bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of renal cell carcinoma (RCC) metastatic to pancreas with a distinct molecular profile and immune cell population.
Authors: Chiang Ryan S. , Ashok Arya , Mauer Elizabeth , Barrett Alex , Hoerner Christian R , Khan Osama A , Kao Chia-Sui , Shah Sumit , Srinivas Sandy , Fan Alice C. , Khaki Ali Raza 
Published: February 2022

366 Background: RCC may metastasize to diverse sites, which confers variable prognosis and treatment response. Pancreatic metastases in RCC have been associated with indolent biology, low genomic instability and decreased inflammation, which may lead to worse responses to immunotherapy. To further investigate this phenomenon, we compared the genomic landscape and immunotherapy biomarkers of metastatic RCC patients with and without pancreatic metastases. Methods: We identified a cohort from the de-identified Tempus database, consisting of patients with metastatic RCC who received next generation sequencing via the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage; whole-exome capture RNA-seq). Records were included if patients had RCC diagnosis and metastases to at least one of: pancreas, liver, brain, or lung (regardless of the presence of other metastases). RCC diagnosis and metastatic sites were determined from abstracted clinical notes received at the time of sequencing. If individuals had multiple xT results, the results from the most recent sample were included (irrespective of tissue site). We compared the prevalence of somatic gene alterations (using false discovery rate corrected q-values) and immunotherapy markers among records with vs without pancreatic metastases. Statistical significance was determined via Wilcoxon rank-sum tests or Chi-squared/Fisher’s exact tests. Results: 654 patients (median age 61, 30% female, 62% clear cell) with metastatic RCC were included. 58 harbored pancreatic metastases and 596 had metastases to sites other than pancreas (36 brain, 88 liver, 358 lung, 114 brain/liver/lung combinations). Females had a significantly higher representation in the group with pancreatic metastases (43% vs 29%, p = 0.02). The group with pancreatic metastases had significantly more PBRM1 alterations (52% vs 25%, q < 0.001), and trended towards more prevalent copy number loss of ALK (22% vs 10%, q = 0.06) and NTRK3 (16% vs 6%, q = 0.08) and less prevalent alterations in CDKN2A (3% vs 13%, q = 0.08), BAP1 (2% vs 13%, q = 0.06) and MTAP (0% vs 9%, q = 0.06). Individuals harboring pancreatic metastases had similar MSI status and TMB, but had lower rates of PD-L1 positivity, lower proportions of B-cells and higher proportion of NK cells in immune cell composition (Table). Conclusions: RCC patients with pancreatic metastases have a distinct molecular profile and lower rates of PD-L1 positivity, which suggests a unique disease biology and potential non-immunogenic phenotype. Further investigation and prospective validation is needed to determine immunotherapy outcomes in this population.[Table: see text]
Utilizing the autoantibody immune response to tumor antigens for kidney cancer early detection.
Authors: Hoerner Christian R , Jhatro Michael , Waitz Rebecca , Kamath Kathy , Zhang Minlu , Dhal Abhilash , Shon John , Fan Alice C. 
Published: February 2022

369 Background: Kidney cancer (renal cell carcinoma, RCC), the 8th most common U.S. cancer, is in need for better cure rates through early detection (5-year relative survival for stage I RCC: ̃95%; for stage IV RCC ̃19%). Autoantibodies are common in cancer and result from the altered expression, localization, or post-translational modification of endogenous proteins in tumor cells (autoantigens) and from the expression of mutated genes that give rise to new proteins (neoantigens). In contrast to cellular immune responses in cancer, autoantibodies are less well characterized, yet hold promise to enable cancer early detection by immune amplification of the ‘cancer signal’ while retaining specificity to cancer types including RCC. Autoantibodies may therefore be useful for kidney cancer early detection and diagnosis. Our goal was to profile the autoantibody repertoire in blood from patients with clear cell RCC (ccRCC), the most common form of RCC, in order to: 1) determine if autoantibodies can be detected in patients with early-stage and late-stage ccRCC; 2) identify common epitopes amongst ccRCC patients that could suggest common RCC antigens; and 3) determine specificity and sensitivity of potential autoantibody biomarkers for ccRCC vs. other non-cancer conditions. Methods: We use the SERA platform (https://serimmune.com/publications/) to compare putative autoantibody signal in blood from 177 patients with ccRCC, 23 with benign kidney lesions, and ̃800 healthy controls. SERA utilizes a random bacterial display 12mer peptide library of 1010 diversity in conjunction with next-generation sequencing to ascertain epitope enrichment across the entire human proteome. Results: We find significant differences in epitope repertoires in ccRCC compared to the healthy human cohort. Patients with ccRCC exhibit a rich repertoire of rare, enriched epitopes which may comprise putative autoantibody signal. This epitope signal is present with high abundance in all ccRCC stages, including stage I ccRCC. In contrast, healthy controls and patients with benign kidney lesions demonstrate more restricted repertoires. However, we do not find evidence of common ccRCC antigens: epitopes are not conserved across large subsets of ccRCC patients. Conclusions: Our initial results suggest that each patient may develop an individualized tumor-associated antibody response. Whether assessing a select epitope panel in a patient’s blood could be useful for ccRCC early detection, or even epitope diversity without needing to identify specific epitopes, warrants further study.
HIF-pathway genes prognostic for progression-free and overall survival in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Tamukong Patrick , Kuhlmann Paige , You Sungyong , Su Shengchen , Wang Yanping , Small Eric Jay , Rini Brian I. , Halabi Susan , Janes Jessica , Freedland Stephen J. , Kim Hyung Lae 
Published: February 2022

370 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by defects in the Von Hippel-Lindau/hypoxia-inducible factor (VHL/HIF) pathway. Several FDA-approved RCC therapies target the products of HIF-response genes. HIF2A is a promising new target and drugs targeting HIF2A are undergoing clinical testing. A better understanding of HIF-related genes may reveal useful biomarkers and drug targets. Methods: Gene expression was determined from 324 archival pretreatment nephrectomy specimens available from the Cancer and Leukemia Group B (CALGB) 90206, a phase III trial of patients treated with INF-α vs. INF-α plus bevacizumab. TaqMan RT-qPCR was performed on the OpenArray platform using RNA extracted from tumor tissue macrodissected based on review of H&E staining by a genitourinary pathologist. HIF pathway genes were assessed across both treatment arms, utilizing the proportional hazards model as predictors of OS and PFS, with time from randomization to death or disease progression as endpoints. Results: A total of 28 HIF-related genes (involved either in canonical or non-canonical HIF regulation) were assessed in univariate PH. Nine of these genes were associated with OS (i.e., HIF2A , VEGFC, VEGFD, TGFA, VHL, CCND1, EGFR, EGLN3 and HSP90AA1); and 6 of them were also associated with PFS (i.e., HIF2A , TGFA, VHL, CCND1 and EGLN3, and HSP90AA1). The HIF isotypes HIF1A and HIF3A were not prognostic, likewise VEGFA and VEGFB. Prolyl hydroxylase domain (PHD) proteins efficiently hydroxylate HIFα in normoxic conditions. PHD isotypes EGLN (1-3) were evaluated and only EGLN3 was associated with OS and PFS. HIF is also regulated by non-canonical pathways that function independent of oxygen concentration. HSP90AA1 was the only non-canonical pathway gene that was prognostic, and it predicted both OS and PFS. When the 9 genes that were prognostic in univariate analysis were used in a backward stepwise multivariate cox regression, VEGFD, TGFA and EGLN3 predicted OS while HIF2A, VHL and TGFA predicted PFS. Conclusions: VHL, HIF2A (but not HIF1A and HIF3A), EGLN3 (but not EGLN1 and EGLN2) and some of the HIF-response genes were prognostic of both OS and PFS. HSP90AA1 was prognostic for OS and PFS, suggesting that the non-canonical HIF pathway also plays a role in disease progression. Future studies should consider these HIF pathway genes as potential drug targets, and as predictors of response to treatments targeting the hypoxia pathway and angiogenesis.[Table: see text]
Intestinal microbiome associated with development of grade 3/4 adverse in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab (N/I) and probiotic support: Results from a phase Ib study.
Authors: Meza Luis A , Dizman Nazli , Bergerot Paulo Gustavo , Dorff Tanya B. , Lyou Yung , Frankel Paul Henry , Llamas Marian , Hsu Joann , Zengin Zeynep Busra , Salgia Nicholas , Malhotra Jasnoor , Chawla Neal Shiv , Gillece John D , Reining Lauren J , Trent Jeffrey M. , Takahashi Motomichi , Oka Kentaro , Higashi Seiya , Highlander Sarah K , Pal Sumanta K. 
Published: February 2022

374 Background: Treatment with N/I with the addition of CBM588, a live bacterial product comprised primarily of Clostridium butyricum, improved PFS and RR versus N/I alone when used as first line treatment for patients with mRCC (Meza et al ASCO 2021). Increased abundance of certain bacterial species in the gut microbiome have been associated with the development of treatment related adverse events (TREAs) in lung cancer patients receiving immunotherapy (Chau et al BMC Cancer 2021). However, this association has not yet been delineated in the setting of mRCC. Here, we present results of an exploratory analysis assessing the differences in stool microbiome composition between patients who experienced grade (G) 3/4 TREAs and those who did not. Methods: Patients were randomized 2:1 to receive N/I with or without CBM588. Stool collection for bacteriomic profiling was planned at baseline and after 12 weeks of therapy for all randomized patients. Whole metagenome sequencing was performed using previously published methods (Dizman et al Cancer Med 2021) and differences in microbiome composition were measured based on the occurrence of G 3/4 TREAs. Results: 30 patients were enrolled and 29 included in the study. At the time of data cutoff (April 15, 2021) the median follow up was 12.2 months (95% confidence intervals [CI], 10.6-13.8). Grade 3/4 TRAEs were experienced in 52, 50, and 53% of patients in the overall cohort, control, and intervention arms, respectively (p = NS). Among the most common G 3/4 TRAEs, subjects experienced fatigue, diarrhea, and hyperglycemia. Patients with a complete set of stool samples were included for the microbiome analysis (n = 26). In patients who experienced G 3/4 TRAEs, a significantly greater baseline abundance of Escherichia coli, Klebsiella spp. and Blautia spp. (p = 0.02, 0.03, 0.05) were seen when compared to those not experiencing G 3/4 TRAEs. In contrast, Bacteroides intestinalis and B. thetaiotamicron, were observed in significantly higher abundances in baseline stool specimens of patients who did not experience G 3/4 TREAs (p = 0.03 for both). No significant differences were seen for any of these species at the 12-week timepoint. Conclusions: We are among the first to investigate the differences in baseline stool microbiome in mRCC patients experiencing G 3/4 TRAEs while receiving immunotherapy. Our results suggest that certain taxa of bacteria are predictors of the development of serious TRAEs. Larger cohorts are needed to corroborate these findings. Clinical trial information: NCT03829111.
Molecular and immune landscape of FH-mutated kidney cancer.
Authors: Al-Share Bayan A , Wu Sharon , Alloghbi Abdurahman , Alkassis Samer , Guastella Anthony , Helmstetter Anthony , Nabhan Chadi , Korn W. Michael , Nazha Bassel , Barata Pedro C. , Ryan Charles J. , McKay Rana R. , Heath Elisabeth I. 
Published: February 2022

382 Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by inactivating germline mutations in fumarate hydratase ( FH), predisposing individuals to development of certain cancers. Sporadic FH mutations have been described in different types of cancers, including kidney cancers, but the implications of somatic mutations are not well described. Here, we characterize the molecular landscape of kidney tumors with FH mutations. Methods: Tumors were analyzed using next generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq). Immune cell fraction was estimated by immune deconvolution (Quantiseq). Significance was determined by chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value <0.05). Results: Of 1956 kidney tumors, 31 had somatic pathogenic or likely pathogenic (P+LP; 1.58%) and 21 had variant of unknown significance (VUS; 1.07%) mutations in FH. Among the most commonly co-mutated genes, VHL (29.03% vs 38.1% vs 55.2%) and PBRM1 (9.68% vs 20% vs 29.8%) were less frequently mutated in P+LP compared to VUS and WT tumors; while NF2 (22.6% vs 5% vs 5.65%) was more frequently mutated in P+LP tumors compared to the others. In P+LP tumors, the HIPPO pathway (22.6% vs 4.76% vs 5.62%) was more frequently altered while the chromatin remodeling pathway (25.8% vs 28.6% vs 51.1%) was less frequently altered compared to VUS or WT tumors. P+LP tumors showed decreased NK cell infiltration (q=0.01) compared to VUS and WT tumors. Additionally, there was a trend towards increased CD8+ T cells and CTLA4 and PDCD1 expression in P+LP tumors compared to VUS but not WT tumors. Of the 1,956 kidney tumors, 315 were of clear cell renal cell carcinoma (ccRCC) histology. P+LP (n=4) ccRCC tumors showed a trend towards higher expression of immune checkpoint genes CTLA4 and IDO1 compared to VUS tumors (n=5). VHL expression was higher in P+LP ccRCC compared to VUS ccRCC tumors. P+LP ccRCC tumors showed a trend toward increased CD4+ (2.59% vs 0%) and CD8+ (2.14% vs 0%) T cells as well as T cell inflammation (25% vs 0%) and median Interferon score compared to VUS ccRCC tumors. Conclusions: P+LP FH mutated kidney tumors may have a different mutational and immune landscape than VUS FH mutated and WT tumors. Despite the small sample size, our study highlights potential therapeutic implications that will require further study.[Table: see text]
Molecular characterization of renal cell carcinoma with venous tumor thrombus: Genomic aberrations with renal vein wall invasion.
Authors: Dong Xiaoxi , Liu Cheng , Jia Shidong , Yu Jianjun , Ma Lulin 
Published: February 2022

385 Background: Renal cell carcinoma (RCC) patients with tumor thrombus (TT) have been observed distinct phenotypes of TT: deeply invading into the wall of renal vein/inferior vena cava (IVC) (DITT) or minimal/non-invasion (NITT), with different surgical strategy and post-thrombectomy outcome. However, the molecular characters of DITT/NITT have not been investigated, due to operational challenges and limited patient access. Methods: In this study, primary tumor and TT samples from 68 patients having IVC thrombectomy were prospectively collected for DNA mutation profiling and RNA expression profiling, using Predicine panel-based next generation sequencing and transcriptome RNA-SEQ, respectively. Next-generation sequencing and bioinformatics data analysis was conducted in Colleges of American Pathologist (CAP)-accredited laboratory in Shanghai, China (Huidu Shanghai Medical Sciences Ltd.). Kaplan–Meier survival analysis was performed to analyze the correlation between DITT/NITT and clinical outcome, and p-values were calculated using log-rank test. Results: When metastasis was detected, patients with DITT showed significantly shorter overall survival comparing to patients with NITT (P < 0.05, log-rank test). However, this difference was not observed in non-metastatic group. Successful sequencing has been achieved in 100% (68/68) patients. NITT tumor bulks more frequently carried mutations in PTEN, TP53 and epigenetic regulators such as SETD2, PBRM1 and KDM5C and had higher expression of cell cycle related pathway genes. In contrast, DITT had lower expression of genes encoding cell adhesion and extracellular matrix molecules such as ADAM33, NCAM1 and FLRT2, which could contribute to higher invasiveness. Conclusions: To our knowledge, this is the first large study to systematically interrogate genomic landscape and molecular features of different TT phenotypes in RCC patients. The differential genomic mutation and gene expression landscapes across the two groups may reflect biologic differences and clinical implications such as tumor invasiveness and aggressiveness.
The prognostic role of sarcopenia and albumin in locally advanced renal cell carcinoma with IVC tumor thrombus.
Authors: Midenberg Eric , Patil Dattatraya H , Medline Alexandra , Higgins Michelle , Williams Milton , Nazha Bassel , Brown Jacqueline T , Ogan Kenneth , Psutka Sarah P. , Bilen Mehmet Asim , Master Viraj A. 
