bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT).
Authors: Mandair Dalvinder , Demetriou George , Diamantopoulos Leonidas-Nikolaos , Devakumar Haran , Popat Rickin , Laskaratos Faidon , Caplin Martyn E. , Toumpanakis Christos 
Published: September 2018

4090 Background: The efficacy of peptide-radiolabelled receptor targeted therapy (PRRT) in patients with well differentiated neuroendocrine tumours has been demonstrated in Phase II and Phase III studies. The recently completed phase IV NETTER-01 demonstrated disease stabilisation or partial response in approximately 80% of patients. However, more studies are needed to identify predictors of PRRT response. We sought to investigate the clinic-pathological characteristics in patients that had radiological progression or death within 12 months of completion of treatment with PRRT. Methods: We performed a retrospective analysis of all patients who had PRRT from 2011-2016. Patient with at least one year of follow-up data from the last treatment dose were included. Patients with evidence of radiological progression within one year of finishing treatment (Group 1) were compared to a similar group with disease stabilisation/response (Group 2)that were matched for age, grade, primary and distribution of metastases. The indication for PRRT was defined as either small volume progression ( < 20%) or progression by RECIST. Results: 307 patients underwent PRRT with Lu-177 or Y-90 DOTATATE during this period. 66 patients in Group 1 were compared to 64 patients in Group 2. There was a significant difference in median overall survival, Group 1 = 21 months compared to Group 2 = 35 months, (p < 0.002). A significantly higher proportion of patients in group 1 had more than 50% liver volume (p < 0.0001). Mean CgA was significantly higher in Group 1, 1250 pg/ml vs 608 pg/ml in Group 2 ( p < 0.03). 18 patients in Group 2 had small volume progression prior to treatment commencement compared to 6 in Group 1 (p < 0.003). Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be conisdered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.
Comprehensive molecular characterization and analysis of muscle-invasive urothelial carcinomas.
Authors: Lerner Seth P. , Robertson Gordon , Kim Jaegil , Cherniack Andrew , Guo Guangwu , Akbani Rehan , Kanchi Rupa S , Hoadley Katherine A. , Hinoue Toshinori , Laird Peter W. , Al-Ahmadie Hikmat , Bellmunt Joaquim , Castro Mauro , Gordenin Dmitry , Mills Gordon B. , Sanchez-Vega Francisco , Shukla Sachet A , Gibb Ewan A , Weinstein John N. , Kwiatkowski David J. ,   TCGA Network
Published: September 2018

4500 Background: We reported the integrated molecular analysis of 131 tumors in 2014 (Nature 507:315, 2014) and now report on the entire cohort of 412 tumors from the TCGA project in chemotherapy-naïve, muscle-invasive urothelial bladder cancer. Methods: Following strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations (WES), DNA methylation, mRNA, non-coding RNA (lncRNA and miRNA) and (phospho-) protein expression, gene fusions, viral integration, pathway perturbation, clinical correlates, outcomes, and histopathology. Results: There was a high overall somatic mutation rate (8.2/Mb), as previously reported. There were 58 significantly mutated genes (SMGs) (MutSig_2CV), increased from 32 in the original report. We identified 5 mutation signatures including APOBEC-a and b, ERCC2, C > T_CpG, and a single ultra-mutated sample with a functional POLE mutation. APOBEC mutagenesis explained 70% of the mutation burden and was associated with survival (p = 0.0013). High mutation burden and neoantigen load were also associated with improved outcome (p = 0.00014 and 0.00078). The previously identified four mRNA subtypes were predicted on the larger set and also identified a novel poor-survival ‘neuronal’ subtype that nevertheless lacked small cell or neuroendocrine histology. Clustering converged for mRNA, lncRNA and miRNA expression, and for inferred activity of gene sets associated with regulator expression. We identified subsets with differential epithelial-mesenchymal transition scores, carcinoma-in-situ scores, and survival, with implications for distinct therapeutic potential. Conclusions: This integrated analysis of 412 TCGA patient samples validates and extends observations from the first 131 patients and significantly increases our power to detect additional low-frequency aberrations. The results provide unique insights into mechanisms of bladder cancer development, and identify novel subsets of MIBC that may benefit from differential treatment approaches.
Subclonal mutational heterogeneity and survival in cisplatin-resistant muscle-invasive bladder cancer.
Authors: Liu David , Abbosh Philip , Keliher Daniel , Reardon Brendan , Mouw Kent William , Taylor-Weiner Amaro , Mullane Stephanie Anne , Han Garam , Teo MinYuen , Kim Jaegil , Al-Ahmadie Hikmat , Iyer Gopa , Dulaimi Essel , Chen David , Hoffman-Censits Jean H. , Carter Scott L. , Bellmunt Joaquim , Plimack Elizabeth R. , Rosenberg Jonathan E. , Van Allen Eliezer Mendel 
Published: September 2018

