bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective, open label, multicenter, randomized phase II trial: Sequential therapy with bevacizumab, RAd001 (everolimus) and axitinib in metastatic renal cell carcinoma (mRCC) (BERAT study).
Authors: Grünwald Viktor , Bergmann Lothar , Goebell Peter J. , Strauss Arne , Meiler Johannes , Hartmann Arndt , Bedke Jens 
Published: May 2019

e16097 Background: Inhibitors of the vascular endothelial growth factor (VEGF), its receptor (Ri) or mammalian target of rapamycin (mTORi) are components of systemic treatment in metastatic renal cell carcinoma (mRCC) and are applied in sequence. We compared the efficacy of VEGFRi and mTORi in 2nd line after failure of bevacizumab/interferon in a phase II trial. Methods: Key inclusion criteria were: measurable mRCC (all histologies), ECOG 0-1, IMDC risk: good or intermediate, adequate organ function. Tumor status was assessed in week 11 and q12 wks., thereafter. Measures of Health-related quality of life (HR-QoL) utilized FKSI-10 and was assessed in week 4, 10 and q12 wks., thereafter. 1st line consisted of bevacizumab 10mg/kg q2wks. + interferon 9*106 IE 3x/week (BEV/IFN). Upon progression or intolerance, patients were re-screened and randomized between VEGFRi (axitinib 5 mg BID, dose-escalation permitted; sunitinib 50 mg OD, 4-2 regimen) and everolimus (EVE) treatment (10 mg OD). Cross-over occurred at time of progression or intolerance. Improvement of 2nd line PFS-rate at 6 mo. from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, ORR, OS, safety and HR-QoL. Results: Between November 2012 and June 2015 a total of 22 of 100 patients were included and at that time stopped for poor accrual. 10 pts. (46%) were randomized to receive 2nd line treatment with everolimus (n = 5) or VEGFRi (n = 5). At study entry (2/10) 20% had nephrectomy. ECOG 0 was recorded in 20% (EVE) and 60% (VEGFRi), respectively. Objective response rate (ORR) to 1st line BEV/IFN was 20%. In 2nd line treatment all patients experienced adverse events (AE). Grade ≥3 AEs occurred in 2/5 (40%) (EVE) and 4/5 (80%) (VEGFRi) pts., respectively. SAEs occurred in 3/5 (60%) in each arm. ORR was 1/5 (20%) for axitinib and 0/5 (0%) for EVE. PFS rate at 180 days was 20% in each arm. Median PFS was 3.7 (EVE) and 2.2 mo. (VEGFRi) HR 1.0 (95%CI 0.26-3.85; p = 0.997). OS was comparable between arms HR 1.12 (95%CI 0.27-4.61; P = 0.872). 7 pts. crossed over to 3rd line treatment. Conclusions: The small number of pts. randomized to EVE or VEGFRi is a major limitation of our trial, but may mirror the current change of treatment reality. However, no significant difference was detected for the PFS rate at 6 mo., indicating the limited activity of EVE or VEGFRi in 2nd line treatment. Clinical trial information: NCT01731158.
Deep learning segmentation of kidneys with renal cell carcinoma.
Authors: Yin Kevin , Liu Chengfeng , Bardis Michelle , Martin Jeremy , Liu Hannah , Ushinsky Alexander , Glavis-Bloom Justin , Chantaduly Chanon , Chow Daniel S. , Houshyar Roozbeh , Chang Peter 
Published: May 2019