Published: February 2022

387 Background: Indicators of body composition and nutritional status, such as lumbar skeletal muscle index (SMI, cm2/m2) and hypoalbuminemia, are associated with adverse outcomes following surgery for localized renal cell carcinoma (RCC) but have yet to be described in patients with RCC and venous tumor thrombus. We hypothesize that preoperative sarcopenia, a severe deficit in lean muscle mass, and hypoalbuminemia will be associated with decreased overall survival (OS) and cancer specific survival (CSS) in nonmetastatic RCC patients undergoing radical nephrectomy and tumor thrombectomy. Methods: We retrospectively analyzed 103 nonmetastatic RCC patients who underwent radical nephrectomy and tumor thrombectomy from 2005 to 2020. Optimally fit BMI (kg/m2) and sex-stratified sarcopenia thresholds were calculated (BMI<30: SMI<47 for males, SMI<38 for females; BMI≥30: SMI<54 for males, SMI<47 for females). Sarcopenia and albumin risk groups were created based on their individual hazard ratios on univariable analysis and defined as low-risk (non-sarcopenic, normal albumin), medium-risk (non-sarcopenic, hypoalbuminemia), high-risk (sarcopenic, normal albumin), and very high-risk (sarcopenic, hypoalbuminemia). Associations between independent and combined sarcopenia and hypoalbuminemia (albumin<3.5 g/dL) with OS and CSS were evaluated using multivariable and Kaplan-Meier analyses. Results: Prevalence of sarcopenia and hypoalbuminemia were 51.2% and 44.7%, respectively. Median follow up time was 24.8 months and median time from preoperative imaging to surgery was 21 days. Sarcopenia was an independent predictor of OS (p=0.003) and CSS (p=0.006) whereas hypoalbuminemia was not (OS: p=0.096; CSS: p=0.718). When analyzing sarcopenia and albumin in combination, the high and very high-risk groups were significantly associated with decreased OS (high-risk: p=0.011; very high-risk: p<0.001) and CSS (high-risk: p=0.011; very high-risk: p=0.017). Kaplan-Meier curves showed a stepwise decline in median OS (p=0.0071) and CSS (p=0.0068) times with increasing risk. Conclusions: Simultaneous sarcopenia and hypoalbuminemia were associated with nearly a seven-fold decrease in OS and CSS in patients undergoing surgery for nonmetastatic RCC with IVC tumor thrombus.[Table: see text]
Sarcopenia as a predictor of perioperative morbidity in metastatic renal cell carcinoma patients undergoing radical nephrectomy and IVC tumor thrombectomy.
Authors: Midenberg Eric , Medline Alexandra , Patil Dattatraya H , Nazha Bassel , Brown Jacqueline T , Ogan Kenneth , Psutka Sarah P. , Bilen Mehmet Asim , Master Viraj A. 
Published: February 2022

388 Background: Preoperative sarcopenia, as determined by the lumbar skeletal muscle index (SMI), has shown potential value for predicting adverse survival outcomes in metastatic renal cell carcinoma (mRCC) patients undergoing cytoreductive surgery. However, its utility for predicting perioperative morbidity in mRCC patients with IVC involvement is poorly elucidated. We hypothesize that preoperative sarcopenia, a severe deficiency in lean muscle mass, will be associated with major surgical complications and longer lengths of hospital stay in mRCC patients managed with radical nephrectomy and tumor thrombectomy. Methods: We retrospectively analyzed 99 mRCC patients who underwent radical nephrectomy and tumor thrombectomy from 2005 to 2020. Sarcopenia was diagnosed using optimally fit body mass index (BMI) and sex-stratified thresholds. For patients with a BMI < 30 kg/m², sarcopenia was defined as a SMI < 47 cm2/m2 for males and SMI < 38 cm2/m2 for females and for those with a BMI≥30 kg/m², as a SMI < 54 cm2/m2 for males and SMI < 47 cm2/m2 for females. Outcome measures were the presence of any major complications within 90 days after surgery, major complications within 1 year after surgery, and length of hospital stay post-nephrectomy ≥7 days. Major complications were defined as grade ≥3a on the Clavien-Dindo classification system. Associations between sarcopenia and major surgical complications and length of hospital stay were evaluated using multivariable analysis. Multivariable models were adjusted for age, race, gender, BMI, Charlson comorbidity index, T and N staging, Fuhrman grade, ECOG Score, and extent of IVC tumor thrombus. Results: Median time from preoperative imaging to surgery was 22 days (IQR 15-29). Of the 57 (58%) patients with preoperative sarcopenia in our cohort, 19 (33%) and 20 (35%) patients experienced a major surgical complication within 3 and 12 months after surgery, respectively, and 34 (60%) patients had a length of stay ≥7 days. Preoperative sarcopenia was significantly associated with the occurrence of a major complication within 90 days (OR = 4.84, 95%CI: 1.30-18.06, p = 0.019) and 1 year (OR = 6.43, 95%CI: 1.66-24.89, p = 0.007) after surgery. The presence of sarcopenia did not significantly change the odds of staying in the hospital for more than 7 days post-nephrectomy (OR = 1.41, 95%CI: 0.45-4.41, p = 0.551). Conclusions: Preoperative sarcopenia was associated with major surgical complications occurring within 3 and 12 months among mRCC patients after radical nephrectomy and tumor thrombectomy. Screening for sarcopenia preoperatively may assist in identifying patients at high-risk for increased perioperative morbidity, which ultimately may permit the implementation of preventive therapeutic strategies. Future validation is needed.