Prevalence of unnecessary kidney function exclusion criteria in urologic oncology clinical trials.

INTRODUCTION: Clinical trials play a pivotal role in advancing treatments for people with cancer, but often struggle with low enrollment. Unnecessarily including kidney function eligibility criteria when a trial's interventions do not have any potential kidney effects may contribute to this problem by needlessly limiting the pool of eligible patients, adding complexity to the patient screening process, and raising issues of inequitable access to trials. For these reasons, we applied custom natural language processing to assess renal function eligibility criteria, and the appropriateness of these exclusions, within phase 3 urologic oncology trials. METHODS: We accessed all phase 3 urologic oncology trials registered on ClinicalTrials.gov from 2007 to 2021. We used a custom natural language processing script to extract kidney function requirements (e.g., creatinine, GFR) from trial free-text records. For each trial, we manually coded whether any trial intervention affected renal function or was renally excreted. Additionally, we recorded the formula used to calculate GFR in each trial. RESULTS: Of 850 trials, 299 (35%) listed kidney function eligibility restrictions, and 432 (51%) tested an intervention with possible renal effects. Of the 299 trials with kidney function exclusions, 124 (41%) tested interventions with no kidney effects. CONCLUSION: There is a major disconnect in urologic oncology clinical trials between renal function exclusions and potential harm to the kidneys from the tested interventions. Standardizing eligibility criteria and restricting enrollment based on renal function only when necessary has the potential to increase the success, access, and applicability of clinical trials.

Urinary Tract Infection and Progression to Pyelonephritis: Group B Streptococcus versus E. coli.

Objective Group B Streptococcus (GBS) colonization of the lower urinary tract in pregnancy is associated with severe infections such as chorioamnionitis, endometritis, and pyelonephritis. The objective of this study was to compare rates of progression to pyelonephritis between GBS and Escherichia coli lower urinary tract infections (LUTIs), as well as compare infectious and obstetric morbidity secondary to these pathogens. Study Design Retrospective cohort of pregnant women with LUTIs (asymptomatic bacteria or acute cystitis [AC]) from a single health system between July 2013 and May 2019. Demographic, infectious, antepartum, and intrapartum data were abstracted from medical records of women with GBS or E. coli LUTI. The primary outcome was progression to pyelonephritis. Secondary outcomes included pyelonephritis-related anemia, sepsis, pyelonephritis length of stay (LOS), median gestational age (GA) at delivery, preterm delivery, and low birth weight (LBW). Logistic regression was used to calculate the adjusted odds of the primary outcome. Results Of 729 pregnant women with urinary colonization, 433 were culture positive for one of the aforementioned bacteria, with 189 (43.6%) having GBS and 244 (56.4%) having E. coli. Women with E. coli were more likely to be younger, use tobacco, have a history of AC, and have a history of preterm birth. Rates of progression to pyelonephritis were markedly higher with E. coli (15.6%) than with GBS (1.1%; p < 0.001). Median LOS for pyelonephritis and pyelonephritis-related morbidities did not differ. Median GA at delivery, preterm delivery, and LBW rates also did not differ. In adjusted analysis, controlling for history of AC, insurance status, tobacco use, prior preterm birth, primary infection type, and maternal age, women with GBS LUTI had markedly decreased odds of developing pyelonephritis in pregnancy compared with those with E. coli (adjusted odds ratio: 0.04, 95% confidence interval: 0.01-0.28). Conclusion Escherichia coli infections progress to pyelonephritis in pregnancy at markedly higher rates than GBS, although obstetric outcomes are similar.

Short-term outcomes after third-time lung transplantation: A single institution experience.

