Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

First-line Systemic Therapy Following Adjuvant Immunotherapy in Renal Cell Carcinoma: An International Multicenter Study.

BACKGROUND AND OBJECTIVE: Adjuvant pembrolizumab significantly improved overall survival (OS) in renal cell carcinoma (RCC), but real-world data on sequential treatment are scarce. We sought to evaluate the clinical outcomes of first-line (1L) systemic therapy following adjuvant immune oncology (IO)-based regimens. METHODS: A retrospective study including patients with recurrent RCC following adjuvant IO across 29 international institutions was conducted. The primary endpoint was progression-free survival (PFS) on 1L systemic therapy estimated using the Kaplan-Meier method. Preplanned subanalyses of clinical outcomes by type of 1L systemic therapy, recurrence timing, and International Metastatic RCC Database Consortium (IMDC) risk groups were performed. Treatment-related adverse events leading to treatment discontinuation, dose reduction, or corticosteroid use were assessed. KEY FINDINGS AND LIMITATIONS: A total of 94 patients were included. Most received adjuvant pembrolizumab (n = 37, 39%), atezolizumab (n = 28, 30%), or nivolumab + ipilimumab (n = 15, 16%). The cohort included 49 (52%) patients who had recurrence within 3 mo of the last adjuvant IO dose, whereas 45 (48%) recurred beyond 3 mo. Bone metastases were significantly higher in tumors recurring at <3 mo (10/49, 20%) than those recurring at >3 mo (1/45, 2.2%; p = 0.008). Most patients received 1L vascular endothelial growth factor-targeted therapy (VEGF-TT; n = 37, 39%), IO + VEGF-TT (n = 26, 28%), or IO + IO (n = 12, 13%). The remaining underwent local therapy. The median follow-up for the 1L systemic therapy cohort was 15 mo. The 18-mo PFS and OS rates were 45% (95% confidence interval [CI]: 34-60) and 85% (95% CI: 75-95), respectively. Treatment-related adverse events occurred in 32 (42%) patients and included skin toxicity (n = 7, 9.2%), fatigue (n = 6, 7.9%), and diarrhea/colitis (n = 4, 5.3%). Limitations included selecting patients from large academic centers and the short follow-up period. CONCLUSIONS AND CLINICAL IMPLICATIONS: A subset of patients with recurrent RCC following adjuvant IO respond to systemic therapies, including VEGF-TT and IO-based regimens. Notably, patients with favorable-risk disease may derive more benefit from VEGF-TT than from IO therapies in this setting. Future approaches utilizing radiographic tools and biomarker-based liquid biopsies are warranted to detect occult metastatic disease and identify candidate patients for adjuvant IO therapy. PATIENT SUMMARY: Adjuvant pembrolizumab significantly improved overall survival in renal cell carcinoma (RCC). There are limited data on clinical outcomes after the recurrence of RCC tumors following adjuvant immunotherapy. In this study, we find that patients respond to subsequent systemic therapies across different treatment options.

Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial.

PURPOSE: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. PATIENTS AND METHODS: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. RESULTS: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%-28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6-11.4) in cohort A and 4.5 months (95% CI, 3.4-13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2-12.3) in cohort A and 13.8 months (95% CI, 3.6-not reached) in cohort C. CONCLUSIONS: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.

Clinical Applications of the Gut Microbiome in Genitourinary Cancers.

Recently recognized as one of the hallmarks of cancer, the microbiome consists of symbiotic microorganisms that play pivotal roles in carcinogenesis, the tumor microenvironment, and responses to therapy. With recent advances in microbiome metagenomic sequencing, a growing body of work has demonstrated that changes in gut microbiome composition are associated with differential responses to immune checkpoint inhibitors (ICIs) because of alterations in cytokine signaling and cytotoxic T-cell recruitment. Therefore, strategies to shape the gut microbiome into a more favorable, immunogenic profile may lead to improved responses with ICIs. Immunotherapy is commonly used in genitourinary (GU) cancers such as renal cell carcinoma, urothelial cancer, and to a limited extent, prostate cancer. However, a subset of patients do not derive clinical benefit with ICIs. Gut microbiome-based interventions are of particular interest given the potential to boost responses to ICIs in preclinical and early-phase prospective studies. Novel approaches using probiotic therapy (live bacterial supplementation) and fecal microbiota transplantation in patients with GU cancers are currently under investigation.

Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma.

Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.

Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration.

