bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of ALT-801, a first-in-class T-cell receptor (TCR)-interleukin (IL)-2 fusion molecule, plus gemcitabine (G) for Bacillus Calmette Guerin (BCG)-resistant non-muscle-invasive bladder cancer (NMIBC).
Authors: Sonpavde Guru , Rosser Charles Joel , Pan Chong-xian , Parikh Rahul Atul , Nix Jeffrey , Gingrich Jeffrey R. , Hernandez Liza , Huang Bee-Yau , Wong Hing C. 
Published: February 2017

451 Background: Novel agents are necessary to treat BCG-resistant NMIBC to avoid radical cystectomy (RC). This phase I clinical trial evaluated the safety and activity of ALT-801, a recombinant humanized TCR-IL-2 fusion protein in BCG-resistant NMIBC. Methods: This is a Phase I trial using the 3+3 design to evaluate intravenous (IV) ALT-801 plus IV G 1000 mg/m2 in BCG-resistant high-risk NMIBC patients (pts) defined as high grade Ta, T1 or carcinoma in situ, size > 4 cm or multi-focal tumors. BCG-intolerant pts, those who refused or were unfit to undergo RC were also eligible. Initially, patients received ALT-801 monotherapy; an amendment added G. Pts received induction of 2 cycles, with a 13-day rest between cycles. Each cycle consisted of 4 doses of ALT-801 on Day 3, Day 5, Day 8, and Day 15 and 2 doses of G, one each on Day 1 and Day 8. Pts who have a biopsy-proven complete response (CR) after induction received one maintenance cycle and underwent response assessment. The initial dose of ALT-801 was 0.08 mg/kg with 2 step-down doses allowed if dose limiting toxicities (DLTs)- 0.06 mg/kg and 0.04 mg/kg. Results: 2 pts in cohort one received ALT-801 alone at 0.08 mg/kg per dose, a 3rd pt received G and ALT-801 at 0.08 mg/kg per dose. Grade ≥ 3 hepatotoxicity in the 3rd patient led to a step-down to 0.06 mg/kg dose. One pt in the 0.06 mg/kg dose experienced a DLT (Grade ≥ 3 hepatotoxicity) and the cohort was expanded to 6 pts with no further DLTs. Other attributed adverse events were: anorexia, pruritus, rash, edema, fatigue, chills. For the 0.06 mg/kg ALT-801 + G regimen, 6 pts received up to 2 cycles of induction and 4 pts received the maintenance cycle. All pts have completed therapy without further DLTs. CR was observed in 3 pts, which was durable in 2 pts lasting ≥ 18 months. Preliminarily immune studies have shown transient IFN-γ and IL-6 but not TNF-α and IL-10 induction after ALT-801 dosing. Conclusions: ALT-801 plus gemcitabine was feasible in BCG-resistant NMIBC and demonstrated immune responses and potential durable clinical activity. Further evaluation in expansion cohorts in a phase Ib/II trial is planned. Clinical trial information: NCT01625260.
Whole-exome sequencing (WES) of penile squamous cell carcinoma (PSCC) to identify multiple recurrent mutations.
Authors: Naik Gurudatta , Chen Dongquan , Crowley Michael , Crossman David , Sexton Katherine C. , Grizzle William E. , Mehta Amitkumar N. , Sonpavde Guru 
Published: February 2017

