STAT1-Deficient HPV E6/E7-Associated Cancers Maintain Host Immunocompetency against Therapeutic Intervention.

Human papillomavirus (HPV) remains a global health concern because it contributes to the initiation of various HPV-associated cancers such as anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancer. In HPV-associated cancers, oncogenesis begins with an HPV infection, which is linked to the activation of the Janus protein tyrosine kinase (JAK)/STAT signaling pathway. Various STAT signaling pathways, such as STAT3 activation, have been well documented for their tumorigenic role, yet the role of STAT1 in tumor formation remains unclear. In the current study, STAT1-/- mice were used to investigate the role of STAT1 in the tumorigenesis of a spontaneous HPV E6/E7-expressing oral tumor model. Subsequently, our candidate HPV DNA vaccine CRT/E7 was administered to determine whether the STAT1-/- host preserves a therapeutic-responsive tumor microenvironment. The results indicated that STAT1-/- induces robust tumorigenesis, yet a controlled tumor response was attained upon CRT/E7 vaccination. Characterizing this treatment effect, immunological analysis found a higher percentage of circulating CD4+ and CD8+ T cells and tumor-specific cytotoxic T cells. In addition, a reduction in exhaustive lymphocyte activity was observed. Further analysis of a whole-cell tumor challenge affirmed these findings, as spontaneous tumor growth was more rapid in STAT1-/- mice. In conclusion, STAT1 deletion accelerates tumorigenesis, but STAT1-/- mice maintains immunocompetency in CRT/E7 treatments.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Clinical characteristics and treatment modalities in women with newly diagnosed advanced high-grade serous epithelial ovarian cancer in Taiwan.

BACKGROUND: This study was designed to investigate the demographics, treatment patterns, and clinical outcomes of patients newly diagnosed with high-grade serous ovarian cancer (HGSOC) in 3 medical centers in Taiwan before the integration of poly (ADP-ribose) polymerase inhibitors in clinical practice. METHODS: A retrospective analysis was conducted on data from patients diagnosed with HGSOC between January 2014 and December 2018 and followed-up for a minimum of 12 months after diagnosis. Descriptive statistics were used to analyze the data, while survival rates were evaluated using the Kaplan‒Meier method. RESULTS: There were 251 patients included in the analysis, and 98.8% received platinum plus paclitaxel chemotherapy (PPCT). Primary cytoreductive surgery (PCS) and interval debulking surgery (IDS) were performed in 78.9% and 17.1% of patients, respectively. The percentage of optimal surgery was higher in the IDS cohort than in the PCS cohort (83.8% vs. 53.6%). Bevacizumab was used as initiation therapy in 16.7% of patients, and maintenance therapy was administered in 6.8%. Advanced age, IDS, and suboptimal surgery were independent poor prognostic factors associated with lower overall survival (OS). Patients with optimal surgery had significantly lower OS and progression-free survival in the IDS cohort than in the PCS cohort. The predictive accuracy was good for OS at the 1-year follow-up. CONCLUSION: Advanced age, IDS, and residual disease are associated with poor OS in patients with HGSOC. Compared to PCS, IDS provides a higher likelihood of optimal surgery but results in a lower probability of survival for patients with HGSOC in Taiwan.

Inguinal nodal metastatic squamous cell carcinoma of unknown primary (CUP) detected 7 years before the diagnosis of vulvar squamous cell carcinoma: A case report.

OBJECTIVE: Metastatic squamous cell carcinoma (SCC) of inguinal lymph node region with unknown origin is a rare condition. A patient was diagnosed to have vulvar SCC 7 years after the initial diagnosis of inguinal nodal metastatic SCC of unknown primary. CASE REPORT: A 59-year-old woman with metastatic SCC of unknown origin in the right inguinal lymph node underwent tumor resection and no evidence of residual disease or possible tumor origin was detected after the surgery and a comprehensive work-up. Seven years later, she was diagnosed to have invasive right vulvar SCC with right pelvic lymph node metastasis. We performed a series of tests to evaluate the relationship between these two events. CONCLUSION: According to our investigation, the possible relationship between the two events could not be ruled out. This case emphasizes the possibility of late recurrence and the importance of long-term follow up for patients with isolated nodal CUP.