BACKGROUND: AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear. METHODS: Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types. RESULTS: In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%). CONCLUSION: In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

Determinants of Bone-Modifying Agent Prescribing for Metastatic Castration-Resistant Prostate Cancer in a National Health Care Delivery System.

PURPOSE: Despite guidelines recommending bone-modifying agents (BMAs) to decrease skeletal-related events (SREs) in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are underutilized. In this retrospective cohort study, we report the factors associated with BMA use in a national health care delivery system. METHODS: We used the Veterans Affairs Corporate Data Warehouse to identify men with mCRPC between 2010 and 2017. BMA prescribing frequency was evaluated, and the association between patient- and disease-specific factors with BMA use was assessed using multivariable logistic regression. RESULTS: Among 3,980 men identified with mCRPC (mean age 73.5 years, 29% Black), 47% received a BMA; median time to BMA from start of mCRPC treatment was 102 days. Factors associated with BMA use included previous BMA use (adjusted odds ratio [aOR], 7.81 [95% CI, 6.48 to 9.47]), diagnosis code for bone metastases (aOR, 1.26 [95% CI, 1.08 to 1.46]), and concomitant corticosteroid use (aOR, 1.53 [95% CI, 1.29 to 1.82]). Decreased BMA use was associated with advancing age (aOR, 0.85 per 10 years [95% CI, 0.78 to 0.92]), Charlson comorbidity index ≥2 (aOR, 0.76 [95% CI, 0.63 to 0.93]), Black race (aOR, 0.83 [95% CI, 0.70 to 0.98]), and decreased estimated glomerular filtration rate (eGFR; aOR, 0.19 [95% CI, 0.11 to 0.32] for eGFR 0-29 mL/minutes; aOR, 0.76 [95% CI, 0.64 to 0.91] for 30-59 mL/minutes). CONCLUSION: Patients who are older, Black, or have more comorbidities are less likely to receive guideline concordant care to prevent SREs. These observations highlight the unique challenges of caring for patients with mCRPC and the need for future studies to increase BMA use in these populations.

Pathogenic Germline Mutational Landscape in Patients With Renal Cell Carcinoma and Associated Clinicopathologic Features.

PURPOSE: A subset of renal cell carcinoma (RCC) cases occur because of a hereditary predisposition. However, the prevalence and profiling of germline alterations in RCC have not been fully characterized. Additionally, clinicopathologic factors associated with pathogenic or likely pathogenic (P/LP) germline variants in patients with RCC remain poorly understood. METHODS: A retrospective analysis of patients with RCC who underwent genetic evaluation was performed. The frequency of P/LP germline variants and genes was evaluated in this cohort. The association between genetic testing outcomes and clinicopathologic features was also assessed. RESULTS: A total of 321 patients with RCC who had germline testing were identified. Within this cohort, 42 patients (13.1%) had P/LP variants. Genes with the most frequent germline mutations were FLCN (n = 10, 3.1%), SDHB (n = 4, 1.2%), VHL (n = 4, 1.2%), MLH1 (n = 3, 0.9%), and CHEK2 (n = 4, 1.2%). Among patients with P/LP variants, 19 (45.2%) had a potentially targetable mutation. The presence of bilateral or multifocal tumors was associated with P/LP variants (P = .0012 and P = .0098, respectively). Patients who had targeted gene testing had higher rates of P/LP variants compared with multigene panel testing (P = .015). Age and family history of cancers (RCC and non-RCC) did not have any statistically significant association with germline testing outcomes. CONCLUSION: Among patients with RCC, unselected for a known familial predisposition, 13.4% had P/LP variants. Almost half of patients with P/LP variants had a potentially targetable mutation. Targeted gene panel testing is a feasible option for patients, particularly if syndromic features are present. Age and family history were not associated with P/LP variants. Future studies are needed to optimize current genetic evaluation criteria to expand the detection of patients with RCC who may have germline mutations.

Clinical implications of AR alterations in advanced prostate cancer: A multi-institutional collaboration.

Background: AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear. Methods: Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types. Results: In total, 540 CRPC patients who received ARTA and had tissue-based (n=321) and/or blood-based (n=244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p=0.03). In the post-ARTA group (n=406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%). Conclusion: To our knowledge, this is the largest real-world clinicogenomics database-driven study exploring the development of ARalterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

Transperitoneal Versus Retroperitoneal Single-port Robotic-assisted Partial Nephrectomy: An Analysis from the Single Port Advanced Research Consortium.