BACKGROUND: Reoperative lung transplantation (LTx) survival has improved over time such that a growing number of patients may present for third-time LTx (L3Tx). To understand the safety of L3Tx, we evaluated perioperative outcomes and 3-year survival after L3Tx at a high-volume US LTx center. METHODS: This retrospective study included all patients who underwent bilateral L3Tx at our institution. Using an optimal matching technique, a primary LTx (L1Tx) cohort was matched 1:2 and a second-time LTx (L2Tx) cohort 1:1. Recipient, operative, and donor characteristics, perioperative outcomes, and 3-year survival were compared among L1Tx, L2Tx, and L3Tx groups. RESULTS: Eleven L3Tx, 11 L2Tx, and 22 L1Tx recipients were included. Among L3Tx recipients, median age at transplant was 37 years and most (73%) had cystic fibrosis. L3Tx was performed median 6.0 and 10.6 years after L2Tx and L1Tx, respectively. Compared to L1Tx and L2Tx recipients, L3Tx recipients had greater intraoperative transfusion requirements, a higher incidence of postoperative complications, and a higher rate of unplanned reoperation. Rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation at 72 hours, reintubation, and in-hospital mortality were similar among groups. There were no differences in 3-year patient (log-rank p = 0.61) or rejection-free survival (log-rank p = 0.34) after L1Tx, L2Tx, and L3Tx. CONCLUSIONS: At our institution, L3Tx was associated with similar perioperative outcomes and 3-year patient survival compared to L1Tx and L2Tx. L3Tx represents the only safe treatment option for patients with allograft failure after L2Tx; however, further investigation is needed to understand the long-term survival and durability of L3Tx.

Same-teams versus different-teams for long distance lung procurement: A cost analysis.

OBJECTIVE: In an era of broader lung sharing, different-team transplantation (DT, procuring team from nonrecipient center) may streamline procurement logistics; however, safety and cost implications of DT remain unclear. To understand whether DT represents a safe means to reduce lung transplant (LTx) costs, we compared posttransplant outcomes and lung procurement and index hospitalization costs among matched DT and same-team transplantation (ST, procuring team from recipient center) cohorts at a single, high-volume institution. We hypothesized that DT reduces costs without compromising outcomes after LTx. METHODS: Patients who underwent DT between January 2016 to May 2020 were included. A cohort of patients who underwent ST was matched 1:3 (nearest neighbor) based on recipient age, disease group, lung allocation score, history of previous LTx, and bilateral versus single LTx. Posttransplant outcomes and costs were compared between groups. RESULTS: In total, 23 DT and 69 matched ST recipients were included. Perioperative outcomes and posttransplant survival were similar between groups. Compared with ST, DT was associated with similar lung procurement and index hospitalization costs (DT vs ST, procurement: median $65,991 vs $58,847, P = .16; index hospitalization: median $294,346 vs $322,189, P = .7). On average, procurement costs increased $3263 less per 100 nautical miles for DT versus ST; DT offered cost-savings when travel distances exceeded approximately 363 nautical miles. CONCLUSIONS: At our institution, DT and ST were associated with similar post-LTx outcomes; DT offered cost-savings with increasing procurement travel distance. These findings suggest that DT may mitigate logistical and financial burdens of lung procurement; however, further investigation in a multi-institutional cohort is warranted.

AAV9-mediated gene delivery to liver grafts during static cold storage in a rat liver transplant model.

Introduction: Recombinant adeno-associated virus (rAAV) is a novel strategy used clinically for gene delivery, but has not been characterized in the context of organ transplantation. We sought to determine the efficacy of rAAV-mediated gene delivery during static cold storage (SCS) prior to liver transplantation. Methods: A triple-plasmid transfection protocol was used to produce rAAV subtype-9 vectors containing firefly luciferase genomes in HEK293 cells. Lewis rat liver grafts were flushed and stored in cold HTK solution. Three experimental groups received rAAV at different doses, administered via the portal vein as a bolus during SCS. A control group did not receive rAAV (N = 2). Recipients then underwent syngeneic liver transplantation. Bioluminescence imaging to quantify in vivo luciferase expression was performed on post-operative days 7, 14, 28, and 56. Results: Control animals demonstrated no bioluminescent activity, while animals receiving rAAV-treated livers had increasing bioluminescence, peaking at four weeks but sustained to the eight-week endpoint. This result was confirmed by experimental endpoint tissue luciferase activity assay. Discussion: rAAV mediates gene transduction in liver grafts when administered during SCS and has potential for gene therapy applications in solid organ transplantation.

Adeno-associated virus mediates gene transduction after static cold storage treatment in rodent lung transplantation.

