Trends over 20 years of antimicrobial prophylaxis for artificial urinary sphincter surgery.

INTRODUCTION AND OBJECTIVE: Perioperative antimicrobial prophylaxis is crucial for prevention of prosthesis and patient morbidity after artificial urinary sphincter (AUS) placement. While antibiotic guidelines exist for many urologic procedures, adoption patterns for AUS surgery are unclear. We aimed to assess trends in antibiotic prophylaxis for AUS and outcomes relative to American Urological Association (AUA) Best Practice guidelines. METHODS: The Premier Healthcare Database was queried from 2000 to 2020. Encounters involving AUS insertion, revision/removal, and associated complications were identified via ICD and CPT codes. Premier charge codes were used to identify antibiotics used during the insertion encounter. AUS-related complication events were found using patient hospital identifiers. Univariable analysis between hospital/patient characteristics and use of guideline-adherent antibiotics was done via chi-squared and Kruskal-Wallis tests. A multivariable logistic mixed effects model was used to assess factors related to the odds of complication, specifically the use of guideline-adherent versus nonadherent regimens. RESULTS: Of 9775 patients with primary AUS surgery, 4310 (44.1%) received guideline-adherent antibiotics. The odds of guideline-adherent regimen use increased 7.7% per year with 53.0% (830/1565) receiving guideline-adherent antibiotics by the end of the study period. Patients with guideline-adherent regimens had a decreased risk of any complication (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.74-0.93) and surgical revision (OR: 0.85, 95% CI: 0.74-0.96) within 3 months; however, no significant difference in infection within was noted (OR: 0.89, 95% CI: 0.68-1.17) within 3 months. CONCLUSIONS: Adherence to AUA antimicrobial guidelines for AUS surgery appears to have increased over the last two decades. While guideline-adherent regimens were associated with decreased risk of any complication and surgical intervention, no significant association was found with risk of infection. Surgeons appear to be increasingly following AUA recommendations for antimicrobial prophylaxis for AUS surgery, however, further level 1 evidence should be obtained to demonstrate conclusive benefit of these regimens.

Multimodal opioid-sparing postoperative pain regimen compared with the standard postoperative pain regimen in vaginal pelvic reconstructive surgery: a multicenter randomized controlled trial.

BACKGROUND: Postoperative pain control after urogynecological surgery has traditionally been opioid centered with frequent narcotic administration. Few studies have addressed optimal pain control strategies for vaginal pelvic reconstructive surgery that limit opioid use. OBJECTIVE: The objective of the study was to determine whether, ice packs, Tylenol, and Toradol, a novel opioid-sparing multimodal postoperative pain regimen has improved pain control compared with the standard postoperative pain regimen in patients undergoing inpatient vaginal pelvic reconstructive surgery. STUDY DESIGN: This was a multicenter randomized controlled trial of women undergoing vaginal pelvic reconstructive surgery. Patients were randomized to the ice packs, Tylenol, and Toradol postoperative pain regimen or the standard regimen. The ice packs, Tylenol, and Toradol regimen consists of around-the-clock ice packs, around-the-clock oral acetaminophen, around-the-clock intravenous ketorolac, and intravenous hydromorphone for breakthrough pain. The standard regimen consists of as-needed ibuprofen, as-needed acetaminophen/oxycodone, and intravenous hydromorphone for breakthrough pain. The primary outcome was postoperative day 1 pain evaluated the morning after surgery using a visual analog scale. Secondary outcomes included the validated Quality of Recovery Questionnaire, satisfaction scores, inpatient narcotic consumption, outpatient pain medication consumption, and visual analog scale scores at other time intervals. In all, 27 patients in each arm were required to detect a mean difference of 25 mm on a 100 mm visual analog scale (90% power). RESULTS: Thirty patients were randomized to ice packs, Tylenol, and Toradol and 33 to the standard therapy. Patient and surgical demographics were similar. The median morning visual analog scale pain score was lower in the ice packs, Tylenol, and Toradol group (20 mm vs 40 mm, P = .03). Numerical median pain scores were lower at the 96 hour phone call in the ice packs, Tylenol, and Toradol group (2 vs 3, P = .04). Patients randomized to the ICE-T regimen received fewer narcotics (expressed in oral morphine equivalents) from the postanesthesia care unit exit to discharge (2.9 vs 20.4, P < .001) and received fewer narcotics during the entire hospitalization (55.7 vs 91.2, P < .001). At 96 hour follow up, patients in the ice packs, Tylenol, and Toradol group used 4.9 ketorolac tablets compared with 4.6 oxycodone/acetaminophen tablets in the standard group (P = .81); however, ice packs, Tylenol, and Toradol patients required more acetaminophen than ibuprofen by patients in the standard arm (10.7 vs 6.2 tablets, P = .012). There were no differences in Quality of Recovery Questionnaire or satisfaction scores either in the morning after surgery or at 96 hour follow up. CONCLUSION: The ice packs, Tylenol, and Toradol multimodal pain regimen offers improved pain control the morning after surgery and 96 hours postoperatively compared with the standard regimen with no differences in patient satisfaction and quality of recovery. Ice packs, Tylenol, and Toradol can significantly limit postoperative inpatient narcotic use and eliminate outpatient narcotic use in patients undergoing vaginal pelvic reconstructive surgery.

