Design and Rationale of the Outcomes Database to Prospectively Assess the Changing Therapy Landscape in Renal Cell Carcinoma Registry: A Multi-institutional, Prospective Study of Patients with Metastatic Renal Cell Carcinoma.

Introduction and hypotheses: The Outcomes Database to prospectivelY aSSEss the changing TherapY landscape in Renal Cell Carcinoma (ODYSSEY RCC) Registry is a large, nationally representative prospective registry of patients with metastatic renal cell carcinoma (mRCC) that aims to provide a real-world picture of longitudinal clinical management and patient experiences that impact clinical outcomes. The primary goal of this study is to understand the cancer management and health-related quality of life in patients with mRCC in routine real-world clinical practice in the USA. Design: This is an observational, phase 4 study with planned enrollment of up to 800 patients aged ≥19 yr with mRCC in the USA. Patients will be identified through electronic health record (EHR) data from the PCORnet network of sites for care received at collaborating sites. A unique aspect of the study is the multiple data sources that will be linked to the EHR data. These include: (1) Medicare claims data, (2) laboratory results, (3) tissue specimens, (4) radiographic images, and (5) patient-reported outcomes, physicians' treatment selection, and discontinuation surveys. Protocol overview: We created a novel data resource that can inform patient care. Investigators have the opportunity to use these to study novel research questions after submitting an ancillary proposal and upon approval of the executive committee. Limitations include the potential for selection bias, residual confounding, and missing information. Summary: The ODYSSEY Registry will provide an advanced data resource that can examine numerous clinical questions related to patient and physician choice, and support methodological research related to omics and artificial intelligence. Patient summary: Cancer medications and treatments are changing rapidly. Collecting data on real-world clinical practice and patient-answered questionnaires will help us better understand cancer management and health-related quality of life while receiving metastatic renal cell carcinoma-specific treatment.

Intensifying Salvage Therapy in Prostate-specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy with Apalutamide, Salvage Radiation, and Docetaxel: The Phase 2 STARTAR Trial.

BACKGROUND AND OBJECTIVE: Androgen deprivation therapy (ADT) with salvage radiation therapy (RT) improves survival for patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) for prostate cancer (PC), but many patients suffer further relapse. This study aims to determine the benefit of the combination of ADT, apalutamide, salvage RT, and docetaxel for high-risk PSA recurrent PC. METHODS: STARTAR is a multicenter, investigator-initiated phase 2 trial of men with PSA recurrent PC after RP. The key inclusion criteria included M0 by computed tomography/bone scan, Gleason 7 with either T3/positive margin/N1 disease or Gleason 8-10 prostate adenocarcinoma, PSA relapse (0.2-4 ng/ml) <4 yr after RP, and fewer than four positive resected lymph nodes. Patients received ADT with apalutamide for 9 mo, RT starting week 8, and then six cycles of docetaxel. The primary endpoint was 36-mo progression-free survival (PFS) with testosterone recovery and compared against the prior STREAM trial. KEY FINDINGS AND LIMITATIONS: We enrolled 39 men, including those with Gleason 8-10 (46%), pN1 (23%); the median PSA was 0.58 ng/ml. The median follow-up was 37 mo. All patients achieved undetectable PSA nadir. At 24 and 36 mo, PFS rates were 84% and 71%, respectively, which improved significantly over 3-yr 47% historic PFS and 54% enzalutamide/ADT/RT (STREAM) PFS rates (p = 0.004 and p = 0.039, respectively). Common any-grade adverse events included 98% hot flashes, 88% fatigue, 77% alopecia, 53% rash (10% G3), and 5% febrile neutropenia. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this phase 2 trial of ADT, apalutamide, salvage RT, and six cycles of docetaxel for high-risk PSA recurrence, the 3-yr PFS rate improved to 71%, indicating feasible and efficacious treatment intensification, with durable remissions beyond historic data. PATIENT SUMMARY: Prostate cancer recurrence after surgical removal of the tumor occurs often, and current treatment options to limit recurrence after surgery are only partially effective. In this study, we found that the addition of an androgen receptor inhibitor and docetaxel chemotherapy to standard postsurgery radiation therapy and androgen deprivation therapy significantly improved progression-free survival at 3 yr after treatment. These results suggest that intensification of treatment after surgery can provide long-term benefit to a subset of patients with high-risk prostate cancer.

Pediatric Device Clinical Trials Activity: 1999-2022.