OBJECTIVE: Adeno-associated virus is a clinically used gene therapy vector but has not been studied in lung transplantation. We sought to determine the efficacy of adeno-associated virus delivery during static cold storage via the airway versus the pulmonary artery before lung transplantation in a rodent model. METHODS: Lewis rat lung grafts were treated with a dose of 8e8 or 4e9 viral genome/µL recombinant adeno-associated virus subtype-9 vectors containing firefly luciferase genomes administered via the pulmonary artery or airway during cold storage. A control group did not receive adeno-associated virus. Recipient syngeneic rats then underwent single left lung transplantation. Animals underwent bioluminescence imaging on postoperative days 7, 14, 28, and 56. Explanted tissues were prepared as lysates to quantify luciferase activity. Immunohistochemistry was performed to evaluate cellular transgene expression patterns. RESULTS: Control animals with no luminescent signal produced a background radiance of 6.1e4 p/s/cm2/sr. In the airway delivery group, mean radiance was greater than the control at 4e9 viral genome/µL postoperative day 7 radiance 6.9e4 p/s/cm2/sr (P = .04). In the pulmonary artery delivery group, we observed greater in vivo luminescence in animals receiving 4e9 viral genome/µL compared with all other groups. However, analysis of tissue lysate revealed greater luminescence in the airway delivery group and suggested off-target expression in heart and liver tissue in the pulmonary artery delivery group. Immunohistochemistry demonstrated transgene staining in distal airway epithelium and alveoli but sparing of the vasculature in the airway delivery group. CONCLUSIONS: Adeno-associated virus mediates gene transduction during static cold storage in rat lung isografts when administered via the airway and pulmonary artery. Airway administration leads to robust transgene expression in respiratory epithelial cells, whereas pulmonary artery administration targets alternative cell types and increases extrapulmonary transgene expression.

Resection of Pubic Symphysis and Cystectomy Significantly Improves Short-Term Patient-Reported Physical Functioning Among Patients With Pubovesical Fistula and Pubic Bone Osteomyelitis.

OBJECTIVE: To investigate the impact of extirpative surgery for pubic bone osteomyelitis with pubovesical fistula on prostate cancer survivors' physical and mental health. MATERIALS AND METHODS: The Short Form 12 (SF-12) is a validated instrument for assessing health-related quality of life (HRQOL). We reviewed a prospectively maintained database of patients treated with extirpative surgery for pubovesical fistula from 2017-2021 who completed the SF-12. Wilcoxon signed-rank and McNemar's tests were used to analyze changes in SF-12 following surgery. Narcotic prescriptions in the year before and after surgery were assessed as an additional measure of pain burden. RESULTS: Eighteen patients were included. Four had pre-operative SF-12s, 3 had post-operative SF-12s, and 11 had both. Median age was 76.5 years (IQR 71.75-80.00). All patients had previous radiation for prostate cancer. Compared to global pre-operative scores, post-operative physical composite scores (PCS) significantly increased (29.95 ± 8.59 vs 42.48 ± 7.18; P <.001), but mental composite scores (MCS) were similar (45.35 ± 9.98 vs 52.21 ± 8.23). When comparing individual, paired pre-operative and post-operative scores there was a significant improvement in PCS (30.56 ± 9.87 vs 45.45 ± 8.56; P = .005), but not MCS (47.49 ± 6.92 vs 51.60 ± 8.88). Median morphine milligram equivalent significantly decreased in the year post-surgery compared to the year prior (103.1, 33.0-250.9 vs 34.25, 0.0-105.9; P = .0008). CONCLUSION: For prostate cancer survivors with pubovesical fistula and pubic bone osteomyelitis, urinary diversion with pubic bone resection improves physical functioning and decreases narcotic prescriptions without untoward effects on mental health.

Structured approach to resolving discordance between PI-RADS v2.1 score and targeted prostate biopsy results: an opportunity for quality improvement.

