Widespread and Functional RNA Circularization in Localized Prostate Cancer.

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.

The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression.

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers.

Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.

AmplificationTimeR: an R package for timing sequential amplification events.

MOTIVATION: Few methods exist for timing individual amplification events in regions of focal amplification. Current methods are also limited in the copy number states that they are able to time. Here we introduce AmplificationTimeR, a method for timing higher level copy number gains and inferring the most parsimonious order of events for regions that have undergone both single gains and whole genome duplication. Our method is an extension of established approaches for timing genomic gains. RESULTS: We can time more copy number states, and in states covered by other methods our results are comparable to previously published methods. AVAILABILITY AND IMPLEMENTATION: AmplificationTimer is freely available as an R package hosted at https://github.com/Wedge-lab/AmplificationTimeR.

Trends in Endometrial Cancer Incidence in the United States by Race/Ethnicity and Age of Onset from 2000 to 2019.

Endometrial cancer is one of few cancers that has continued to rise in incidence over the past decade with disproportionate increases in adults younger than 50 years old. We used data from the Surveillance, Epidemiology, and End Results Registry (2000-2019) to examine endometrial cancer incidence trends by race/ethnicity and age of onset among women in the United States. Case counts and proportions, age-adjusted incidence rates (per 100,000), and average annual percent changes were calculated by race/ethnicity, overall and stratified by age of onset (early vs late). We found a disproportionate increase in endometrial cancer incidence among women of color, for both early and late onset endometrial cancer. The highest increases in early onset endometrial cancer (<50 years old) were observed among American Indian/Alaska Native women (4.8), followed by Black (3.3), Hispanic/Latina (3.1), and Asian and Pacific Islander women (2.4), whereas white women (0.9) had the lowest increase. Late onset (>50 years old) endometrial cancer incidence followed a similar pattern, with the greatest increases for women of color. The increasing burden of endometrial cancer among women of color, particularly those younger than 50 years old, is a major public health problem necessitating further research and clinical efforts focused on health equity.

Conversations with LGBT+ scientists about visibility, leadership and climbing the career ladder.

February is LGBT+ history month, and to celebrate, Journal of Cell Science Editorial Advisory Board member David Bryant organised a conversation with a selection of scientists to explore their experiences of being LGBT+ in academia.

Oral pimonidazole unveils clinicopathologic and epigenetic features of hypoxic tumour aggressiveness in localized prostate cancer.

BACKGROUND: Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation. METHODS: A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets. RESULTS: Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types. CONCLUSIONS: Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.

Short-term survival analysis of a risk-adjusted model for ovarian cancer care.

OBJECTIVE: To quantify the impact on short-term ovarian cancer survival associated with treatment at high-performing hospitals using the observed-to-expected ratio (O/E) for adherence to ovarian cancer treatment guidelines as a risk-adjusted measure of hospital quality care. METHODS: This was a retrospective population-based study of stage I-IV invasive epithelial ovarian cancer reported to California Cancer Registry 1996-2017. A fit logistic regression model, risk-adjusted for patient and disease characteristics, was used to calculate O/E for each hospital stratified by hospital annual case volume. Cox proportional hazards model was used for survival analyses at 3, 6, 12, 24 months and stratified according to sociodemographic characteristics. RESULTS: The study population included 35,725 subjects treated at 443 hospitals: Low-O/E - 26.4% of cases; Intermediate-O/E - 55.5% of cases; and High-O/E - 18.1% of cases. Overall median survival by hospital category was: High-O/E = 72.5 months (95% CI = 68.6-78.6 months), Intermediate-O/E = 68.6 months (95% CI = 65.9-71.6 months), Low-O/E = 47.0 months (95% CI = 44.2-49.2 months). Initial treatment at a High-O/E hospital (HR = 1.00) was a statistically significant and independent predictor of improved short-term survival compared to Low-O/E hospitals at 3 months (HR = 1.46, 95% CI = 1.29-1.65), 6 months (HR = 1.35, 95% CI = 1.22-1.50), 12 months (HR = 1.27, 95% CI = 1.17-1.38), and 24 months (HR = 1.19, 95% CI = 1.11-1.27). Significant and independent associations between improved sort-term survival and High/O/E care were observed for Whites, Hispanics, Asian/Pacific Islanders (A/PI), across SES strata, and among all payer categories. CONCLUSION: Ovarian cancer care at a High-O/E hospital is an independent predictor of improved outcome and the survival advantage is disproportionately weighted toward the short-term time horizon following diagnosis.

Medicolegal, infrastructural, and financial aspects in gynecologic cancer surgery and their implications in decision making processes: Quo Vadis?

