Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade.

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.

Safety and effectiveness of zero antimicrobial prophylaxis protocol for outpatient cystourethroscopy.

OBJECTIVES: To examine compliance and clinical outcomes after implementation of a zero antimicrobial prophylaxis protocol for outpatient cystoscopy in an academic centre. PATIENTS AND METHODS: Medical records of all patients who underwent diagnostic cystoscopy in the year preceding and year following protocol implementation were evaluated for urinary tract infection (UTI) diagnosis within 30 days of cystoscopy. Variables compared between groups included age, sex, smoking history, benign prostatic hyperplasia (BPH) diagnosis, diabetes mellitus, immunosuppression, catheter use (indwelling, suprapubic, or intermittent), and previous lower urinary tract reconstruction (augmentation cystoplasty or neobladder). UTI was defined using the National Surgical Quality Improvement Program definition. Rates were compared between groups, and statistical analyses were performed using chi-squared and Fisher's exact tests and multivariable logistic regression, with significance defined as α < 0.05. RESULTS: In total, 941 patients were included in the analysis (72% men), 513 before protocol initiation, and 427 after. Groups were similar with regard to demographic variables and potential risk factors for infection. After protocol implementation, there was a significant reduction in patients receiving procedural antimicrobial prophylaxis (30% vs 15%; P < 0.001). The incidence of UTI after cystoscopy was slightly higher in the post-protocol group (2.9-3.7%), but the difference was not statistically significant (chi-squared = 0.56, P = 0.45). The incidence of UTI did not significantly differ with procedural antibiotic prophylaxis or with other antibiotic use at time of cystoscopy. Five out of a total of 31 UTIs (16%) over the study period resulted in fever, and four (13%) resulted in urosepsis. The probability of neither complication differed significantly between pre- and post-protocol groups. The only significant patient-level predictor of post-cystoscopy UTI was catheter use (odds ratio 1.48, 95% confidence interval 1.06-2.06). CONCLUSION: Protocol implementation led to a significant decrease in procedural antimicrobial prophylaxis, indicating protocols may be effective tools in promoting antibiotic stewardship. UTI incidence did not change significantly under the protocol, and antibiotic prophylaxis did not decrease infection rate. Our results support catheter use as a risk factor for post-cystoscopy infection, but other patient variables, including those present in the American Urological Association Best Practice statement, were not predictive. In total, this analysis suggests that decreasing antibiotic prophylaxis for cystourethroscopy is safe and can be effective in the outpatient setting.

Unconventional Bladder Preservation: Factors Predicting Failure to Receive Definitive Surgery following Chemotherapy for Nonmetastatic Muscle Invasive Bladder Cancer in the National Cancer Database.

PURPOSE: Neoadjuvant chemotherapy is an important adjunct to cystectomy for managing muscle invasive bladder cancer. Using the National Cancer Database we investigated factors that predict failure to undergo surgery following multi-agent chemotherapy for nonmetastatic muscle invasive bladder cancer. MATERIALS AND METHODS: We performed a cohort study in patients diagnosed with cT2-4aN0M0 urothelial cell carcinoma of the bladder between 2004 and 2013 who underwent multi-agent chemotherapy. We excluded those with surgery prior to chemotherapy, clinical T4b disease and those who received radiotherapy. Socioeconomic and clinical predictors, including time from diagnosis to treatment, were analyzed using logistic regression for the receipt of surgery after chemotherapy. Cox proportional hazards modeling was applied to perform time dependent analysis. RESULTS: Of the 4,640 patients who met our study inclusion and exclusion criteria 4,244 (91%) proceeded to surgery. Negative predictors of surgery included African American or Hispanic race (OR 0.58, p = 0.007 and 0.48, p = 0.002, respectively), increasing age (OR 0.44, p <0.001) and greater time between diagnosis and chemotherapy initiation (fourth quartile greater than 59 days, OR 0.51, p <0.001). African American race (HR 0.79, p <0.001), Medicare (HR 0.86, p <0.001) and other government insurance (HR 0.73, p <0.001) were associated with delayed chemotherapy. CONCLUSIONS: Increasing age, African American or Hispanic race and longer time to chemotherapy predicted failure to undergo surgery. Furthermore, African American race was associated with delayed chemotherapy. Chemotherapy was also delayed in patients on Medicare or other government insurance. Longer time to neoadjuvant chemotherapy is a modifiable risk factor that should be closely observed in multimodal cancer treatment.

Diagnosis of Perinatal Mental Health Conditions Following Medicaid Expansion to Include Low-Income Immigrants.

