bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNAseq in addition to next generation sequencing in advanced genitourinary cancers reveals transcriptomic silencing of DNA mutations: Implications for resistance to targeted therapeutics.
Authors: Adashek Jacob J. , Kato Shumei , Parulkar Rahul , Szeto Christopher , Reddy Sandeep K. , Kurzrock Razelle 
Published: March 2019

583 Background: Next generation sequencing (NGS) for advanced tumors is becoming more routine. However, not all patients respond to precision matched treatments. We hypothesized that one potential reason for treatment failure with targeted therapy could be discrepancies between DNA alterations and RNA expression. Methods: Tumor samples from patients with metastatic kidney, bladder, and prostate cancer were analyzed by whole exome or whole genome NGS and RNA sequencing (CLIA-certified laboratory; NantOmics LLC, Santa Cruz, CA). Only known pathogenic driver alterations were analyzed in the current study. Results: Of 45 patients, 10 had kidney cancer, 18 had bladder cancer; and 17 had prostate cancer. Median age was 66 years (range, 28 - 86). The most commonly altered genes were TP53 (35.6% [16/45]), PIK3CA (15.6% [7/45]), FGFR3 (11.1% [5/45]), ALK (8.9% [4/45]), and ATM (8.9% [4/45]). In total, 86 pathogenic DNA alterations were identified; 17 of these (19.8%) were not observed at the RNA level. Among 45 patients, 31.1% (14/45) had ≥1 DNA alteration that was not expressed at the RNA level. Discordance between DNA and RNA was seen in 40% of patients with kidney cancer (4/10), 28% of patients with bladder cancer (5/18), and 29% with prostate cancer (5/17). Examples of genes that had pathogenic DNA alterations not seen at the RNA level included ALK (four discordant cases), KDR (three discordant cases) and GNAS (one discordant case). On the other hand, alterations involving certain genes showed 100% concordance between DNA and RNA: TP53 [N = 16], PIK3CA [N = 7], and FGFR3 [N = 5]). Conclusions: A significant number of patients with genitourinary tumors had DNA alterations that are silenced at the RNA level (19.8%). Transcriptomic silencing merits additional investigation as a mechanism that could mediate resistance to therapeutics targeted at cognate alterations.
Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).
Authors: Labriola Matthew , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , White James R , Weingartner Elizabeth , Kong Eric , Simone Peter , Papp Eniko , Gerding Kelly , Simmons John , George Daniel J. , Zhang Tian 
Published: March 2019

589 Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICI therapy at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also analyzed with the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies.
Using PSMA (prostate-specific membrane antigen) evaluation on prostate biopsies for risk stratification at time of initial diagnosis.
Authors: Hupe Marie C. , Philippi Christian , Roth Doris , Kuempers Christiane , Ribbat-Idel Julika , Becker Finn , Joerg Vincent , Duensing Stefan , Lubczyk Verena , Kirfel Jutta , Sailer Verena , Kuefer Rainer , Perner Sven , Merseburger Axel Stuart , Offermann Anne 
Published: March 2019

6 Background: Stratifying prostate cancer (PCa) patients into risk groups at time of initial diagnosis for individual treatment decision is still a major clinical challenge. PSMA expression has emerged as a promising prognostic biomarker since its overexpression in radical prostatectomy specimens (RP) has been linked to disease recurrence. Aim of our study was to assess the prognostic value of PSMA on prostate biopsies (Bx) thus improving risk stratification at time of initial diagnosis. Methods: Immunohistochemistry for PSMA expression was performed on 294 Bx with corresponding RP, 621 primary tumor foci from 242 RP, 43 locally advanced or recurrent tumors, 34 lymph node metastases, 78 distant metastases, and 52 benign prostatic samples. Grade group, PSA, TNM-, and R-status were assessed as clinico-pathologic features. Primary endpoint was recurrence-free survival (RFS). Chi-square, ANOVA-analyses, Cox regression and log rank tests were performed for statistical analyses. Results: PSMA expression significantly associates with grade group and initial PSA level. Elevated PSMA expression on both RP and Bx significantly correlates with an increased risk of disease recurrence after curative surgery. 5-year RFS rates are 88.2%, 74.2%, 67.7%, and 26.8% for patients with no, low, medium, or high PSMA expression on Bx, respectively. Elevated PSMA level on Bx predict a 4-fold increased risk of disease recurrence independently from initial PSA and grade group on Bx. PSMA expression significantly increases during PCa progression. Conclusions: PSMA qualifies as an independent prognostic biomarker on Bx at time of initial diagnosis in addition to the established markers PSA and grade group. PSMA predicts disease recurrence following curative surgery and potentially improves the discrimination indolent vs. aggressive disease. We propose the routine assessment of PSMA expression on Bx for outcome prediction and risk stratification at time of initial diagnosis prior to treatment decision.
Postoperative long-term prognosis of localized renal cell carcinoma after partial or radical nephrectomy: Analysis of cancer metastasis and deaths during a more than five-year follow-up.
Authors: Park Sang Hyun , Kim Taek Sang , Joung Jae Young , Kim Sung Han , Chung Jinsoo 
Published: March 2019