Surgical decision making is complex and involves a combination of analytic, intuitive, and cognitive processes. Medicolegal, infrastructural, and financial factors may influence these processes depending on the context and setting, but to what extent can they influence surgical decision making in gynecologic oncology? This scoping review evaluates existing literature related to medicolegal, infrastructural, and financial aspects of gynecologic cancer surgery and their implications in surgical decision making. Our objective was to summarize the findings and limitations of published research, identify gaps in the literature, and make recommendations for future research to inform policy.

Cytoreductive surgery plus chemotherapy versus chemotherapy alone for recurrent epithelial ovarian cancer.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of secondary CRS and chemotherapy in comparison to chemotherapy alone for women with platinum-sensitive recurrent epithelial ovarian cancer.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Differential Effects of Race, Socioeconomic Status, and Insurance on Disease-Specific Survival in Rectal Cancer.

BACKGROUND: National Comprehensive Cancer Network guideline adherence improves cancer outcomes. In rectal cancer, guideline adherence is distributed differently by race/ethnicity, socioeconomic status, and insurance. OBJECTIVE: This study aimed to determine the independent effects of race/ethnicity, socioeconomic status, and insurance status on rectal cancer survival after accounting for differences in guideline adherence. DESIGN: This was a retrospective study. SETTINGS: The study was conducted using the California Cancer Registry. PATIENTS: This study included patients aged 18 to 79 years diagnosed with rectal adenocarcinoma between January 1, 2004, and December 31, 2017, with follow-up through November 30, 2018. Investigators determined whether patients received guideline-adherent care. MAIN OUTCOME MEASURES: ORs and 95% CIs were used for logistic regression to analyze patients receiving guideline-adherent care. Disease-specific survival analysis was calculated using Cox regression models. RESULTS: A total of 30,118 patients were examined. Factors associated with higher odds of guideline adherence included Asian and Hispanic race/ethnicity, managed care insurance, and high socioeconomic status. Asians (HR, 0.80; 95% CI, 0.72-0.88; p < 0.001) and Hispanics (HR, 0.91; 95% CI, 0.83-0.99; p = 0.0279) had better disease-specific survival in the nonadherent group. Race/ethnicity were not factors associated with disease-specific survival in the guideline adherent group. Medicaid disease-specific survival was worse in both the nonadherent group (HR, 1.56; 95% CI, 1.40-1.73; p < 0.0001) and the guideline-adherent group (HR, 1.18; 95% CI, 1.08-1.30; p = 0.0005). Disease-specific survival of the lowest socioeconomic status was worse in both the nonadherent group (HR, 1.42; 95% CI, 1.27-1.59) and the guideline-adherent group (HR, 1.20; 95% CI, 1.08-1.34). LIMITATIONS: Limitations included unmeasured confounders and the retrospective nature of the review. CONCLUSIONS: Race, socioeconomic status, and insurance are associated with guideline adherence in rectal cancer. Race/ethnicity was not associated with differences in disease-specific survival in the guideline-adherent group. Medicaid and lowest socioeconomic status had worse disease-specific survival in both the guideline nonadherent group and the guideline-adherent group. See Video Abstract at http://links.lww.com/DCR/B954 . EFECTOS DIFERENCIALES DE LA RAZA, EL NIVEL SOCIOECONMICO COBERTURA SOBRE LA SUPERVIVENCIA ESPECFICA DE LA ENFERMEDAD EN EL CNCER DE RECTO: ANTECEDENTES: El cumplimiento de las guías de la National Comprehensive Cancer Network mejora los resultados del cáncer. En el cáncer de recto, el cumplimiento de las guías se distribuye de manera diferente según la raza/origen étnico, nivel socioeconómico y el cobertura médica.OBJETIVO: Determinar los efectos independientes de la raza/origen étnico, el nivel socioeconómico y el estado de cobertura médica en la supervivencia del cáncer de recto después de tener en cuenta las diferencias en el cumplimiento de las guías.DISEÑO: Este fue un estudio retrospectivo.ENTORNO CLINICO: El estudio se realizó utilizando el Registro de Cáncer de California.PACIENTES: Pacientes de 18 a 79 años diagnosticados con adenocarcinoma rectal entre el 1 de enero de 2004 y el 31 de diciembre de 2017 con seguimiento hasta el 30 de noviembre de 2018. Los investigadores determinaron si los pacientes recibieron atención siguiendo las guías.PRINCIPALES MEDIDAS DE RESULTADO: Se utilizaron razones de probabilidad e intervalos de confianza del 95 % para la regresión logística para analizar a los pacientes que recibían atención con adherencia a las guías. El análisis de supervivencia específico de la enfermedad se calculó utilizando modelos de regresión de Cox.RESULTADOS: Se analizaron un total de 30.118 pacientes. Los factores asociados con mayores probabilidades de cumplimiento de las guías incluyeron raza/etnicidad asiática e hispana, seguro de atención administrada y nivel socioeconómico alto. Los asiáticos e hispanos tuvieron una mejor supervivencia específica de la enfermedad en el grupo no adherente HR 0,80 (95 % CI 0,72 - 0,88, p < 0,001) y HR 0,91 (95 % CI 0,83 - 0,99, p = 0,0279). La raza o el origen étnico no fueron factores asociados con la supervivencia específica de la enfermedad en el grupo que cumplió con las guías. La supervivencia específica de la enfermedad de Medicaid fue peor tanto en el grupo no adherente HR 1,56 (IC del 95 % 1,40 - 1,73, p < 0,0001) como en el grupo adherente a las guías HR 1,18 (IC del 95 % 1,08 - 1,30, p = 0,0005). La supervivencia específica de la enfermedad del nivel socioeconómico más bajo fue peor tanto en el grupo no adherente HR 1,42 (IC del 95 %: 1,27 a 1,59) como en el grupo adherente a las guías HR 1,20 (IC del 95 %: 1,08 a 1,34).LIMITACIONES: Las limitaciones incluyeron factores de confusión no medidos y la naturaleza retrospectiva de la revisión.CONCLUSIONES: La raza, el nivel socioeconómico y cobertura médica están asociados con la adherencia a las guías en el cáncer de recto. La raza/etnicidad no se asoció con diferencias en la supervivencia específica de la enfermedad en el grupo que cumplió con las guías. Medicaid y el nivel socioeconómico más bajo tuvieron peor supervivencia específica de la enfermedad tanto en el grupo que no cumplió con las guías como en los grupos que cumplieron. Consulte Video Resumen en http://links.lww.com/DCR/B954 . (Traducción- Dr. Francisco M. Abarca-Rendon).