e16098 Background: Renal cell carcinoma (RCC) is the most common kidney malignancy and the eighth most common cancer overall, with more than 60,000 new cases and nearly 15,000 deaths in the United States each year. The majority of RCC is asymptomatic and detected incidentally on computed tomography (CT) scans performed for other indications. Multiple prior studies have highlighted the potential for a lesion to be missed or mischaracterized. Artificial intelligence (AI), the mimicking of human cognition by computers, has promise for improving radiological accuracy. Convolutional neural networks (CNNs), a type of AI, apply a feed-forward design to an artificial neural network. Multi-layered CNNs thus have application in biomedical imaging and radiology. In this study we describe an approach for automatic localization and segmentation of the kidneys on contrast enhanced CT scan. Methods: This IRB approved retrospective study included patients who were diagnosed with RCC and had an abdominal CT scan with IV contrast from 2011 to 2019. For each abdominal CT scan, the kidneys and any renal lesions were manually segmented by a board-certified abdominal radiologist on the coronal post-contrast phase of the CT scan. Two CNNs were developed and trained to segment the kidneys automatically. Initially, the CNN implemented a regression algorithm that predicted a 3D bounding box around each kidney. Subsequently, the second CNN used a 3D/3D U-Net algorithm that received the bounding cube as its input and outlined the kidney as an output. After training, the CNN algorithms were assessed by a Sørensen-Dice coefficient. Results: The first CNN that predicted a 3D bounding box around each kidney was trained on 127 abdominal CT exams. The second CNN that segmented the kidneys with RCC was trained on 259 bounding boxes that encompassed the kidneys. The Sørensen–Dice coefficient for segmentation of the kidneys with RCC was 0.92. Conclusions: These results demonstrate that two CNNs can be used in succession to segment the kidneys with RCC on a coronal CT image with high accuracy. Moreover, as the subjects included patients with RCC, medical renal disease, and cystic renal disease, the outcome further supports the role of CNN in evaluation of complex cases rather than pristine training sets. Future work will focus on segmentation of RCC lesions.
Detection of circulating tumor DNA in patients with metastatic clear cell renal cell carcinoma.
Authors: Nappi Lucia , Bacon Jack , Annala Matti , Soleimani Maryam , Lavoie Jean-Michel , Chi Kim N. , Wyatt Alexander William , Kollmannsberger Christian K. 
Published: May 2019

e16105 Background: Clear cell renal cell carcinoma (ccRCC) represents the most common presentation of kidney cancer. Patient outcomes have significantly improved with the approval of several targeted agents over the past decade. However, the lack of predictive biomarkers has hampered treatment optimization. Circulating tumor DNA (ctDNA) has emerged as an effective, minimally-invasive alternative to tissue for profiling the tumor genome in other tumors. Methods: Blood samples were collected from patients (pts) with metastatic ccRCC for next-generation sequencing of cell free DNA and germline DNA. Targeted sequencing was performed using the Roche Human Oncology Design panel of 981 genes to a median depth of 937x unique reads. Matched FFPE tissue was available from 14 pts and profiled using the same assay. Results: Samples from 52 metastatic, treatment-naïve pts were analyzed. Germline mutations were detected in 6/52 (11%) of the pts with the most frequent abnormalities affecting ATM, PALB2, RAD51D, CHEK2, BRCA1. Median ctDNA fraction was 3.9% (2-40%) with a median of 2 mutations/pt. Somatic mutations were detected in 29/52 (56%) of the samples; of those, 15/29 (51%) of pts harbored RCC-related genes mutations, 3/29 (10%) non-coding mutations and 10/29 (34%) alterations in non RCC-associated genes. Median variant allele frequency was 1.9% (1-22%). Consistent with tissue-based reports, VHL, BAP1, PBRM1, and TP53 were the most frequently altered genes. Lastly, 50% of the patient-matched FFPE tissue samples shared a fully concordant mutation profile. Conclusions: We confirmed a high prevalence of germline mutations in pts with ccRCC. The rate of ctDNA detection in metastatic ccRCC appears to be lower than in other metastatic solid tumors. Furthermore, it is not yet clear whether all the detected somatic alterations are strictly ccRCC-ctDNA dependent. Nevertheless, a quarter of pts exhibited clinically-informative ccRCC associated alterations in their liquid biopsy. These findings suggest that ctDNA is a promising tool for genomic profiling in a subset of patients with metastatic ccRCC.
A novel predictive biomarker of immunotherapy response in metastatic renal cell carcinoma (mRCC): The lymphocyte microRNA expression profile.
Authors: Incorvaia Lorena , Fanale Daniele , Badalamenti Giuseppe , Rinaldi Gaetana , Vincenzi Bruno , De Luca Ida , Galvano Antonio , Corsini Lidia Rita , Gristina Valerio , Guarini Aurelia , Simonato Alchiede , Tonini Giuseppe , Bazan Viviana , Gori Stefania , Porta Camillo , Russo Antonio 
Published: May 2019