BACKGROUND: In the surgical management of kidney tumors, such as in multiport technology, single-port (SP) robotic-assisted partial nephrectomy (RAPN) can be performed using the transperitoneal (TP) or retroperitoneal (RP) approach. However, there is a dearth of literature on the efficacy and safety of either approach for SP RAPN. OBJECTIVE: To compare the peri- and postoperative outcomes of the TP and RP approaches for SP RAPN. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort study using data from the Single Port Advanced Research Consortium (SPARC) database of five institutions. All patients underwent SP RAPN for a renal mass between 2019 and 2022. INTERVENTION: TP versus RP SP RAPN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics, and peri- and postoperative outcomes were compared between both the approaches using χ2 test, Fisher exact test, Mann-Whitney U test, and Student t test. RESULTS AND LIMITATIONS: A total of 219 patients (121 [55.25%] TP, 98 [44.75%] RP) were included in the study. Of them, 115 (51.51%) were male, and the mean age was 60 ± 11 yr. RP had a significantly higher proportion of posterior tumors (54 [55.10%] RP vs 28 [23.14%] TP, p < 0.001), while other baseline characteristics were comparable between both the approaches. There was no statistically significant difference in ischemia time (18 ± 9 vs 18 ± 11 min, p = 0.898), operative time (147 ± 67 vs 146 ± 70 min, p = 0.925), estimated blood loss (p = 0.167), length of stay (1.06 ± 2.25 vs 1.33 ± 1.05 d, p = 0.270), overall complications (5 [5.10%] vs 7 [5.79%]), and major complication rate (2 [2.04%] vs 2 [1.65%], p = 1.000). No difference was observed in positive surgical margin rate (p = 0.472) or delta eGFR at median 6-mo follow-up (p = 0.273). Limitations include retrospective design and no long-term follow-up. CONCLUSIONS: With proper patient selection based on patient and tumor characteristics, surgeons can opt for either the TP or the RP approach for SP RAPN, and maintain satisfactory outcomes. PATIENT SUMMARY: The use of a single port (SP) is a novel technology for performing robotic surgery. Robotic-assisted partial nephrectomy (RAPN) is a surgery to remove a portion of the kidney due to kidney cancer. Depending on patient characteristics and surgeons' preference, SP can be performed via two approaches for RAPN: through the abdomen or through the space behind the abdominal cavity. We compared outcomes between these two approaches for patients receiving SP RAPN, finding that they were comparable. We conclude that with proper patient selection based on patient and tumor characteristics, surgeons can opt for either the TP or the RP approach for SP RAPN, and maintain satisfactory outcomes.

A Phase 2 Trial of Nab-paclitaxel in Combination With Anti-PD1 Therapy in Advanced Urothelial Cancer.

PURPOSE: Immune checkpoint inhibitor therapy and nab-paclitaxel have each shown efficacy in platinum-refractory advanced urothelial cancer. We conducted a single-arm phase 2 trial of the combination of nab-paclitaxel and pembrolizumab in platinum-refractory or cisplatin-ineligible advanced urothelial cancer (NCT03240016). MATERIALS AND METHODS: Eligible patients had RECIST 1.1 measurable and cisplatin-ineligible or platinum-refractory advanced urothelial cancer. Patients received nab-paclitaxel at starting dose of 125 mg/m2 intravenously on days 1 and 8 and pembrolizumab 200 mg intravenously on day 1 in 21-day cycles until progression, intolerable toxicity, or death. Nab-paclitaxel was permitted to be discontinued after 6 cycles. The nab-paclitaxel starting dose was reduced to 100 mg/m2 after planned interim analysis. Primary end point was overall response rate by RECIST 1.1. Secondary end points included safety/toxicity, duration of response, progression-free survival), and overall survival. RESULTS: Between February 2018 and April 2021, 36 response-evaluable patients were enrolled. There was an equal split of platinum-refractory and cisplatin-ineligible patients. Confirmed overall response rate was 50.0% (18/36) including 3 complete and 15 partial responses; 31/36 patients experienced some tumor shrinkage. At a median follow-up of 19.7 months, median duration of response was 4.4 months (95% CI: 4.0-8.6), median progression-free survival 6.8 months (95% CI: 4.4-not reached), and median overall survival 18.2 months (95% CI: 10.6-not reached). Grade ≥3 adverse events occurred in 21/36 patients including fatigue (n=6) and anemia (n=4). Ten patients had immune-mediated adverse events. CONCLUSIONS: The combination of nab-paclitaxel and pembrolizumab exhibited promising activity in advanced urothelial cancer and warrants further study in this population. After reduction in nab-paclitaxel starting dose, no unanticipated or unexpected toxicities emerged.