Prostate cancer.

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.

Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancer: A meta-analysis.

BACKGROUND: The value of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery (CRS) for epithelial ovarian cancer (EOC) is controversial and its use remains experimental in most national and international guidelines. We wished to systematically evaluate all available evidence. METHODS: A comprehensive review of data from MEDLINE, EMBASE, and Cochrane Library databases was conducted from the first report on HIPEC in EOC till April 3, 2022. Progression-free survival (PFS) and overall survival (OS) were compared between the HIPEC and control groups. This meta-analysis was registered with PROSPERO (CRD42021265810). RESULTS: Fifteen studies (10 case-control studies and 5 randomized controlled trials [RCTs]) were included in the present meta-analysis. Based on the time interval between the last systemic chemotherapy exposure and timing of CRS +/- HIPEC, all studies and patients' cohorts we classified into recent (<6 months; n = 9 studies/patients cohorts) and non-recent (≥6 months, n = 8 studies/patients cohorts) chemotherapy exposure groups. In the recent chemotherapy exposure group, HIPEC was associated with improvement of both PFS (HR, 0.585; 95% CI, 0.422-0.811) and OS (HR, 0.519; 95% CI, 0.346-0.777). On the contrary, in the non-recent chemotherapy exposure group, HIPEC failed to significantly affect PFS (HR, 1.037; 95% CI, 0.684-1.571) or OS (HR, 0.932; 95% CI, 0.607-1.430). Consistent results were observed in subsequent sensitivity analyses. CONCLUSION: Our present meta-analysis demonstrates that the value of HIPEC at CRS for EOC appears to depend on the timing of the last systemic chemotherapy exposure. Future trials are awaited to define the role of HIPEC in EOC.

DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities.

MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.

Guideline-adherent treatment, sociodemographic disparities, and cause-specific survival for endometrial carcinomas.

