Global mosquito observations dashboard (GMOD): creating a user-friendly web interface fueled by citizen science to monitor invasive and vector mosquitoes.

BACKGROUND: Mosquitoes and the diseases they transmit pose a significant public health threat worldwide, causing more fatalities than any other animal. To effectively combat this issue, there is a need for increased public awareness and mosquito control. However, traditional surveillance programs are time-consuming, expensive, and lack scalability. Fortunately, the widespread availability of mobile devices with high-resolution cameras presents a unique opportunity for mosquito surveillance. In response to this, the Global Mosquito Observations Dashboard (GMOD) was developed as a free, public platform to improve the detection and monitoring of invasive and vector mosquitoes through citizen science participation worldwide. METHODS: GMOD is an interactive web interface that collects and displays mosquito observation and habitat data supplied by four datastreams with data generated by citizen scientists worldwide. By providing information on the locations and times of observations, the platform enables the visualization of mosquito population trends and ranges. It also serves as an educational resource, encouraging collaboration and data sharing. The data acquired and displayed on GMOD is freely available in multiple formats and can be accessed from any device with an internet connection. RESULTS: Since its launch less than a year ago, GMOD has already proven its value. It has successfully integrated and processed large volumes of real-time data (~ 300,000 observations), offering valuable and actionable insights into mosquito species prevalence, abundance, and potential distributions, as well as engaging citizens in community-based surveillance programs. CONCLUSIONS: GMOD is a cloud-based platform that provides open access to mosquito vector data obtained from citizen science programs. Its user-friendly interface and data filters make it valuable for researchers, mosquito control personnel, and other stakeholders. With its expanding data resources and the potential for machine learning integration, GMOD is poised to support public health initiatives aimed at reducing the spread of mosquito-borne diseases in a cost-effective manner, particularly in regions where traditional surveillance methods are limited. GMOD is continually evolving, with ongoing development of powerful artificial intelligence algorithms to identify mosquito species and other features from submitted data. The future of citizen science holds great promise, and GMOD stands as an exciting initiative in this field.

Vitreoretinal Findings in Nonarteritic Ischemic Optic Neuropathy.

BACKGROUND: Although nonarteritic anterior ischemic optic neuropathy (NAION) is considered a disorder that primarily affects the optic nerve head, optical coherence tomography (OCT) shows peripapillary and foveal subretinal fluid associated with optic disc swelling from NAION. We sought to further evaluate retinal and vitreous changes in patients with NAION. METHODS: Patients diagnosed with NAION at the New England Eye Center between 2013 and 2017 were evaluated using OCT. The presence and distribution of subretinal fluid was analyzed. Evidence of other vitreoretinal changes, including vitreopapillary traction (VPT) and the presence of hyperreflective dots (HRD), were also determined. RESULTS: Twenty-five eyes from 20 patients who presented within 4 weeks of symptom onset were assessed. Peripapillary subretinal fluid was seen in 16 eyes (64%). Of those eyes, the subretinal fluid extended into the macula in 4 eyes (16%). Visual acuity improved in 2 of 4 eyes after subfoveal fluid resolution. Intraretinal cysts located in the peripapillary region were seen in 8 eyes (32%), HRD were noted in 11 (44.0%). There was no evidence of VPT. CONCLUSIONS: A substantial number of patients with NAION have subretinal fluid on OCT, consistent with prior reports. Resolution of subfoveal fluid may result in some recovery of visual acuity. Other retinal changes, such as intraretinal cysts and HRD, are present but have unclear implications. We did not find evidence of a primary role of VPT in the pathophysiology of NAION.

Multiple Cranial Neuropathies as the Initial Presentation of Primary Ductal Adenocarcinoma of the Lacrimal Gland.

Primary ductal adenocarcinoma of the lacrimal gland is a rare, aggressive malignancy that clinically and histologically resembles salivary duct carcinoma. Similar to other malignant epithelial lacrimal gland tumors, ductal adenocarcinoma typically presents with unilateral proptosis, pain, upper eyelid swelling, palpable mass, diplopia, ptosis, and blurred or decreased vision. Rarely, primary malignant epithelial lacrimal gland tumors may first present with multiple cranial neuropathies due to occult spread to the cavernous sinus, as in this case. With such a vast differential diagnosis, a practical yet systematic approach to multiple cranial neuropathies, as guided by clinical history, exam, and neuroimaging, allows for a more targeted diagnostic evaluation, especially when multiple diagnostic tests and interventions return unrevealing. A repeat biopsy or complete excision of the lacrimal gland may be necessary to yield the correct diagnosis.

FGF21 prevents low-protein diet-induced renal inflammation in aged mice.

Low-protein (LP) diets extend lifespan through a comprehensive improvement in metabolic health across multiple tissues and organs. Many of these metabolic responses to protein restriction are secondary to transcriptional activation and release of FGF21 from the liver. However, the effects of an LP diet on the kidney in the context of aging has not been examined. Therefore, the goal of the current study was to investigate the impact of chronic consumption of an LP diet on the kidney in aging mice lacking FGF21. Wild-type (WT; C57BL/6J) and FGF21 knockout (KO) mice were fed a normal protein diet (20% casein) or an LP (5% casein) diet ad libitum from 3 to 22 mo of age. The LP diet led to a decrease in kidney weight and urinary albumin-to-creatinine ratio in both WT and FGF21 KO mice. Although the LP diet produced only mild fibrosis and infiltration of leukocytes in WT kidneys, the effects were significantly exacerbated by the absence of FGF21. Accordingly, transcriptomic analysis showed that inflammation-related pathways were significantly enriched and upregulated in response to LP diet in FGF21 KO mice but not WT mice. Collectively, these data demonstrate that the LP diet negatively affected the kidney during aging, but in the absence of FGF21, the LP diet-induced renal damage and inflammation were significantly worse, indicating a protective role of FGF21 in the kidney.NEW & NOTEWORTHY Long-term protein restriction is not advantageous for an otherwise healthy, aging kidney, as it facilitates the development of renal tubular injury and inflammatory cell infiltration. We provide evidence using FGF21 knockout animals that FGF21 is essential to counteract the renal injury and inflammation during aging on a low-protein diet.

QUANTITATIVE TOPOGRAPHIC CURVATURE MAPS OF THE POSTERIOR EYE UTILIZING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Deformations of the retina such as staphylomas in myopia or scleral flattening in high intracranial pressure can be challenging to quantify with en face imaging. We describe an optical coherence tomography-based method for the generation of quantitative posterior eye topography maps in normal and pathologic eyes. METHODS: Using "whole eye" optical coherence tomography, we corrected for subjects' optical distortions to generate spatially accurate posterior eye optical coherence tomography volumes and created local curvature (KM, mm-1) topography maps for each consented subject. We imaged nine subjects, three normal, two with myopic degeneration, and four with papilledema including one that was imaged longitudinally. RESULTS: Normal subjects mean temporal KM was 0.0923 mm-1, nasal KM was 0.0927 mm-1, and KM local variability was 0.0162 mm-1. In myopic degeneration, subjects KM local variability was higher at 0.0836 mm-1. In papilledema subjects nasal KM was flatter compared with temporal KM (0.0709 vs. 0.0885 mm-1). Mean intrasession KM repeatability for all subjects was 0.0036 mm-1. CONCLUSION: We have developed an optical coherence tomography based method for quantitative posterior eye topography that offers the ability to analyze local curvature with micron scale resolution and offers the potential to help clinicians and researchers characterize subtle, local retinal deformations earlier in patients and follow their development over time.

The Evolving Role of Rituximab in Adult Minimal Change Glomerulopathy.

BACKGROUND: Minimal-change glomerulopathy is defined histologically by the presence of normal glomeruli on light microscopy and diffuse podocyte effacement on electron microscopy. Although effective in children, corticosteroid treatment in adults is more variable and time to response can be prolonged. Data to support rituximab use in adults with corticosteroid-dependent or resistant minimal-change glomerulopathy are limited. Here, we describe the clinical course of adults with corticosteroid-dependent or -resistant minimal-change glomerulopathy who received rituximab. METHODS: Demographic and clinical data were collected and analyzed from all adult patients with native kidney, biopsy-proven, minimal-change glomerulopathy who were administered rituximab between 2009 and 2014 and cared for at the UNC Kidney Center. RESULTS: Ten patients with corticosteroid-resistant (n = 5) or corticosteroid-dependent (n = 5) idiopathic minimal-change glomerulopathy were treated with rituximab between 2009 and 2014. Rituximab treatment induced remission in all 10 patients with a median time to remission of 2 months. The median time from rituximab to corticosteroid discontinuation was 3.5 months. The median remission time was 29 months and follow-up time was 39.5 months. No serious adverse events attributable to rituximab were observed. CONCLUSION: Rituximab induced remission in all patients with corticosteroid-dependent or -resistant minimal-change glomerulopathy, and may hold great therapeutic potential with good efficacy and minimal toxicity. Mounting evidence implies that a well-conducted randomized controlled clinical trial using rituximab in adults with minimal-change glomerulopathy in both corticosteroid-resistant and corticosteroid-dependent patients is warranted.

Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. METHODS: Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. RESULTS: Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. DISCUSSION: Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Thrombosis Rates and Genetic Thrombophilia Risk Among Patients With Advanced Germ Cell Tumors Treated With Chemotherapy.