484 Background: Molecular alterations and drivers of PSCC, an orphan malignancy, remain unclear. The Cancer Genome Atlas is not studying PSCC and the Catalogue of Somatic Mutations in Cancer has performed targeted analyses only. We report WES of PSCC tumors from a group of patients (pts). Methods: Freshfrozen macrodissected PSCC tumor tissue and adjacent normal tissue samples were procured from the Cooperative Human Tissue Network. DNA was isolated from tissue sections by phenol chloroform extraction. Exome capture was performed with the Agilent SureSelect clinical research exome kit and whole exome-seq was done on the Illumina HiSeq2500 with paired end 100bp chemistry. Raw sequence data in Fastq format were aligned to human reference genome and quantified, and compared by using a local instance of Galaxy (galaxy.uabgrid.uab.edu). These data were analyzed for mutations (SNPs) analysis, by Partek Genomic Suite/Flow(PGS, Partek, St. Louis, MO) for variance calling against human reference genome (hg19) as referenced to dbSNP; and copy number variants (cnv) by FishingCNV tool together with picard tools/samtools/GATK). We focused on missense mutations and amplifications among ≥ 2 tumor samples but not in normal samples as they may cause upregulation of gene/protein function, which may be therapeutically actionable. Results: PSCC tumors were available from 11 patients and adjacent normal tissue from 3 patients. The 10 most common genes with > 4 missense mutations among ≥ 2 tumor samples overall were the following in decreasing order of frequency: MUC4, HLA-DPA1, MUC16, XIRP2, SSPO, TTN, FCGBP, PABPC3, ALPK2 and MKI67. The top upstream transcriptional regulators were PIH1D3, PRDM5, PTK2, Coup-Tf and NBEAL2. When examining candidate actionable genes, recurrent missense alterations were seen in PIK3C2A and PIK3C2G. Additional analysis will study alterations in functional domains and cnv. Conclusions: WES identified a relatively high mutation burden in PSCC withrecurrent missense mutations in multiple genes, notably including the PI3K gene among potentially actionable genes. Validation of these findings and further study of downstream effects is required.
The impact of chemotherapy on cognition: A longitudinal study in testicular cancer.
Authors: Toner Guy C. , Whitford Hayley S. , Kalinowski Pawel , Grimison Peter S. , Stockler Martin R. , Martin Andrew James , Davis Ian D. , Olver Ian N. ,   ANZUP Cancer Trials Group
Published: February 2017

487 Background: Neuropsychological assessments suggest chemotherapy may lead to cognitive impairment but causal links remain unclear. Prospective longitudinal studies are needed to address methodological limitations, with different chemotherapy regimens, appropriate controls and adjusting confounders. Methods: This 16 centre, prospective observational study accrued 145 patients with testicular cancer treated with surgery, or surgery + chemotherapy, as determined by disease staging. Cognition was assessed by CogHealth, a 10-minute online playing-card format tool designed to overcome language limitations, assessment burden, and practice/ceiling effects. Quality of life, fatigue, anxiety, depression and self-perceived cognitive function were also assessed. Comparisons were made between baseline (≤6 months from orchidectomy/pre-chemotherapy) and follow-Up (12-18 months), for 3 groups with sufficient data; cisplatin-based chemotherapy (BEP/EP, n=41), carboplatin (n=20), and controls (n=41). Results: With age as a covariate, linear mixed models were used to compare the 3 groups over time. There were no significant differences between groups over time for cognitive tasks assessing psychomotor function, complex decision making, visual learning, working memory, and visual attention; self-perceived cognitive function matched actual performance. At baseline, for fatigue (p = 0.008), BEP/EP scored significantly worse than carboplatin (d = -0.75) and control groups (d = -0.80). For anxiety (p = 0.005), BEP/EP scored worse than controls (d = -0.91). For all groups anxiety (p = 0.03), emotional (p = 0.001) and functional wellbeing (p = 0.002), improved over time. BEP/EP with poorest scores at baseline, improved the most by follow-up (d = 0.63, -1.24, -1.17, respectively). Only physical wellbeing showed significant effects (p ≤ 0.03) for group, time, and a differing pattern of change across groups; the BEP/EP group scoring worse at baseline compared to carboplatin (d = -0.94) and control groups (d = -1.16), improving by follow-Up (d = -1.21). Conclusions: For patients with testicular cancer there were no statistically significant differences between groups for cognition scores or self-reported cognitive function. Clinical trial information: 12609000545268.
Association of a combined panel of tumor infiltrating lymphocytes, plasma cells, and macrophages with recurrence of localized clear cell (cc) renal cell carcinoma (RCC) undergoing surgery.
Authors: Ghatalia Pooja , Gordetsky Jennifer , Bae Sejong , Watkins Stacey M , Sudarshan Sunil , Naik Gurudatta , Sonpavde Guru 
Published: February 2017