BACKGROUND: Adherence to National Comprehensive Cancer Network guidelines have been adopted as the standard of care for various cancers and have been cited to have survival benefits. Few studies have examined the association of adherent treatment and endometrial cancer survival among various racial/ethnic groups and socioeconomic statuses. METHODS: Between January 1, 2006 and December 31, 2015, 83,673 women diagnosed with endometrial carcinomas were identified from the Surveillance, Epidemiology, and End Results database. Descriptive statistics of demographic and clinical characteristics were performed. Cox-proportional hazards models were used to examine the effect on cause-specific survival for adherence to guidelines across racial/ethnic and socioeconomic groups. RESULTS: Within our sample, 59.5% were treated according to guidelines. Nonadherence to treatment guidelines was significantly associated with decreased survival compared with adherent care (adjusted hazard ratio [HR], 1.59; 95% CI, 1.52-1.67). Being of Black (adjusted HR, 1.41; 95% CI, 1.32-1.51) or Native Hawaiian/Pacific Islander (adjusted HR, 1.44; 95% CI, 1.19-1.73) race/ethnicity compared with White women was significantly associated with worse survival. Being of Asian race/ethnicity (adjusted HR, 0.86, 95% CI, 0.78-0.94) was significantly associated with improved survival compared with White women. Lower neighborhood socioeconomic status was associated with a negative effect on survival relative to women in the highest socioeconomic status category. CONCLUSIONS: Findings from this study suggest treatment adherence is an independent predictor of improved survival; however, improved survival was not observed equally among all racial/ethnic and socioeconomic status groups. LAY SUMMARY: The National Comprehensive Cancer Network (NCCN) has developed guidelines for physicians to follow in treating various cancers. Within this study of 83,673 women with endometrial cancer, 59.5% of women were treated according to the NCCN guidelines. The findings suggest following NCCN guidelines for treatment of endometrial cancer improves survival. Black or Native Hawaiian/Pacific Islander race and lower neighborhood socioeconomic status has worse survival rates compared with other groups, indicating the importance of exploring other factors that may shape treatment across racial/ethnic and socioeconomic status groups.

Ambient air pollution and ovarian cancer survival in California.

OBJECTIVE: To examine whether exposure to ambient ozone, particulate matter with diameter less than 2.5 µm (PM2.5), nitrogen dioxide (NO2), and distance to major roadways (DTR) impact ovarian cancer-specific survival, while considering differences by stage, race/ethnicity, and socioeconomic status. METHODS: Women diagnosed with epithelial ovarian cancer from 1996 to 2014 were identified through the California Cancer Registry and followed through 2016. Women's geocoded addresses were linked to pollutant exposure data and averaged over the follow-up period. Pollutants were considered independently and in multi-pollutant models. Cox proportional hazards models assessed hazards of disease-specific death due to environmental exposures, controlling for important covariates, with additional models stratified by stage at diagnosis, race/ethnicity and socioeconomic status. RESULTS: PM2.5 and NO2, but not ozone or DTR, were significantly associated with survival in univariate models. In a multi-pollutant model for PM2.5, ozone, and DTR, an interquartile range increase in PM2.5 (Hazard Ratio [HR], 1.45; 95% Confidence Interval [CI], 1.41-1.49) was associated with worse prognosis. Similarly, in the multi-pollutant model with NO2, ozone, and DTR, women with higher NO2 exposures (HR for 20.0-30.0 ppb, 1.30; 95% CI, 1.25-1.36 and HR for >30.0 ppb, 2.48; 95% CI, 2.32-2.66) had greater mortality compared to the lowest exposed (<20.0 ppb). Stratified results show the effects of the pollutants differed by race/ethnicity and were magnified among women diagnosed in early stages. CONCLUSIONS: Our analyses suggest that greater exposure to NO2 and PM2.5 may adversely impact ovarian cancer-specific survival, independent of sociodemographic and treatment factors. These findings warrant further study.

Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis.

OBJECTIVE: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers. METHODS: In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival. RESULTS: Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 µg/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001). CONCLUSIONS: Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors.

Looking at cancer health disparities in gynecologic oncology in 2020.

PURPOSE OF REVIEW: To summarize the most recent evidence on gynecologic cancer disparities and to describe studies investigating the social determinants of health and receipt of evidence-based care and potential interventions to address inequities in care. RECENT FINDINGS: Significant disparities in disease-specific survival by race/ethnicity, socioeconomic status, and payer status have persisted in women with gynecologic cancers. Compared with white women, black women have an increased likelihood of disease-specific mortality for endometrial cancer and are less likely to receive guideline-adherent care for ovarian cancer. The Covid-19 pandemic has brought significant attention to the structural barriers that contribute to persistent health disparities and how community-based partnerships with a focus on policy interventions are needed for equitable gynecologic cancer outcomes. SUMMARY: In this review, we discuss structural barriers contributing to racial inequities, the role of Medicaid payer status and receipt of quality cancer care, gender, and racial workforce diversity, and community-based partnerships to create evidence-based interventions to address disparities.

Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer.

BACKGROUND: The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer. METHODS: Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia. RESULTS: Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells. CONCLUSION: Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer.