Inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma.

BACKGROUND AND OBJECTIVE: Severe asthma is a heterogeneous disease with subtype classification according to dominant airway infiltrates, including eosinophilic (Type 2 high), or non-eosinophilic asthma. Non-eosinophilic asthma is further divided into paucigranulocytic or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in the airways. Severe non-eosinophilic asthma has few effective treatments and many patients do not qualify for biologic therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease and has proven a valuable therapeutic target. We hypothesized that the CFTR may also play a role in non-eosinophilic asthma. METHODS: Patient-derived human bronchial epithelial cells (hBECs) were isolated and differentiated at the air-liquid interface. Single cell RNA-sequencing (scRNAseq) was used to identify epithelial cell subtypes and transcriptional activity. Ion transport was investigated with Ussing chambers and immunofluorescent quantification of ionocyte abundance in human airway epithelial cells and murine models of asthma. RESULTS: We identified that hBECs from patients with non-eosinophilic asthma had reduced CFTR function, and did not differentiate into CFTR-expressing ionocytes compared to those from eosinophilic asthma or healthy donors. Similarly, ionocytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic asthma. Treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture led to a reduction in ionocytes. CONCLUSION: Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target.

Association of chronic kidney disease with postoperative outcomes: a national surgical quality improvement program (NSQIP) multi-specialty surgical cohort analysis.

BACKGROUND: Chronic kidney disease (CKD) is associated with higher incidence of major surgery. No studies have evaluated the association between preoperative kidney function and postoperative outcomes across a wide spectrum of procedures. We aimed to evaluate the association between CKD and 30-day postoperative outcomes across surgical specialties. METHODS: We selected adult patients undergoing surgery across eight specialties. The primary study endpoint was major complications, defined as death, unplanned reoperation, cardiac complication, or stroke within 30 days following surgery. Secondary outcomes included Clavien-Dindo high-grade complications, as well as cardiac, pulmonary, infectious, and thromboembolic complications. Multivariable regression was performed to evaluate the association between CKD and 30-day postoperative complications, adjusted for baseline characteristics, surgical specialty, and operative time. RESULTS: In total, 1,912,682 patients were included. The odds of major complications (adjusted odds ratio [aOR] 2.14 [95% confidence interval (CI): 2.07, 2.21]), death (aOR 3.03 [95% CI: 2.88, 3.19]), unplanned reoperation (aOR 1.57 [95% CI: 1.51, 1.64]), cardiac complication (aOR 3.51 [95% CI: 3.25, 3.80]), and stroke (aOR 1.89 [95% CI: 1.64, 2.17]) were greater for patients with CKD stage 5 vs. stage 1. A similar pattern was observed for the secondary endpoints. CONCLUSION: This population-based study demonstrates the negative impact of CKD on operative outcomes across a diverse range of procedures and patients.

Adjuvant immunotherapy in high-risk muscle invasive urothelial carcinoma: A systematic review and meta-analysis of randomized clinical trials.

Despite surgical resection, many patients with muscle invasive urothelial carcinoma (MIUC) experience recurrence. Adjuvant immune checkpoint inhibition (ICI) following radical resection in patients with MIUC demonstrates disparate outcomes among phase III randomized controlled trials (RCTs). Our objective was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with MIUC and evaluate the overall safety profile of ICIs in this setting. The protocol was registered with PROSPERO, CRD42022352587. We searched MEDLINE, Embase, CENTRAL, and relevant conference proceedings from inception up to January 29, 2024. Only phase III RCTs comparing adjuvant ICI versus placebo/observation were selected. Study screening and selection, along with data extraction was performed in duplicate according to a predefined registered protocol. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used. Quality assessment was performed using the Cochrane risk-of-bias (RoB 2) tool for randomized trials. The primary and secondary endpoints were DFS and serious adverse events, respectively. All outcomes were analyzed using random-effects meta-analysis owing to inter-study heterogeneity. Sensitivity and subgroup analyses were performed to identify potential sources of heterogeneity. A priori defined subgroups of interest included positive program death-ligand 1 (PD-L1) expression, previous use of neoadjuvant chemotherapy (NAC), primary tumor origin, pathologic lymph node status, and baseline Eastern Cooperative Oncology Group performance status. Pooled results across the 3 RCTs (2,220 patients) demonstrated significantly improved DFS for patients treated with ICI in the intention-to-treat cohorts (HR 0.76, 95% CI 0.65-0.90). There was considerable clinical and statistical heterogeneity (I2 = 44%) due to differences in inclusion criteria and interventions. Overall, there was a low risk of bias among the RCTs. Regarding subgroup analyses, there was significant benefit among patients with negative PD-L1 expression (HR 0.76, 95% CI 0.64-0.90), those who received prior NAC (HR 0.69, 95% CI 0.52-0.91), and patients with lower tract (HR 0.71, 95% CI 0.55-0.92) but not upper tract disease (HR 1.21, 95% CI 0.87-1.68). This pooled analysis of DFS and safety provides support for ICI utilization in the setting of high-risk resected MIUC.

Association Between Surgeon Sex and Days Alive at Home Following Surgery: A Population-Based Cohort Study.

Objective: The objective of this study was to measure potential associations between surgeon sex and number of days alive and at home (DAH). Background: Patients treated by female surgeons appear to have lower rates of mortality, complications, readmissions, and healthcare costs when compared with male surgeons. DAH is a validated measure, shown to better capture the patient experience of postoperative recovery. Methods: We conducted a retrospective study of adults (≥18 years of age) undergoing common surgeries between January 01, 2007 and December 31, 2019 in Ontario, Canada. The outcome measures were the number of DAH within 30-, 90-, and 365-days. The data was summarized using descriptive statistics and adjusted using multivariable generalized estimating equations. Results: During the study period, 1,165,711 individuals were included, of which 61.9% (N = 721,575) were female. Those managed by a female surgeon experienced a higher mean number of DAH when compared with male surgeons at 365 days (351.7 vs. 342.1 days; P < 0.001) and at each earlier time point. This remained consistent following adjustment for covariates, with patients of female surgeons experiencing a higher number of DAH at all time points, including at 365 days (343.2 [339.5-347.1] vs. 339.4 [335.9-343.0] days). Multivariable regression modeling revealed that patients of male surgeons had a significantly lower number of DAH versus female surgeons. Conclusions: Patients of female surgeons experienced a higher number of DAH when compared with those treated by male surgeons at all time points. More time spent at home after surgery may in turn lower costs of care, resource utilization, and potentially improve quality of life. Further studies are needed to examine these findings across other care contexts.

Superstition in Surgery: A Population-Based Cohort Study to Assess the Association Between Surgery on Friday the 13th and Postoperative Outcomes.

Objective: We sought to examine whether the outcomes of patients who receive a surgical procedure on Friday the 13th differ from patients who receive surgery on flanking Fridays. Background: Numerous studies have demonstrated that increased anxiety from the provider or patient around the time of surgery can lead to worse outcomes. Superstitious patients often express significant concern and anxiety when undergoing a surgical procedure on Friday the 13th. Methods: A retrospective, population-based cohort study of 19,747 adults undergoing 1 of 25 common surgical procedures on Friday the 13th or flanking control Fridays (Friday the 6th and Friday the 20th) between January 1, 2007, and December 31, 2019, with 1 year of follow-up. The main outcomes included death, readmission, and complications at 30 days (short-term), 90 days (intermediate-term), and 1 year (long-term). Results: A total of 7,349 (37.2%) underwent surgery on Friday the 13th, and 12,398 (62.8%) underwent surgery on a flanking Friday during the study period. Patient characteristics were similar between the 2 groups. We found no evidence that patients receiving surgery on Friday the 13th group were more likely to experience the composite primary outcome at 30 days [adjusted odds ratio (aOR) = 1.02 (95% CI = 0.94-1.09)], 90 days [aOR = 0.97 (95% CI = 0.90-1.04)], and 1 year [aOR = 0.99 (95% CI = 0.94-1.04)] after surgery. Conclusion: Patients receiving surgery on Friday the 13th do not appear to fare worse than those treated on ordinary Fridays with respect to the composite outcome.

Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience.

INTRODUCTION: First-line systemic therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemoimmunotherapy trials failed to show a clear benefit over chemotherapy alone. We used real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy, or combination chemoimmunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). MATERIALS AND METHODS: We used the National Cancer Database to identify patients with stage IV mUC diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. RESULTS: In our cohort of 4,169 patients, multivariable analysis identified increasing age (RRR: 1.07, 95%CI, 1.06-1.08) and comorbidity burden (, as independent predictors of receiving immunotherapy. Treatment at an academic facility was associated with increased likelihood of combination treatment (RRR: 1.29, 95%CI, 1.01-1.65). After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95%CI, 0.62-0.83) was associated with improved survival compared to chemotherapy. CONCLUSIONS: Patients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Utilization of chemoimmunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy.

Contemporary morbidity and mortality of open versus robotic cystectomy for bladder cancer: An analysis of the National Surgical Quality Improvement Program (NSQIP) procedure targeted cystectomy database.

OBJECTIVES: To evaluate the association between surgical modality (RARC vs. ORC) and the risk of 30-day complications. MATERIALS AND METHODS: We utilized the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) Cystectomy-Targeted database from 2019 to 2021. The primary outcome was a composite of major complications including 30-day mortality, reoperation, cardiac events, and stroke. Secondary outcomes included individual major and cystectomy-specific complications. Propensity score matching (PSM) was employed to minimize inherent differences within our cohort. We performed logistic regression to assess the association between outcomes of interest and operative modality. RESULTS: We found no difference between operative modality and the primary outcome, however, RARC was associated with a 70% lower risk of 30-day mortality (OR 0.30, 95% CI 0.13-0.70) and had favorable outcomes with respect to respiratory, deep venous thrombosis, wound complications, and length of stay. Limitations are related to residual confounding given the observational methodology. CONCLUSIONS: RARC was associated with reduced risk of multiple 30-day complications, including mortality, as well as organ system and cystectomy-specific outcomes. These data support the clinical benefit of increased adoption of RARC.

Association Between Anesthesiologist Sex and Patients' Postoperative Outcomes: A Population-based Cohort Study.

OBJECTIVE: To examine the association of anesthesiologist sex on postoperative outcomes. BACKGROUND: Differences in patient postoperative outcomes exist, depending on whether the primary surgeon is male or female, with better outcomes seen among patients treated by female surgeons. Whether the intraoperative anesthesiologist's sex is associated with differential postoperative patient outcomes is unknown. METHODS: We performed a population-based, retrospective cohort study among adult patients undergoing one of 25 common elective or emergent surgical procedures from 2007 to 2019 in Ontario, Canada. We assessed the association between the sex of the intraoperative anesthesiologist and the primary end point of the adverse postoperative outcome, defined as death, readmission, or complication within 30 days after surgery, using generalized estimating equations. RESULTS: Among 1,165,711 patients treated by 3006 surgeons and 1477 anesthesiologists, 311,822 (26.7%) received care from a female anesthesiologist and 853,889 (73.3%) from a male anesthesiologist. Overall, 10.8% of patients experienced one or more adverse postoperative outcomes, of whom 1.1% died. Multivariable adjusted rates of the composite primary end point were higher among patients treated by male anesthesiologists (10.6%) compared with female anesthesiologists (10.4%; adjusted odds ratio 1.02, 95% CI: 1.00-1.05, P =0.048). CONCLUSIONS: We demonstrated a significant association between sex of the intraoperative anesthesiologist and patient short-term outcomes after surgery in a large cohort study. This study supports the growing literature of improved patient outcomes among female practitioners. The underlying mechanisms of why outcomes differ between male and female physicians remain elusive and require further in-depth study.

Impact of Social Disparities on 5-Year Survival Rates in Pediatric Hematologic Malignancies.

BACKGROUND: Socioeconomic disparities exist in pediatric patients with hematologic malignancies, leading to suboptimal survival rates. Social determinants of health impact health outcomes, and in children, they may not only lead to worse survival outcomes but carry over into late effects in adult life. The social deprivation index (SDI) is a composite score using geographic county data to measure social determinants of health. Using the SDI, the purpose of the present study is to stratify survival outcomes in pediatric patients with hematologic malignancies based on area deprivation. METHODS: A retrospective cohort study was performed using the national Surveillance, Epidemiology, and End Results oncology registry in the USA from 1975 to 2016 based on county-level data. Pediatric patients (≤18 y old) with a diagnosis of leukemia or lymphoma based on the International Classification for Oncology, third edition (ICD-O-3) were used for inclusion criteria. Patients were grouped by cancer subtype for leukemia into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia while for lymphoma into non-Hodgkin's lymphoma and Hodgkin's lymphoma. SDI scores were calculated for each patient and divided into quartiles, with Q1 being the lowest area of deprivation and Q4 being the highest, respectively. RESULTS: A total of 38,318 leukemia and lymphoma patients were included. Quartile data demonstrated stratification in survival based on area deprivation for ALL, with no survival differences in the other cancer subtypes. Patients with ALL from the most deprived area had a roughly 3% difference in both overall and cancer-specific morality at 5 years compared with the least deprived area. CONCLUSION: Disparities in pediatric patients with ALL represent a significant area for quality improvement. Social programs may have value in improving survival outcomes and could rely on metrics such as SDI.

Surgeon Sex and Health Care Costs for Patients Undergoing Common Surgical Procedures.

Importance: Prior research has shown differences in postoperative outcomes for patients treated by female and male surgeons. It is important to understand, from a health system and payer perspective, whether surgical health care costs differ according to the surgeon's sex. Objective: To examine the association between surgeon sex and health care costs among patients undergoing surgery. Design, Setting, and Participants: This population-based, retrospective cohort study included adult patients undergoing 1 of 25 common elective or emergent surgical procedures between January 1, 2007, and December 31, 2019, in Ontario, Canada. Analysis was performed from October 2022 to March 2023. Exposure: Surgeon sex. Main Outcome and Measure: The primary outcome was total health care costs assessed 1 year following surgery. Secondarily, total health care costs at 30 and 90 days, as well as specific cost categories, were assessed. Generalized estimating equations were used with procedure-level clustering to compare costs between patients undergoing equivalent surgeries performed by female and male surgeons, with further adjustment for patient-, surgeon-, anesthesiologist-, hospital-, and procedure-level covariates. Results: Among 1 165 711 included patients, 151 054 were treated by a female surgeon and 1 014 657 were treated by a male surgeon. Analyzed at the procedure-specific level and accounting for patient-, surgeon-, anesthesiologist-, and hospital-level covariates, 1-year total health care costs were higher for patients treated by male surgeons ($24 882; 95% CI, $20 780-$29 794) than female surgeons ($18 517; 95% CI, $16 080-$21 324) (adjusted absolute difference, $6365; 95% CI, $3491-9238; adjusted relative risk, 1.10; 95% CI, 1.05-1.14). Similar patterns were observed at 30 days (adjusted absolute difference, $3115; 95% CI, $1682-$4548) and 90 days (adjusted absolute difference, $4228; 95% CI, $2255-$6202). Conclusions and Relevance: This analysis found lower 30-day, 90-day, and 1-year health care costs for patients treated by female surgeons compared with those treated by male surgeons. These data further underscore the importance of creating inclusive policies and environments supportive of women surgeons to improve recruitment and retention of a more diverse and representative workforce.

Comparative real-world survival outcomes of muscle-invasive bladder cancer treated with bladder-only vs. whole-pelvis concurrent chemoradiation.