604 Background: We performed a long-term follow-up study to evaluate the survival and metastatic outcomes of non-metastatic renal cell carcinoma (RCC) after curative removal of tumor. Methods: We retrospectively reviewed the clinical and pathological features of 5434 patients with localized renal cell carcinoma admitted to five Korean tertiary-care institutions between 2000 and 2012, who had undergone curative surgeries with partial or radical nephrectomy with/without lymph nodal dissection. The patients below the age of 19 years (N=9) with benign histology (N=24), and with no follow-up records (N=540) were excluded. A total of 4861 patients, followed-up for at least 1 year after the surgery, were enrolled finally. The deaths were defined as intraoperative, postoperative or RCC-related deaths. We analyzed the metastasis-free survival, cancer-specific survival, and overall survival outcomes according to the pathological stages. Results: The median age of patients at the time of surgery, male-to-female ratios, median follow-up duration, overall survival and metastasis-free survival times were 56 years (range: 19-94 years), 3471/1390 (71.4%/28.6%), 33.7 months (range: 12-297 months), 175.1 months (12-297.1 months), and 61 months (range: 12-94 months), respectively. A total of 518 (10.7%) deaths, including 338 (7.0%) RCC-related death and 164 (3.3%) deaths related to other causes were reported. Metastasis and recurrences were observed in 140 (2.9%) and 462 (9.5%) patients, respectively. The respective pathologic T1/2/3/4/x and N1 stages, namely, 3757/389/644/57/6 (77.3/8.0/13.3/1.2/0.1%) and 133 (2.7%) were observed. The rates of histological types of clear cell papillary/ chromophobe/ collecting duct/ unclassified/ MLCRCCLMP/ mixed cell papillary/ unknown were 83.4%/ 1.5%/ 7.1%/ 0.4%/ 1.1%/ 0.5%/ 0.2%/ 0.3%/ 0.1%/ 5.3%. The 10-year metastasis-free survival rate was 86.0% including 100%, 91.0%, 64.1%, and 11.8% incidence for stages I, II, III, and IV, respectively. Conclusions: The long-term survival was seen among patients who underwent nephrectomy for non-metastatic renal cell carcinoma.
Patterns of response of organ specific metastasis in patients with metastatic renal cell cancer (mRCC) treated with an immune checkpoint inhibitor (CPI) post tyrosine kinase inhibitor (TKI).
Authors: Picardo Sarah Louise , Iafolla Marco Adelmo James , Sridhar Srikala S. , Sacher Adrian G. , Hansen Aaron Richard 
Published: March 2019

