Abby L. Grier

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety.

Background: Anitens are a family of oral N-terminal domain inhibitors of the androgen receptor (AR). In prostate cancer, they may help overcome AR resistance mechanisms at the ligand-binding domain, which is the binding site of approved androgen receptor pathway inhibitors like enzalutamide. Masofaniten (EPI-7386) is a next-generation aniten with promising activity and safety in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: In this investigator-initiated, phase II, single-arm, single-institution trial, patients with treatment-naïve metastatic hormone-sensitive prostate cancer (mHSPC) were enrolled in a Simon 2-stage study design to receive the combination of masofaniten 600 mg BID and enzalutamide 160 mg daily with androgen deprivation therapy (ADT). The study was designed to enroll 35 patients (13 patients in stage 1, then 22 patients in stage 2). The trial would move to stage 2 if 9 or more subjects achieved a biochemical response at 6 months. Results: Thirteen patients were screened and enrolled into stage 1. Five were African American, and 8 were Caucasian. The median age was 68 years (range 52-75) at time of enrollment. Median follow-up time was 9.9 months (range 7.7-13.6). Ten of 13 patients (77% with 95% CI: 50%-92%) achieved a PSA <0.2 ng/mL at 6 months, achieving the threshold to move on to stage 2. Only one patient had disease progression to mCRPC and died of disease at the time of data cutoff. Patients continued enzalutamide and ADT after trial closure. Conclusion: The combination of masofaniten and enzalutamide for treatment-naïve mHSPC did show efficacy and had an acceptable safety profile. These results support further investigation of the dual AR blockade in mHSPC (ClinicalTrials.gov Identifier: NCT06312670).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymatic disorder, affects over 500 million people worldwide and is often linked to exercise intolerance due to oxidative stress, but its true impact on physical performance remains unclear. This study aimed to evaluate the physiological and metabolic effects of G6PD deficiency on endurance capacity. Using humanized mice carrying the African G6PD variant [V68M; N126D] (hG6PD_A−), we show that despite reduced pentose phosphate pathway activity, these mice exhibit a 10.8% increase in treadmill critical speed (CS)—suggesting enhanced endurance capacity. Multi-omics profiling across red blood cells, plasma, skeletal muscle, spleen, kidney, and liver reveals metabolic adaptations, including elevated glycolysis, fatty acid oxidation, and increased mitochondrial activity, alongside heightened oxidative phosphorylation in muscle and accelerated red blood cell turnover in the spleen and liver. These findings indicate that systemic metabolic reprogramming may offset antioxidant deficiencies, potentially conferring a performance advantage. Given that G6PD deficiency affects up to 13% of African Americans and is associated with cardiovascular health disparities, our results challenge conventional exercise restrictions and highlight the need for personalized exercise guidelines for affected individuals.

Background Diabetic ketoacidosis is an acute, potentially life-threatening, metabolic complication and often first presentation of type 1 diabetes (T1D) mellitus. Here, we investigated the metabolic and lipid profiles from pediatric patients with T1D, at initial diagnosis and after two weeks of insulin treatment, employing findings from patients affected by maple syrup urine disease (MSUD) and the Recipient Epidemiology and Donor Evaluation Study (REDS) III RBC Omics. Methods 27 patients with newly onset T1D were assessed at the University of Campania “L. Vanvitelli” at first diagnosis and 2 weeks after therapy with insulin. As part of the REDS-III RBC Omics, whole blood was collected from 13,091 healthy blood donors. Whole blood was also collected from 3 patients with MSUD by biallelic inactivating mutation of BCKDHA. Metabolomics and Lipidomics were performed via UHPLC-MS/MS. Results Our findings highlight a newly identified associations among short-chain hydroxyacyl-carnitines, ketoacidosis, and hematological alterations in T1D. An associative linkage with SNPs in the regions coding for branched chain ketoacid dehydrogenase A and B (BCDHKA/B) is noted by leveraging measurements of the same metabolites in over 13,000 healthy genetically characterized donor volunteers. MSUD, a rare genetic disorder characterized by inactivating mutations of the BCDHKA gene leading to inability to metabolize branched-chain amino acids, manifests a strong association between the branched-chain amino acid-derived ketoacids, associated acyl-carnitines, and acidosis. Conclusions These results indicate that T1D hematological alterations at onset might act as biomarkers linked to circulating levels of short-chain acyl-carnitines, providing risk stratification for T1D and potentially for MSUD. Carnitine metabolism may be a promising therapeutic target for both diseases.