4512 Background: Biomarkers of survival and resistance in chemotherapy-resistant muscle-invasive bladder cancer (MIBC) are not well-characterized, but may inform management in this setting. Methods: Matched pre- and post-neoadjuvant cisplatin-based chemotherapy (NAC) tumor samples were obtained from 30 MIBC patients with gross residual disease (≥ pT2) at cystectomy, followed by whole exome sequencing of these “trios” (pre- and post-NAC tumor with matched germline samples). Phylogenetic analysis of matched tumor samples was performed to identify subclones, their associated mutations, and the corresponding enrichment in post-treatment tumors. Intratumoral heterogeneity was assessed by the proportion of mutations that were subclonal; the number of inferred subclones; and associated with overall survival using a Cox Proportional Hazards model. Results: Increased proportion of subclonal mutations in post-treatment tumors was associated with worse overall survival (HRR 1.86 [95% CI 1.12-3.06], p = 0.02), whereas pre-treatment proportion of subclonal mutations was only borderline statistically significant (HRR 1.48 [95% CI 0.99-2.20], p = 0.052). The total number of inferred tumor subclones in pre- or post-treatment tumor (or both) was associated with overall survival (HRR 1.60 [95% CI 1.05-2.43], p = 0.03), interpreted as a 60% increase in death rate per additional inferred subclone. While no single gene was statistically significantly enriched for new alterations in the post-chemotherapy resistant samples, we observed new post-treatment amplifications in cell-cycle genes ( E2F3, c-JUN), biallelic events in cell-cycle regulators ( FBXW7), and amplification of immune checkpoint genes ( PDL1/2). Conclusions: These results suggest that intratumoral heterogeneity (particularly post-therapy) predicts survival in a chemotherapy-resistant cohort. Further, alterations in cell cycle regulation may contribute to the mechanism of chemotherapy resistance. Finally, we observe evidence of immune checkpoint gene amplification post-treatment, suggesting that testing immune checkpoint blockade during NAC or, in high risk patients, following NAC may be warranted.
Phase II study of pazopanib in patients with von Hippel-Lindau disease.
Authors: Jonasch Eric , Gombos Dan S. , Waguespack Steven G. , Marcott Valerie , Liu Diane D , Weldon Justin Alexander , Bird Shelly , Robichaux Christine , Tannir Nizar M. , Woodson Ashley Henriksen , Fuller Greg , McCutcheon Ian E. , Matin Surena F. 
Published: September 2018

4516 Background: Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited disorder. Affected individuals develop vascular neoplastic lesions in multiple sites including eye, brain, pancreas, adrenal and kidney. Standards of care include surveillance imaging and surgical intervention. We hypothesized that treatment of VHL related lesions with an antiangiogenic agent would result in shrinkage of all lesion types. We chose the multikinase inhibitor pazopanib to test this hypothesis. Methods: After obtaining IRB approval, patients with clinical features or genetic confirmation of VHL disease and with measurable lesions were treated with pazopanib 800mg PO daily for two 12-week cycles. Efficacy was determined by RECIST after two cycles. Patients had the option to continue therapy if considered in patient’s best interest. Continuous monitoring for any lesion progression and drug discontinuation due to toxicity during the whole period of the treatment was planned. Results: Patients were enrolled (N=32) and treated (N=31) between 1/2012 and 6/2016. Median age was 37 (range 19-67). 23 patients had genomically confirmed VHL disease; four had family and personal history but had not undergone genetic testing, and five patients had clinical features of VHL disease and negative genetic testing. A median of two cycles (range 1-12) of therapy was administered. Of 31 evaluable patients, 13 (42%) showed a response, 18 patients had stable disease and no patients had PD as best response. Responses were seen in renal (2 CR and 29 PR/59 total), pancreatic (9 PR/17 total) and CNS 2 PR/49 total) target lesions. The most common side effect was diarrhea (grades 1 and 2) experienced in 14 patients. Twelve patients dose reduced to 600 mg and 6 to 400 mg pazopanib PO daily. Eight patients discontinued therapy due to adverse events of whom 4 experienced transaminitis. One patient experienced a grade V CNS hemorrhage. Conclusions: This is the largest prospective VHL disease specific therapeutic study performed to date. Pazopanib resulted in significant and sustained disease control for the majority of VHL patients enrolled on the study, with an acceptable safety profile. This agent may be considered as an alternative to surgical intervention in patients with VHL disease. Clinical trial information: NCT01436227.
Comparison of somatic mutation profiles from cell free DNA (cfDNA) versus tissue in metastatic urothelial carcinoma (mUC).
Authors: Cheng Michael L. , Shady Maha , Cipolla Catharine Kline , Funt Samuel , Arcila Maria E. , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Bajorin Dean F. , Berger Michael F. , Tsui Dana , Solit David B. , Iyer Gopa 
Published: September 2018