605 Background: Both TKIs and the novel immune CPIs targeting PD/PDL1 are now standard treatments for patients with mRCC. Mixed responses in metastatic lesions have been observed. We examined organ specific radiologic responses in a cohort of patients with mRCC who were initially treated with TKI followed by CPI. Methods: We identified patients who were treated with first line TKI followed by CPI from a prospectively maintained database of all mRCC patients treated at our institution from 2010 to 2018. We examined best response to TKI and CPI, as well as organ specific responses to TKI and CPI. Statistical analysis was performed using odds ratios and Fishers exact test. Results: We identified 31 patients with evaluable disease who were treated with a TKI followed by CPI. Best responses to TKI were partial response (PR) (n = 7), stable disease (SD) (n = 17) and progressive disease (PD) (n = 6). Of TKI responders, 4 had lesions in ≥2 organs respond and 3 had a lesion in a single organ respond. Of the 3 patients who responded to CPI, all had lesions in ≥2 organs respond. Patients who had PD to TKI did not respond to CPI. Organ specific metastases at time of initiation of TKI and CPI are described in the table. In lung lesions, the odds of a response to CPI with or without an initial response to TKI were 0.16 and 0.57 respectively (OR 0.29, p = 0.595). In lymph node (LN) metastases, the odds of a response to CPI with or without an initial response to TKI were 0.16 and 0.62 respectively (OR 0.27, p = 0.354). Two patients had a response to TKI in the liver but none had a response to subsequent CPI. Of 3 patients who had a response to TKI in the renal primary, 1 had a response to CPI. Conclusions: In this small series, these data suggest that first line TKI response may dictate subsequent CPI response in an organ specific manner, with higher numbers of CPI responses in lung and LN metastases in patients who did not have TKI response in these organs. This may be due to immune modulation by prior TKI or to tumor heterogeneity. Studies are needed to further elucidate this phenomenon. [Table: see text]
Body mass index (BMI) and toxicities and association with clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Bilen Mehmet Asim 
Published: March 2019

613 Background: BMI has been explored as a prognostic factor in cancer pts and treatment-related toxicities have been associated with responses to VEGF-targeted therapy in mRCC pts. We investigated the association of BMI and adverse events (AEs) and CO in mRCC pts treated with cabo. Methods: A retrospective analysis of 65 pts with mRCC treated with cabo at Winship Cancer Institute from 2016 to 2018 was performed. Overall survival (OS), progression-free survival (PFS), and objective response (OR) were used to measure CO. OS and PFS were calculated from first cabo dose to death and radiographic or clinical progression, respectively. An OR was defined as a partial response (PR) or a complete response (CR) using RECISTv1.1. BMI was collected at baseline (BL) and 6 (±2) weeks after cabo initiation. AEs were obtained from clinic notes. Univariate analysis (UVA) of association between BMI and CO was carried out using logistic regression model for OR and proportional hazard model for OS and PFS. Results: The median age was 63 years and 26% were African American. The majority were either IMDC intermediate or poor-risk (59% and 34%, respectively). Most pts (67%) had a BMI ≥ 25 and the median BMI at BL was 26.6. There was no difference in incidence of AEs between pts with BMI < 25 and pts with BMI ≥ 25. Gastrointestinal (GI) AEs incidence was also comparable among pts with a BMI ≥ 25 (62%) and pts with BMI < 25 (57%, p = 0.666). Increased BMI at 6W was significantly associated with prolonged OS and increased baseline BMI at BL showed a trend towards longer OS (Table). Conclusions: Increased BMI may be associated with improved CO in mRCC pts treated with cabo, but there may not be a difference in AEs based on BMI. Larger analyses are needed to validate these findings. [Table: see text]
Fecal microbiota transplantation for TKI-induced diarrhea in patients with metastatic renal cell carcinoma.
Authors: Rossi Ernesto , Ianiro Gianluca , Maiorano Brigida Anna , Iacovelli Roberto , Lopetuso Loris , Settanni Carlo Romano , Masucci Luca , Quaranta Gianluca , Sanguinetti Maurizio , Bria Emilio , Gasbarrini Antonio , Tortora Giampaolo , Cammarota Giovanni , Schinzari Giovanni 
Published: March 2019