BACKGROUND: Prostate multiparametric magnetic resonance imaging (mpMRI) can identify lesions within the prostate with characteristics identified in Prostate Imaging Reporting and Data System (PI-RADS) v2.1 associated with clinically significant prostate cancer (csPCa) or Gleason grade group (GGG) ≥ 2 at biopsy. OBJECTIVE: To assess concordance (PI-RADS 5 lesions with csPCa) of PI-RADS v2/2.1 with targeted, fusion biopsy results and to examine causes of discordance (PI-RADS 5 lesions without csPCa) with aim to provide a structured approach to resolving discordances and develop quality improvement (QI) protocols. METHODS: A retrospective study of 392 patients who underwent mpMRI at 3 Tesla followed by fusion biopsy. PI-RADS v2/2.1 scores were assigned to lesions identified on mpMRI and compared to biopsy results expressed as GGG. Positive predictive value (PPV) of PI-RADS v2/2.1 was calculated for all prostate cancer and csPCa. Discordant cases were re-reviewed by a radiologist with expertise in prostate mpMRI to determine reason for discordance. RESULTS: A total of 521 lesions were identified on mpMRI. 121/521 (23.2%), 310/524 (59.5%), and 90/521 (17.3%) were PI-RADS 5, 4, and 3, respectively. PPV of PI-RADS 5, 4, and 3 for all PCa and csPCa was 0.80, 0.55, 0.24 and 0.63, 0.33, and 0.09, respectively. 45 cases of discordant biopsy results for PI-RADS 5 lesions were found with 27 deemed "true" discordances or "unresolved" discordances where imaging re-review confirmed PI-RADS appropriateness, while 18 were deemed "false" or resolved discordances due to downgrading of PI-RADS scores based on imaging re-review. Adjusting for resolved discordances on re-review, the PPV of PI-RADS 5 lesions for csPCa was deemed to be 0.74 and upon adjusting for presence of csPCa found in cases of unresolved discordance, PPV rose to 0.83 for PI-RADS 5 lesions. CONCLUSION: Although PIRADS 5 lesions are considered high risk for csPCa, the PPV is not 100% and a diagnostic dilemma occurs when targeted biopsy returns discordant. While PI-RADS score is downgraded in some cases upon imaging re-review, a number of "false" or "unresolved" discordances were identified in which MRI re-review confirmed initial PI-RADS score and subsequent pathology confirmed presence of csPCa in these lesions. CLINICAL IMPACT: We propose a structured approach to resolving discordant biopsy results using multi-disciplinary re-review of imaging and archived biopsy strikes as a quality improvement pathway. Further work is needed to determine the value of re-biopsy in cases of unresolved discordance and to develop robust QI systems for prostate MRI.

Patient-Reported and Physiologic Outcomes Following Pelvic Exenteration for Non-Repairable Radiated Rectourethral Fistula.

OBJECTIVE: To investigate the impact of pelvic exenteration (PelvEX) on patient-reported pain, distress, and quality of life along with physiologic indicators of health in cancer survivors with radiated, non-repairable rectourethral fistula (RUF). MATERIALS AND METHODS: We reviewed a prospectively maintained quality improvement database of RUF patients at our institution from 2012 to 2020. Patients with radiated, non-repairable RUF who underwent PelvEX and had follow up to 1 year were included. Pain and distress scores were collected preoperatively and at 1-year follow up. Number of narcotic prescriptions in the 3 months before surgery and the year after surgery were abstracted. Short Form 12 surveys were administered in the postoperative period. Serum albumin, creatinine, carbon dioxide, hematocrit, and glucose were abstracted from electronic health records. Statistical analysis was performed using Wilcoxon signed-rank and Mann-Whitney tests. RESULTS: Eleven patients met inclusion criteria. Patient-reported pain significantly decreased at 1 year follow-up compared to preoperative scores (median pre: 4 vs 1 year post: 0, P = .0312). Patient-reported distress significantly decreased pre- versus post-PelvEX (median pre: 5 vs post: 0, P = .0156). At the time of postoperative pain and distress surveys, 9 (82.8%) patients did not have narcotic prescriptions. Postoperative Short Form 12 scores were similar to an age-matched United States population (mental: P = .3125; physical: P = .1484). Serum-based indicators of health were not different in the pre- versus postoperative period (all P >.05). CONCLUSION: PelvEX may be a valuable treatment option to decrease patient-reported pain and distress without compromising quality of life or physiologic health in patients with radiated, non-repairable RUF.

Two Compartment Evaluation of Liver Grafts During Acellular Room Temperature Machine Perfusion (acRTMP) in a Rat Liver Transplant Model.