Importance: For some low-income people, access to care during pregnancy is not guaranteed through Medicaid, based on their immigration status. While states have the option to extend Emergency Medicaid coverage for prenatal and postpartum care, many states have not expanded coverage. Objective: To determine whether receipt of first prenatal care services and subsequently receipt of postpartum care through extensions of Emergency Medicaid coverage were associated with increases in diagnosis and treatment of perinatal mental health conditions. Design, Setting, and Participants: This cohort study used linked Medicaid claims and birth certificate data from 2010 to 2020 with a difference-in-difference design to compare the rollout of first prenatal care coverage in 2013 and then postpartum services in Oregon in 2018 with a comparison state, South Carolina, which did not cover prenatal or postpartum care as part of Emergency Medicaid and only covered emergent conditions and obstetric hospital admissions. Medicaid claims and birth certificate data were linked by Medicaid identification number prior to receipt by the study team. Participants included recipients of Emergency Medicaid who gave birth in Oregon or South Carolina. Data were analyzed from April 1 to October 15, 2023. Exposure: Medicaid coverage of prenatal care and Medicaid coverage of postpartum care. Main Outcomes and Measures: The main outcome was the diagnosis of a perinatal mental health condition within 60 days postpartum. Secondary outcomes included treatment of a mood disorder with medication or talk therapy. Results: The study sample included 43 889 births to Emergency Medicaid recipients who were mainly aged 20 to 34 years (32 895 individuals [75.0%]), multiparous (33 887 individuals [77.2%]), and living in metropolitan areas (32 464 individuals [74.0%]). Following Oregon's policy change to offer prenatal coverage to pregnant individuals through Emergency Medicaid, there was a significant increase in diagnosis frequency (4.1 [95% CI, 1.7-6.5] percentage points) and a significant difference between states in treatment for perinatal mental health conditions (27.3 [95% CI, 13.2-41.4] percentage points). Postpartum Medicaid coverage (in addition to prenatal Medicaid coverage) was associated with an increase of 2.6 (95% CI, 0.6-4.6) percentage points in any mental health condition being diagnosed, but there was no statistically significant difference in receipt of mental health treatment. Conclusions and Relevance: These findings suggest that changing Emergency Medicaid policy to include coverage for prenatal and 60 days of postpartum care for immigrants is foundational to improving maternal mental health. Expanded postpartum coverage length, or culturally competent interventions, may be needed to optimize receipt of postpartum treatment.

Differences between rural and urban residence in the detection and treatment of perinatal mood and anxiety disorders.

BACKGROUND: Perinatal mood and anxiety disorders are common, serious complications of pregnancy. Disparities exist by race and income in the prevalence and treatment of these conditions, and overall treatment rates remain low. Outside of pregnancy, a small body of literature suggests that rural residency may contribute to higher rates of depression for those who identify as women. However, among more diverse populations, evidence suggests urban residency may be associated with higher rates of depression among women of color. It is not known whether these trends hold for mood and anxiety disorders during pregnancy and postpartum. OBJECTIVE: We examined differences in the detection and treatment of perinatal mood and anxiety disorders by rural and urban residents and assessed if the observed differences varied by maternal race or ethnicity. STUDY DESIGN: We conducted a cross-sectional study using linked Medicaid claims and birth certificate records from Oregon and South Carolina from 2016 to 2020. We identified perinatal mood and anxiety disorder diagnoses during the perinatal period (pregnancy and within 60 days postpartum) using International Classification of Disease 10th edition codes and enumerated receipt of pharmacotherapy and psychotherapy treatment using Medicaid claims. We used logistic regression models controlling for relevant clinical and sociodemographic characteristics to estimate associations between rural residence and mood disorder detection and treatment. RESULTS: Among the 185,809 births in our sample, 27% of births (n=50,820) were to people who lived in rural areas and 73% (n=134,989) to those in urban areas. The prevalence of any perinatal mood and anxiety disorders diagnosis was higher for urban residents (19.5%) than for rural residents (18.0%; P<.001). Overall treatment rates were low among people with a perinatal mood and anxiety disorder (42% [n=14,789]). In our adjusted models, those living in urban areas had higher odds of a perinatal mood and anxiety disorder diagnosis (adjusted odds ratio, 1.059 [95% confidence interval, 1.059-1.059], P<.001). We found a significant interaction between maternal race and rurality (P<.001). When we stratified by race, we found that among those who identified as Black, the odds of a perinatal mood and anxiety disorder diagnosis were increased for urban residents (odds ratio, 1.188 [95% confidence interval, 1.188-1.188]), whereas among those who identified as White, there were no such increased odds (odds ratio, 1.027 [95% confidence interval, 0.843-1.252]). CONCLUSION: We saw small but meaningful differences between rural and urban residents in perinatal mood and anxiety disorder diagnosis rates. We detected an interaction between race and rural vs urban maternal residence that impacted the observed differences. By elucidating the intersection between race and other sociodemographic factors, we hope more targeted and meaningful investments can be made in the communities most in need.

