Optimization of wet granulation process for manufacturing Rivaroxban generic immediate-release tablets using PBPK modeling and simulations.

Granulation is the critical process for the pharmaceutical development of poorly water-soluble drug products. Poorly formulated products have challenges in dissolution and bioequivalence studies. Rivaroxaban (RXB) is a poorly soluble drug and has 66% fasting bioavailability at a high strength of 20 mg. Establishing the bioequivalence between test and reference products for high strength requires comparative dissolution profiles and bioequivalence. Improper granulation products and the rest of the batches failed in virtual bioequivalence. The present study provided insight into the optimization of the wet granulation process for manufacturing RXB generic immediate-release tablets using PBPK modeling and simulations. Furthermore, PBPK models are not only useful for formulation optimization but also for process optimization during pharmaceutical product development. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00249-6.

Fevogrit, a polyherbal medicine, mitigates endotoxin (lipopolysaccharide)-induced fever in Wistar rats by regulating pro-inflammatory cytokine levels.

BACKGROUND: Fever is characterized by an upregulation of the thermoregulatory set-point after the body encounters any pathological challenge. It is accompanied by uncomfortable sickness behaviors and may be harmful in patients with other comorbidities. We have explored the impact of an Ayurvedic medicine, Fevogrit, in an endotoxin (lipopolysaccharide)-induced fever model in Wistar rats. METHODS: Active phytoconstituents of Fevogrit were identified and quantified using ultra-high-performance liquid chromatography (UHPLC) platform. For the in-vivo study, fever was induced in male Wistar rats by the intraperitoneal administration of lipopolysaccharide (LPS), obtained from Escherichia coli. The animals were allocated to normal control, disease control, Paracetamol treated and Fevogrit treated groups. The rectal temperature of animals was recorded at different time points using a digital thermometer. At the 6-h time point, levels of TNF-α, IL-1ß and IL-6 cytokines were analyzed in serum. Additionally, the mRNA expression of these cytokines was determined in hypothalamus, 24 h post-LPS administration. RESULTS: UHPLC analysis of Fevogrit revealed the presence of picroside I, picroside II, vanillic acid, cinnamic acid, magnoflorine and cordifolioside A, as bioactive constituents with known anti-inflammatory properties. Fevogrit treatment efficiently reduces the LPS-induced rise in the rectal temperature of animals. The levels and gene expression of TNF-α, IL-1ß and IL-6 in serum and hypothalamus, respectively, was also significantly reduced by Fevogrit treatment. CONCLUSION: The findings of the study demonstrated that Fevogrit can suppress LPS-induced fever by inhibiting peripheral or central inflammatory signaling pathways and could well be a viable treatment for infection-induced increase in body temperatures.

Solitary Pancreatic Metastasis from an Ovarian Carcinoma: A Diagnostic Perplexity.

Ovarian cancer presenting as an isolated pancreatic metastasis after years of treatment is extremely rare. Most such patients are easily misdiagnosed as a case of primary pancreatic cancer. We herein describe a unique case of posttreatment high-grade serous papillary ovarian carcinoma metastasizing to the pancreas that mimicked primary pancreatic cancer and caused a diagnostic dilemma. The approach to such a case, pathogenesis, differential diagnosis, management, and a brief literature review is also presented.

Eosin Y-catalyzed reductive homocoupling of para-quinone methides under visible-light.

In this manuscript, we demonstrate a visible-light driven dimerization of para-quinone methides using eosin Y catalyst via a reductive homocoupling process. This mild and operationally simple methodology was found to be compatible with a variety of differently substituted para-quinone methides and a broad range of tetra-arylethane derivatives were obtained in moderate to good yields (47%-87%).

Variations in anxiety and emotional support among first-year college students across different learning modes (distance and face-to-face) during COVID-19.