Ventral-onlay buccal mucosal graft urethroplasty for the treatment of female urethral stricture: a step-by-step video for Female Pelvic Reconstructive Surgeons.

INTRODUCTION AND HYPOTHESIS: Female urethral stricture is a relatively uncommon disease. Conservative management with repeated urethral dilation often leads to unsatisfactory results. Although treatment of female urethral stricture with urethral reconstruction using a variety of surgical techniques is a surgical option, female pelvic reconstructive surgeons have limited exposure to these procedures in their training. The purpose of this video is to demonstrate a step-by-step ventral-onlay buccal mucosal graft urethroplasty in a patient with female urethral stricture disease. METHODS: We use a live action surgical video to describe the harvest of a buccal mucosal graft and ventral-onlay urethroplasty. RESULTS: This video provides a step-by-step approach to a ventral urethroplasty using a buccal mucosal graft. It can be used to educate and train those performing female pelvic reconstructive surgery. CONCLUSION: Pelvic surgeons should be familiar with the management of female urethral stricture, including surgical treatment options such as urethral reconstruction. This video may be used to facilitate the reproducibility and comprehension of the ventral urethroplasty procedure.

Urethral Outcomes of the Labia Minora Ring Flap for Metoidioplasty and Phalloplasty.

OBJECTIVE: To determine urethral outcomes of single-stage metoidioplasty and radial forearm free flap (RFFF) phalloplasty using the labia minora ring flap for urethral lengthening (UL). METHODS: A retrospective review was performed of patients undergoing single-stage metoidioplasty and RFFF phalloplasty utilizing the labia minora ring flap technique. The ring flap consists of endodermal labia minora tissue ventral to the clitoris and surrounding the vaginal introitus. During metoidioplasty, the ring flap accounts for the entirety of UL. During RFFF phalloplasty, the ring flap becomes the pars fixa (PF) urethra. The primary outcomes measured were rates of fistula, stricture, and surgical revision. RESULTS: Between November 2017 and August 2023, 311 patients underwent metoidioplasty or RFFF phalloplasty (mean follow-up 37 months). Of the 69 metoidioplasties, urethrocutaneous fistulas developed in 11 patients (16%); strictures occurred in 4 (6%). Of the 242 phalloplasty patients, there were 71 fistulas (29%), 56 of which resolved spontaneously. Strictures developed in 44 patients (18%). Twenty-five patients (10%) developed both a stricture and fistula. Surgical repair was required in 8/69 (12%) metoidioplasty patients and in 46/242 (19%) RFFF phalloplasty patients for an overall revision rate of 17%. CONCLUSION: UL during metoidioplasty or RFFF phalloplasty can be accomplished in a single stage using the labia minora ring flap with comparable surgical revision rates to previously described techniques. This approach can also be applied to other phalloplasty techniques. Many fistulas of the PF urethra resolve spontaneously. Higher urethral revision rates were seen in phalloplasty compared to metoidioplasty.

Caring for sexual and gender minority patients with genitourinary cancer: A primer for inclusive practices.