INTRODUCTION: Men with advanced germ cell tumors (GCT) treated with chemotherapy are at high risk of venous thromboembolism (VTE). Predictors of VTE may identify patients who would benefit from prophylactic anticoagulation. PATIENTS AND METHODS: Men with advanced GCT (Stage IS, II, III) treated with chemotherapy were identified at 2 centers. High genomic risk was defined from a 5 single nucleotide polymorphism (SNP) germline panel. Logistic regression was used to evaluate the impact of genomic risk on VTE within 6 months of chemotherapy initiation. Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) was used to build models to predict VTE based on clinical variables and an 86 SNP panel. RESULTS: This 123-patient cohort experienced a VTE rate of 26% with an incidence of high genomic risk of 21%. Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5-3.5, P = .54). Incorporation of clinical variables (Khorana score, N3 status and elevated LDH) resulted in adjusted OR 2.1 (95% CI 0.7-6.5, P = .18). A combined model using clinical variables and 86 SNPs performed similarly (AUC 0.77) compared to clinical variables alone (AUC 0.72). CONCLUSIONS: A previously established 5-SNP panel was not associated with VTE among patients with GCT receiving chemotherapy. However, multivariable models based on clinical variables alone warrant further validation to inform prophylactic anticoagulation strategies.

The macronutrient content of a meal modulates subsequent 'dessert' intake, via Fibroblast Growth Factor 21 (FGF21).

Pharmacological administration of Fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load meal could reduce the later consumption of sweet desserts. Here, we tested the prediction that individuals eating a low P: E pre-load meal, and next offered a highly palatable sweet 'dessert', would eat less of the sugary snack compared to controls, due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals eating a low protein pre-load meal, and subsequently offered a very high-protein pellet as 'dessert' or snack, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21 ΔL ) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21 ΔL mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load is not sufficient to reduce later consumption of sweet dessert, though it effectively increases the subsequent intake of dietary protein in male mice.

Dietary protein restriction modulates 'dessert' intake after a meal, via fibroblast growth factor 21 (FGF21).

Pharmacological administration of fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load diet could reduce the consumption of sweet desserts in sated mice. Here, we tested the prediction that individuals maintained on a low P: E diet, and offered a highly palatable sweet 'dessert' following a pre-load meal, would eat less of the sugary snack compared to controls-due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals maintained on the low P: E diet, and offered a very high-protein pellet as 'dessert' or snack after a meal, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21ΔL) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21ΔL mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load diet is not sufficient to reduce the consumption of sweet desserts, though it effectively increases the subsequent intake of dietary protein in male mice.

RNA-Based Homologous Recombination Deficiency Signature Detects Homologous Recombination Deficiency-RNA+ Patients With and Without Homologous Recombination Repair Gene Pathogenic Alterations in Men With Prostate Cancer.

PURPOSE: Homologous recombination deficiency (HRD) is a well-described phenotype of some prostate cancers; however, current biomarkers for HRD are imperfect and rely on detection of single gene alterations in the homologous recombination repair (HRR) pathway, which may not capture the complexity of HRD biology. RNA signature-based methods of HRD identification present a potentially dynamic assessment of the HRD phenotype; however, its relationship with HRR gene alterations is not well characterized in prostate cancer. METHODS: A HRD assay on the basis of an RNA signature associated with biallelic BRCA1/2 loss was applied to a retrospective cohort study of 985 men with prostate cancer analyzed on the Tempus xT platform. HRD status was defined by a binary threshold on a continuous scale. RESULTS: In this cohort, of the 126 (13%) patients found to be HRD+ by RNA signature (HRD-RNA+), 100 (79%) had no coexisting HRR gene alteration. Among samples with biallelic BRCA1/2 loss, 78% (7/9) were classified as HRD-RNA+, while 8% (2/25) of samples with BRCA1/2 monoallelic loss were HRD-RNA+. Biallelic and monoallelic ATM loss exhibited HRD-RNA+ at a lower prevalence: 6.7% (1/15) and 7.1% (1/14), respectively, compared with HRD-RNA+ prevalence among samples without any HRR gene loss (13%; 100/782). HRD-RNA+ was associated with a significantly higher prevalence of TP53 and AR gene alterations relative to HRD-RNA- after correction for multiple comparisons, 59% versus 39% (q = 0.003) and 23% versus 12% (q = 0.024), respectively. CONCLUSION: Use of an RNA-based HRD signature significantly expands the fraction of patients with prostate cancer who may derive benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) compared with using HRR gene mutations alone. Further studies are needed to evaluate functional HRD significance and inform future usage as a predictive biomarker for PARPi selection.

Prognostic value of galectin-1 and galectin-3 expression in localized urothelial bladder cancer.

Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins with a wide range of biological activity, including regulation of cellular adhesion, proliferation, and apoptosis in solid tumors. Prior small studies have reported that Gal-3 expression is associated with progression of disease in urothelial carcinoma (UC), from non-muscle invasive UC progression to muscle invasive UC. We assessed Gal-1 and Gal-3 protein expression H-score utilizing a tissue microarray (TMA) created from 301 cystectomy specimens. Methods: Immunohistochemistry for Gal-1 and Gal-3 was performed on TMA generated from tumor blocks from chemotherapy naïve cystectomy specimens. The variable of interest, H-score, was defined as the product of the percentage of cells staining positive (0-100) and intensity score (0-3) scored by a single pathologist. Survival end points were analyzed using Kaplan-Meier and Cox Proportional Hazards methods. Clinical data including Charlson Comorbidity Index (CCI), pathologic tumor (T) stage, tumor size, node stage, and surgical margins, were included in multivariable analysis. Results: We found that Gal-1 and Gal-3 expression correlated with intratumoral T stage (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, P<0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, P<0.01). However, the highest intratumoral H-score per cystectomy core did not independently predict for recurrence-free survival (RFS) (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.65) or OS (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.72) in this cohort. Significant intratumoral heterogeneity was present for both Gal-1 and Gal-3, with an average difference between the highest and lowest H score was 95 for Gal-1 and 109 for Gal-3 for cystectomy specimens with more than one biopsy. Conclusions: Gal-1 and Gal-3 H-score per bladder did not independently predict for RFS or OS. Intra-tumoral Gal-1/Gal-3 heterogeneity complicates the use of Gal-1 and Gal-3 expression as a prognostic biomarker. Future studies should consider the evaluation of serum and urinary galectins as an approach to mitigate tumor heterogeneity.

Tetra-kis[µ-N-(2,4,6-trimethyl-phen-yl)acetamidato]-κ4N:O;κ4O:N-bis-[(benzo-nitrile-κN)rhodium(II)](Rh-Rh).

The title structure, [Rh2(C11H14NO)4(C7H5N)2], contains a dinuclear Rh complex of point symmetry -4 with an Rh-Rh unit and two benzonitrile ligands located in special positions along the twofold axis passing through -4. Four symmetry-equivalent mesitylacetamidate ligands bridge the Rh-Rh unit. Thus, each Rh(II) atom has an approximately octa-hedral coordination by one Rh [Rh-Rh = 2.4290 (6) Å], two acetamidate O atoms trans to each other [Rh-O = 2.044 (3) Å], two acetamidate N atoms trans to each other [Rh-N = 2.091 (4) Å], and a benzonitrile N atom trans to Rh [Rh-N = 2.222 (3) Å]. The structure is held together by weak van der Waals forces.

Millennials Seeking Healthcare: Examining the Degree to Which Patients Utilize Online Resources.

Introduction: According to the 2020 U.S. Census, a Silver Tsunami is looming, with more than 75.4 million persons aged 57 to 75 expected to need more costly medical care. However, a larger wave of 83.1 million Millennials nearing adulthood is approaching rapidly. Therefore, it is important to understand how this population finds their physician and what may influence this decision. Methods: Paper-based surveys were administered to adult patients at primary care and geriatric clinics located at the University of Kansas Medical Center in Kansas City, Kansas. Questions included demographic information, utilization and influence of online reviews, and the effects negative and positive reviews have on a patient's choice of physician. Descriptive statistics were calculated for respondent characteristics and survey responses. Chi-square and McNemar's tests were performed to evaluate differences between age and gender groups, and to determine how influential review ratings are in choosing a physician for medical care. Statistical significance was determined at the 0.05 level. Results: A sample of 284 patients completed the survey (44.35 ± 17.54 years old [range = 18-90], 60.6% female, 57.4% white). Of Millennials, 67.2% read online reviews before choosing a physician. Millennials were significantly more likely to read online reviews before choosing a physician (p = 0.004) and utilize online resources to search for a new physician (p < 0.001) than older patients. Conclusions: Millennials were more likely to research online reviews before choosing a physician. Therefore, an online review presence will be beneficial to one's practice to acquire this new wave of patients.

FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk.

The liver regulates energy partitioning and use in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor 21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate use to reduce hepatic lipid storage. Here we report that FGF21 altered hepatic transcriptional and metabolic responses, and reduced liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor → cAMP → exchange protein directly activated by cAMP signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.

A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer.

BACKGROUND: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. METHODS: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. RESULTS: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51-85 years), and men had received a median of two prior therapies (range 1-3). Median PSA was 54 ng/dl (range 0-393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6-3.6 months), and median overall survival was 7.4 months (85% CI 2.8-12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. CONCLUSIONS: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.

Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor response in metastatic renal cell carcinoma.

BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.

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.