siRNA) and YHO-1701.
Results: YHO-1701 inhibited the growth of OC cell lines by preventing STAT3 dimerization and decreasing the expression of its downstream signaling molecule, survivin. The growth of PDCs and spheroids obtained from patients with primary and recurrent OCs was significantly inhibited. Antitumor effect was observed in the SKOV3 xenograft mice with YHO-1701. YHO-1701 induced apoptosis in OC cells. Additionally, p53 and/or MAPK signaling pathways were upregulated in SKOV3 cells incubated with YHO-1701 and in those with STAT3 siRNA.
Conclusion: Our results showed that YHO-1701 suppressed cell growth in PDCs of OC, accompanied by survivin inhibition, and a decrease in the number of peritoneal metastasis in the mice by YHO-1701, compared with those treated with control. Therefore, YHO-1701 could be a promising candidate agent for treating OC.
In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005-2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progression-free survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55-4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20-8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs. 50.6%, aHR=4.54, 95% CI=2.60-7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.
The primary aim of this study was to conduct a methodical examination and assessment of the prognostic efficacy exhibited by magnetic resonance imaging (MRI)-derived radiomic models concerning the preoperative prediction of lymph-vascular space infiltration (LVSI) in cervical cancer cases. A comprehensive and thorough exploration of pertinent academic literature was undertaken by two investigators, employing the resources of the Embase, PubMed, Web of Science, and Cochrane Library databases. The scope of this research was bounded by a publication cutoff date of May 15, 2023. The inclusion criteria encompassed studies that utilized radiomic models based on MRI to prognosticate the accuracy of preoperative LVSI estimation in instances of cervical cancer. The Diagnostic Accuracy Studies-2 framework and the Radiomic Quality Score metric were employed. This investigation included nine distinct research studies, enrolling a total of 1,406 patients. The diagnostic performance metrics of MRI-based radiomic models in the prediction of preoperative LVSI among cervical cancer patients were determined as follows: sensitivity of 83% (95% confidence interval [CI]=77%-87%), specificity of 74% (95% CI=69%-79%), and a corresponding AUC of summary receiver operating characteristic measuring 0.86 (95% CI=0.82-0.88). The results of the synthesized meta-analysis did not reveal substantial heterogeneity.This meta-analysis suggests the robust diagnostic proficiency of the MRI-based radiomic model in the prognostication of preoperative LVSI within the cohort of cervical cancer patients. In the future, radiomics holds the potential to emerge as a widely applicable noninvasive modality for the early detection of LVSI in the context of cervical cancer.
Objective: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer.
Methods: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival.
Results: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months.
Conclusion: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients.
Trial registration: ClinicalTrials.gov Identifier: NCT03759587.
Objective: Minimally invasive radical hysterectomy has a worse prognosis than open surgery, but the reasons for the poor prognosis remain unclear. Tumor spillage occurs when the tumor is exposed to the surgical field and has been suggested to be related to a poor prognosis. This study aimed to compare the prognostic value of tumor spillage in laparoscopic radical hysterectomy and evaluate whether tumor spillage prevention improves oncological safety.
Methods: We compared the prognosis of patients who underwent laparoscopic radical hysterectomy between December 2014 and November 2021 with or without tumor spillage prevention, including surgeries without prevention and those with failed prevention. Prevention consisted of vaginal cuff formation or closure of the vaginal canal with clips to prevent tumor exposure at the time of colpotomy. The primary endpoint was disease-free survival, which was adjusted using propensity scores to compare patients.
Results: In total, 165 patients received tumor spillage prevention, and 61 did not or failed to receive such prevention. The median follow-up was 4.4 years. Patients who did not undergo prevention or failed prevention had significantly shorter disease-free survival than those who did (hazard ratio [HR]=3.54; 95% confidence interval [CI]=1.23-10.23). The same trend was observed after adjusting for propensity score matching. Patients who did not or failed to receive prevention were more likely to experience local recurrence (HR=4.01; 95% CI=1.13-14.24).
Conclusion: Tumor spillage prevention was associated with longer disease-free survival in laparoscopic radical hysterectomy.
Objective: In this study, we evaluated the role of prolonged progestin treatment on atypical endometrial hyperplasia (AEH) patients who did not achieve complete regression (CR) after at least 3 months of progestin treatment. Possible prognostic factors predicting disease regression and recurrence were also assessed.
Methods: We retrospectively identified patients who had histologically confirmed persistent disease after at least 3 months of progestin treatment at two tertiary centers in Korea and Taiwan. Clinicopathologic factors and clinical outcomes were obtained from medical records. Logistic regression was used to analyze the relationship between covariates and the probability of CR and relapse.
Results: Fifty-two patients were included. Thirty-seven of 52 patients (71.2%) achieved CR after prolonged progestin treatment. Median time from starting progestin treatment to CR was 12.0 months. Daily administration of medroxyprogesterone acetate ≥200 mg or megestrol acetate ≥80 mg was associated with higher probability of regression. Nineteen of 37 patients (51.4%) experienced recurrence, with median time from CR to relapse of 15.0 months. Body mass index ≥27 was associated with higher relapse probability. Twelve of 16 patients with disease progression to endometrial carcinoma underwent surgery. The 12 cases had stage I tumors and lived without disease.
Conclusion: Extension of progestin treatment course is feasible for AEH patients without an initial response to progestin. Higher daily progestin dosage was associated with higher probability of CR, and obesity was associated with higher risk of relapse. The patients without an initial response to progestins and whose AEH progressed to endometrial carcinoma had good prognoses.
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