Recognizing sexual orientation and gender identity (SOGI) is paramount in the management of genitourinary cancers, as sexual and gender minority (SGM) individuals encounter unique healthcare challenges leading to disparities. SGM patients often confront systemic barriers, provider biases, and scarcity of tailored resources, resulting in diminished satisfaction and adverse health outcomes. The evaluation and treatment of genitourinary cancers in SGM patients demand a nuanced, multidisciplinary approach that focuses on the unique health determinants often overlooked by the healthcare system. This review highlights recommendations for the inclusivity of SGM patients within the clinic, from inclusive signage to gender inclusive language. For the evaluation and treatment of SGM patients with genitourinary cancers, it is recommended to employ organ-based language, to utilize validated questionnaires encompassing mental health, sexual behavior, and patient-reported outcomes, and to provide timely referrals to social work and onco-fertility when appropriate. Ultimately, approaching inclusivity through education targeted at both SGM patients and healthcare providers is pivotal for centering care around the patient, improving the quality of life and outcomes for SGM patients facing genitourinary cancers.

Legal Outcomes of Litigation After Iatrogenic Genitourinary Trauma.

OBJECTIVE: To evaluate plaintiff and defendant characteristics associated with iatrogenic genitourinary (GU) trauma litigation and outcomes of closed claims. METHODS: LexisNexis was queried in April 2023 using terms related to GU organs and injury, and manually reviewed for iatrogenic cases. Case details including defendant, organ involvement, and legal outcome were obtained. Multinomial regression analysis was performed to identify factors associated with outcome. RESULTS: Four hundred ten cases involving 611 defendants were identified, with the ureter the most commonly affected organ (202/410, 49.3%). Most cases involved adult plaintiffs (380, 92.7%) and resulted in favor of the defense (227, 55.4%). Injuries resulted most frequently from gynecologic surgeries (179, 43.7%). Defendants were most commonly obstetricians/gynecologists (243/611, 39.8%) and urologists (168, 27.5%). Penile (OR 6.3 [95% CI 2.5-16.1]) and urethral (OR 4.8 [2.0-11.7]) injuries were associated with greater odds of a plaintiff verdict relative to ureter injury. A plaintiff verdict was also more likely when defendants were academic hospitals compared to individual practitioners (OR 4.3 [1.9-9.9]). In cases ruling in favor of the plaintiff, indemnity payments were larger when the defendants were comprised of individual practitioners compared to a hospital or medical group (median $549,613 vs $250,000, P <.001). CONCLUSION: Urologists may be involved in medical malpractice lawsuits for iatrogenic injury even when they are uninvolved in the index procedure. Most cases that reach litigation result in defense verdicts regardless of the GU organ injured. Defendant characteristics associated with plaintiff verdicts are more nuanced, and providers should be aware of potential downstream effects of litigation.

Uncovering the interhospital price variations for vasectomies in the United States.

Due to the historic lack of transparency in healthcare pricing in the United States, the degree of price variation for vasectomy is largely unknown. Our study aims to assess characteristics of hospitals reporting prices for vasectomy as well as price variation associated with hospital factors and insurance status. A cross-sectional analysis was performed in October, 2022 using the Turquoise Database which compiles publicly available hospital pricing data. The database was queried for vasectomy prices to identify the cash (paid by patients not using insurance), commercial (negotiated by private insurers) and Medicare and Medicaid prices for vasectomies. Hospital characteristics of those that reported a price for vasectomy and those that did not were compared and pricing differences based on hospital ownership and reimbursement source were determined using multivariable linear regression analysis. Overall, only 24.7% (1657/6700) of hospitals reported a price for vasectomy. Those that reported a price had more beds (median 117 vs 80, p < 0.001), more physicians (median 1745 vs 1275, p < 0.001). They were also more likely to be nonprofit hospitals (77% vs 14%, p < 0.001) and to be in well-resourced areas (ADI 91.7 vs 94.4, p < 0.001). Both commercial prices and cash prices for vasectomy were lower at nonprofit hospitals than at for-profit hospitals (commercial: $1959.47 vs $2861.56, p < 0.001; cash: $1429.74 vs $3185.37, p < 0.001). Our study highlights the current state of pricing transparency for vasectomy in the United States. Patients may be counseled to consider seeking vasectomy at a nonprofit hospital to reduce their costs, especially when paying with cash. These findings also suggest a need for new policies to target areas with decreased price transparency to reduce price disparities.

Trends in testosterone prescription during the release of society guidelines.