INTRODUCTION: Elective pelvic nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT ) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiation (WP-CCR) compared to bladder-only (BO )-CCR has not been demonstrated. Using real-world data from the National Cancer Database (NCDB ), we sought to compare the overall survival (OS ) between BO-CCR and WP-CCR for MIBC. METHODS: Using the 2020 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2019. We selected patients with clinical T2-T4aN0M0 disease receiving CCR as first-line treatment. CCR was defined as transurethral resection of bladder tumor followed by ≥40 Gy radiation to the bladder with concurrent single- or multiple-agent chemotherapy. Based on elective nodal irradiation status, patients were stratified as having received BO-CCR vs. WP-CCR. OS analysis was performed using summary three-month conditional landmark, inverse probability treatment weighting (IPTW)-adjusted Kaplan-Meier estimates, and Cox regression. RESULTS: A total of 604 patients receiving CCR for MIBC were identified: 367 (60.8%) BO-CCR and 237 (39.2%) WP-CCR. Before IPTW, the groups were imbalanced in terms of baseline characteristics. The median followup of the weighted population was 42.3 months (interquartile range 18.1-49.1 months). In IPTW-adjusted Cox proportional hazards regression analysis, WP-CCR was associated with a significant OS benefit compared to BO-CCR (adjusted hazard ratio 0.72, 95% confidence interval 0.54-0.96, p=0.026). CONCLUSIONS: In the setting of CCR for N0 MIBC, this retrospective NCDB analysis revealed that WP-CCR was associated with a benefit in OS compared to BO-CCR.

Postoperative Discharge Destination Impacts 30-Day Outcomes: A National Surgical Quality Improvement Program Multi-Specialty Surgical Cohort Analysis.

Surgical patients can be discharged to a variety of facilities which vary widely in intensity of care. Postoperative readmissions have been found to be more strongly associated with post-discharge events than pre-discharge complications, indicating the importance of discharge destination. We sought to evaluate the association between discharge destination and 30-day outcomes. A retrospective cohort study was conducted using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Patients were dichotomized based on discharge destination: home versus non-home. The main outcome of interest was 30-day unplanned readmission. The secondary outcomes included post-discharge pulmonary, infectious, thromboembolic, and bleeding complications, as well as death. In this cohort study of over 1.5 million patients undergoing common surgical procedures across eight surgical specialties, we found non-home discharge to be associated with adverse 30-day post-operative outcomes, namely, unplanned readmissions, post-discharge pulmonary, infectious, thromboembolic, and bleeding complications, as well as death. Non-home discharge is associated with worse 30-day outcomes among patients undergoing common surgical procedures. Patients and caregivers should be counseled regarding discharge destination, as non-home discharge is associated with adverse post-operative outcomes.

Surgeon Sex and Long-Term Postoperative Outcomes Among Patients Undergoing Common Surgeries.