Ultrasonic presentation variation of patients with pathological evidence of endometrial atrophy.

OBJECTIVE: Post-menopausal bleeding is one of the most common reasons for attending the gynecology outpatient clinic. The major proportion of the symptoms is endometrial atrophy (about 60%) despite of the endometrial thickness is over 4 mm. Therefore, the aim of this study is to evaluate the endometrial thickness under sonogram in the women with atrophic endometrium, with or without post-menopausal vaginal bleeding. MATERIALS AND METHODS: This is a retrospective study and we enrolled 237 post-menopausal women with pathological evidence of atrophic endometrium from Jan. 2014 to Dec. 2018 in Mackay Memorial hospital. Patient's characteristics taken into account were age, vaginal bleeding status, the methods of obtaining endometrial tissue, hormonal replacement therapy and breast cancer history under tamoxifen treatment. Endometrial thickness was classified as ≤ 4 mm, >4 mm-10 mm and >10 mm. We calculated the proportion of the characteristic mentioned before. RESULTS: In total, 237 patients were enrolled and 35 patients were excluded; therefore, the remaining 202 patients were analyzed. There were 42 (20.8%), 109 (54%) and 51 (25.2%) patients with endometrial thickness ≤4 mm, >4 mm-10 mm and >10 mm respectively. There was significant difference in the numbers of patients with post-menopausal bleeding (p = 0.002) and breast cancer history under tamoxifen therapy (p < 0.05) among the three groups. CONCLUSION: In the patients with endometrial atrophy, the endometrial thickness may be variable. There were only 20.8% of patients with endometrial thickness less than 4 mm in our study. Before endometrial sampling, comprehensive evaluation of the morphology of endometrium under image study, the patient's symptoms and medical history is important.

Association of malignant ascites with systemic inflammation and muscle loss after treatment in advanced-stage ovarian cancer.

BACKGROUND: Malignant ascites is prevalent in advanced-stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced-stage ovarian cancer. METHODS: We evaluated 307 patients with advanced-stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum-based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre-surgery and post-chemotherapy portal-venous phase contrast-enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator. RESULTS: The median (range) age was 53 (23-83) years. The median duration (range) of follow-up was 5.2 (1.1-11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: -3.9% vs. 2.2%, P < 0.001; SMD: -4.0% vs. -0.4%, P < 0.001; albumin: -4.4% vs. 2.1%, P < 0.001; PNI: -8.4% vs. -0.1%, P < 0.001; NLR: 20.6% vs. -29.4%, P < 0.001; and PLR: 1.7% vs. -19.4%, P < 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P < 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: ß = -3.19, P < 0.001; NLR change: ß = -0.02, P = 0.003; albumin change: ß = 0.37, P < 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: ß = -1.28, P = 0.02; NLR change: ß = -0.02, P < 0.001; PNI change: ß = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.61, 95% confidence interval [CI]: -2.22 to -1.08) and albumin change (indirect effects = -2.92, 95% CI: -4.01 to -1.94). Ascites had a direct effect on SMD change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.76, 95% CI: -2.34 to -1.22) and PNI change (indirect effects = -2.00, 95% CI: -2.79 to -1.36). CONCLUSIONS: Malignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced-stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.

Explainable machine learning model for predicting skeletal muscle loss during surgery and adjuvant chemotherapy in ovarian cancer.