The American Urological Association and Endocrine Society published guidelines for the management of testosterone deficiency in 2018. Testosterone prescription patterns have varied widely recently, owing to increased public interest and emerging data on the safety of testosterone therapy. The effect of guideline publication on testosterone prescribing is unknown. Thus, we aimed to assess testosterone prescription trends using Medicare prescriber data. Specialties with over 100 testosterone prescribers from 2016-2019 were analyzed. Nine specialties were included (in order of descending prescription frequency): family practice, internal medicine, urology, endocrinology, nurse practitioners, physician assistants, general practice, infectious disease, and emergency medicine. The number of prescribers grew by a mean of 8.8% annually. There was a significant increase in average claims per provider from 2016 to 2019 (26.4 to 28.7, p < 0.0001), with the steepest increase occurring between 2017 and 2018 when the guidelines were released (27.2 to 28.1, p = 0.015). The largest increase in claims per provider was among urologists. Advanced practice providers comprised 7.5% of Medicare testosterone claims in 2016 and 11.6% in 2019. While no causation can be established, these results suggest that professional society guidelines are associated with increasing numbers of testosterone claims per provider, especially among urologists. The changing demographics of prescribers justifies targeted education and further research.

Glans Adipodermal Augmentation for Management of Neophallus Fat Atrophy After Penile Implant Insertion: Surgical Technique and Outcomes.

OBJECTIVE: To describe our surgical technique and outcomes of glans augmentation with autologous adipodermal or acellular dermal matrix (ADM) interposition grafts for fat atrophy of the neophallus following penile implant insertion. METHODS: We retrospectively reviewed the outcomes of glans augmentation in phalloplasty patients presenting with fat atrophy following penile prosthesis insertion. Glans augmentation is performed by making a small posterior coronal incision to preserve the shaft-to-glans dermal blood supply. A plane is made between the glans skin and the capsule of the distal penile implant cylinder. An adipodermal graft or ADM sheet graft is then sized to the glans dissection space and inserted, covering the implant capsule and filling the glans. The graft harvest site and posterior coronal incisions are then closed. The primary postoperative outcome was the recurrence of implant glans skin impingement or erosion. RESULTS: From October 2017 through January 2023, 15 patients underwent glans augmentation after penile prosthesis insertion. The mean follow-up was 20 months. Adipodermal grafts were placed in 12 (80%) patients and ADM grafts in 3 (20%) patients. Two patients developed complications requiring surgical revision and 3 patients are considering a secondary glans augmentation, for a potential surgical revision rate of 33% (5/15). There were no wound infections, implant infections, or erosions. CONCLUSION: Glans augmentation with adipodermal or ADM graft interposition between the glans skin and implant capsule improves the neophallus appearance and may help prevent future implant erosion in phalloplasty patients who develop fat atrophy after penile implant insertion.

Favorable Safety Outcomes of Delayed Primary Closure of Large Fournier's Gangrene Skin Defects.

OBJECTIVE: To assess the feasibility and safety of delayed primary closure (DPC) in Fournier's gangrene (FG) patients with large genital defects. METHODS: A single institution retrospective review was performed from October 2020 to December 2022 of adult males that underwent DPC for FG. All patients underwent standard medical management and were assessed for DPC eligibility by the urology service. Clinical data on patient factors and outcomes were collected, and descriptive statistics were assessed. RESULTS: Of 16 patients that underwent DPC, the average age was 61.1years and body mass index was 34.6 kg/m2. Median Charlson Comorbidity Index was 3.5 (IQR 2-5.3) and Fournier's Gangrene Severity Index was 6.5 (IQR 4.8-8). Median number of debridements was 2.5 (IQR 2-3), with a time to closure of 6.5days (IQR 3-11) and length of stay of 13days (IQR 9-16.3). Mean genital defect size was 119 cm2 (range 44-346 cm2). Eight patients (50%) were closed using scrotal flaps alone while other patients had advancement flaps using the inner thigh, lower abdomen, and perineum. The majority of patients were discharged home directly (63%). There were four Clavien-Dindo III complications: two partial flap necrosis, one wound dehiscence, and one instance of bleeding. Of patients with follow-up, 6/15 (40.0%) had no known complications. CONCLUSION: DPC is safe and effective for a range of patients presenting with FG. Patients with large defects may benefit from less complex wound management and direct discharge home.

Surgical Outcomes at a Single Institution of Infrapubic Insertion of Malleable Penile Prosthesis in Transmen.