Association of Prenatal Care Expansion With Use of Antidiabetic Agents During Pregnancies Among Latina Emergency Medicaid Recipients With Gestational Diabetes.

Importance: Access to necessary prenatal care is not guaranteed through Medicaid for some people with low income based on their immigration status. Although states have the option to extend emergency Medicaid coverage for prenatal care, many states have not expanded coverage. Objective: To evaluate whether the receipt of prenatal care services through the extension of emergency Medicaid coverage is associated with an increase in antidiabetic medication use among Latina patients with gestational diabetes. Design, Setting, and Participants: This cohort study used linked Medicaid claims and birth certificate data on live births to 4869 Latina patients from October 1, 2010, to December 31, 2019, with a difference-in-differences design to compare the rollout of prenatal care and services in Oregon in 2013 with a comparison state, South Carolina, that did not cover prenatal or postpartum care. Exposure: Medicaid coverage of prenatal care. Main Outcomes and Measures: The main outcome was the receipt of antidiabetic agents. Secondary outcomes included hypertensive disorders, cesarean delivery, postpartum contraception, and a newborn morbidity composite outcome (large size for gestational age, neonatal intensive care unit admission, and preterm birth). Results: The study sample included live births to 4869 Latina patients (mean [SD] age, 32.7 [5.5] years [range, 12-44 years]) enrolled in emergency Medicaid who were mainly aged 25 to 34 years (1499 of 2907 [51.6%]), multiparous (2626 of 2907 [90.3%]), and living in urban areas (2299 of 2907 [79.1%]). After Oregon's policy change to offer prenatal coverage to individuals receiving emergency Medicaid, there was a large and significant increase in the receipt of antidiabetic agents among all people with diabetes during pregnancy (gestational diabetes). Prior to the policy, only 0.3% of all Latina emergency Medicaid recipients with gestational diabetes (2 of 617) received any medication (oral agents or insulin) to manage their blood glucose level. After the policy change, 28.8% of all patients with gestational diabetes (295 of 1023) received medication to manage their blood glucose level, translating to a 27.9-percentage-point increase (95% CI, 24.5-31.2 percentage points) in the receipt of antidiabetic agents in the adjusted model. The policy was also associated with a 10.4-percentage-point (95% CI, 5.3-15.5 percentage points) increase in insulin use during pregnancy among all patients with gestational diabetes. We observed an increase in postpartum contraceptive use (21.2 percentage points; 95% CI, 14.9-27.5 percentage points), the majority of which was due to postpartum sterilization (increase of 16.1 percentage points; 95% CI, 10.4-21.8 percentage points). We did not observe a significant association with gestational hypertension, cesarean births, or newborn health. Conclusions and Relevance: This retrospective cohort study suggests that expanded emergency Medicaid benefits that included prenatal care were associated with an increased use of antidiabetic medications and postpartum contraception during pregnancy.

The vasal fluid proteomic profile and microscopic sperm presence at time of vasectomy reversal.

BACKGROUND: The microscopic characteristics of vasal fluid at time of vasectomy reversal (VR) guide operative decision making and predict fertility outcomes. The proteomic profile of this vasal fluid has not been described or correlated with the microscopic fluid appearance. To characterize the vasal fluid proteome at time of VR and evaluate the variation of the vasal fluid proteome with respect to microscopic presence of sperm. METHODS: A prospective cohort study was conducted enrolling twenty-five men undergoing VR for infertility and/or pain at a University-affiliated hospital. Vasal fluid samples obtained at time of VR were grouped based on presence of sperm on light microscopy at time of VR. Proteomic profiles were generated using liquid chromatography/ tandem mass spectrometry, and MS/MS protein spectral counts compared between individuals and treatment groups, controlling for less than 5% protein false discovery rate (FDR). Proteins were matched with the human swissprot database using the Comet search engine, and categorized by Gene Ontology (GO) terms. RESULTS: There was large variability between the 46 vasal fluid samples collected, with 1,692 unique proteins detected. The three most abundant proteins were Lactotransferrin, Cysteine-rich secretory protein 1, A-kinase anchor protein 4. There was no correlation between the proteome and microscopic sperm presence. Prevalent GO terms included viral process, signal transduction, innate immune response, protein folding and spermatogenesis. CONCLUSIONS: We describe the proteome and the most common proteins in vasal fluid at time of VR. Numerable sperm, testis and epididymis specific proteins were present even in the absence of sperm on microscopy. Further evaluation is needed to determine if a protein biomarker may better guide operative decision making and predict VR fertility outcomes.