502 Background: Tumor infiltrating Programmed-Death (PD)-1 and FoxP3-expressing lymphocytes and macrophages appear to be associated with higher risk of recurrence in patients (pts) with ccRCC undergoing surgery for localized disease. We aimed to combine the presence of morphologically identified lymphocytes, plasma cells and macrophages into a readily available composite immune cell panel and to evaluate its association with tumor recurrence. Methods: We identified pts with ccRCC who underwent nephrectomy at UAB for whom we had annotation for objective tumor recurrence and a minimum follow-up of 2 years. Central pathology review was conducted by a single urologic oncology certified pathologist to capture pathologic variables (stage, grade, necrosis, histologic components, cystic changes) and immune cell (lymphocyte/plasma cell/macrophage) infiltration. Logistic regression (univariate and multivariate) analyses were conducted to evaluate the association of these variables with tumor recurrence. Results: Of the 159 identified and evaluable pts, 33 (20.7%) recurred and 126 did not. On univariate analyses, sarcomatoid/rhabdoid histologic components, lymphocyte/plasma cell infiltration, necrosis, pathological T stage and histologic grade were all statistically significantly associated with a risk of recurrence (p < 0.05). On multivariate analysis, in addition to pathologic stage (p = 0.0018), only the combination of higher lymphocyte/plasma cell and macrophage infiltration (p = 0.0347) was independently associated with recurrence; patients were 8.7 times more likely to recur (95% CI: 1.66, 45.28). Conclusions: A readily available and widely applicable composite panel of morphologically identified lymphocytes, plasma cells and macrophages infiltrating the tumor predicts recurrence of pts with localized ccRCC undergoing surgery, after controlling for clinical and pathologic prognostic factors. Our hypothesis-generating data require validation and further interrogation of specific markers expressed on immune cells may refine an immune panel that confers prognostic impact.
Everolimus and sunitinib as first- and second-line treatments of patients with metastatic papillary renal cell carcinoma (pRCC): A retrospective study of the GETUG (Groupe Français d’Etude des Tumeurs Uro-Génitales).
Authors: Linassier Claude , Albiges Laurence , Chevreau Christine , Laguerre Brigitte , Oudard Stephane , Gross-Goupil Marine , Gravis Gwenaelle , Goldwasser Francois , Rolland Frederic , Delva Remy , Moise Laura , Tourani Jean-Marc , Vassal Cecile , Zanetta Sylvie , Penel Nicolas , Flechon Aude , Theodore Christine , Barthelemy Philippe , Saldana Carolina , Escudier Bernard 
Published: February 2017

505 Background: pRCC accounts for 15% of all renal cancers. Two French prospective phase II trials demonstrated efficacy of both Sun and Eve in first-line treatment of metastatic disease (RAPTOR (NCT00688753) and SUPAP (NCT00541008)). Most patients (pts) usually receive the alternate drug at progression. We report the first series of drug sequencing in pRCCs. Methods: We updated clinical data of metastatic pts with pathologically documented pRCC, who were treated in firs line or more with Sun or Eve, from 2/06 to 6/15, in 24 GETUG centers. Results: 196 pts (166 men, 30 women), median aged of 61 years, with histological subtypes (HST) I (28 pts), II (122 pts) or unclassified (46 pts), were treated for metastatic pRCC in 1st-line: group 1 Su 50 mg daily 4/6 weeks (n=158 pts) ; group 2 Eve 10 mg daily (n=38 pts). 76 pts were included in the RAPTOR or SUPAP studies. The median follow-up was 59.5 months. We found no difference between the 2 groups in terms of patients’ characteristics, clinical benefit in first-line (CR+PR+SD) (71% vs 72%; p=0.95) or progression-free survival (PFS) (PFS-1: 5.7 vs 4.6 months; p=0.152). Reasons for treatment discontinuation were tumor progression (74% vs 70%) or toxicity (26 vs 30%) (p=0.58). 134 pts received the alternative drug in second-line (group 1: Eve; group 2: Sun) with similar clinical benefit (64% vs 58%; p=0.69) and median PFS (PFS-2: 3.5 vs 3.0 months p=0.98). Overall survival (OS) did not differ between the two groups (16.4 vs 17.6 months; p=0.58). Age, Karnofsky performance status < 80 (KPS-80), HST, platelet (Plts) and absolute neutrophil counts (ANC), hemoglobin and calcium levels, time from diagnosis to metastases (TTM) were studied as prognostic variables. In multivariable analysis, only Plts and KPS-80 had prognostic impact on EFS-1, whereas ANC, KPS-80 and TTM were prognostic for OS. We found a trend in favor of HST I vs non I, with no statistical difference in terms of PFS or OS. Conclusions: In this large retrospective series of metastatic pRCC pts, Sun and Eve had good compliance and similar efficacy in terms of first-, second-line PFS and overall survival.
Understanding the genomic underpinnings of metastatic chromophobe renal cell carcinoma.
Authors: Casuscelli Jozefina , Wang Patricia , Redzematovic Almedina , Lee William , Seshan Venkatraman E. , Shen Ronglai , Donin Nicholas , Chen Yingbei , Cheville John C. , Pantuck Allan J. , Thompson Robert Houston , Coleman Jonathan A. , Russo Paul , Reuter Victor E. , Tickoo Satish , Hakimi A. Ari , Hsieh James 
Published: February 2017