e16109 Background: Predicting which patient with metastatic renal cell carcinoma (mRCC) will benefit from immune checkpoints inhibitors (ICPIs) still remain an issue. Biological factors particular to certain individuals have a clear effect on variation in response. Emerging evidence suggests that small non-coding RNA, such as microRNAs (miRNAs), are critical modulators of numerous cellular processes, including immune surveillance. The main aim of this study was to analyze the lymphocyte miRNA expression profile in mRCC patients and dynamic changes after the treatment with ICPI, in order to investigate the molecular mechanisms and signaling pathways involved in ICPI response and their potential role as predictive biomarker. Methods: Total RNA and miRNAs were isolated from peripheral lymphocytes of 14 mRCC patients, treated with nivolumab as second line. The blood samples were collected before nivolumab treatment (T0) and at progression disease (T1). The quality and quantity of miRNAs were assessed using the miRNeasy Mini Kit, 2100 Bioanalyzer and spectrophotometer NanoDrop ND-1000. Through a TaqMan Low Density Array A human microRNA microarray analysis, the expression profile of 377 lymphocyte miRNAs was analyzed. A cut off of fold change > 2 was considered for up-regulated miRNAs and < 0.3 for down-regulated. The patients were divided into 2 groups: patients with PD within 6 months of treatment (G1), and patients with stable therapy response (RC, RP or SD) over 12 months (G2). Results: Microarray analysis showed a subset of 59 miRNAs involved in several cancer-related processes, including cell cycle regulation, PI3K/Akt, FOXO and HIF-1 signaling pathways, differentially expressed in peripheral lymphocytes of mRCC of G1 and G2 group of patients. Among all miRNAs analyzed, several were deregulated, such as miR-155, miR-22, miR-24, miR-484, miR-335 and miR-492, some up-regulated and others down-regulated. This deregulation of specific miRNAs was different into G1 and G2 groups, and seem to be related with the duration of response to ICPI. Conclusions: Our data, for the first time, study the expression profile of miRNAs in the peripheral lymphocytes, and show a correlation between deregulation of miRNAs and response to Nivolumab. These knowledge could help to identify potential biomarkers predictive of response to ICPIs for the personalization of treatment.
Comparative analysis of profiles of second-line stage IV renal cell carcinoma patients by first-line to second-line treatment sequencing in the United States.
Authors: DaSilva Corrina , Spindel Julie , Franceschetti Alessandra 
Published: May 2019

e16110 Background: Treatment of metastatic renal cell carcinoma (RCC) is evolving. With new agents, 2nd line (2L) therapies becoming frontline (1L) options, and growing research on outcomes, optimal treatment sequencing is increasingly complex. Methods: Real world data from Ipsos Global Oncology Monitor©: geographically representative physicians in US reported on 1,120 stage IV RCC anti-cancer drug-treated patients seen in consultation from 10/2017–9/2018, providing patient demographics, current and historic treatment data. Analysis of 1L to 2L treatment algorithm was conducted for current 2L patients. Patient profiles of 2 most frequent algorithms [TKI-TKI (n = 298) and TKI-CKI (n = 443)] were compared using inferential statistics. Results: Patients treated with 1L TKI and 2L CKI (TKI-CKI) vs. those treated with 1L TKI and 2L TKI (TKI-TKI) are older (mean: 65.8 vs 62.7; p < 0.05), have metastases in ≥ 2 sites (52% vs 36%; p < 0.01) and maintained 1L treatment for longer (mean: 10.0 vs 8.8 months; p < 0.05). 2L CKI patients were more likely to have achieved CR, VGPR or PR from 1L TKI (60% vs. 50%; p < 0.05) and less likely to have distant progression (19% vs. 26%; p < 0.05) or discontinued 1L TKI due to toxicities (9% vs. 16%; p < 0.01). 2L CKIs are more likely prescribed due to new clinical data (20% vs 12%; p < 0.05) and biomarker results (7% vs 2%; p < 0.05); 2L TKIs are prescribed more for convenience (10% vs 4%; p < 0.01). Physicians prescribed 2L CKIs more frequently with intent to extend life (53% vs 40%; p < 0.01) than palliative intent (47% vs 60%; p < 0.05). TKI-CKI patients were more involved in 2L treatment choice (17% vs 8%; p < 0.01) and physicians stated higher satisfaction with their current CKI (36% vs 26%; p < 0.01) relative to TKI-TKI patients.Conclusions: TKI-CKI patients are likely to have a more progressed disease, but also to have had a more positive outcome from 1L TKI, suggesting a therapeutic strategy driven by clinical attributes. New clinical data reinforce prescribing CKIs to extend life rather than for palliative purposes. When prescribing CKIs, patient involvement is higher (possibly due to mode of administration requiring more commitment) and physicians are more satisfied with results (despite these patients being older and with more metastases).
Stereotactic radiotherapy for stage I renal cell carcinoma: Overall survival and treatment trends compared to thermal ablation and surgical resection.
Authors: Uhlig Annemarie , Uhlig Johannes , Trojan Lutz , Kim Hyun S. 
Published: May 2019