BACKGROUND: Skeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on computed tomography (CT) scans, this labour-intensive process can impair its utility in clinical practice. This study aimed to develop a machine learning (ML) model to predict muscle loss based on clinical data and to interpret the ML model by applying SHapley Additive exPlanations (SHAP) method. METHODS: This study included the data of 617 patients with ovarian cancer who underwent primary debulking surgery and platinum-based chemotherapy at a tertiary centre between 2010 and 2019. The cohort data were split into training and test sets based on the treatment time. External validation was performed using 140 patients from a different tertiary centre. The skeletal muscle index (SMI) was measured from pre- and post-treatment CT scans, and a decrease in SMI ≥ 5% was defined as muscle loss. We evaluated five ML models to predict muscle loss, and their performance was determined using the area under the receiver operating characteristic curve (AUC) and F1 score. The features for analysis included demographic and disease-specific characteristics and relative changes in body mass index (BMI), albumin, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The SHAP method was applied to determine the importance of the features and interpret the ML models. RESULTS: The median (inter-quartile range) age of the cohort was 52 (46-59) years. After treatment, 204 patients (33.1%) experienced muscle loss in the training and test datasets, while 44 (31.4%) patients experienced muscle loss in the external validation dataset. Among the five evaluated ML models, the random forest model achieved the highest AUC (0.856, 95% confidence interval: 0.854-0.859) and F1 score (0.726, 95% confidence interval: 0.722-0.730). In the external validation, the random forest model outperformed all ML models with an AUC of 0.874 and an F1 score of 0.741. The results of the SHAP method showed that the albumin change, BMI change, malignant ascites, NLR change, and PLR change were the most important factors in muscle loss. At the patient level, SHAP force plots demonstrated insightful interpretation of our random forest model to predict muscle loss. CONCLUSIONS: Explainable ML model was developed using clinical data to identify patients experiencing muscle loss after treatment and provide information of feature contribution. Using the SHAP method, clinicians may better understand the contributors to muscle loss and target interventions to counteract muscle loss.

Managing the transition in cervical screening methods for Taiwan: Policy recommendations and perspectives.

Since government-provided annual cervical cytology testing for all Taiwanese women aged 30 years or older became available in 1995, both cervical cancer incidence and death have decreased significantly. However, with the 2018 introduction of the national immunization program for human papillomavirus (HPV) vaccination in all schoolgirls aged 13-15 years old, the positive predictive value of cytology testing is expected to decrease with rising vaccination rates, and therefore a transition to more sensitive HPV-based testing may be needed. This position paper, derived from discussions by a panel of experts in cervical cancer screening, provides short-, medium-, and long-term policy recommendations to manage the transition between cervical screening methods for Taiwan. The recommendations include concrete suggestions regarding testing procedures, standards, accreditation, monitoring, promotion, and implementation. It is hoped that comprehensive preparation and management of this transition will enable Taiwan to repeat the previous successes of the cervical cytology testing program.

Association of prognostic nutritional index with muscle loss and survival in patients with ovarian cancer treated with primary debulking surgery and chemotherapy.

PURPOSE: Sarcopenia is prevalent in ovarian cancer and contributes to poor survival. This study is aimed at investigating the association of prognostic nutritional index (PNI) with muscle loss and survival outcomes in patients with ovarian cancer. METHODS: This retrospective study analyzed 650 patients with ovarian cancer treated with primary debulking surgery and adjuvant platinum-based chemotherapy at a tertiary center from 2010 to 2019. PNI-low was defined as a pretreatment PNI of < 47.2. Skeletal muscle index (SMI) was measured on pre- and posttreatment computed tomography (CT) at L3. The cut-off for the SMI loss associated with all-cause mortality was calculated using maximally selected rank statistics. RESULTS: The median follow-up was 4.2 years, and 226 deaths (34.8%) were observed. With a median duration of 176 days (interquartile range: 166-187) between CT scans, patients experienced an average decrease in SMI of 1.7% (P < 0.001). The cut-off for SMI loss as a predictor of mortality was - 4.2%. PNI-low was independently associated with SMI loss (odds ratio: 1.97, P = 0.001). On multivariable analysis of all-cause mortality, PNI-low and SMI loss were independently associated with all-cause mortality (hazard ratio: 1.43, P = 0.017; hazard ratio: 2.27, P < 0.001, respectively). Patients with both SMI loss and PNI-low (vs. neither) had triple the risk of all-cause mortality (hazard ratio: 3.10, P < 0.001). CONCLUSIONS: PNI is a predictor of muscle loss during treatment for ovarian cancer. PNI and muscle loss are additively associated with poor survival. PNI can help clinicians guide multimodal interventions to preserve muscle and optimize survival outcomes.