College students with more emotional support experience lower levels of anxiety and other psychosocial and behavioral problems. During the COVID-19 pandemic, the emotional well-being of college students was additionally challenged by an abrupt shift to distance learning followed by a return to face-to-face classes. In this exploratory study, we compared the levels of perceived emotional support and anxiety among incoming first-year undergraduate students, prior to starting classes, which included different learning modes in five semesters of instruction from 2021-2023 (three distance semesters and two face-to-face semesters). Data from 8659 undergraduate students were extracted from a Mexican state university database, corresponding to students' responses collected during new student orientation week. Participants were students in the arts and humanities (9.7%), social and legal sciences (38%), life and health sciences (28.9%), and engineering and architecture (23.4%). Anxiety levels were measured with the GAD-7 scale, and emotional support was measured using a subscale of the PERACT-R (To go through with resilience) inventory. Comparisons of emotional support and anxiety scores among semesters revealed highly significant differences with small effect sizes. Anxiety levels increased significantly with mean average of 6.65 SD(5.52) during the baseline measure to the highest in 2022-2 to 7.53 SD(5.3) and Emotional Support decreased systematically each semester from baseline mean = 8.03 SD(2.0) to the lowest 7.52 SD(1.8) in 2022-2. The results show that a return to face-to-face classes was associated with increased anxiety levels, whereas levels of emotional support systematically decreased across the five semesters. MANOVA analysis revealed significant differences in anxiety and emotional support scores between semesters, with peaks during the learning mode semester that students returned to face-to-face classes after distance learning even after adjusting for gender. Given that the effect of emotional support on anxiety may be related to success in future educational and professional activities, it is important to develop interventions to restore and increase college students' emotional support levels and develop anxiety management strategies.

Head and Neck Cancer Patient Population, Management, and Oncologic Outcomes from the COVID-19 Pandemic.

The COVID-19 pandemic precipitated drastic changes in cancer care. Its impact on the U.S. head and neck cancer population has yet to be fully understood. This study aims to understand the impact of pandemic-related changes on the head and neck cancer population. An observational study of head and neck cancer patients at a single institution during the spring of 2020 and 2019 was performed. Clinical characteristics and survival outcomes were analyzed. In 2020, 54 head and neck cancer patients were evaluated in the department of radiation oncology vs. 74 patients seen in 2019; 42% of the patients were female in 2019 versus 24% in 2020 (p = 0.036). The median follow-up time was 19.4 and 31 months for 2020 and 2019, respectively. After adjusting for stage, the relapse-free survival probability at 6 and 12 months was 79% and 69% in 2020 vs. 96% and 89% in 2019, respectively (p = 0.036). There was no significant difference in the overall survival, with 94% and 89% in 2020 and 2019, respectively (p = 0.61). Twenty-one percent of patients received induction chemotherapy in 2020 versus 5% in 2019 (p = 0.011); significantly more treatment incompletions occurred in 2020, 9% vs. 0% in 2019 (p = 0.012). Moreover, the stage-adjusted RFS differed between cohorts, suggesting head and neck cancer patients seen during the initial wave of COVID-19 may experience worse oncologic outcomes.

Renogrit attenuates Vancomycin-induced nephrotoxicity in human renal spheroids and in Sprague-Dawley rats by regulating kidney injury biomarkers and creatinine/urea clearance.

Vancomycin, is widely used against methicillin-resistant bacterial infections. However, Vancomycin accumulation causes nephrotoxicity which leads to an impairment in the filtration mechanisms of kidney. Traditional herbal medicines hold potential for treatment of drug-induced nephrotoxicity. Herein, we investigated protective properties of plant-based medicine Renogrit against Vancomycin-induced kidney injury. Phytometabolite analysis of Renogrit was performed by UHPLC. Spheroids formed from human proximal tubular cell (HK-2) were used for in vitro evaluation of Vancomycin-induced alterations in cell viability, P-gp functionality, NAG, KIM-1 levels, and mRNA expression of NGAL and MMP-7. The in vivo efficacy of Renogrit against Vancomycin-induced nephrotoxicity was further evaluated in Sprague-Dawley (SD) rats by measurement of BUN, serum creatinine, and their respective clearances. Moreover, eGFR, kidney-to-body weight ratio, GSH/GSSG ratio, KIM-1, NAG levels and mRNA expression of KIM-1 and osteopontin were also analyzed. Changes in histopathology of kidney and hematological parameters were also observed. Renogrit treatment led to an increase in cell viability, normalization of P-gp functionality, decrease in levels of NAG, KIM-1, and reduction in mRNA expression of NGAL and MMP-7. In Vancomycin-challenged SD rats, Renogrit treatment normalized altered kidney functions, histological, and hematological parameters. Our findings revealed that Renogrit holds a clinico-therapeutic potential for alleviating Vancomycin-associated nephrotoxicity.