OBJECTIVES: This study assessed the state of pediatric medical device (PMD) development by comparing PMD clinical trials to pediatric trials evaluating drugs and biologics, from 1999 to 2022. METHODS: The site www.clinicaltrials.gov was used to identify and quantify both PMD clinical trials and pediatric trials for drugs and biologics. Clinical specialty was also assessed. The institutions included were the 7 children's hospitals primarily affiliated with the Food and Drug Administration (FDA) Pediatric Device Consortia (PDC) grant program between 2018 and 2023. For a national comparison, an additional search assessed PMD trials across all US medical institutions. RESULTS: A total of 243 PMD clinical trials were identified at the FDA-PDC institutions on the basis of the year of initiation; the average number of PMD trials initiated per year per institution was 1.5 from 1999 to 2022. However, PMD trials significantly increased during the period 2014 to 2022 compared with 1999 to 2013 (P < .001); the rate of initiation of drug and biologic pediatric trials demonstrated no significant differences between these time periods. A national survey of all institutions initiating PMD trials, and drugs and biologics trials, identified 1885 PMD trials out of a total 12 943. A comparable trend was noted in the national survey with initiation of PMD trials increasing significantly from 2014 to 2022 (P < .001), compared with 1999 to 2013, whereas the rate of initiation of drug and biologic trials during these periods did not demonstrate a significant change. CONCLUSIONS: Although pediatric clinical trial initiation for drugs and biologics remained stable from 1999 to 2022, the rate of new PMD trials significantly increased during the period 2014 to 2022 at FDA-PDC institutions and nationally.

Immune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer.

Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Lessons Learned From the First-In-Human Compassionate Use of Connect-EA™ in Ten Patients With Esophageal Atresia.

INTRODUCTION: Delayed primary repair of esophageal atresia in patients with high-risk physiologic and anatomic comorbidities remains a daunting challenge with an increased risk for peri-operative morbidity and mortality via conventional repair. The Connect-EA device facilitates the endoscopic creation of a secure esophageal anastomosis. This follow-up study reports our long-term outcomes with the novel esophageal magnetic compression anastomosis (EMCA) Connect-EA device for EA repair, as well as lessons learned from the ten first-in-human cases. We propose an algorithm to maximize the advantages of the device for EA repair. METHODS: Under compassionate use approval, from June 2019 to December 2022, ten patients with prohibitive surgical or medical risk factors underwent attempted EMCA with this device. All patients underwent prior gastrostomy, tracheoesophageal fistula ligation (if necessary), and demonstrated pouch apposition prior to EMCA. RESULTS: Successful device deployment and EMCA formation were achieved in nine patients (90%). Mean time to anastomosis formation was 8 days (range 5-14) and the device was retrieved endoscopically in five (56%) cases. At median follow-up of 22 months (range 4-45), seven patients (78%) are tolerating oral nutrition. Balloon dilations (median 4, range 1-11) were performed either prophylactically for radiographic asymptomatic anastomotic narrowing (n = 7, 78%) or to treat clinically-significant anastomotic narrowing (n = 2, 22%) with no ongoing dilations at 3-month follow up post-repair. CONCLUSION: EMCA with the Connect-EA device is a safe and feasible minimally-invasive alterative for EA repair in high-risk surgical patients. Promising post-operative outcomes warrant further Phase I investigation. LEVEL OF EVIDENCE: IV, Case series of novel operative technique without comparison group.

Spatial Relationships in the Tumor Microenvironment Demonstrate Association with Pathologic Response to Neoadjuvant Chemoimmunotherapy in Muscle-invasive Bladder Cancer.

BACKGROUND: Platinum-based neoadjuvant chemotherapy (NAC) is standard for patients with muscle-invasive bladder cancer (MIBC). Pathologic response (complete: ypT0N0 and partial:

Evaluation of a Magnetic Compression Anastomosis for Jejunoileal Partial Diversion in Rhesus Macaques.

PURPOSE: Metabolic surgery remains underutilized for treating type 2 diabetes, as less invasive alternative interventions with improved risk profiles are needed. We conducted a pilot study to evaluate the feasibility of a novel magnetic compression device to create a patent limited caliber side-to-side jejunoileal partial diversion in a nonhuman primate model. MATERIALS AND METHODS: Using an established nonhuman primate model of diet-induced insulin resistance, a magnetic compression device was used to create a side-to-side jejunoileal anastomosis. Primary outcomes evaluated feasibility (e.g., device mating and anastomosis patency) and safety (e.g., device-related complications). Secondary outcomes evaluated the device's ability to produce metabolic changes associated with jejunoileal partial diversion (e.g., homeostatic model assessment of insulin resistance [HOMA-IR] and body weight). RESULTS: Device mating, spontaneous detachment, and excretion occurred in all animals (n = 5). There were no device-related adverse events. Upon completion of the study, ex vivo anastomoses were widely patent with healthy mucosa and no evidence of stricture. At 6 weeks post-device placement, HOMA-IR improved to below baseline values (p < 0.05). Total weight also decreased in a linear fashion (R2 = 0.97) with total weight loss at 6 weeks post-device placement of 14.4% (p < 0.05). CONCLUSION: The use of this novel magnetic compression device to create a limited caliber side-to-side jejunoileal anastomosis is safe and likely feasible in a nonhuman primate model. The observed glucoregulatory and metabolic effects of a partial jejunoileal bypass with this device warrant further investigation to validate the long-term glucometabolic impact of this approach.