Importance: Sex- and gender-based differences in a surgeon's medical practice and communication may be factors in patients' perioperative outcomes. Patients treated by female surgeons have improved 30-day outcomes. However, whether these outcomes persist over longer follow-up has not been assessed. Objective: To examine whether surgeon sex is associated with 90-day and 1-year outcomes among patients undergoing common surgeries. Design, Setting, and Participants: A population-based retrospective cohort study was conducted in adults in Ontario, Canada, undergoing 1 of 25 common elective or emergent surgeries between January 1, 2007, and December 31, 2019. Analysis was performed between July 15 and October 20, 2022. Exposure: Surgeon sex. Main Outcomes and Measures: An adverse postoperative event, defined as the composite of death, readmission, or complication, was assessed at 90 days and 1 year following surgery. Secondarily, each of these outcomes was assessed individually. Outcomes were compared between patients treated by female and male surgeons using generalized estimating equations with clustering at the level of the surgical procedure, accounting for patient-, procedure-, surgeon-, anesthesiologist-, and facility-level covariates. Results: Among 1 165 711 included patients, 151 054 were treated by a female and 1 014 657 by a male surgeon. Overall, 14.3% of the patients had 1 or more adverse postoperative outcomes at 90 days and 25.0% had 1 or more adverse postoperative outcomes 1 year following surgery. Among these, 2.0% of patients died within 90 days and 4.3% died within 1 year. Multivariable-adjusted rates of the composite end point were higher among patients treated by male than female surgeons at both 90 days (13.9% vs 12.5%; adjusted odds ratio [AOR], 1.08; 95% CI, 1.03-1.13) and 1 year (25.0% vs 20.7%; AOR, 1.06; 95% CI, 1.01-1.12). Similar patterns were observed for mortality at 90 days (0.8% vs 0.5%; AOR 1.25; 95% CI, 1.12-1.39) and 1 year (2.4% vs 1.6%; AOR, 1.24; 95% CI, 1.13-1.36). Conclusions and Relevance: After accounting for patient, procedure, surgeon, anesthesiologist, and hospital characteristics, the findings of this cohort study suggest that patients treated by female surgeons have lower rates of adverse postoperative outcomes including death at 90 days and 1 year after surgery compared with those treated by male surgeons. These findings further support differences in patient outcomes based on physician sex that warrant deeper study regarding underlying causes and potential solutions.

The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth.

Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in ß-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC50 in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.

The impact of socioeconomic status on the survival of men with early-onset prostate cancer.

Prostate cancer (PCa) is generally considered a disease of older men; however, about 10% of new diagnoses in the US occur in men ≤ 55 years old. Socioeconomic status (SES) has been shown to influence survival in patients with PCa; however, the impact of SES on men with early-onset PCa remains undescribed. Using the National Cancer Database, we identified adult men ≤ 55 years of age with a diagnosis of prostatic adenocarcinoma between 2004-2018. Descriptive statistics were used to characterize differences among different SES groups. Kaplan-Meier (KM) and Cox regression analyses were used to assess the effect of SES on overall survival (OS). A total of 112,563 young patients with PCa with a median follow-up of 79.0 months were identified. Compared to high SES patients, low SES patients were more likely to be African American (42.4% vs. 8.6%; P<0.001), Hispanic (9.5% vs. 2.7%; P<0.001), and uninsured (5.2% vs. 1.1%; P<0.001); they were also more likely to live in a rural area (3.2% vs. 0.1%; P<0.001) and have stage IV disease (5.5% vs. 3.1%; P<0.001). KM analysis showed that a decreasing SES was directly associated with lower rates of OS (log-rank test P<0.001). On multivariable analysis, SES was found to have a negative effect on OS (low SES vs. high SES; hazard ratio [HR] 1.54; 95% confidence interval [CI] 1.41-1.68; P<0.001). In patients with early-onset PCa, SES was associated with lower OS. SES may be considered when implementing programs to improve the management of patients with early-onset PCa.

Impact of social disparities on 10 year survival rates in paediatric cancers: a cohort study.

Background: Studies reporting on the impact of social determinants of health on childhood cancer are limited. The current study aimed to examine the relationship between health disparities, as measured by the social deprivation index, and mortality in paediatric oncology patients using a population-based national database. Methods: In this cohort study of children across all paediatric cancers, survival rates were determined using the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2016. The social deprivation index was used to measure and assess healthcare disparities and specifically the impact on both overall and cancer-specific survival. Hazard ratios were used to assess the association of area deprivation. Findings: The study cohort was composed of 99,542 patients with paediatric cancer. Patients had a median age of 10 years old (IQR: 3-16) with 46,109 (46.3%) of female sex. Based on race, 79,984 (80.4%) of patients were identified as white while 10,801 (10.9%) were identified as Black. Patients from socially deprived areas had significantly higher hazard of death overall for both non-metastatic [1.27 (95% CI: 1.19-1.36)] and metastatic presentations [1.09 (95% CI: 1.05-1.15)] compared to in more socially affluent areas. Interpretation: Patients from the most socially deprived areas had lower rates of overall and cancer-specific survival compared to patients from socially affluent areas. With an increase in childhood cancer survivors, implementation of social determinant indices, such as the social deprivation index, might aid improvement in healthcare outcomes for the most vulnerable patients. Funding: There was no study sponsor or extramural funding.