Open versus robot-assisted radical cystectomy: 30-day perioperative comparison and predictors for cost-to-patient, complication, and readmission.

The objectives of this study are to evaluate if robotic cystectomy demonstrates reduced complications, readmissions, and cost-to-patient compared to open approach 30-day post-operatively, and to identify predictors of complication, readmission, and cost-to-patient. This retrospective cohort study analyzed 249 patients who underwent open (n = 149) or robotic (n = 100) cystectomy from 2009 to 2015 at our institution. Outcomes included 30-day post-operative complication, readmission, and cost-to-patient charges. We used modified Clavien-Dindo/MSKCC classifications. Multivariable logistic and linear regression models were used to evaluate associations to outcomes and to build predictive models. Patient, clinical, and surgical characteristics differed by open and robotic groups, respectively, only for estimated blood loss (median: 600 versus 150 cc, p < 0.01), operative time (mean: 6.19 versus 6.85 h, p < 0.01), and length of stay (median: 7 versus 5 days, p < 0.01). Complication: frequency of patients with at least one 30-day complication was 85% compared to 66% (p < 0.01). Minor gastrointestinal and bleeding complications were increased in the open group (50% versus 41%, p = 0.01; 52% versus 11%, p < 0.01, respectively). Fifty percent of patients required blood transfusion in open compared to 11% (p < 0.01). Patients in the open group experienced more major complications (19% versus 10%, p = 0.04). Robotic approach was a predictor for fewer complications (OR 0.44, 95% CI 0.20-0.99, p = 0.049). Readmission: no significant difference in number of patients readmitted was found. Cost-to-patient: Robotic approach predicted an 18% reduction in total cost-to-patient compared to open approach (p < 0.01). Robotic cystectomy demonstrated reduced total cost-to-patient when taking into account all 30-day post-operative services with fewer complications compared to open cystectomy.

Prophylactic antibiotics following radical cystectomy reduces urinary tract infections and readmission for sepsis from a urinary source.

INTRODUCTION: Urinary tract infections (UTI) and sepsis contribute significantly to the morbidity associated with cystectomy and urinary diversion in the first 30 days. We hypothesized that continuous antibiotic prophylaxis decreased UTIs in the first 30 days following radical cystectomy. METHODS: Patients with urothelial carcinoma of the bladder who underwent a radical cystectomy with urinary diversion for bladder cancer at Oregon Health and Science University from January 2014 to May 2015 were included in the study. The ureteral stents were kept for 3 weeks in both groups. In October 2014, we enacted a Department Quality Initiative to reduce UTIs. Following the initiative, all radical cystectomy patients were discharged home on antibiotic prophylaxis following a postoperative urine culture obtained during hospitalization. To evaluate the effectiveness of the initiative, the last 42 patients before the initiative were compared to the first 42 patients after the initiative with regard to the rate of UTI in the first 30 days following surgery. We used a combination of comprehensive chart review and the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP) to determine UTI and readmission for urosepsis in the first 30 days following surgery. This ensured accurate capture of all patients developing a UTI. RESULTS: A total of 12% in the prophylactic antibiotic group had a documented UTI, whereas 36% in the no antibiotic group had a urinary tract infection (P<0.004). A total of 1 (2%) patient in the antibiotic group was readmitted for urosepsis whereas 7 (17%) patients in the no antibiotic group were admitted for urosepsis (P = 0.02). There was no association noted between urine culture at discharge and the development of UTI in the 30-day postdischarge period (P = 0.75). The median time to UTI was 19 days and the most common organism was Enterococcus (32%). Thirty-percent of patients not receiving prophylaxis developed a UTI 1 day after ureteral stent removal. No patients had a UTI following stent removal in the prophylaxis group. No adverse antibiotic related events were noted. CONCLUSION: Prophylactic antibiotics in the 30 days following radical cystectomy is associated with a significant decrease in urinary tract infections and readmission from urosepsis after surgery.

Reconsidering vasectomy reversal over assisted reproduction in older couples.