513 Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.
Mutation burden and tumor neoantigens in RCC patients (pts) treated with nivolumab.
Authors: Voss Martin Henner , Hellmann Matthew David , Chen Yingbei , Gold Theresa Margaret , Lambert Courtney Rose , VanAllen Eliezer , Choueiri Toni K. , Snyder Charen Alexandra , Motzer Robert J. 
Published: February 2017

514 Background: Durable benefit with CTLA4 or PD1 blockade associates with high somatic mutation burden in melanoma and lung cancer (Snyder, NEJM 2014; Rizvi, Science 2015). The same studies suggest that tumor neoantigens arising from somatic mutations may be mediating this association. For RCC, a disease with a comparatively low mutation burden but good response to PD1 directed therapy, such associations are unknown. To examine these concepts, we used whole exome (WES) and transcriptome (RNAseq) sequencing of RCC samples from pts treated with nivolumab (Nivo). Methods: WES and RNASeq were performed on frozen pre-treatment tumor/normal tissue for 7 pts treated with Nivo and 1 pt treated with ipilimumab/Nivo (Ipi/Nivo) x 4 followed by Nivo. Efficacy was assessed by RECIST. Neoantigen prediction and HLA typing were performed in silico using NetMHC3.2 and ATHLATES, respectively. Expression of predicted neoantigens and putative pathways of resistance/response were investigated using DESeq-normalized reads. Results: Two of 7 Nivo-monotherapy pts achieved durable clinical benefit (DCB, PR > 12 months); 1 pt had a non-durable PR (5 months). For 2 Nivo/DCB pts, the burden of non-synonymous somatic mutations was 113 and 224 compared to a median of 95 in those with no DCB (range 53-124). The ratio of predicted neoantigens/total mutations was higher for pts with DCB/Objective response (all ≥ 0.5) compared to those with progressive disease (all < 0.5). The Ipi/Nivo pt experienced > 95% tumor regression ongoing 2+ years, but harbored the lowest mutation count (29) and lowest neoantigen/mutation ratio ( < 0.2) in the cohort. Across all pts, 80% of predicted neoantigens were expressed. Further, RNASeq findings differed distinctly for DCB vs. non-DCB pts in various genes of interest, including mediators of antigen presentation to T-cells (HLA-A, -B, -C; B2M) and composition of other immune regulators (CSF1R, LGALS1), but not for PDL1. Conclusions: In RCC, somatic mutations, particularly those causing tumor neoantigens, and the counterbalance between molecular immune compartments may be determinants of treatment benefit from Nivo and warrant future study. Their impact might be distinctly different in pts treated with combination immunotherapy.
Risk of hyperglycemia attributable to everolimus in renal cell and non–renal cell carcinoma patients: A meta-analysis.
Authors: Xu Kevin Y , Shameem Raji , Wu Shenhong 
Published: February 2017