Potential role for protein kinase D inhibitors in prostate cancer.

Protein kinase D (PrKD), a novel serine-threonine kinase, belongs to a family of calcium calmodulin kinases that consists of three isoforms: PrKD1, PrKD2, and PrKD3. The PrKD isoforms play a major role in pathologic processes such as cardiac hypertrophy and cancer progression. The charter member of the family, PrKD1, is the most extensively studied isoform. PrKD play a dual role as both a proto-oncogene and a tumor suppressor depending on the cellular context. The duplicity of PrKD can be highlighted in advanced prostate cancer (PCa) where expression of PrKD1 is suppressed whereas the expressions of PrKD2 and PrKD3 are upregulated to aid in cancer progression. As understanding of the PrKD signaling pathways has been better elucidated, interest has been garnered in the development of PrKD inhibitors. The broad-spectrum kinase inhibitor staurosporine acts as a potent PrKD inhibitor and is the most well-known; however, several other novel and more specific PrKD inhibitors have been developed over the last two decades. While there is tremendous potential for PrKD inhibitors to be used in a clinical setting, none has progressed beyond preclinical trials due to a variety of challenges. In this review, we focus on PrKD signaling in PCa and the potential role of PrKD inhibitors therein, and explore the possible clinical outcomes based on known function and expression of PrKD isoforms at different stages of PCa.

Morbidity and mortality of multivisceral resection with radical nephrectomy for locally advanced renal cell carcinoma: An analysis of the National Surgical Quality Improvement Program (NSQIP) database.

INTRODUCTION: Locally advanced renal cell carcinoma (RCC) can rarely invade into adjacent abdominal viscera without clinical evidence of distant metastases. The role of multivisceral resection (MVR) of involved adjacent organs at the time of radical nephrectomy (RN) remains poorly described and quantified. Using a national database, we aimed to evaluate the association between RN+MVR and 30-day postoperative complications. METHODS AND MATERIALS: We conducted a retrospective cohort study of adult patients undergoing RN for RCC with and without MVR between 2005 and 2020 using the ACS-NSQIP database. The primary outcome was a composite of any of the following 30-day major postoperative complications: mortality, reoperation, cardiac event, and neurologic event. Secondary outcomes included individual components of the composite primary outcome, as well as infectious and venous thromboembolic complications, unplanned intubation and ventilation, transfusion, readmission, and prolonged length of stay (LOS). Groups were balanced using propensity score matching. Likelihood of complications was assessed by conditional logistic regression adjusted for unbalanced total operation time. Postoperative complications were compared by Fisher's exact test among subtypes of resection. RESULTS: A total of 12,417 patients were identified: 12,193 (98.2%) undergoing RN alone and 224 (1.8%) undergoing RN+MVR. Patients undergoing RN+MVR were more likely to experience major complications (odds ratio [OR] 2.46; 95% confidence interval [CI] 1.28-4.74). However, there was no significant association between RN+MVR and postoperative mortality (OR 2.49; 95% CI 0.89-7.01). RN+MVR was associated with higher rates of reoperation (OR 7.85; 95% CI 2.38-25.8), sepsis (OR 5.45; 95% CI 1.83-16.2), surgical site infection (OR 4.41; 95% CI 2.14-9.07), blood transfusion (OR 2.24; 95% CI 1.55-3.22), readmission (OR 1.78; 95% CI 1.11-2.84), infectious complications (OR 2.62; 95% CI 1.62-4.24), and longer hospital stay (5 days [IQR 3-8] vs. 4 days [IQR 3-7]; OR 2.31 [95% CI 2.13-3.03]).  There was no heterogeneity in the association between subtype of MVR and major complication rate. CONCLUSION: Undergoing RN+MVR is associated with an increased risk of 30-day postoperative morbidity, including infectious complications, reoperation, blood transfusion, prolonged LOS, and readmission.