4533 Background: Next-generation sequencing (NGS) of cfDNA is an emerging non-invasive strategy to define tumor mutation profiles that counters spatial and temporal limitations of sequencing single tissue specimens. We examined the feasibility of NGS of cfDNA in mUC and compared mutation profiles from cfDNA to results of tissue NGS previously performed in the clinical setting. Methods: Plasma cfDNA was collected in mUC pts and analyzed using a capture-based NGS assay (MSK-IMPACT) targeting 341-468 genes. NGS profiles from cfDNA and archival tumor tissue (using the same assay) were analyzed in parallel with an established bioinformatics pipeline to identify somatic variants. Results: In 26 pts, NGS analysis of cfDNA detected ≥1 somatic mutations (range 1-21) in 69% (18/26). For 15 pts, NGS data was available from archival tissue (11 primary tumors, 3 metastases, and matched primary/metastatic tissue in 1 case). The interval between cfDNA and tissue collection ranged from 35 days to > 4 yrs. 73% (11/15) of pts received intervening treatment, including 47% (7/15) with chemotherapy, 67% (10/15) with immunotherapy, and 40% (6/15) with both. In 40% (6/15), cfDNA harbored alterations not found in archival tumor tissue. In 73% (11/15), some mutations within archival tissue were not detected in cfDNA, including hotspot HER2 S310F and FGFR3 S249C mutations. Tumor and cfDNA mutation profiles were identical in 20% (3/15), with the tumor/cfDNA interval in this group ranging from 35 days to < 1.5 yrs. Somatic alterations including hotspot ERCC2 P463A and PIK3CA E545K mutations were detected in cfDNA from 3 pts where archival tumor tissue NGS failed. Thus, cfDNA identified new mutations in 50% (9/18) of pts for whom cfDNA identified somatic mutations and tissue NGS was previously attempted. Conclusions: NGS of cfDNA from mUC pts is feasible and successfully detected actionable alterations when archival tumor sequencing failed. The differences between tumor and cfDNA mutation profiles in many pts may reflect tumor evolution or intratumor heterogeneity. Mutation profiles in mUC may be incompletely assessed with NGS of archival tissue, and further investigation of plasma cfDNA for genomic profiling is warranted.
Efficacy of epirubicin-paclitaxel (EPI-TAX) prior to high-dose chemotherapy (HDCT) in germ cell tumors (GCTs): A 17-year experience.
Authors: Lotz Jean-Pierre , Soares Daniele Grazziotin , Culine Stephane , Laverdant Benjamin , Kieffer Anne , Dabi Yohann , Gligorov Joseph , Selle Frederic 
Published: September 2018

