Characterizing replisome disassembly in human cells.

To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2LRR1-driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for "backup" mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes.

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.

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.

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.

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.

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.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

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.

Survival Effect of Maximal Cytoreductive Surgery for Advanced Ovarian Carcinoma During the Platinum Era: A Meta-Analysis.

PURPOSE: To evaluate the relative effect of percent maximal cytoreductive surgery and other prognostic variables on survival among cohorts of patients with advanced-stage ovarian carcinoma treated with platinum-based chemotherapy. MATERIALS AND METHODS: Eighty-one cohorts of patients with stage III or IV ovarian carcinoma (6,885 patients) were identified from articles in MEDLINE (1989 through 1998). Linear regression models, with weighted correlation calculations, were used to assess the effects on log median survival time of the proportion of each cohort undergoing maximal cytoreduction, dose-intensity of the platinum compound administered, proportion of patients with stage IV disease, median age, and year of publication. RESULTS: There was a statistically significant positive correlation between percent maximal cytoreduction and log median survival time, and this correlation remained significant after controlling for all other variables (P < .001). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. When actuarial survival was estimated, cohorts with ≤ 25% maximal cytoreduction had a mean weighted median survival time of 22.7 months, whereas cohorts with more than 75% maximal cytoreduction had a mean weighted median survival time of 33.9 months-an increase of 50%. The relationship between platinum dose-intensity and log median survival time was not statistically significant. CONCLUSION: During the platinum era, maximal cytoreduction was one of the most powerful determinants of cohort survival among patients with stage III or IV ovarian carcinoma. Consistent referral of patients with apparent advanced ovarian cancer to expert centers for primary surgery may be the best means currently available for improving overall survival.

Fertility sparing treatment of vaginal clear cell adenocarcinoma in a DES-Naïve young woman.

Background: Primary vaginal cancer is rare and comprises 1-2% of female genital tract cancers. Among the types of vaginal cancer, adenocarcinoma accounts for only 10% with the peak incidence in women less than 20 years old. Clear cell type vaginal adenocarcinoma is most associated with exposure to diethylstilbestrol (DES) in-utero. Case: We present a case of an 18-year-old nulliparous woman, DES-exposure naive, who was diagnosed with stage I clear cell vaginal adenocarcinoma during a routine pelvic exam for abnormal vaginal bleeding. She underwent a fertility-preserving radical vaginectomy and pelvic lymphadenectomy with neovagina creation and uterovaginal cervical reconstruction. She has been without disease for 28 months. Conclusion: Although rare, vaginal cancer can be diagnosed on routine women's health exams. Early screening and diagnosis allow for innovative fertility-preserving surgical approaches without compromising oncologic outcomes. To our knowledge, this is the first case of a fertility-preserving radical vaginectomy, neovagina creation using a vertical rectus abdominis myocutaneous (VRAM) flap, and uterocervicovaginal reconstruction to successfully treat early stage clear cell vaginal adenocarcinoma with surgery alone, sparing the patient from adjuvant chemotherapy or radiation.

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.

Population-Based Analysis of National Comprehensive Cancer Network (NCCN) Guideline Adherence for Patients with Anal Squamous Cell Carcinoma in California.

PURPOSE: We analyzed adherence to the National Comprehensive Cancer Network treatment guidelines for anal squamous cell carcinoma in California and the associated impacts on survival. METHODS: This was a retrospective study of patients in the California Cancer Registry aged 18 to 79 years with recent diagnoses of anal squamous cell carcinoma. Predefined criteria were used to determine adherence. Adjusted odds ratios and 95% confidence intervals were estimated for those receiving adherent care. Disease-specific survival (DSS) and overall survival (OS) were examined with a Cox proportional hazards model. RESULTS: 4740 patients were analyzed. Female sex was positively associated with adherent care. Medicaid status and low socioeconomic status were negatively associated with adherent care. Non-adherent care was associated with worse OS (Adjusted HR 1.87, 95% CI = 1.66, 2.12, p < 0.0001). DSS was worse in patients receiving non-adherent care (Adjusted HR 1.96, 95% CI = 1.56, 2.46, p < 0.0001). Female sex was associated with improved DSS and OS. Black race, Medicare/Medicaid, and low socioeconomic status were associated with worse OS. CONCLUSIONS: Male patients, those with Medicaid insurance, or those with low socioeconomic status are less likely to receive adherent care. Adherent care was associated with improved DSS and OS in anal carcinoma patients.

First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. CONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

A polygenic two-hit hypothesis for prostate cancer.

Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

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).

T-Cell Infiltration and Clonality May Identify Distinct Survival Groups in Colorectal Cancer: Development and Validation of a Prognostic Model Based on The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC).

Predicting the survival outcomes of patients with colorectal cancer (CRC) remains challenging. We investigated the prognostic significance of the transcriptome and tumour-infiltrating lymphocyte T-cell receptor (TIL/Tc-TCR) repertoire and analysed TIL/Tc-TCR sequences of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) CRC cohorts. Using a multivariate Cox regression, we tested whether TIL/Tc-TCR repertoire, patient and tumour characteristics (stage, sidedness, total non-synonymous mutations, microsatellite instability (MSI) and transcriptional signatures) correlated with patient overall survival (OS) and designed a prognostic nomogram. A multivariate analysis (C-index = 0.75) showed that only patient age, disease stage, TIL/Tc degree of infiltration and clonality were independent prognostic factors for OS. The cut-offs for patients' allocation to TIL/Tc abundance subgroups were determined using a strategy of maximally selected rank statistics with the OptimalCutpoints R package. These were "high", "low" and "very high" (90 th percentile) TIL/Tc infiltration-stratified OS (median not reached, 67 and 44.3 months; p < 0.001); the results were validated in the CPTAC cohort. TIL/Tc clonality was prognostic (median OS in "high" vs. "low" clonality not reached and 67.3 months; p = 0.041) and independent of TIL/Tc infiltration. Whilst tumour sidedness was not prognostic, the "very highly" infiltrated tumours were prevalent among right-sided CRCs (p = 0.039) and showed distinct immunological features, with lower Th1 signature (p = 0.004), higher PD-L1 expression (p < 0.001) and likely enrichment in highly suppressory IL1R1+ Tregs (FoxP3 and IL1R1 overexpression, p < 0.001). TIL/Tc abundance and clonality are independent prognosticators in CRC and, combined with clinical variables, refine risk stratification. We identified a subset of CRCs with "very high" TIL/Tc infiltration, poor prognosis and distinct genetic and immunologic features, which may benefit from alternative therapeutic approaches. These results need validation in prospective patient cohorts.

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.