A questionnaire study on disparity of cervical cancer prevention programs in Asia-Oceania.

BACKGROUND: Despite the introduction of cervical cancer screening and human papillomavirus (HPV) vaccines, the utilization pattern was not standardized. The aim of this study was to elicit the current prevention care in Asia-Oceania. METHODS: An online questionnaire was circulated to different countries/cities in Asia-Oceania. The primary objective was to evaluate the coverage of HPV vaccination and cervical screening programs. The secondary objectives were to study the structures of these programs. Five case scenarios were set to understand how the respondents manage the abnormal screening results. RESULTS: Fourteen respondents from 10 countries/cities had participated. Cervical cancer ranked the first in Myanmar and Nepal. About 10%-15% did not have national vaccination or screening program. The estimated coverage rate for vaccination and screening varied from less than 1% to 70%, which the coverage ran in parallel with the incidence and mortality rates of cervical cancer. All regions approved HPV vaccines, although only four provided free or subsidized programs for nonavalent vaccine. Cervical cytology remained the most common screening tool, and 20%-30% relied heavily on visual inspection using acetic acid. The screening age groups varied in different regions. From the case scenarios, it was noted that some respondents tended to offer more frequent screening tests or colposcopy than recommended by international guidelines. CONCLUSION: This study revealed discrepancy in the practice of cervical cancer prevention in Asia-Oceania especially access to HPV vaccines. There is an urgent need for a global collaboration to eliminate cervical cancer by public education, reforming services, and medical training.

Contrasting clinical characteristics and treatment patterns in women with newly diagnosed advanced-stage epithelial ovarian cancer in Australia, South Korea and Taiwan.

OBJECTIVE: The real-world INFORM study analyzed sociodemographics, treatment patterns and clinical outcomes for patients with newly diagnosed advanced epithelial ovarian cancer (EOC) in Australia, South Korea (S.Korea) and Taiwan preceding incorporation of poly(ADP-ribose) polymerase inhibitors into clinical practice. METHODS: Retrospective data from patients diagnosed with EOC (high-grade serous EOC for Taiwan) between January 2014 and December 2018 with ≥12 months follow-up from diagnosis were analyzed descriptively. Survival was evaluated by Kaplan-Meier with two-sided 95% confidence interval (CI). RESULTS: Of the 987 patients (Australia, 223; S.Korea, 513; Taiwan, 251), 98% received platinum-based chemotherapy (CT). In S.Korea and Taiwan 76.0% and 78.9% respectively underwent primary cytoreductive surgery; in Australia, 56.5% had interval debulking surgery. Bevacizumab was included in primary/maintenance therapy for 22.4%, 14.6% and 6.8% of patients in Australia, S.Korea and Taiwan, respectively. Patients receiving bevacizumab were high-risk (reimbursement policy) and achieved similar real-world progression-free survival (PFS) compared with CT only. Overall, the median real-world PFS (months; 95% CI) was similar across Australia (16.0 [14.63-18.08]), S.Korea (17.7 [16.18-19.27]) and Taiwan (19.1 [17.56-22.29]). CONCLUSION: This study reveals poor prognosis despite differences in demographics and treatment patterns for patients with EOC across Asia-Pacific suggesting the need for biomarker-driven novel therapies to improve outcomes.

EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer.

BACKGROUND: In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. METHODS: Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1-16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. RESULTS: Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77-13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08-12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. CONCLUSIONS: Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain.

Optimal prophylactic para-aortic radiotherapy in locally advanced cervical cancer: anatomy-based versus margin-based delineation.

OBJECTIVE: Precise delineation of the para-aortic nodal region is critical for the optimal therapeutic ratio of prophylactic para-aortic radiotherapy. We aimed to evaluate the para-aortic control and patient-reported gastrointestinal toxicity in patients with locally advanced cervical cancer who received anatomy-based or margin-based prophylactic para-aortic radiotherapy. METHODS: We analyzed 160 patients with locally advanced cervical cancer who received prophylactic extended-field radiotherapy between January 2014 and November 2019 at two tertiary centers. Para-aortic nodal regions were delineated based on the anatomic principle-based atlas or marginal expansion from the aorta and inferior vena cava. The Patient-Reported Outcome version of the Common Terminology Criteria for Adverse Events was used to assess acute gastrointestinal toxicity, and a score of ≥3 was defined as severe gastrointestinal toxicity. RESULTS: Seventy-six (47.5%) and 84 (52.5%) patients received anatomy-based and margin-based prophylactic para-aortic radiotherapy, respectively. The median follow-up was 40.1 months (IQR 25.5-58.9). Para-aortic nodal failures occurred in one (1.3%) patient in the anatomy-based para-aortic radiotherapy group and in one (1.2%) patient in the margin-based para-aortic radiotherapy group (p=1.00). There was no in-field or marginal para-aortic nodal failure. The 3-year para-aortic recurrence-free survival for anatomy-based and margin-based para-aortic radiotherapy was 98.6% and 98.8%, respectively (p=0.94). Patients who received anatomy-based para-aortic radiotherapy reported less severe acute gastrointestinal toxicity than those who received margin-based para-aortic radiotherapy (13.2% vs 29.8%, p=0.01). A comparison of gastrointestinal toxicities showed that patients who received anatomy-based para-aortic radiotherapy reported significantly less severe gastrointestinal toxicity than those who received margin-based para-aortic radiotherapy in terms of frequency of diarrhea (7.9% vs 20.2%, p=0.03), severity of abdominal pain (3.9% vs 14.3%, p=0.03), and interference of abdominal pain (2.6% vs 11.9%, p=0.03). CONCLUSION: Anatomy-based prophylactic para-aortic radiotherapy achieved excellent para-aortic control and a lower incidence of severe patient-reported gastrointestinal toxicity. These findings suggest that anatomy-based delineation optimizes clinical outcomes of prophylactic para-aortic radiotherapy in locally advanced cervical cancer.

Survival with Cemiplimab in Recurrent Cervical Cancer.

BACKGROUND: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. METHODS: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. RESULTS: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. CONCLUSIONS: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Hyperthermic intraperitoneal chemotherapy enhances antitumor effects on ovarian cancer through immune-mediated cancer stem cell targeting.

PURPOSE: We aimed to determine the effects and possible mechanisms of hyperthermic intraperitoneal chemotherapy (HIPEC) in targeting ovarian cancer stem-like cells (CSCs). METHODS: Murine ovarian cancer cell lines presenting CSC surface markers were grown intraperitoneally in both immunocompetent and immunodeficient mice, which were then treated by intraperitoneal hyperthermia with the chemotherapeutic agents: paclitaxel and cisplatin. Tumor growth was measured by non-invasive luminescent imaging. Intraperitoneal immune cells, such as CD4+, CD8+ T cells, macrophages, and dendritic cells, were evaluated through flow cytometry analysis. RESULTS: Combined hyperthermia and chemotherapy exhibited an efficient therapeutic effect in the immunocompetent mice. However, a similar effect was not observed in the immunodeficient mice. Intraperitoneal hyperthermia increased the number of Intraperitoneal macrophages and dendritic cells that were lost due to chemotherapy. Compared with ovarian cancer bulk cells, CSCs were more susceptible to phagocytosis by macrophages. CONCLUSION: We demonstrated that the superior therapeutic efficacy and reduced proportion of CSCs associated with intraperitoneal hyperthermic chemotherapy were immune-related. Hyperthermia recruits the phagocytes that target surviving CSCs after chemotherapy. These results provide a novel mechanism for the efficacy of HIPEC in treating ovarian cancer.

Massive metastasis of breast cancer to female genital organs.

OBJECTIVE: Breast cancer metastasis to the female genital tract is rare, and the ovaries are the most frequent site of extragenital cancer metastasis. The uterus and cervix have been rarely reported as the site of metastasis. CASE REPORT: A 57-year-old woman diagnosed with invasive lobular carcinoma of the left breast 2 years prior was undergoing tamoxifen treatment. She presented with a right breast mass and postmenopausal bleeding. Synchronous right breast invasive lobular carcinoma with endometrium metastasis was diagnosed. The metastasis tumor involved the endometrium, myometrium, cervix, ovaries, and fallopian tubes. CONCLUSION: We noted the rarity of massive metastasis of the female genital tract from breast cancer. Gynecological surveillance and prompt evaluation of the endometrium led to timely diagnosis and treatment.