Beyond the gut: spectrum of magnetic surgery devices.

Since the 1970s, magnetic force has been used to augment modern surgical techniques with the aims of minimizing surgical trauma and optimizing minimally-invasive systems. The majority of current clinical applications for magnetic surgery are largely centered around gastrointestinal uses-such as gastrointestinal or bilioenteric anastomosis creation, stricturoplasty, sphincter augmentation, and the guidance of nasoenteric feeding tubes. However, as the field of magnetic surgery continues to advance, the development and clinical implementation of magnetic devices has expanded to treat a variety of non-gastrointestinal disorders including musculoskeletal (pectus excavatum, scoliosis), respiratory (obstructive sleep apnea), cardiovascular (coronary artery stenosis, end-stage renal disease), and genitourinary (stricture, nephrolithiasis) conditions. The purpose of this review is to discuss the current state of innovative magnetic surgical devices under clinical investigation or commercially available for the treatment of non-gastrointestinal disorders.

Single-nuclei multiomic analyses identify human cardiac lymphatic endothelial cells associated with coronary arteries in the epicardium.

Cardiac lymphatic vessels play important roles in fluid homeostasis, inflammation, disease, and regeneration of the heart. The developing cardiac lymphatics in human fetal hearts are closely associated with coronary arteries, similar to those in zebrafish hearts. We identify a population of cardiac lymphatic endothelial cells (LECs) that reside in the epicardium. Single-nuclei multiomic analysis of the human fetal heart reveals the plasticity and heterogeneity of the cardiac endothelium. Furthermore, we find that VEGFC is highly expressed in arterial endothelial cells and epicardium-derived cells, providing a molecular basis for the arterial association of cardiac lymphatic development. Using a cell-type-specific integrative analysis, we identify a population of cardiac lymphatic endothelial cells marked by the PROX1 and the lymphangiocrine RELN and enriched in binding motifs of erythroblast transformation specific (ETS) variant (ETV) transcription factors. We report the in vivo molecular characterization of human cardiac lymphatics and provide a valuable resource to understand fetal heart development.

Patient Preferences for Adjuvant Treatment in Muscle-Invasive Urothelial Carcinoma: A Multi-Country Discrete Choice Experiment.

Purpose: The evolving treatment landscape in muscle-invasive urothelial carcinoma creates challenges for clinicians and patients in selecting the most appropriate therapy. Here, we aimed to understand adjuvant treatment preferences among patients with muscle-invasive urothelial carcinoma who underwent radical resection, including tradeoffs between efficacy outcomes and toxicity risks. Patients and Methods: An observational, cross-sectional study utilizing a discrete choice experiment was conducted across the United States, United Kingdom, Canada, France, and Germany via a web-based survey. Patients ≥18 years of age who self-reported as having been diagnosed with muscle-invasive urothelial carcinoma were included. Patients indicated their preferences between hypothetical treatment profiles varying in eight attributes relating to efficacy, regimen, and side effects. Preference weights were estimated using hierarchical Bayesian logistic regression; relative attribute importance estimates were calculated. Results: Overall, 207 patients were included (age ≥56 years, 65.7%; male, 54.1%). Patients chose adjuvant treatment 91.2% of the time vs no treatment. Prolonging overall survival from 25 to 78 months was most important, followed by reducing serious side effect risks. Increasing disease-free survival from 12 to 24 months was more important than decreasing risks of fatigue from 54% to 15% and nausea from 53% to 7%. Treatment with the shortest dosing regimen was more important for patients who received neoadjuvant chemotherapy vs patients who did not receive neoadjuvant chemotherapy; prolonging overall survival was more important than reducing the risk of a serious side effect in non-US patients; the opposite was found in the United States. Conclusion: Patients with muscle-invasive urothelial carcinoma who underwent radical resection preferred adjuvant treatment over no treatment regardless of side effects. Patients prioritized overall survival improvements followed by a reduced side effect profile.