Visible-light-mediated radical reactions of indoles with para-quinone methides using eosin Y as an organophotoredox catalyst.

Herein, we demonstrate a redox-neutral, operationally simple, atom-economical, and additive-free approach for the synthesis of indolyl diarylmethanes via a radical reaction of indoles with para-quinone methides (p-QMs) under visible-light mediated reaction conditions using eosin Y as an organophotoredox catalyst. This protocol was found to be compatible with a wide range of differently substituted p-QMs and indoles in organic as well as in aqueous media under visible-light irradiation, furnishing the desired products in good to excellent yields.

Acid-catalysed intramolecular Friedel-Crafts annulation of hetero-atom-functionalized para-quinone methides: access to O-, S- and N-based heterocycles.

We describe here an acid-mediated one-pot approach to access substituted xanthene and thioxanthane derivatives from ortho-heteroaryl phenyl-substituted para-quinone methides via 1,6 intramolecular arylation. The scope of this work was further elaborated to the synthesis of 10H-indolo[1,2-a]indole-based heterocyclic systems using indole based para-quinone methides.

Divya-WeightGo combined with moderate aerobic exercise remediates adiposopathy, insulin resistance, serum biomarkers, and hepatic lipid accumulation in high-fat diet-induced obese mice.

Obesity has become an unprecedented epidemic worldwide owing to a prolonged imbalance between energy intake and expenditure. Available therapies primarily suppress energy intake but often fail to produce sustained fat loss, necessitating a more efficacious strategy to combat obesity. In this study, a polyherbal formulation, Divya-WeightGo (DWG) has been investigated for its anti-obesity activity using in-vitro and in-vivo assays. Ultra-high performance liquid chromatography (UHPLC) analysis revealed the presence of phytocompounds including gallic acid, methyl gallate, corilagin, ellagic acid, pentagalloyl glucose, withaferin A and hydroxycitric acid, proven to aid in weight loss. The exposure of 3T3-L1 cells to DWG at cytosafe concentrations inhibited lipid and triglyceride accumulation and downregulated the expression of several adipogenic and lipogenic markers like PPARy, C/EBPα, C/EBPß, SREBP-1c, FASN and DGAT1. DWG reduced LPS-induced pro-inflammatory cytokine release and NF-κB activity in THP-1 cells. The in-vivo anti-obesity activity of DWG, both alone and in combination with moderate aerobic exercise, was assessed in a high fat diet-induced obese mouse model. DWG mitigated the obesity associated increased body weight gain, feed efficiency ratio, glucose intolerance, diminished insulin sensitivity, dyslipidemia, altered liver function profile, lipid accumulation and adiposopathy in obese mice, alone as well as in combination intervention, with better efficacy in the combination approach. Thus, the findings of this study suggest that DWG could be a promising therapeutic avenue to treat obesity through attenuation of lipid and fat accumulation in liver and adipose tissues and could be utilized as an adjunct with lifestyle interventions to combat obesity and associated complications.

Construction of heterocycle-fused tetrahydrocarbazoles through a formal [3 + 3]-annulation of 2-indolylmethanols with para-quinone methides.

A metal-free approach for the synthesis of tetrahydroindolo[2,3-b]carbazoles has been developed through an acid-mediated one-pot [3 + 3]-annulation of 2-indolylmethanols and 3-indolyl-substituted para-quinone methides. This operationally simple protocol allowed us to prepare many unsymmetrical tetrahydroindolo[2,3-b]carbazoles in good to excellent yields with a broad substrate scope. This concept was also elaborated to the synthesis of tetrahydrothieno[2,3-b]carbazoles and tetrahydrothieno[3,2-b]carbazoles.

Clinical and Social Outcomes of Cochlear Implantation in Older Prelinguals.