DNA methylation marker for the triage of hrHPV positive women in cervical cancer screening: Real-world evidence in Taiwan.

OBJECTIVE: Human papillomavirus (HPV) testing as the primary cervical cancer screening followed by reflex cytology if high-risk HPV is present (hrHPV+) is recently adopted in some countries. However, reflex cytology's sensitivity is variable, and a suitable triage approach for hrHPV+ remains controversial. Here, we compared the performance of three triage tools in hrHPV+ women. METHODS: Three triage tools-cytology, HPV16/18 genotyping, and DNA methylation biomarker PAX1m-were analyzed for their clinical performance in hrHPV+ women. In addition, women without cervical cancer at enrollment were followed for histologically confirmed high-grade cervical intraepithelial neoplasia or worse (CIN3+) annually using Papanicolaou smear. RESULTS: Of 4762 women aged ≥20 years enrolled, 502 (10.5%) were hrHPV+. PAX1m and cytology demonstrated similar accuracy (>90%), sensitivity (>78%), and specificity (>92%) as triage tools in 429 hrHPV+ women aged 30-64 years. PAX1m had better accuracy and specificity (91.6% and 92.5%, respectively) than HPV16/18 (76.9% and 76.8%, respectively). The incidence of CIN3+ among hrHPV+ women was 10.7 cases/1000 person-years. The incidence was significantly greater in PAX1m-positive women than in PAX1m-negative women. CONCLUSIONS: PAX1m has comparable clinical performance to cytology and better accuracy and specificity than HPV16/18 as the triage tool for detecting CIN3+ in hrHPV+ women. The PAX1m assay is thus a promising molecular-based triage tool for early detection of CIN and predicting disease progression in hrHPV+ women. It can be especially useful in countries where adequate cytology-based infrastructure is lacking, such as some Southeast Asian countries, for cervical cancer screening and prevention.

Association of bowel radiation dose-volume with skeletal muscle loss during pelvic intensity-modulated radiotherapy in cervical cancer.

BACKGROUND: Radiation-induced bowel damage may compromise nutrient absorption and digestion and affect body composition during pelvic radiotherapy in patients with locally advanced cervical cancer (LACC). This study aimed to evaluate the relationship between bowel radiation dose-volume and body composition changes during pelvic radiotherapy. METHODS: Data of 301 LACC patients treated with chemoradiotherapy were analyzed. Changes in skeletal muscle index (SMI) and density (SMD), and total adipose tissue index (TATI) were measured from computed tomography images at the L3 vertebral level. A reduction in SMI, SMD, or TATI of ≥10% was classified as "loss." Bowel V45 indicates the bowel volume (mL) receiving a radiation dose of ≥45 Gy. The relationship between body composition and bowel V45 was analyzed using logistic regression models. RESULTS: After treatment, 61 (20.3%), 81 (26.9%), and 97 (32.2%) patients experienced SMI, SMD, and TATI loss, respectively. Increased bowel V45 was independently associated with increased odds of SMI loss (odds ratio [OR]: 1.012; 95% confidence interval [CI]: 1.007-1.018; p<0.001) and TATI loss (OR: 1.006; 95% CI: 1.001-1.010; p=0.01), but not with SMD loss (OR: 1.005; 95% CI: 1.000-1.009; p=0.054). The cut-off value with the highest accuracy for predicting SMI loss was V45 ≥222 mL; a higher rate of SMI loss was noted in 40.0% of patients with V45 ≥222 mL than in 13.7% of patients with V45 <222 mL (p<0.001). CONCLUSIONS: Higher bowel dose-volume was significantly associated with muscle loss during pelvic radiotherapy. Bowel dose-volume consideration is required in individualized nutritional counseling and supportive care in clinical practice.