Assessing the utility of molecular diagnostic classification for cancers of unknown primary.

BACKGROUND: Roughly 5% of metastatic cancers present with uncertain origin, for which molecular classification could influence subsequent management; however, prior studies of molecular diagnostic classifiers have reported mixed results with regard to clinical impact. In this retrospective study, we evaluated the utility of a novel molecular diagnostic classifier by assessing theoretical changes in treatment and additional testing recommendations from oncologists before and after the review of classifier predictions. METHODS: We retrospectively analyzed de-identified records from 289 patients with a consensus diagnosis of cancer of uncertain/unknown primary (CUP). Two (or three, if adjudication was required) independent oncologists separately reviewed patient clinical information to determine the course of treatment before they reviewed results from the molecular diagnostic classifier and subsequently evaluated whether the predicted diagnosis would alter their treatment plan. RESULTS: Results from the molecular diagnostic classifier changed the consensus oncologist-reported treatment recommendations for 235 out of 289 patients (81.3%). At the level of individual oncologist reviews (n = 414), 64.7% (n = 268) of treatment recommendations were based on CUP guidelines prior to review of results from the molecular diagnostic classifier. After seeing classifier results, 98.1% (n = 207) of the reviews, where treatment was specified (n = 211), were guided by the tissue of origin-specific guidelines. Overall, 89.9% of the 414 total reviews either expressed strong agreement (n = 242) or agreement (n = 130) that the molecular diagnostic classifier result increased confidence in selecting the most appropriate treatment regimen. CONCLUSIONS: A retrospective review of CUP cases demonstrates that a novel molecular diagnostic classifier could affect treatment in the majority of patients, supporting its clinical utility. Further studies are needed to prospectively evaluate whether the use of molecular diagnostic classifiers improves clinical outcomes in CUP patients.

Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors.

BACKGROUND: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Relationship Between Pretreatment Body Composition and Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma Receiving First-Line Ipilimumab Plus Nivolumab.

INTRODUCTION: Biomarkers are needed to identify patients with metastatic renal cell carcinoma (mRCC) most likely to benefit from immune checkpoint inhibitors. We examined associations between radiographically assessed body composition (BC) variables and body mass index (BMI) with clinical outcomes for patients with mRCC receiving first-line ipilimumab + nivolumab (ipi/nivo). PATIENTS AND METHODS: We retrospectively reviewed all patients with mRCC treated with first-line ipi/nivo at one institution before June 1, 2021 with an analyzable baseline computed tomography (CT) scan. BC variables (skeletal muscle index [SMI], subcutaneous adipose tissue index [SATI], and visceral adipose tissue index [VATI]) were measured using baseline CT scans. Relationships between BC variables and clinical outcomes were examined using Cox proportional hazard regression models. RESULTS: Ninety-nine patients were analyzed (74% male, 64% overweight/obese, 75% low SMI). Controlling for age, IMDC risk, and sex (for BMI analyses), high vs. low SMI (HR=2.433, CI: 1.397-4.238, P=.0017), high vs. low SATI (HR=1.641, CI: 1.023-2.632, P=.0398), and obese BMI (≥ 30 kg/m2) vs. normal/overweight BMI (<30 kg/m2) (HR=1.859, CI: 1.156-2.989, P=.0105) were significantly associated with progression-free survival (PFS). Median overall survival (OS) for low SMI patients was higher (42.74 months, CI: 26.84, NR) than median OS for high SMI patients (27.01 months, CI: 15.28, NR) (adjusted HR=1.728, CI: 0.909-3.285, P=.0952). No BC variables were significantly associated with OS or objective response rate. CONCLUSIONS: Low SMI and low SATI were associated with significantly better PFS for patients with mRCC receiving first-line ipi/nivo. Radiographic BC variables may be useful prognostic biomarkers in this setting.

Feasibility of home-based exercise training in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Home-based training increases accessibility to exercise and mitigates the side effects of hormone therapy for prostate cancer (PC). However, it is unknown if men with more advanced disease are willing to partake in such interventions. PURPOSE: To determine the feasibility of a home-based exercise intervention in men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: mCRPC patients on androgen receptor signaling inhibitors (ARSI) were prescribed a 12-week, home-based exercise intervention using resistance bands and walking. Feasibility was assessed using recruitment, retention, adherence, and outcome capture. Physiological changes and patient reported outcomes were assessed before and after the intervention. RESULTS: Of the 62 referrals, 47 were eligible with 22 men performing baseline testing (47% recruitment rate) and 16 completing the intervention (73% retention). Task completion was >86% for all physiological tests. Walking adherence was 80% and resistance training was 63%, the latter falling short of the study target (75%). Training increased thigh muscle cross-sectional area by 22%, time to exhaustion by 19% (both p < 0.05) and peak oxygen uptake by 6% (p = 0.057). Improvements in short physical performance battery scores and 400 m walk demonstrated moderate effect sizes that did not reach significance. CONCLUSIONS: Home-based exercise is feasible during ARSI treatment for mCRPC. Greater endurance capacity and localized hypertrophy appear as the primary improvements following training. These preliminary findings suggest home-based training may increase exercise accessibility, with important lessons that will inform subsequent trials investigating the efficacy of home-based exercise interventions during mCRPC.

Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration.

The epicardium, a mesothelial cell tissue that encompasses vertebrate hearts, supports heart regeneration after injury through paracrine effects and as a source of multipotent progenitors. However, the progenitor state in the adult epicardium has yet to be defined. Through single-cell RNA-sequencing of isolated epicardial cells from uninjured and regenerating adult zebrafish hearts, we define the epithelial and mesenchymal subsets of the epicardium. We further identify a transiently activated epicardial progenitor cell (aEPC) subpopulation marked by ptx3a and col12a1b expression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra+hapln1a+ mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgfß pathway. Conditional ablation of aEPCs blocks heart regeneration through reduced nrg1 expression and mesenchymal cell number. Our findings identify a transient progenitor population of the adult epicardium that is indispensable for heart regeneration and highlight it as a potential target for enhancing cardiac repair.

The Rearing of Maternal-Fetal Surgery: The Maturation of a Field from Conception to Adulthood.

Maternal-fetal surgery is fraught with inherent controversy from within the medical community and general public. Despite these challenges, the field of maternal-fetal surgery evolved into an international enterprise. Carefully nurtured by pioneers with foresight and resilience, the field navigated ethical dilemmas with rigorous scientific methodology, collaboration, transparency, and accordance. These central pillars are consistent throughout the brief but momentous history of maternal-fetal surgery, serving as the catalyst for its success. The maturation of fetal intervention is an exemplar of technological innovation propelling clinical innovation, as well as a celebration of mastering the delicate balance between caution and optimism.

Intramyocardial Injection for the Study of Cardiac Lymphatic Function in Zebrafish.

Zebrafish have proved to be an important model for studying cardiovascular formation and function during postembryonic development and regeneration. The present protocol describes a method for injecting fluorescent tracers into the zebrafish myocardium to study interstitial fluid and debris uptake into cardiac lymphatic vessels. To do so, microspheres (200 nm diameter) and quantum dots (<10 nm diameter) are introduced into the myocardium of live zebrafish, which can be tracked using ex vivo confocal microscopy. These tracers are then tracked intermittently over several hours to follow clearance from the myocardium into cardiac lymphatic vessels. Quantum dots are transported through cardiac lymphatic vessels away from the heart, while larger microspheres remain at the injection site for over three weeks. This method of intramyocardial injection can be extended to other uses, including the injection of encapsulated MS or hydrogels to locally release cells, proteins, or compounds of interest to a targeted region of the heart.

The Association between a Decrease in On-Treatment Neutrophil-to-Eosinophil Ratio (NER) at Week 6 after Ipilimumab Plus Nivolumab Initiation and Improved Clinical Outcomes in Metastatic Renal Cell Carcinoma.

A lower baseline neutrophil-to-eosinophil ratio (NER) has been associated with improved responses to immune checkpoint inhibitors (ICI)-treated metastatic renal cell carcinoma (mRCC). This study investigated the decrease in NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. A retrospective study of ipi/nivo-treated mRCC at two US academic cancer centers was conducted. A landmark analysis at week 6 was performed to assess the association between the change in NER and clinical responses (progression-free survival (PFS)/overall survival (OS)). Week 6 NER was modeled as a continuous variable, after log transformation (Ln NER), and a categorical variable by percent change. There were 150 mRCC patients included: 78% had clear cell histology, and 78% were IMDC intermediate/poor risk. In multivariable regression analysis, every decrease of 1 unit of Ln NER at week 6 was associated with improved PFS (adjusted hazard ratio (AHR): 0.78, p-value:0.005) and OS (AHR: 0.67, p-value: 0.002). When NER was modeled by percent change, decreased NER > 50% was associated with improved PFS (AHR: 0.55, p-value: 0.03) and OS (AHR: 0.37, p-value: 0.02). The decrease in week 6 NER was associated with improved PFS/OS in ipi/nivo-treated mRCC. Prospective studies are warranted to validate NER change as a biomarker to predict ICI responses.