Background: Subnormothermic machine perfusion (SNMP) of liver grafts is currently less clinically developed than normothermic and hypothermic approaches, but may have logistical advantages. At intermediate temperatures, the oxygen demand of the graft is low enough to be satisfied with an acellular perfusate, obviating the need for oxygen carrying molecules. This intermediate metabolic rate, however, is sufficient to support the production of bile, which is emerging as an important indicator of graft injury and viability. In this study, we hypothesized that the biliary compartment would be more sensitive than perfusate in detecting graft injury during SNMP. Methods: To test this hypothesis in a rat model, we performed liver transplants with DCD and control liver grafts after 1 h of acellular room temperature machine perfusion (acRTMP) or static cold storage (SCS). Point of care liver function tests were measured in biliary and perfusate samples after 1 h of machine perfusion. Following transplantation, rats were sacrificed at 24 h for assessment of post-transplant graft function and histology. Results: All point-of-care liver function tests were significantly more concentrated in the biliary compartment than the perfusate compartment during acRTMP. DCD liver grafts could be distinguished from control liver grafts by significantly higher markers of hepatocyte injury (AST, ALT) in the biliary compartment, but not in the perfusate compartment. Classical markers of cholangiocyte injury, such as gammy-glut amyl transferase (GGT), amylase (AML), and alkaline phosphatase were detectable in the biliary compartment, but not in the perfusate compartment. In comparison to SCS, graft preservation by acRTMP produced a significant survival benefit in DCD liver transplantation (75 vs. 0%, p < 0.0030). Conclusion: Together, these findings demonstrate that during acRTMP, the biliary compartment may be a more sensitive indicator of graft injury than the perfusate compartment. Moreover, acRTMP provides superior graft preservation to SCS in rat DCD liver transplantation.

Bad bugs: antibiotic-resistant bacteriuria in pregnancy and risk of pyelonephritis.

BACKGROUND: The introduction of antibiotics has significantly reduced morbidity and mortality from microbial infections, but the rise of antibiotic-resistant and multidrug-resistant microbes is of increasing clinical concern. Few studies have examined the prevalence and impact of antibiotic resistance in common antenatal infections. OBJECTIVE: This study aimed to determine whether pregnant women with a urine culture positive for antibiotic-resistant or multidrug-resistant gram-negative bacteria are at increased risk of developing pyelonephritis than pregnant women infected with antibiotic-susceptible organisms. STUDY DESIGN: This was a retrospective cohort study of pregnant women with asymptomatic bacteriuria or acute cystitis from a single health system from July 2013 to May 2019. Women with gram-negative antibiotic-resistant (resistance to 1-2 antibiotic classes) and multidrug-resistant (resistance to ≥3 antibiotic classes) lower urinary tract infections were compared with women with antibiotic-susceptible urinary tract infections in terms of demographic, infectious, antepartum, and intrapartum data. The primary outcome was pyelonephritis, defined as a billing code for pyelonephritis plus fever or flank pain. The secondary outcomes were length of stay in the hospital because of pyelonephritis, a composite of pyelonephritis complications (renal abscess, sepsis, and intensive care unit admission), and preterm delivery. The differences in the primary outcome were analyzed using multivariate logistic regression. RESULTS: A total of 573 women were eligible for inclusion. Of the 573 women, 334 (58%) had gram-negative bacteria on urine culture. Of the 334 cases, 173 (52%) were antibiotic susceptible, 74 (22%) were antibiotic resistant, and 87 (26%) were multidrug resistant. Women with antibiotic-resistant and multidrug-resistant infections were more likely to have hypertension (P=.004), to be Black (P=.03), to have public insurance (P=.002), and to experience more urinary infections (P=.001). Pyelonephritis was more common in women with antibiotic-resistant (adjusted odds ratio, 2.27; 95% confidence interval, 1.08-4.78) and multidrug-resistant (adjusted odds ratio, 3.06; 95% confidence interval, 1.57-5.96) infections than in women with antibiotic-susceptible urinary tract infections. Length of stay, preterm delivery, and pyelonephritis complications did not differ between antibiotic-susceptible and antibiotic-resistant and multidrug-resistant infections. CONCLUSION: In an age of increasing antibiotic resistance, more than one-half of pregnant women with bacteriuria experience at least 1 infection with an antibiotic-resistant organism. These resistance patterns have a real clinical impact as pregnant women with antibiotic-resistant gram-negative lower urinary tract infections have an estimated 2- to 3-fold increased odds of developing pyelonephritis.

Lower Urinary Pathogens: Do More Pathogenic Bacteria Increase the Risk of Pyelonephritis?