OBJECTIVE: To describe our technique for the infrapubic approach for malleable penile prosthesis (MPP) insertion after phalloplasty in transgender men and review surgical outcomes. METHODS: The infrapubic prosthesis insertion technique involves a horizontal incision anterior to the pubic symphysis, allowing dissection of the neophallus tract and anchor site on the pubic symphysis. Surgical outcomes by a single surgeon using a Spectra or Genesis MPP between October 2017 and May 2022 were retrospectively reviewed. Complications were categorized into erosions, infections, device detachment, device malposition, pain or activity limitation, urethral injury, and flap loss. Implant survival kinetics were assessed by evaluating time to surgical revision. RESULTS: Forty patients underwent infrapubic MPP insertion; 35 patients had a prior radial forearm free flap (RFFF) and 5 had a prior anterolateral thigh flap (ALT) phalloplasty. Of 30 patients who maintained follow-up, mean follow-up was 34.9 months. Complications were not mutually exclusive, with 7 implant detachments from the anchor site, 3 malpositions, 2 with pain/activity limitation, and 1 infection. Surgical revision was required in 12/30 patients (40%). There were no neophallus erosions, flap loss, nor urethral injuries. More complications occurred with the Spectra (9/17 or 53%) than the Genesis MPP (3/13 or 23%), but this was not statistically significant (P = .10). CONCLUSION: Infrapubic insertion in transmen after phalloplasty using commercially available MPPs is safe compared with other post-phalloplasty penile prosthesis insertion techniques, with similarly high surgical revision rates. Further study of techniques is needed to improve outcomes after penile prosthesis insertion in transmen.

Microsurgical Denervation of the Spermatic Cord: A Historical Perspective and Recent Developments.

INTRODUCTION: The management of chronic scrotal pain is long and varied, with historical treatment algorithms typically ending with orchiectomy. Microsurgical denervation of the spermatic cord (MDSC) is a testicle-sparing option for patients who have failed conservative treatment options and over its forty-year history has seen many technical refinements. OBJECTIVES: To review the history and development of MDSC and discuss the outcomes of different surgical techniques. METHODS: A literature review using PubMed and Google Scholar was conducted to identify studies pertaining to surgical treatment of CSP, MDSC, and outcomes. Search terms included "chronic," "scrotal pain," "orchialgia," "spermatic cord," "denervation," and "microsurgery." RESULTS: We included 21 case reports and series since the first seminal paper describing MDSC technique in 1978. Additional studies that challenged existing conventions or described novel techniques are also discussed. The current standard procedure utilizes a subinguinal incision and a surgical microscope. Open, robotic, and laparoscopic approaches to MDSC have been described, but access to minimally invasive instruments may be limited outside of developed nations. Pain reduction following preoperative spermatic cord predicts success of MDSC. Methods for identifying and preserving the testicular and deferential arteries vary depending on surgeon preference but appear to have comparable outcomes. Future developments in MDSC involve targeted denervation, minimizing collateral thermal injury, and alternative techniques to visualize arterial supply. CONCLUSION: For patients suffering from CSP, MDSC is a well-studied technique that may offer appropriately selected patients' relief. Future investigation comparing targeted vs full MDSC as well as in vivo study of new techniques are needed to continue to improve outcomes. Sun HH, Tay KS, Jesse E, et al. Microsurgical Denervation of the Spermatic Cord: A Historical Perspective and Recent Developments. Sex Med Rev 2022;10:791-799.

Duplex renal collecting system presenting with hydroureteronephrosis following pelvic organ prolapse and sacrocolpopexy in an adult female.

Duplex collecting systems are common congenital abnormalities of the urinary tract but are infrequently reported in adult populations. This abnormality can present with hydroureteronephrosis secondary to urinary tract obstruction or concomitant vesicoureteral reflux (VUR), recurrent urinary tract infections (UTIs), and urinary incontinence. Options for surgical management include common-sheath ureteral reimplantation, uretero-ureterostomy, pyelostomy, and heminephroureterectomy. We report the case of a 39-year-old female with a duplex kidney who presented with severe hydroureteronephrosis following a sacrocolpopexy.

Microsurgical Denervation of the Spermatic Cord: A Historical Perspective and Recent Developments.