e16111 Background: Stereotactic radiotherapy (SRT) is a non-invasive treatment modality that is currently evaluated for use in renal cell cancer (RCC). We aimed to evaluate current utilization of SRT for stage I RCC and compare associated overall survival with thermal ablation (TA) and partial nephrectomy (PN). Methods: The 2004-2015 United States National Cancer Database was searched for histopathologically approved stage I RCC treated with PN, cryoablation (CRA), radiofrequency- or microwave-ablation (RFA/MWA) or SRT. Patients were propensity score matched to account for potential confounders. Overall survival (OS) was evaluated with Kaplan-Meier plots, log-rank tests and Cox proportional hazards models. Results: A total of 91,965 patients were included (SRT n = 174; PN n = 82,913; CRA n = 5,446; RFA/MWA n = 3,432).Stage I SRT patients tended to be older females with fewer comorbidities and treated at non-academic centers in New England states. After propensity score matching, a cohort of n = 660 patients was obtained with well-balanced distribution of confounders between the different treatment strategies. In the matched cohort, OS following SRT was inferior to PN and thermal ablation (PN vs. SRT HR = 0.33, 95% CI: 0.22-0.50, p < 0.001; CRA vs. SRT HR = 0.44, 95% CI: 0.30 – 0.66, p < 0.001; RFA/MWA vs. SRT HR = 0.53, 95% CI: 0.36-0.77, p < 0.001). OS following CRA was comparable to PN (HR = 1.35, 95% CI: 0.84-2.18, p = 0.216), while OS following RFA/MWA was inferior to PN (HR = 1.61, 95% CI: 1.01-2.56, p = 0.046). OS rates are summarized in table 1. Conclusions: Only a minority of RCC patients receive SRT. In stage I RCC, current renal SRT protocols yield lower overall survival compared to thermal ablation and resection, while CRA and PN show comparable outcomes. Based on the current body of evidence, SRT for RCC should be reserved for clinical trials or exceptional clinical circumstances.[Table: see text]
Hypoxia signaling and immune infiltration in a presurgical trial of sunitinib in patients with clear cell renal cell carcinoma (RCC).
Authors: Hasanov Elshad , Peterson Christine B , Matin Surena F. , Wood Christopher G. , Sircar Kanishka , Tannir Nizar M. , Jonasch Eric 
Published: May 2019

e16115 Background: Presurgical clinical trial design allow for pharmacodynamically relevant tissue collection that can inform regarding drivers of tumor biology. An unmet need is the ability to identify tumors that may respond to immunotherapy and the underlying mechanism of immune infiltration. Methods: This single arm phase II study was designed to test efficacy and safety of presurgical sunitinib treatment in metastatic RCC, and to identify drivers of tumor biology. Patients (pts) with metastatic RCC and a resectable primary received sunitinib 50mg PO daily for four weeks, and underwent restaging. If deemed a candidate, pts underwent cytoreductive nephrectomy (CN) during their second cycle of sunitinib, with last dose administered the day before surgery. Pts were restaged postoperatively and continued on sunitinib if no progressive disease was seen. Genomic and histological characteristics of RCC were evaluated for correlations between response and biological features. Results: Between June 2008 and October 2011, 50 pts were enrolled. 41 underwent CN. Seven pts showed refractory disease and were not considered surgical candidates. No sunitinib related perioperative toxicities were observed. Six pts progressed on first postoperative imaging studies, with three patients developing new brain metastases. Median progression free survival (PFS) was 8.6 months, and overall survival was 38 months. Objective response rate was 30 percent with 2 pts demonstrating a complete response. Analysis on 39 pts showed HIF1a staining was significantly associated with PFS (p = 0.023*, univariate Cox model), with a hazard ratio (HR) of 1.028 (95% CI, 1.004-1.053). This association remained significant in a multivariate Cox model adjusting for age and gender (p = 0.019*). In addition, HIF1a correlated with multiple immune markers (CD8, CD45RO, PD1, Treg, CD68, and LAG3). Analysis of genomic correlates is ongoing. Conclusions: Presurgical sunitinib therapy in RCC is safe and efficacious. HIF1a staining is associated with shorter PFS, and with increased immune infiltration. Tissue HIF1a should be explored as a marker, and studied mechanistically as a driver of the immune microenvironment in RCC. Clinical trial information: NCT00715442.
A study of tobacco abuse as a risk factor for adrenal cortical carcinoma.
Authors: Kolodney Joanna Amy , Kolodney Michael , Patterson Jessica , Hagen Rachael , Smolkin Matthew , Hobbs Gerald , Hogan Thomas F. , Hafez Maria , Albandar Heidar 
Published: May 2019