OBJECTIVE: Outside of pregnancy, urinary pathogens such as Proteus and Klebsiella are considered more pathogenic than E. coli. During pregnancy, the implications of lower urinary tract infection (LUTI) with more pathogenic bacteria are unclear. Thus, we sought to compare the risk of progression from LUTI to pyelonephritis among women infected with these more pathogenic urinary bacteria to those infected with E. coli. STUDY DESIGN: Retrospective cohort of pregnant women with LUTI at single tertiary center from July 2013 to May 2019. Pathogenic infections (PI) were defined as asymptomatic bacteriuria or acute cystitis urinary cultures positive for Proteus, Klebsiella, Enterobacter, Citrobacter, Acinetobacter, Staphylococcus, or Raoultella species. Demographic, infectious, antepartum, and postpartum data abstracted. Pregnant women with PI compared with those with E. coli. Primary outcome was progression to pyelonephritis. Secondary outcomes included pyelonephritis length of stay (LOS) >6 days, preterm birth (PTB), low birthweight (LBW), and measures of pyelonephritis-related morbidity. RESULTS: Of 686 pregnant women with LUTIs, 313 had urine culture growing out either PI or E. coli, with 59 (12%) growing PI and 254 (54%) growing E. coli. Women with PI were more likely to be African American, have chronic hypertension, and have history of preeclampsia. The primary species causing PI were Klebsiella (n = 29) and Proteus (n = 11). PI were not more likely to progress to pyelonephritis than E. coli LUTIs (10.9 vs. 14.5%; p = 0.67). Median LOS for pyelonephritis and other measures of pyelonephritis-related morbidity did not differ nor did PTB or LBW rates. After controlling for race, body mass index, history of preeclampsia, and history of pyelonephritis, PI were not associated with increased odds of progression to pyelonephritis (adjusted odds ratio: 0.69, 95% confidence interval: 0.27-1.80). CONCLUSION: Bacteria traditionally considered to be more pathogenic outside of pregnancy do not progress to pyelonephritis at higher rates than E. coli in pregnancy, and are associated with similar pyelonephritis-related morbidity. Larger studies are needed to confirm these findings. KEY POINTS: · Little is known about impact of uropathogen on progression to pyelonephritis and obstetric outcomes.. · Rates of progression to pyelonephritis from UTI did not vary by uropathogen.. · Pyelonephritis-related morbidities and preterm birth rates were also similar among uropathogens..

Duct of Luschka Bile Leak Following Deceased Donor Liver Transplant.

BACKGROUND Biliary leak is a relatively uncommon but potentially severe complication of liver transplantation. Duct of Luschka (also known as subvesical bile ducts) is a term that refers to a number of accessory biliary ducts. While leaks from Ducts of Luschka are well-described in the field of hepatobiliary surgery, only 2 case reports of such leaks exist in the setting of liver transplant. CASE REPORT We report the first case of a Duct of Luschka biliary leak seen after DCD liver transplant in a 41-year-old woman with cirrhosis secondary to primary sclerosing cholangitis. The patient underwent surgical re-exploration in the immediate postoperative period due to bilious output from a surgical drain. A Duct of Luschka was found intraoperatively at the gallbladder fossa and was oversewn. Apart from immunosuppression-related neutropenia, the patient recovered uneventfully. CONCLUSIONS Given the variability in preoperative detection of subvesical bile ducts, accessory bile duct leak remains an important consideration in the liver transplant perioperative period. The prevalence of Ducts of Luschka and the relative risk of leakage from such subvesical bile ducts in liver transplants compared to cholecystectomies are unclear. Further research into anatomical accessory bile duct variants and preoperative techniques for detecting such ducts is warranted.

The Importance of Early Diagnosis and Management of Pediatric Neurogenic Bladder Dysfunction.

Neurogenic bladder dysfunction is a major source of urologic morbidity in children, especially in those with spina bifida (SB). Complications from progression of bladder dysfunction can include urinary tract infections (UTIs), urinary incontinence, upper tract deterioration, and renal dysfunction or failure. In these children, there has been a recent trend toward proactive rather than expectant management of neurogenic bladder. However, there is a lack of consensus on how to best achieve the three main goals of neurogenic bladder management: 1) preserving kidney function, 2) achieving continence (if desired by the family/individual), and 3) achieving social and functional urologic independence (if appropriate). Hence, our objective was to perform a narrative literature review to evaluate the approaches to diagnosis and management of pediatric neurogenic bladder dysfunction, with special focus on children with SB. The approach strategies vary across a spectrum, with a proactive strategy on one end of the spectrum and an expectant strategy at the other end. The proactive management strategy is characterized by early and frequent labs, imaging, and urodynamic (UDS) evaluation, with early initiation of clean intermittent catheterization (CIC) and proceeding with pharmacotherapy, or surgery if indicated. The expectant management strategy prioritizes surveillance labs and imaging prior to proceeding with invasive assessments and interventions such as UDS or pharmacotherapy. Both treatment strategies are currently utilized and data have historically been inconclusive in demonstrating efficacy of one regimen over the other. We performed a narrative literature evaluating proactive and expectant treatment strategies as they relate to diagnostics and management of Spina Bifida. From the available literature and our practice, a proactive strategy favors greater benefit in preventative management and may decrease risk of renal dysfunction compared with expectant management.