4557 Background: GCTs patients (pts) relapsing after conventional-dose salvage chemotherapy (CDCT) are candidates to receive HDCT with hematopoietic stem cell (SC) support. We have previously reported (Ann Oncol 2014; 25:1775-82) that non-refractory pts can benefit from HDCT. We here analyzed the efficacy of the induction regimen EPI-TAX. Methods: All male GCTs pts treated by EPI-TAX between 1998 and 2015 were identified from clinical records at Tenon Hospital. Primary aim was response rate after EPI-TAX. Secondary aims were efficacy of SC harvest, Beyer score, toxicities and overall survival (OS) after HDCT. Kaplan-Meier methods were used for analysis. Results: Of the 170 pts treated (EPI 100 mg/m2, TAX 250 mg/m2, days 1-15), 142 (83.5%) had received > 2 previous lines of CDCT. 79 (46.5%) had disease progression at the time of treatment and 44 were absolutely refractory to cisplatin. The other pts were in remission (65) or had stable disease (SD, 26). Most of pts (75.3%) had Beyer score > 1. Following EPI-TAX, favorable responses were achieved in 140 pts (82.4%,CI95% 79.8-85.0; 21 complete responses, 68 partial responses and 51 SD). EPI-TAX was able to control disease in 56 (70.9%, CI95% 61.0-80.8) out of 79 pts who were in progression. Beyer score after EPI-TAX resulted 0 in 70.6% of pts. Successful harvested of SC was achieved in 146 (85.8%, CI95% 80.5-91.1) pts. EPI-TAX was well tolerated with peripheral neuropathy as the main non-hematopoietic toxicity. Treatment discontinuation was needed in 3 (1.8%) pts and 2 (1.2%) related deaths were observed. Following EPI-TAX, 155 (91.2%) pts received HDCT. HDCT was given in consolidation, once progressive disease was controlled by EPI-TAX or for progressive pts. With a median follow-up of 31 months (0.5-223) the 2- and 10-years OS for the subgroup consolidation were 78.2% (95%CI 69.1-87.4) and 66.9% (95%CI 55.4-78.6). Disease control by EPI-TAX resulted in 55.8% (95%CI 42.4-69.2) and 38.2% (95%CI 24.9-51.4) 2- and 10-y OS compared to 14.6% (95%CI 0-33.2, logrank p = 0.006) 2-y OS for progressive pts. Conclusions: EPI-TAX is effective to collect SC and to control disease of pts who were in progression after CDCT allowing them to receive HDCT.
Applying radiomics to predict pathology of post chemotherapy retroperitoneal nodal masses in germ cell tumors (GCT).
Authors: Lewin Jeremy Howard , Dufort Paul , Halankar Jaydeep , O'Malley Martin , Jewett Michael A.S. , Hamilton Robert James , Gupta Abha A. , Lorenzo Armando J. , Traubici Jeffrey , Nayan Madhur , Leao Ricardo Romao Nazario , Warde Padraig Richard , Chung Peter W. M. , Anson-Cartwright Lynn , Sweet Joan , Hansen Aaron Richard , Metser Ur , Bedard Philippe L. 
Published: September 2018

4559 Background: After chemotherapy, > 50% of patients (pts) with metastatic testicular GCT who undergo retroperitoneal lymph node dissection (RPNLD) for residual masses are found to have fibrosis (F) alone on pathological examination. To minimize overtreatment, better prediction algorithms are needed to identify pts with F who can avoid RPLND. Radiomics uses image processing techniques to extract quantitative textures/features from tumor regions of interest (ROI) to train a classifier that predicts pathological findings. We hypothesized that radiomics may identify pts with a high predicted likelihood of F who may avoid RPLND. Methods: Pts with GCT who had an RPLND for nodal masses > 1cm after first line platinum chemotherapy were included. Preoperative contrast enhanced axial CT images of retroperitoneal ROI were manually contoured. 153 radiomics features trained a radial basis function support vector machine classifier to discriminate between viable GCT /Mature Teratoma (T) vs F. Nested ten-fold cross-validation protocol was employed to determine classifier accuracy. Clinical variables and restricted size criteria were used to optimize the classifier. Results: A total of 82 pts with 102 ROI were analyzed (GCT: 21; T: 41; F: 40). The discriminative accuracy of radiomics to identify GCT/T vs F was 72%(±2.2)(AUC: 0.74 (±0.028); positive predictive value: 67% (48-92%); negative predictive value: 74% (62-84%)(p = 0.001)). No major predictive differences were identified when data was restricted by varying maximal axial diameters (AUC range: 0.58(±0.05) - 0.74(±0.03)). Prediction algorithm using clinical variables alone identified an AUC of 0.71 (±0.15). When these variables were added to the radiomic signature, the best performing classifier was identified when axial tumors were limited to diameter < 2cm (accuracy: 88.2 (±4.4); AUC: 0.80 (±0.05)(p = 0.02)). Conclusions: A predictive radiomics algorithm had an overall discriminative accuracy of 72% that improved to 88% when combined with clinical details. Further independent validation is required to assess whether radiomics, in conjunction with standard clinical predictors, may allow pts with a high predicted likelihood of F to avoid RPLND.
Microvessel density as a prognostic marker in high-risk renal cell carcinoma.
Authors: Weiss Sarah A. , Puligandla Maneka , Jilaveanu Lucia , Haas Naomi B. , Wang Xin Victoria , Zito Christopher , Boeke Marta , Neumeister Veronique , Manola Judith , DiPaola Robert S. , Kluger Harriet M. 
Published: September 2018