The geriatric nutritional risk index predicts complications after nephrectomy for renal cancer

ABSTRACT Purpose: We examined if malnutrition, as defined by the Geriatric Nutritional Risk Index (GNRI), is independently associated with 30-day postoperative complications in patients undergoing nephrectomy for the treatment of renal cancer. Materials and methods: Using the American College of Surgeons National Surgical Quality Improvement Program database from 2006-2019, we identified patients ≥65 years old who underwent nephrectomy for renal cancer. The following formula for GNRI was used to define preoperative nutritional status: 1.489 x serum albumin (g/L) + 41.7 x (current body weight [kg]/ ideal body weight [kg]). Based on the GNRI, patients were classified as having no (> 98), moderate (92-98), or severe malnutrition (< 92). After adjusting for potential confounders, multivariable logistic regression analyses were performed to assess the association between GNRI and 30-day postoperative complications. Odds ratios (OR) with 95% confidence intervals (CI) were reported. Results: A total of 7,683 patients were identified, of which 1,241 (16.2%) and 872 (11.3%) had moderate and severe malnutrition, respectively. Compared to normal nutrition, moderate and severe malnutrition were significantly associated with a greater odds of superficial surgical site infection, progressive renal insufficiency, readmission, extended length of stay, and non-home discharge. Severe malnutrition was also associated with urinary tract infection (OR 2.10, 95% CI 1.31-3.35) and septic shock (OR 2.93, 95% CI 1.21-7.07). Conclusion: Malnutrition, as defined by a GNRI ≤ 98, is an independent predictor of 30-day complications following nephrectomy. The GNRI could be used to counsel elderly patients with renal cancer prior to nephrectomy.

Does care fragmentation in patients with bladder cancer lead to worse outcomes?

INTRODUCTION: Care fragmentation may influence oncologic outcomes. The impact of care fragmentation on the outcomes of patients receiving neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) is not well defined. We aimed to compare outcomes between patients who received fragmented care (FC) versus non-fragmented care (NFC). METHODS: The National Cancer Database was queried for adult (≥18 years old) patients with cT2-T4aN0M0 urothelial carcinoma of the bladder receiving NAC followed by RC between 2004 and 2017. Patients were dichotomized based on whether they received FC (defined as receiving NAC at a different facility from where RC was performed) or NFC (defined as receiving NAC and RC at a single facility). The main outcome of interest was overall survival (OS). Secondary outcomes included time from diagnosis to treatment (NAC and RC) and perioperative outcomes. Kaplan-Meier survival estimates were calculated after stratifying by type of care received. Multivariable Cox regression analysis was performed to evaluate the association between FC and OS in the context of other clinically relevant covariates. RESULTS: A total of 2223 patients were included: 1035 (46.6%) received FC whereas 1188 (53.4%) received NFC. Factors associated with FC included greater travel distance, higher comorbidity burden, and surgical treatment at a high-volume facility. Patients who received FC had a slightly longer median time to RC (160 vs. 154 days, P = 0.001). However, on Kaplan-Meier analysis no differences in median OS were found between the two groups. On multivariable Cox regression analysis, factors associated with worse OS included age, advanced TNM stage, lymphovascular invasion, and positive surgical margins; yet FC was not associated with worse OS (hazard ratio [HR] 1.02; 95% confidence interval [CI] 0.88-1.17). On subgroup analysis, we found that FC received at academic facilities (HR 0.76; 95% CI 0.58-0.99), as well as NFC received at high-volume centers (HR 0.65; 95% CI 0.43-0.98), were associated with a decrease in overall mortality. CONCLUSIONS: Fragmented care is not associated with worse survival outcomes in patients with MIBC receiving NAC followed by RC.