INTRODUCTION: The management of chronic scrotal pain is long and varied, with historical treatment algorithms typically ending with orchiectomy. Microsurgical denervation of the spermatic cord (MDSC) is a testicle-sparing option for patients who have failed conservative treatment options and over its forty-year history has seen many technical refinements. OBJECTIVES: To review the history and development of MDSC and discuss the outcomes of different surgical techniques. METHODS: A literature review using PubMed and Google Scholar was conducted to identify studies pertaining to surgical treatment of CSP, MDSC, and outcomes. Search terms included "chronic," "scrotal pain," "orchialgia," "spermatic cord," "denervation," and "microsurgery." RESULTS: We included 21 case reports and series since the first seminal paper describing MDSC technique in 1978. Additional studies that challenged existing conventions or described novel techniques are also discussed. The current standard procedure utilizes a subinguinal incision and a surgical microscope. Open, robotic, and laparoscopic approaches to MDSC have been described, but access to minimally invasive instruments may be limited outside of developed nations. Pain reduction following preoperative spermatic cord predicts success of MDSC. Methods for identifying and preserving the testicular and deferential arteries vary depending on surgeon preference but appear to have comparable outcomes. Future developments in MDSC involve targeted denervation, minimizing collateral thermal injury, and alternative techniques to visualize arterial supply. CONCLUSION: For patients suffering from CSP, MDSC is a well-studied technique that may offer appropriately selected patients' relief. Future investigation comparing targeted vs full MDSC as well as in vivo study of new techniques are needed to continue to improve outcomes.

Cost of Care in Open Cystectomy Patients Across Time and Space: Does it matter?

BACKGROUND: Many variables may affect the cost of open radical cystectomy (RC) care, including surgical approach, diversion type, patient comorbidities, and postoperative complications. OBJECTIVE: To determine factors associated with changes in cost of care following open radical cystectomy (ORC) for bladder cancer using the National Inpatient Sample (NIS). METHODS: Patients in the NIS with a diagnosis of bladder cancer who underwent ORC with ileal conduit from 2012-2017 using ICD-9-CM and ICD-10-CM codes were identified. Baseline demographics including age, race, region, postoperative complications, and length of stay were obtained. Univariable and multivariable logistic regression were used to identify factors associated with cost variation including demographics, clinical characteristics, surgical factors, and discharge quarter (Q1-Q4). RESULTS: 5,189 patients were included in the analysis, with 4,379 at urban teaching hospitals. On multivariable regression analysis, female sex [$1,734 ($1,024-2,444) p < 0.001)], a greater Elixhauser comorbidity score [$93 ($62-124), p < 0.001], presence of any inpatient complication [$1,531 ($894-2,168), p < 0.001], and greater length of stay [$1,665 ($1,536-1,793), p < 0.001] were associated with a greater cost of hospitalization. Discharge in Q3 (July to September) relative to Q2 (April to June) was associated with a higher cost [$1,113 ($292-1,933), p = 0.008. Trends were similar at urban non-teaching and rural hospitals, except discharge quarter was not associated with a significant change in cost. CONCLUSIONS: Significant differences in cost of ORC with ileal conduit exist with respect to patient sex, medical comorbidities, and discharge timing. These differences may relate to greater disease burden in female patients, patient complexity, and variation in postoperative care in academic programs.

Understanding Pharmacokinetic Disconnect in Preclinical Species for 4-Aminoquinolines: Consequences of Low Permeability and High P-glycoprotein Efflux Ratio on Rat and Dog Oral Pharmacokinetics.

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies. Structurally similar analogues incorporating polarity at C-7 position of 4-aminoquinoline resulted in identification of GSKC - GSKF. Interestingly, following oral administration to rat at similar low dose, GSKC - GSKF demonstrated significantly low systemic drug exposure compared to GSKA and GSKB (3-17-fold difference). However, in dog, dose normalized oral systemic exposure for GSKC - GSKF was comparable to GSKA and GSKB (within 2-fold). A series of studies were conducted to understand the disconnect which highlighted that an intrinsic reduction in permeability and high P-glycoprotein (P-gp) efflux ratio for C-7 substituted analogues were driving pharmacokinetic disconnect between rat and dog. Oral absorption was minimally impacted in dog by P-gp mediated efflux compared to rat because the leakier gastrointestinal tract in dog likely overcomes this effect.

Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.].

Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.