Beyond Expert Opinion: A Comparison of Antibiotic Regimens for Infectious Urinary Tract Pathology in Pregnancy.

Objective Outside pregnancy, nitrofurantoin, ciprofloxacin and sulfamethoxazole-trimethoprim (SMZ-TMP) are first-line therapy (FLT) for lower urinary tract infections (LUTIs). Optimal antibiotics for LUTI have been extrapolated based on expert opinion. Progression to pyelonephritis and adverse obstetric outcomes were compared between women who received FLT and those given alternative antibiotics. Methods This study includes a retrospective cohort of women with LUTI, including asymptomatic bacteriuria and acute cystitis at single health care system from July 2013 to May 2019. Women receiving FLT, defined as nitrofurantoin or SMZ-TMP, were compared with those receiving nonfirst-line therapy (nFLT). Primary outcome was progression to pyelonephritis. Secondary outcomes included pyelonephritis-related anemia, sepsis, length of stay, preterm birth (PTB), and low birth weight (LBW). Logistic regression was used to calculate odds of outcomes. Results Of 476 women, 336 (70.6%) received FLT and 140 (29.4%) received nFLT. Women receiving FLT were more likely having BMI ≥ 40 ( p = 0.04). Progression to pyelonephritis did not differ (5.8 vs. 8.2%; p = 0.44), nor did other pyelonephritis-related outcomes. After controlling for confounders, no difference in odds of progression to pyelonephritis was seen (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 0.42, 2.49). FLT was not associated with PTB or LBW (aOR 0.60, 95% CI 0.29, 1.26) after controlling for confounders. Conclusion Receipt of antibiotics other than nitrofurantoin or SMZ-TMP for LUTI in pregnancy was not associated with increased risk of progression to pyelonephritis, PTB, or LBW.

Proteomic and Phosphoproteomic Analysis Reveals that Neurokinin-1 Receptor (NK1R) Blockade with Aprepitant in Human Keratinocytes Activates a Distinct Subdomain of EGFR Signaling: Implications for the Anti-Pruritic Activity of NK1R Antagonists.

Background: Epidermal growth factor receptor (EGFR) inhibitors can cause serious cutaneous toxicities, including pruritus and papulopustular acneiform skin eruptions. Increasingly, the neurokinin-1 receptor (NK1R) antagonist aprepitant is being utilized as an anti-pruritic agent in the treatment of EGFR-inhibitor induced pruritus. Aprepitant is believed to reduce itching by blocking NK1R on the surface of dermal mast cells. However, the effects of aprepitant on human keratinocytes remains unexplored. Methods: Herein, we examine the effects of aprepitant on EGFR stimulation in HaCaT cells using a phosphoproteomic approach including reverse phase protein arrays and Ingenuity Pathway Analysis. Changes in EGFR phosphorylation were visualized using Western blotting and the effect of EGF and aprepitant on the growth of HaCaT cells was determined using the WST-1 Cell Proliferation Assay System. Results: We found that aprepitant increased the phosphorylation of EGFR, as well as 10 of the 23 intracellular proteins phosphorylated by EGF. Analysis of phosphoproteomic data using Ingenuity Pathway Analysis software revealed that 5 of the top 10 pathways activated by EGF and aprepitant are shared. Conclusions: We propose that aprepitant produces its antipruritic effects by partially activating EGFR. Activation of EGFR by aprepitant was also seen in primary human keratinocytes. In addition to itch reduction through partial activation of shared EGFR pathways, aprepitant exerts a dose-dependent cytotoxicity to epithelial cells, which may contribute to its antitumor effects.

Identification of NRAS isoform 2 overexpression as a mechanism facilitating BRAF inhibitor resistance in malignant melanoma.

Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform 2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform 2 was overexpressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform 2 in BRAFi resistant cells restored sensitivity to BRAFi compared with controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform 2 overexpressing cells compared with isoform 1 overexpressing cells. Immunoprecipitation of isoform 2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform 2. NRAS isoform 2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.