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder causing impaired branched-chain amino acid (BCAA) catabolism and systemic metabolic dysregulation. MSUD has an incidence of approximately 1 in 185,000 U.S. births, with much higher prevalence in the Mennonite communities (up to 1 in 400 live births due to the c.1312T > A p.Tyr438Asn BCKDHA founder mutation). Using a multiomic approach integrating metabolomics, lipidomics, and proteomics, we analyzed blood samples from three patients on a BCAA-restricted diet (MSUD_DR), two MSUD patients who received liver transplants (MSUD_LT), and six healthy controls. Gene ontology analysis of integrated omics data confirmed systemic metabolic imbalances in MSUD, highlighting increases in glycolysis, oxidative phosphorylation, and purine metabolism. Lipidomic analysis revealed disruptions in sphingolipids and lysophosphatidylcholines, affecting signaling and membrane integrity. Liver transplantation corrected some abnormalities, but key metabolites and proteins remained altered. Proteomic analysis revealed significant alterations in redox homeostasis, energy metabolism, and cytoskeletal organization with partial recovery post-transplantation. Post-translational modifications indicated ongoing oxidative stress and immune activation in the MSUDLT group. Elevated levels of l-isoleucine, l-valine, and their ketoacids persisted post-transplant, correlating with impaired amino acid metabolism, lipid remodeling, and protein folding. These findings provide insights into MSUD-associated metabolic dysfunction and highlight potential therapeutic targets.

Sickle cell disease and β-Thalassemia are two of the most prevalent hemoglobinopathies worldwide. Both occur due to genetic mutations within the HBB gene and are characterized by red blood cell dysfunction, anemia, and end-organ injury. The spleen and liver are the primary organs where erythrophagocytosis, engulfing the red blood cells, occurs in these diseases. Understanding metabolism and protein composition within these tissues can therefore inform the extent of hemolysis and disease progression. We utilized a multiomics approach to highlight metabolomic and proteomic differences in the spleen and liver. The Berkley sickle cell disease (Berk-SS), heterozygous B1/B2 globin gene deletion (Hbb^Th3/+) a known β-Thalassemia model, and wildtype (WT, C57/Bl6) murine models were evaluated in this report. This analysis showed Berk-SS and Hbb^Th3/+ shared distinct antioxidant and immunosuppressive splenic phenotypes compared to WT mice with divergence in purine metabolism, gluconeogenesis, and glycolysis. In contrast, Berk-SS mice have a distinct liver pro-inflammatory phenotype not shared by Hbb^Th3/+ or WT mice. Together, these data emphasize that metabolic and proteomic reprogramming of the spleen and livers in Berk-SS and Hbb^Th3/+mice may be relevant to the individual disease processes.

Background: An immune checkpoint inhibitor (ICI) backbone is a standard of care for frontline metastatic clear cell renal cell carcinoma, involving either ICI doublet or tyrosine kinase inhibitor (TKI) with ICI. These phase 3 trials used a sunitinib control arm. The optimal regimen is uncertain. Objective: To compare long-term responders of these trials using extended follow-up data stratified by International Metastatic RCC Database Consortium risk group. Methods: Phase 3 trial data (CheckMate 214, KEYNOTE-426, CheckMate 9ER, and CLEAR) with a minimum follow-up of four years was used. Pseudo individual patient data (IPD) was obtained from Kaplan-Meier curves using the graph digitizer software IPDfromKM R package to extract coordinates of points on the curves and to apply a numerical algorithm to reconstruct progression-free survival (PFS) and overall survival (OS) results. Durable response (DR) was defined as PFS ≥ 24 months, extreme durable response (EDR) as PFS ≥ 36 months, and long-term OS as OS ≥ 48 months. Results: For the favorable risk group, lenvatinib-pembrolizumab had the highest DR and EDR, while ipilimumab-nivolumab had the lowest DR, and cabozantinib-nivolumab had the lowest EDR; there was no difference in long-term OS among the regimens ( p = 0.11). For the intermediate/poor risk group, lenvatinib-pembrolizumab also had the highest DR and EDR compared to other regimens with similar DR and EDR; there was also no difference in long-term OS among the regimens ( p = 0.22). Conclusion: TKI-ICI was overall associated with higher DR and EDR regardless of risk status compared to ICI doublet. Yet, OS at 48 months were similar when stratified by favorable versus intermediate/poor risk.