Case report: Immune-mediated meibomian gland dysfunction following pembrolizumab therapy for advanced urothelial carcinoma.

Ocular immune-related adverse events are a relatively rare complication of immune checkpoint inhibitors. Common ocular toxicities range from dry eyes to inflammatory uveitis and ocular myasthenia gravis. Here, we present the case of a 55-year-old woman with recurrent urothelial carcinoma of the ureter after initially being managed with neoadjuvant cisplatin-based chemotherapy and surgical resection. She was treated with pembrolizumab which was complicated by immune-mediated pneumonitis after the eighth cycle, which was managed with a prolonged steroid course. The patient also developed red eyes along with recurrent styes. Eye examination revealed decreased tear breakup time, expression of thick and turbid meibum, and meibomian gland atrophy on infrared meibography. The patient was diagnosed with suspected immune-mediated meibomian gland dysfunction (MGD) as a result of pembrolizumab, a previously unreported complication of immunotherapy. The goal of MGD therapy is to stabilize the tear film and minimize evaporation with lipid-based lubricants and other conservative treatments.

Chronic kidney disease and radical cystectomy for bladder cancer: perioperative and oncologic outcomes in 1,214 patients.

INTRODUCTION AND OBJECTIVE: To assess the impact of chronic kidney disease (CKD) on outcomes after radical cystectomy (RC) in patients with bladder cancer treated within a high-volume tertiary referral center. METHODS: We identified 1,214 patients who underwent RC with intent to cure from 2009 to 2019. The Modification of Diet in Renal Disease (MDRD) GFR (ml/min/1.73 m²) was calculated and patients were categorized by baseline GFR: Group A = GFR > 60, Group B = GFR > 30-59 and Group C = GFR < 30. Pre-, intra- and postoperative characteristics, oncological outcomes, and 90-day perioperative outcomes were compared. Multivariable logistic regression was used to control for confounding variables. RESULTS: We identified 722 (59.5%) patients in Group A, 448 (36.9%) in Group B, and 44 (3.6%) in Group C. Patients with worse CKD were older and had significantly worse overall comorbidity (all P < 0.001). Neoadjuvant chemotherapy was used in 352 patients (29%), including 182 (25.2%) in Group A, 153 in Group B (35.3%), and 12 in Group C (27.3%). On univariate analysis, worse CKD was associated with higher pathologic stage, lymph node metastases and positive soft tissue margins (all P < 0.0001). The rates of blood transfusion, 90-day complications and readmissions were higher in patients with worse CKD (P < 0.0001, P = 0.02, P = 0.04, respectively). Patients with worse CKD had worse overall survival (77% vs. 73% vs. 55%, P < 0.0001). On multivariable analysis, worse CKD was independently associated with adverse pathology (≥pT3 or node positive) (OR = 6.96, 95%CI 3.20-15.12), 90-day readmissions (OR 2.09, 95%CI 1.11-3.94) and perioperative transfusion (OR 2.08, 95%CI 1.05-4.11). Receipt of neoadjuvant chemotherapy was significantly associated with a decreased risk of adverse pathology (OR 0.51, 95%CI 0.36-0.74) and increased risk of transfusion (OR 2.24, 95%CI 1.70-2.96), but not with mortality, complications, readmissions or length or stay. CONCLUSION: CKD is prevalent in patients undergoing radical cystectomy. We found CKD to be independently associated with a higher likelihood of adverse pathology, 90-day readmissions, and transfusion.

Long-term renal function in patients with chronic kidney disease following radical cystectomy and orthotopic neobladder.