e16119 Background: Smoking has been suggested as a risk factor for adrenal cortical carcinoma (ACC), but, due to the rarity of this tumor, this hypothesis has only been inferred from single study using a mixed population of adrenal tumors that included pheochromocytoma and neuroblastoma as well as ACC. Methods: De-identified IRB exempted records were analyzed for age, gender, and smoking history in adult patients diagnosed with ACC in both the West Virginia University database containing 2,699,193 patients and, in the larger TriNetX database of 21,426,477 patients from 2008-2018. In addition, the statewide ratio of smoking to ACC prevalence was computed in all 50 states using data from SEER and the CDC. Results: Given the high rate of both tobacco use and ACC in the West Virginia Health System, we hypothesized that smoking contributed to increased prevalence of ACC in our state. We compared the rates of ACC and smoking in all 50 states using data from SEER. Among the 50 states, West Virginia had the highest smoking rate and the second highest rate of ACC. Utah had the lowest rate of smoking and the third lowest rate of ACC. The sample correlation between statewide smoking and ACC is .4177 indicating a significant association between the two (p = .0035). From 2008 to 2018, 20 patients with ICD10 code c74.0 (ACC) were abstracted from our EMR system. Examination of the individual charts determined 15 of the 20 patients had confirmed ACC diagnosis. This cohort was compared with matched age and gender matched controls. In the control group, there 13.3% were smokers while in the ACC group, 60% were smokers. The difference is significant (p = .0005) (OR) = 9.75 (95% CI; (2.54, 37.38). We next reviewed the larger TriNetX database and found that the prevalence of smoking in the ACC group to be 35.2% as compared to 9.0% in the TriNetX group(p-value < .0001). Conclusions: Our retrospective review strongly supports smoking as a major risk factor ACC. To our knowledge, this is the first study to demonstrate a strong association of smoking in a cohort of biopsy proven ACCs.
Whole genome and transcriptome analysis (WGTA) of metastatic adrenocortical carcinoma (mACC).
Authors: Lavoie Jean-Michel , Csizmok Veronika , Wang Gang , Williamson Laura , Marra Marco A. , Laskin Janessa J. , Jones Steven J. M. , Renouf Daniel John , Kollmannsberger Christian K. 
Published: May 2019

e16123 Background: mACC is a rare disease, and no standard treatments exist beyond cytotoxic chemotherapy and mitotane. Recurrent molecular changes have been described, but their clinical significance is still poorly understood, and whether they can guide treatment is unknown. Methods: The genomic and transcriptomic profiles of 6 pts with mACC were analyzed as part of a prospective molecular profiling clinical trial (NCT02155621). Findings were correlated with histopathological and clinical data. Results: Whole genome sequencing of six ACC tumors and matched normal tissues was performed; whole-transcriptome sequencing was performed on five of the six tumors. All cases met Weiss criteria for ACC (including 1 pt with oncocytic ACC). Profiling revealed gain of function variations in CTNBB1 gene in 3 cases (p.S45A, p.S45P and homozygous deletion of exons 2 and 3). A stop-gained mutation (Q167*) and a homozygous copy loss of TP53 gene was observed in 2 cases; mutations of CTNBB1 and TP53 co-occurred in one case. Variations in other DNA repair genes included germline FANCA Q1362* and somatic BRCA2 E790* stop-gained mutations, and a structural variation in RAD52. Copy number amplification was observed for KDM5A (2/6) and RAD52 (2/6), while NF1 (1/6), CDKN2A (1/6), CDKN2B (1/6) and RB1 (2/6) were subjected to homozygous copy losses. Average ploidy models: one diploid, 4 triploid and one tetraploid case; whole chromosome copy losses and gains were seen in all samples. Three cases showed high homologous repair deficiency scores; associated with respectively, an in-frame deletion of V613 in ATM, a TP53 homozygous loss, and a structural variant of RAD52. All six cases exhibit signature 3 or signature 8. At last follow-up, 2 pts remained alive. Treatments included cytotoxic chemotherapy, mitotane, streptozotocin, sunitinib, avelumab with a SMAC mimetic (NCT02022098), a TTK inhibitor (NCT02792465) on the basis of a CTNNB1 mutation and temozolomide with olaparib on the basis of ATM loss. Conclusions: Our findings recapitulate published data on the molecular profile of mACC and support previous findings of large scale chromosomal variation. We identify new potential drivers in chromatin remodelling, cell cycle, and DNA damage repair genes.