515 Background: Everolimus has been used widely in cancer patients and is associated with the development of hyperglycemia. Due to confounding factors, everolimus’ specific impact on hyperglycemia has not been well understood. We performed a meta-analysis to determine the risk of hyperglycemia attributable to everolimus in cancer patients of varying tumor types. Methods: PubMed and ASCO conference abstracts up to June 2015 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which everolimus was compared to placebo in cancer patients with or without additional cancer therapies. Heterogeneity tests were performed to examine between-study differences in hyperglycemia. The incidence and relative risk of all-grade and high-grade hyperglycemia attributable to everolimus were determined using random- or fixed-effects models. Results: A total of 7 phase III and 2 phase II RCTs with various tumors were included in our analysis. Everolimus significantly increased the risk of all-grade (RR = 2.60, 95% CI: 2.03-3.31, P < 0.001) and high-grade (RR = 3.00, 95% CI: 1.72-5.23; P < 0.001) hyperglycemia. The incidences of all-grade and high-grade hyperglycemia attributable to everolimus were 6.8% (95% CI: 3.4-13.2%) and 2.5% (95%: 1.2-4.9%) respectively. The everolimus-specific risk of all-grade hyperglycemia varied significantly with tumor types (P < 0.001), with the highest incidence seen in renal cell carcinoma (27.2%, 95% CI: 22.2-32.8%) and the lowest in breast cancer (3.3%, 95% CI: 1.3-8.2%). No significant variation was found between everolimus alone or everolimus in combination with other agents. Similar results were also found for the risk of high-grade hyperglycemia attributable to everolimus. Conclusions: The specific contribution of everolimus to both all-grade and high-grade hyperglycemia may be modified significantly by tumor types. Close monitoring should be given to patients with renal cell carcinoma.
Change in International mRCC Database Consortium (IMDC) prognostic category and implications for efficacy of second-line targeted therapy.
Authors: Davis Ian D. , Xie Wanling , Pezaro Carmel Jo , Donskov Frede , Wells Connor , Agarwal Neeraj , Srinivas Sandhya , Yuasa Takeshi , Beuselinck Benoit , Wood Lori , Ernst D. Scott , Kanesvaran Ravindran , Knox Jennifer J. , Pantuck Allan J. , Saleem Sadia , Alva Ajjai Shivaram , Rini Brian I. , Lee Jae-Lyun , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2017

534 Background: Currently no predictive markers exist for choosing second-line targeted therapy (2L) in metastatic renal cell carcinoma (mRCC). A change in IMDC prognostic group when calculated at first-line therapy (1L) and 2L and its association with 2L efficacy was examined. Methods: The IMDC database was interrogated for patients who received 1L VEGF inhibitors (VEGFi) and then 2L with VEGFi or an mTOR inhibitor (mTORi). IMDC prognostic categories (Favorable, F; Intermediate, I; Poor, P) were defined prior to each line of therapy. Overall survival (OS), time to treatment failure (TTF) and response to 1L or 2L were assessed in relation to change in IMDC prognostic risk category. Results: Data for 1516 patients were analyzed; 89% had clear cell histology. Prognostic risk categories at 1L were F: 21.7%; I: 59.5%; P: 18.8%. 60.3% of patients remained in the same risk category at start of 2L; 9.0% improved (3% I→F; 6% P→I); 30.7% deteriorated (14% F → I or P; 16% I → P). Improvement in prognostic risk category was associated with better response and longer duration of 1L. Patients who improved prognostic risk (I → F or P → I), or maintained I or F grouping, had longer TTF if they remained on VEGFi for 2L compared to those who switched to mTORi (p < 0.05). In contrast, patients whose risk category deteriorated (F → I or P) may be more likely to benefit from switching to mTORi. Conclusions: Changes in IMDC prognostic category may predict the subsequent clinical course of patients with aRCC and provide a rational basis for selection of subsequent therapy. [Table: see text]