OBJECTIVE: To evaluate long-term renal function in patients with chronic kidney disease (CKD) Stage IIIa who underwent radical cystectomy and orthotopic neobladder (RC/ONB) compared to matched controls. PATIENTS AND METHODS: Using our Institutional Review Board-approved institutional database, patients with a glomerular filtration rate (GFR) of 45-59.9 mL/min/1.73 m2 who underwent RC/ONB were identified. A control group of patients with a GFR of ≥60 mL/min/1.73 m2 was selected. Groups were matched based on age, baseline hypertension/diabetes mellitus, perioperative chemotherapy, and preoperative hydronephrosis. A decrease in GFR of >10 mL/min/1.73 m2 during the follow-up was considered significant. A multivariate Cox regression analysis was performed to identify predictors of GFR decline in each group. RESULTS: Of 1237 patients who underwent RC/ONB, 508 patients were included (254 per group). The mean preoperative GFR was 53.3 mL/min/1.73 m2 in the study group and 78.8 mL/min/1.73 m2 in controls. The median follow-up was 3.7 years. During follow-up, GFR stayed at or above baseline in 51% of the study patients compared to 46% of the controls (P = 0.5). The mean time to a significant GFR decline in the study patients was significantly longer compared to the controls (5.6 vs 2 years, respectively; P < 0.001). In multivariate analysis, neoadjuvant chemotherapy was found to be the strongest predictor of a significant GFR decline as well as GFR decline below baseline (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.29, P = 0.004; and HR 2.15, 95% CI 1.4-3.29, P < 0.001, respectively). CONCLUSION: Patients with CKD Stage IIIa who undergo ONB appear to have comparable long-term renal function to those with a GFR of ≥60 mL/min/1.73 m2 . An ONB reconstruction is a safe option for patients with CKD Stage IIIa desiring a continent diversion.

Updated Review of the Pacific Asynchronous Telehealth System's Impact on Military Pediatric Teleconsultations.

Introduction: The Pacific Asynchronous TeleHealth (PATH) system is an asynchronous provider-to-provider teleconsultation platform utilized by military medical facilities throughout the Western Pacific Region. This study focused on PATH utilization for pediatric cases and its impact on patient transfers and cost avoidance. Methods: This retrospective analysis reviewed PATH cases from March 2017 to February 2020 for patients aged 0-17 years. We reviewed the referring users' responses to survey questions related to the impact of PATH consultation on patient travel for in-person subspecialty care and the need for local referral. Data for cost avoidance were estimated using per diem rates and airline flight costs for Fiscal Year 2020. Results: A total of 2,448 pediatric consultations were submitted from 29 military medical facilities. Pediatric Pulmonology (n = 557, 24.5%), Pediatric Cardiology (n = 446, 19.6%), and Pediatric Neurology (n = 236, 10.37%) had the highest percentage of pediatric teleconsults. Approximately 42% of referring users completed the survey questions. Among survey respondents, 710 (69.4%) indicated that unnecessary patient transfers were prevented, equating to a cost savings of ∼$3.3 million. Conclusions: We observed robust utilization of the PATH system by pediatric providers in the Military Health System that ultimately resulted in substantial cost avoidance. This asynchronous telemedicine platform is a vital asset in locations with limited access or travel restriction to medical specialists, such as during pandemics.

Primary bone lymphoma of the ilium successfully treated without radiation.

The addition of radiation therapy to chemotherapy and impact on outcomes in primary bone lymphoma is not clear. Nonetheless, tumor location must be considered as radiation to marrow-rich bone areas can lead to myelosuppression and myelotoxicity.

Doublecortin-like kinase 1 promotes hepatocyte clonogenicity and oncogenic programming via non-canonical ß-catenin-dependent mechanism.

Chronic liver injury is a risk factor for cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms that regulate the decision between normal injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a tumor stem cell marker, is induced during cirrhosis and HCC. Here, we demonstrate that DCLK1-overexpressing primary human hepatocytes formed spheroids in suspension cultures. Spheroids derived from DCLK1-overexpressing hepatoma cells showed high level expression of active ß-catenin, α-fetoprotein, and SOX9, suggesting that DCLK1 overexpression induces clonogenicity and dedifferentiated phenotypes in hepatoma cells. DCLK1 overexpression in hepatoma cells also increased phosphorylation of GSK-3ß at Ser9. This was associated with an induction of a 48-kDa active ß-catenin with a preserved hypophosphorylated N-terminus that interacted with nuclear TCF-4 resulting in luciferase reporter activity and cyclin D1 expression. DCLK1 downregulation inhibited 48-kDa ß-catenin expression. The proteasome inhibitor bortezomib did not block the 48-kDa ß-catenin, instead, caused a threefold accumulation, suggesting a proteasome-independent mechanism. Liver tissues from patients with cirrhosis and HCC revealed epithelial co-staining of DCLK1 and active ß-catenin, and cleaved E-cadherin. Repopulated DCLK1-overexpressing primary human hepatocytes in humanized FRG mouse livers demonstrated active ß-catenin. In conclusion, DCLK1 regulates oncogenic signaling and clonogenicity of hepatocytes by a novel non-canonical/atypical ß-catenin-dependent mechanism.