615 Background: Diarrhea is a common adverse event of tyrosine kinase inhibitors (TKI). No standard treatment for TKI-induced diarrhea has been established, although probiotics are commonly used. In several patients TKI dose reduction is necessary. Data showing the interplay between microbiota and TKI-induced diarrhea are reported. The therapeutic modulation of gut microbiota could be useful to ameliorate TKI-related diarrhea. Our study aims to explore the efficacy and safety of fecal microbiota transplantation (FMT), compared with current clinical practice approach, for the treatment of TKI-associated diarrhea in patients with metastatic renal cell carcinoma. Methods: Patients on treatment with Pazopanib/Sunitinib as first line therapy for metastatic renal cell carcinoma and TKI-associated diarrhea (³ 4 stools per day over baseline) were randomize to receive FMT from healthy donor by colonoscopy (fresh faeces) or probiotics (L. casei DG). The primary endpoint was the resolution of TKI-related diarrhea. Baseline fecal samples were collected from all patients and donors. All patients were followed up 7, 15, 30 and 60 days after the treatment for diarrhea. Results: 21 subjects, 10 in FMT arm and 11 in control arm, have been enrolled. At 7 day-follow-up, TKI-related diarrhea disappeared in 10 patients of the FMT group and in 6 patients of the control group (100% vs 54.5%, p = 0.02). At 15-day and 30-day, 9 patients in the FMT group and 0 patients in the control group experienced resolution of diarrhea (90% vs 0%, p = 0.0001). At 60-days 8/10 patients in FMT arm did not have diarrhea. Dose reduction was necessary in 4 patients of the control group. No serious adverse events associated with any of the two treatment protocols were observed. Metagenomic analyses on collected stool samples are ongoing. Conclusions: This open-label randomised controlled trial showed the effectiveness and safety of FMT compared with probiotics in curing TKI-related diarrhea in patients with metastatic renal cell carcinoma, avoiding the necessity of dose reduction. Considering the increasing evidence, the modulation of microbiota trough FMT could also affect the efficacy of immunotherapy for metastatic renal cell carcinoma.
Genomic biomarkers of response to nivolumab/ipilimumab (nivo/ipi) and nivolumab (nivo) monotherapy in 108 patients with advanced renal cell carcinoma.
Authors: Lee Chung-Han , Di Natale Renzo G , Chowell Diego , Makarov Vladimir , Redzematovic Almedina , Murray Samuel J. , Carlo Maria Isabel , Voss Martin Henner , Feldman Darren R. , Motzer Robert J. , Chan Timothy An-thy , Hakimi A. Ari 
Published: March 2019

641 Background: Both the combination of nivo/ipi and nivo monotherapy have shown efficacy across multiple malignancies including clear cell Renal Cell Carcinoma (ccRCC). Biomarkers such as tumor mutation burden (TMB) are prognostic in other malignancies, however, remain unvalidated in ccRCC. This study investigates genomic biomarkers associated with nivo/ipi and nivo clinical response. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor derived DNA from nivo/ipi and nivo treated patients from MSKCC and publicly available WES datasets (Miao D, Science, 2018, 359: 6377). Somatic mutations, TMB, neoantigen load (NA), and HLA zyogosity were correlated to objective response rate (ORR), progression free survival (PFS), and Overall Survival (OS). Alterations occurring in < 10% of the cohort were considered non-evaluable (NE). Results: 108 patients had tumors studied; 32 patients with nivo/ipi and 76 patients with nivo therapy. No individual factors showed significant correlations to ORR or both PFS and OS. In the combined cohort, homozygosity at HLA-C was associated with shorter OS (HR=2.55 95% CI 1.17-5.57; P=0.02). In the nivo/ipi cohort, TMB (HR=0.36 95% CI 0.16-0.84; P=0.02) and NA (HR=0.43 95% CI 0.19-0.98; P=0.04) were associated with longer PFS. Conclusions: Increased TMB and NA load may predict for improved outcomes, and homozygosity at HLA loci may predict for worse outcomes. The predictors of response to nivo may not be generalizable to nivo/ipi. To rule out artifacts of multiple testing in a small cohort, validation in a larger dataset is necessary. [Table: see text]
Effect of immunotherapy (IO) on primary renal tumor in metastatic renal cell cancer (mRCC).
Authors: Jamet Antoine , Caramella Caroline , Guida Annalisa , Arfi-Rouche Julia , Merabet Zahira , Colomba Emeline , Escudier Bernard , Albiges Laurence 
Published: March 2019