BACKGROUND AND OBJECTIVES: Cochlear implantation in late implanted prelinguals necessitates a complex decision-making process for clinicians and patients due to the uncertainty of achieving adequate benefit in auditory and speech perception. This study longitudinally evaluated clinical and social outcomes of prelingually deaf children with implantation in their late childhood. Subjects and. METHODS: A total of 113 (49 females and 64 males) participants, with an age range of 5-15 years, were assessed for the pre-implant parameters such as hearing loss etiology, aided responses, anatomical aspects, and psychological evaluation. The Category of Auditory Performance, Speech Awareness Threshold, Speech Reception Threshold, and Speech Discrimination Score were administered to assess the patient's auditory skills. Further, the Speech Intelligibility Rating scale was administered to evaluate the patient's speech intelligibility at 3, 6, 9, 12, 18, and 24 months post-surgery. Subjectively perceived benefits were evaluated using the satisfaction rating scale and a questionnaire. RESULTS: The statistical results showed a significant impact of cochlear implantation in all domains. Positive impact and improvement post-implantation were noted in all the spheres, including auditory, linguistic, social, and educational. CONCLUSIONS: The study highlighted that the outcomes of a cochlear implant at a later age might not parallel with the implantation at a younger age. However, this still provides measurable benefits even after a longer period of auditory deprivation.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases.

PURPOSE: Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. METHODS AND MATERIALS: Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. RESULTS: Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P = .03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P < 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. CONCLUSIONS: The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

High Failure Rates in Young Nonsmoker Nondrinkers With Squamous Cell Carcinoma of the Oral Tongue.

OBJECTIVE(S): There has been a disproportionate increase in the incidence of young patients with squamous cell carcinoma of the oral tongue (SCCOT). The purpose of this study was to compare young patients to older patients with SCCOT without prior drinking or smoking history as this population is poorly characterized in the literature. METHODS: A retrospective review of patients presenting to our institution with SCCOT was performed. The clinical and pathologic characteristics, as well as, outcomes were compared between younger patients (age ≤45) and older patients (age >45). Outcome analysis was performed using Kaplan Meier method. Multivariable Cox proportional hazard models were performed for age and stage. RESULTS: Eighty-two patients (38 young, 44 old) were included in this study. Median follow-up was 29.4 months. When compared to the older cohort (age >45), the younger cohort (age ≤45) demonstrated lower rates of 5-year locoregional control (LC) (79.6% vs. 52.5%, p = 0.043) and distant metastasis-free survival (88.1% vs. 61.8%, p = 0.006). Both cohorts demonstrated similar overall survival rates (55.5% vs. 58.1%) and disease-specific survival (66.2% vs. 58.1%). Of patients experiencing locoregional failure with available radiation therapy plans and PET scans in younger cohorts (n = 7), 100% demonstrated in-field failures. Multivariable Cox proportional hazards demonstrated age was an independent predictor of DMFS (p = 0.004) and the advanced stage was a predictor of DSS (p = 0.03). CONCLUSIONS: Young, nondrinker, nonsmokers with SCCOT demonstrate high rates of locoregional recurrence, distant metastasis, and in-field failures. Future studies are warranted to determine underlying mechanisms driving pathogenesis in this unique cohort. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1110-1121, 2023.

Perspectives of undergraduate medical students regarding competency-based curriculum.

Background The competency-based undergraduate medical curriculum has a number of new elements. Few authors have attempted to understand the students' viewpoints on the curriculum. We assessed undergraduate students perspectives and ratings about various elements after 2 years of implementation of the curriculum. Methods We included 240 students (2019 and 2020 admission). An invitation letter-cum-information sheet was sent to all the students by email informing them about the study, keeping their identity confidential and the implied consent. A validated questionnaire based on a 5-point Likert scale including 35 closed-ended questions eliciting the students' perception on various elements of the new curriculum and a rating scale from 1 to 5 was designed. Data collection was done using Google forms. Results Of the 240 respondents, 192 (80%) had positive perceptions for the Foundation Course, Attitude, Ethics and Communication skills, Early Clinical Exposure and Community Health Visits. Integrated Teaching, Small Group Teaching and Assessments were viewed less positively (62.9%-75%) and Self-directed Learning received the lowest positive responses (57%-58%). For training as a doctor, the elements considered most valuable were Early Clinical Exposure (70.4%) and Community Health Visits (70.4%) while the least were Logbooks (35.5%) and Reflections (34.2%). Conclusions Students found Early Clinical Exposure and Community Health Visits the most valuable elements whereas Self-directed Learning, Logbooks and Reflections were rated as the least useful.

Management of Older Adults with Locally Advanced Head and Neck Cancer.