Reduction in Medical Evacuations from Iraq and Syria Following Introduction of an Asynchronous Telehealth System.

INTRODUCTION: While deployed, military medical personnel manage routine medical issues that fall under the category of Disease Non-Battle Injury (DNBI). The 86th Combat Support Hospital (CSH) partnered with Combined Joint Task Force-Operation Inherent Resolve (CJTF-OIR) Surgeon Cell, and Special Operations Joint Task Force-Operation Inherent Resolve (SOJTF-OIR) Surgeon Cell, to introduce the Health Experts onLine Portal (HELP) telemedicine system to medical personnel in Iraq and Syria. HELP is an asynchronous (store and forward) online system that provides secure provider-to-provider teleconsultation services for routine patient care and medical evacuation (MEDEVAC) coordination. The goal was to reduce the need for MEDEVAC by providing expert consultation to medical providers in farther-forward deployed units. MATERIAL AND METHODS: In June 2017, the 86th CSH launched HELP telemedicine services for Kuwait. Following the successful implementation of the telemedicine system in Kuwait, the 86th CSH leadership partnered with CJTF-OIR and SOJTF-OIR medical leadership in launching the system within Iraq and Syria as well as making the system available to all deployed locations in Central Command (CENTCOM). This was a prospective cohort study designed to determine if having convenient and secure access to remote subspecialty consultation would be associated with a reduction in routine MEDEVACs from far forward in the battle space. In August 2017, new-user training was completed and the program launched in Iraq and Syria. This study analyzes the baseline MEDEVAC rate in 3 months before the implementation of HELP telemedicine compared to 3 months following the implementation. RESULTS: Iraq and Syria cases in the HELP telemedicine system accounted for 17.2% (76) of total CENTCOM telemedicine case volume over the 7-month study period. Comparing the 3-month period before and after implementation of HELP, use of asynchronous telemedicine in Iraq and Syria was associated with a reduction in total MEDEVACs from 157 to 68 (56.7% reduction, p < 0.001). DNBI represented the majority of the change, (65.0% reduction, p < 0.001). MEDEVAC for battle-related injuries decreased slightly from 13 to 6 per 3-month period (p = 0.03). CONCLUSIONS: This is the first prospective study to demonstrate an association between the initiation of asynchronous telemedicine capabilities in a combat zone and decreased MEDEVACs. Annualized numbers would predict a reduction of 328 MEDEVACs/year for each 10,000 personnel by utilizing asynchronous telemedicine. This represents a significant potential cost savings of $1.2 million/year through avoidance of routine medical movement of personnel and supports unit readiness by retaining service members in areas of combat operations.

Complications of Methamphetamine Use in Orthopaedic Trauma.

OBJECTIVES: To determine whether methamphetamine (MA) users are at an increased risk for complications compared to matched controls in the setting of orthopaedic trauma. DESIGN: Retrospective cohort study. SETTING: Academic Level-1 Trauma Center. PATIENTS: MA users and matched controls. INTERVENTION: MA use. MAIN OUTCOME MEASUREMENTS: Infection, Deep Vein Thrombosis (DVT), and nonunion. RESULTS: Five hundred sixty-seven patients were included in our study (189 MA users, 378 matched controls). On univariate analysis, MA users had a higher incidence of DVT (3.2% vs. 0.5%), but no statistically significant difference in infection or nonunion rates. MA users also had a higher incidence of intensive care unit admission (36.0% vs. 27.8%), leaving the hospital against medical advice (9.0% vs. 2.1%), nonadherence to weightbearing precautions (18.8% vs. 7.3%), and a higher incidence of loss of follow-up (47.1% vs. 30.4%). However, MA users had a lower incidence of surgical treatment for orthopaedic injuries (51.9% vs. 65.9%). When surgical treatment was pursued, more trips to the operating room were required for orthopaedic injuries in the MA group (2.6 vs. 1.5 trips). On multivariate analysis, MA users continued to demonstrate a higher incidence of DVT and a lower incidence of operative management, but more trips to the operating room when surgical management was pursued, a higher admission rate to the intensive care unit, and a greater incidence of loss of follow-up. CONCLUSIONS: MA use is associated with increased inpatient and outpatient complications. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.