4565 Background: Increased vascularity is a hallmark of renal cell carcinomas (RCC), particularly clear cell RCC. The vascular endothelial growth factor (VEGF) pathway, implicated in tumor angiogenesis, is dysregulated in RCC. The phase 3 trial ECOG-ACRIN E2805 enrolled 1,943 patients (pts) with resected high-risk RCC (pT1b high grade to pT4 any grade or N any). Pts were randomized to adjuvant sunitinib, sorafenib, or placebo. Our aim was to determine the prognostic and predictive role of microvessel density (MVD), VEGF receptors, and ligands in nephrectomy specimens. Methods: We obtainedpre-treatment primary RCC tissue from 822 pts and built tissue microarrays using 3 cores from each sample. Using quantitative immunofluorescence we measured tumor MVD (area of CD34-expressing cells) and intensity of the VEGF/VEGF-R family (VEGF-R1, R2, R3 and VEGF-A, B, C, D) in tumor cells. We tested for association with disease-free survival (DFS) and overall survival (OS) by the stratified log-rank test. Associations with treatment arm and clinicopathologic variables were determined. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p = 0.021, HR 0.63) and for pts treated in the placebo group (p = 0.014). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p = 0.060). High VEGFD expression overall was associated with shorter OS (p = 0.027) but not for placebo (p = 0.16). Yet high MVD was not associated with improved DFS (p = 1.00). High MVD correlated with above-median age ( > 56) (p = 0.032), Fuhrman grade I/II (p < 0.001), clear cell histology (p < 0.001), and absence of necrosis (p < 0.001) but not with gender, sarcomatoid features, lymphovascular invasion, or tumor size. In multivariable analysis, MVD remained independently associated with improved OS for the entire cohort (p = 0.013). Conclusions: High MVD in nephrectomy specimens of high-risk RCC pts is associated with improved OS, regardless of treatment arm. MVD is thus an independent prognostic, rather than predictive, biomarker. Further studies should assess whether incorporating MVD into clinical models will predict outcome in resected high-risk RCC pts and if MVD can be used for pt selection for adjuvant therapy.
Clinical outcomes by nephrectomy status in METEOR, a randomized phase 3 trial of cabozantinib (cabo) vs everolimus (eve) in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Tannir Nizar M. , Powles Thomas , Escudier Bernard J. , Donskov Frede , Grünwald Viktor , Sternberg Cora N. , Schmidinger Manuela , Schoffski Patrick , Szczylik Cezary , Peltola Katriina Johanna , Nosov Dmitry , Melichar Bohuslav , Clary Douglas O. , Scheffold Christian , Motzer Robert J. , Choueiri Toni K. 
Published: September 2018

4570 Background: Most pts with advanced RCC undergo nephrectomy (Nx) as curative or palliative therapy. In a retrospective analysis of pts treated with targeted therapy, pts who were older and had more comorbidities and higher tumor grade were less likely to have had Nx. Pts without Nx had shorter overall survival (OS) than pts with Nx (Hanna, J Clin Oncol 2016). Here we report outcomes for cabo vs eve in pts with advanced RCC with or without prior Nx in the phase 3 METEOR trial (NCT01865747). Methods: 658 pts with clear cell RCC and ≥1 prior VEGFR TKI were randomized 1:1 to receive cabo at 60 mg qd or eve at 10 mg qd. Stratification was by MSKCC risk group and number of prior VEGFR TKIs. Endpoints included progression-free survival (PFS), OS, and objective response rate (ORR). Results: 85% of enrolled pts had prior Nx of which 7% were partial; 15% had no prior nephrectomy (NoNx). Baseline characteristics, including Karnofsky performance status (KPS), MSKCC risk group, time from diagnosis to randomization, and median sum of diameters (SoD) for tumor target lesions, were less favorable for the NoNx subgroup (Table). Improved PFS and OS with cabo vs eve were observed regardless of Nx status. For the Nx subgroup, the hazard ratio (HR) was 0.51 (95% CI 0.41-0.64) for PFS and 0.66 (95% CI 0.52-0.84) for OS; for the NoNx subgroup, the HR was 0.51 (95% CI 0.30-0.86) for PFS and 0.75 (95% CI 0.44-1.27) for OS. Median OS was longer in the Nx subgroup for both treatment arms (Table). ORR per independent radiology committee (IRC) for cabo vs eve was 17% vs 4% for Nx and 21% vs 2% for NoNx. Grade 3 or 4 adverse events for both subgroups were generally consistent with the safety profiles of cabo and eve in the overall population. Conclusions: Cabo improved PFS, ORR, and OS compared with eve in pts with advanced RCC irrespective of nephrectomy status. Clinical trial information: NCT01865747. [Table: see text]