649 Background: Recent data showed that cytoreductive nephrectomy (CN) should not be performed prior to systemic therapy in intermediate and poor risk groups. Immune checkpoint inhibitors (ICI) are now approved in first and second line in mRCC, but ICI effect on the primary tumor is unknown. Methods: All patients (pts) treated with ICI for mRCC without prior CN were retrospectively collected and sequential computed tomography (CT) scan evaluated for response. Primary objective was Objective Response Rate (ORR) in the primary renal tumor in the primary RECIST 1.1. Secondary objective included systemic ORR and nephrometry score changes. Results: A total of 20 pts were treated with ICI with primary tumor in situ between 12/2012 and 10/2018. Among these, CT scans were available for evaluation of response for 19 primary tumors in 18 pts. Median age was 59.5 years. Pathology was 16 clear cell RCC, 2 translocation RCC, 1 Collecting duct carcinoma. Baseline median primary renal tumor size was 7.3 cm. ICI was used in first line setting in 7 pts, in second line or beyond in 13 pts. IMDC risk group at ICI start was favourable in 2 pts, intermediate in 9 pts and poor in 9 pts. ICI used was NIVOLUMAB(N) single agent in 13 pts or in combination in 7 pts (6 N-IPILIMUMAB and 1 N-VEGFRTKI). After a median follow up of 6.5 month from ICI start and a median duration of immunotherapy of 3.0 month, ORR on the primary tumor, was 3/19 (16%) (1 CR and 2 PR), 14 tumors (74%) were stable, and 2 had PD as best response. Median change in primary renal tumor was -1%. ICI use did not change nephrometry score. At extra renal assessment, ORR (systemic) was 5/18 (28%), (2 CR, 3 PR), 5 (28%) SD, and 8 (44%) PD (including 1 with new lesion and 1 with non-target lesion PD). Interestingly, 4 pts/18 (22%) had mixed response with opposite response between primary and systemic response. Furthermore, 11/18 (61%) would not classified in same RECIST group (CR, PR, SD, PD) between primary and metastatic sites assessment. Conclusions: To our knowledge, we report the first cohort of patients treated with ICI investigating the response on the primary tumor. ICI can induce a significant reduction in primary renal tumor, especially complete response and therefore raise the question of delayed CN in responders under ICI.
Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: A single center, single arm trial.
Authors: Chatzkel Jonathan Alexander , Swank Jennifer , Ludlow Steven , Lombardi Kristina , Croft Cortlin , Artigas Yesenia , Rodriguez Yazmin , Terraciano Tina , Hart Sarah , Rembisz Jennifer , Johnson Elaine , Schell Michael J. , Yao Jiqiang , Zhang Jingsong , Fishman Mayer N. 
Published: March 2019

657 Background: Ligation of IL-2 receptor or blockade of PD-1 receptor may change lymphocytes to induce regression of cancers with diverse histology or site of origin. Single agent objective response rates of 14-25% have been reported for IL-2 therapy of metastatic clear cell RCC (ccRCC). A response rate of 33% was observed in pembrolizumab treated ccRCC patients. Nivolumab treated ccRCC patients were observed to have early intratumoral migration of lymphocytes. A case report of IL-2 induced major regression right after no change on nivolumab therapy suggested that combining the two means of lymphocyte stimulation could be effective. Other trials combining IL-2 receptor agonists (NKTR-214) and PD-1 blockade have also reported regression of ccRCC. Distinctive attributes of high dose IL-2 therapy are the required inpatient stay and the durability of the complete responses. Methods: This single-institution, single arm study addresses the safety and feasibility of the combination of IL-2 and pembrolizumab in the treatment of metastatic ccRCC. Subjects are treated on four nine-week blocks, as follows: Pembrolizumab is given on weeks 1, 4, and 7 of each block. Patients are admitted for 5 doses of high dose IL-2 (given over ~ 33 hours/3 days) on weeks 2, 3, 5, and 6 of blocks 2 and 3. Safety is monitored by a Pocock boundary of .05 likelihood of 0.15 dose limiting toxicity rate. The Simon 2-stage alternative hypothesis for the sample size was a 45+% major response rate vs null hypothesis < 20%, at alpha = 0.10, 90% power. Results: No accrual stop for safety was triggered. Thirteen of the first 18 patients responded, substantially exceeding the requirement of 8+/24 combination-treated patients to reject the null. Seven patients responded after receiving pembrolizumab alone, six after starting combination therapy in block 2. Accrual is completed; at 27. Kaplan-Meier analysis projects ORR of 69%, with ORR 90%-lower confidence bound of 55%. Conclusions: The combination of high dose IL-2 and pembrolizumab is feasible, with a high response rate, justifying further exploration of this dual immune treatment of metastatic ccRCC. Clinical trial information: NCT02964078.