OBJECTIVE: To provide pregnancy and live birth rates from a contemporary series of vasectomy reversals in men with female partners aged ≥35 years and to correlate the results with IVF. SETTING: Tertiary academic referral center. DESIGN: Retrospective comparative study of prospectively collected database. PATIENT(S): Two hundred forty-six men who underwent vasectomy reversal for fertility with female partner aged ≥35 years. INTERVENTION(S): Vasovasostomy or vasoepididymostomy. MAIN OUTCOME MEASURE(S): Correlation of pregnancy and live birth rate of this cohort by age groups with most recently published pregnancy and live birth rate per IVF cycle. RESULT(S): One hundred thirty-six men who underwent vasectomy reversal between 2006 and 2014 met our inclusion criteria. Overall pregnancy and live birth rates were 35% and 30%, respectively. Subgroup analysis by female age groups (35-37, 38-40, >40 years) demonstrated pregnancy and live birth rates comparable to those per IVF cycle by age groups according to a recently published (2015) national report. CONCLUSION(S): Vasectomy reversal should be strongly considered in men with a partner aged ≤40 years. Additionally, vasectomy reversal can be considered in carefully selected patients even with a partner aged >40 years.

The long-term incidence of urinary tract infection after endoscopic management of vesicoureteral reflux.

OBJECTIVE: To evaluate the long-term urinary tract infection (UTI) rates after endoscopic correction of vesicoureteral reflux and the possible risk factors for urinary infection. MATERIALS AND METHODS: A retrospective study of patients who underwent endoscopic management of vesicoureteral reflux at a single institution from 2001 to 2011 was performed. Patients were followed up for a minimum of 1 year. Voiding cystourethrograms were completed 3 months postoperatively. UTI questionnaire pertaining to the patient's UTI history before and after the surgery was mailed to each patient. Data were first evaluated looking only at culture-confirmed UTIs, and a second analysis included all patient-reported and culture-confirmed urinary infections. Factors considered in the analysis included sex, age, preoperative dimercaptosuccinic acid (DMSA) scan, reflux on postoperative voiding cystourethrogram, voiding dysfunction, and preoperative reflux grade. RESULTS: Data on 175 patients for a minimum of 1 year were collected. There were 34 of 175 confirmed UTIs after endoscopic management, and 11 confirmed febrile UTIs. There were no significant predictors of febrile or afebrile UTIs in this group. Fifty-three of 175 patients (30%) experienced any UTI, 19 of which were febrile (10%). In this group, recurrent reflux was the only significant predictor of UTI (P=.03) and febrile UTIs (P=.04). Patients with more UTIs preoperatively were more likely to have a postoperative febrile UTI. CONCLUSION: Rates of UTI and febrile UTI in endoscopic management are similar and no better than those for open ureteral reimplantation. Longer follow-up suggests an association of recurrent reflux and preoperative UTI rates as predictors of postoperative febrile UTIs. These patients benefit from closer postoperative observation.

Penile fracture: outcomes of early surgical intervention.

OBJECTIVE: To report a series of penile fractures, describing preoperative evaluation, surgical repair, and long-term outcomes. PATIENTS AND METHODS: Medical records from Northwestern Memorial Hospital and Oregon Health & Science University from 2002 to 2011 were reviewed. Clinical presentation, preoperative evaluation, time from injury, mechanism and site of injury, and presence of urethral injury were assessed. Outcomes including erectile dysfunction, penile curvature, and voiding symptoms were evaluated using International Prostate Symptom Score and International Index of Erectile Function scores. RESULTS: Twenty-nine patients with 30 separate episodes of penile fractures presenting to the emergency room were identified. Mean patient age was 43 ± 9.6 years. The time from presentation to the initiation of surgery was 5.5 ± 4.4 hours. Mechanism of injury was intercourse in 26 of 30 fractures with the remaining attributed to masturbation or "rolling over." Immediate surgical repair was offered to all patients. Twenty-seven patients underwent surgery. Urethral injury was noted in 5 of the 27. The site of fracture was at the proximal shaft in 11, mid shaft in 12, and distal shaft in 4 patients. The mean follow-up period was 14.3 ± 15.8 weeks. Nine patients reported new mild erectile dysfunction or penile curvature. One patient reported new irritative voiding symptoms. CONCLUSION: The most common mechanism of penile fracture was from sexual intercourse, and frequent concomitant urethral injuries were observed. The frequency of concomitant urethral injury was higher than in previous studies. Although we observed high incidence of erectile dysfunction or penile curvature with early surgical repair, we retain it as the favored approach.