Thirty percent of patients with head and neck squamous cell carcinoma (HNSCC) are at least 70 years of age. This number continues to rise as life expectancy continues to increase. Still, older adults with HNSCC remain underrepresented in clinical trials, resulting in ambiguity on optimal management. Older adults are a complex patient population, often requiring increased support due to issues relating to functional and performance status, medical comorbidities, and medication management. Furthermore, in older adults with HNSCC, many of these conditions are independently associated with increased toxicity and worse outcomes. Toxicity in the older adult remains difficult to predict and to understand, and as treatment decisions are based on treatment tolerability, it is essential to understand the toxicities and how to minimize them. Novel predictive scores are being developed specifically for older adults with HNSCC to understand toxicity and to assist in personalized treatment decisions. There are clinical trials presently underway that are investigating shortened radiation courses and novel, less toxic systemic treatments in this population. In the forthcoming sections, we provide a detailed overview of the clinical data, treatment paradigms, and considerations in this population. This review provides a comprehensive overview of existing clinical data and clinical considerations in the older adult head and neck cancer population. Additionally, we provide a detailed overview of pertinent current and ongoing clinical trials, as well as future areas for investigation.

Objective Comparison of Benefits Derived From Contralateral Routing of Signal Hearing Aid and Bone Conduction Device in Noisy Surroundings in Patients With Single-Sided Deafness.

BACKGROUND AND OBJECTIVES: Single-sided deafness (SSD) leads to non-participation of the diseased ear in generating adequate auditory input, which results in poor speech discrimination in noisy surroundings. The present study objectively compared the audiological benefits rendered by contralateral routing of signal (CROS) hearing aid and bone conduction device (BCD) in patients with SSD >70 dB HL using the modified hearing in noise test (HINT). MATERIALS AND METHODS: Patients with SSD >70 dB HL in poor and clinically normal hearing in the better ear were enrolled. Patients aged <18 or >70 years, with a history of neurological insult or ear infection in the last 3 months, mental retardation, psychiatric or developmental disorders, and diabetes were excluded. Modified HINT was performed with the affected ear unaided, aided with CROS hearing aid, and with BCD, generating three groups. Noise signal was presented at a fixed intensity of 65 dB at the neutral position in the center and speech signal was presented to either ear sequentially. The test was repeated with the speech signal fixed at the neutral position and the noise signal presented to either ear. RESULTS: BCD led to a better signal-to-noise ratio (SNR) than CROS hearing aid in all situations except when noise was centralized and speech was presented to the affected ear. CONCLUSIONS: A benefit was observed when auditory rehabilitation was used for the affected ear as demonstrated by better SNR scores. The results showed that BCD performed better than CROS hearing aid.

Bias in Patient Experience Scores in Radiation Oncology: A Multicenter Retrospective Analysis.

PURPOSE: Patient experience scores are increasingly important in measuring quality of care and determining reimbursement from payers, including the Hospital Value-Based Purchasing Program and the Radiation Oncology Model. However, the role of bias in patient experience scores in oncology is unknown, raising the possibility that such payment structures may inadvertently perpetuate bias in reimbursement. Therefore, the authors characterized patient-, physician-, and practice-level predictors of patient experience scores in patients undergoing radiation therapy. METHODS: The authors retrospectively reviewed patient experience surveys for radiation oncology patients treated at two large multisite academic cancer centers. The outcome was responses on four survey questions. Covariates included self-reported patient demographics, physician characteristics, practice setting characteristics, and wait-time rating linked to each survey. Multivariable ordinal regression models were fitted to identify predictors of receiving a higher score on each of the survey questions. RESULTS: In total, 2,868 patients completed surveys and were included in the analysis. Patient experience scores were generally high, with >90% of respondents answering 5 of 5 on the four survey items. Physician gender was not associated with any measured patient experience outcomes (P > 0.40 for all). Independent predictors of higher score included a wait-time experience classified as "good" compared with "not good" (q < .001 for all). CONCLUSIONS: Oncology practices aiming to improve patient experience scores may wish to focus their attention on improving wait times for patients. Although a difference in patient experience scores on the basis of physician gender was not observed, such bias is likely to be complex, and further research is needed to characterize its effects.

Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study.

BACKGROUND: Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. METHODS: RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. RESULTS: Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. CONCLUSIONS: Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.