tbuckley/cabot-search huggingface dataset:
Genomic predictors of recurrence (R) or progression (P) in high grade T1 (HGT1) non-muscle invasive (NMI) bladder cancer.
Authors: Joaquim Bellmunt, Jaegil Kim, Stephanie A. Mullane, Brendan Reardon, Anna Orsola, Eliezer VanAllen, Gad Getz, David J. Kwiatkowski
Journal: Journal of Clinical Oncology (2016)

4539 Background: HGT1 NMI tumors have a 40% risk of R and 21% risk of P. Distinguishing aggressive versus indolent HGT1 disease is critical to decide which patients will benefit from early cystectomy. We examined genetic features associated with recurrence and progression. Methods: FFPE tumor/normal (T/N) samples were available from a clinically annotated cohort with HGT1 (7.4 y f/u), who were managed in a uniform manner using TURB and BCG. Clinical outcome was classified as: non-recurrent disease < 4 years (good outcome, GO), recurrent (R), or progression to MI or M1 (PD). 37 primary T/N matched sample pairs were subject to WES followed by Broad standard analysis pipelines, yielding 27 QC-passed T/N pairs (exome coverage > 23 Mb). Results: TP53 mutations (8/27) were most common in PD samples (2-R/ 6-PD, P = 0.009 by Fisher's test, FDR = 0.2) while RB1 mutations (6/27) were enriched in GO samples (5-GO/ 1-PD, P = 0.024, FDR = 0.24). Other recurrent mutations not enriched by clinical subtype ( > 4) included ERBB3, KDM6A, STAG2, and KMT2C. Three mutational signatures were identified from single nucleotide variants: APOBEC (67%), C > T at CpG (4%), COSMIC-5 (unknown origin) (29%). The COSMIC-5 signature was enriched in GO samples (P = 0.03 by Mann-Whitney between GO vs PD+R (median 32% vs 4%). The sample with highest mutation-rate had more than 80% COSMIC-5 signature mutations, and an ERCC2 S246Y mutation. Two most common focal copy number events were CDKN2A deletions (2-GO/3-R/4-PD) and 1q23 amplification (AMP) spanning MCL1 (2-GO/4-R/2-PD) and PVRL4 (1-GO/3-R/3-PD). Recurrent focal AMP ( > 4 samples) also included MDM2(3-GO/2-R/1-PD), CCNE1 (3-R/2-PD), YWHAZ (1-GO/1-R/2-PD), and ERBB2 (2-GO/1-R/1-PD). Combined AMPs in E2F3/CCND1/CCNE1 were enriched in PD or R samples (5-R/4-PD, P = 0.01 Fisher's test, FDR = 0.14) and co-occurred with TP53 mutation (6 of 8 TP53 mutations, P = 0.006, FDR = 0.12). Conclusions: Analysis of mutations and copy number alterations in HGT1 bladder tumors may improve prediction of good outcome vs. recurrence or progression, enabling a management strategy of early cystectomy for those with poor prognosis, and continued observation for those with predicted good outcome.
Treatment patterns in recurrent/metastatic head and neck squamous cell carcinoma in the US.
Authors: Eric S. Nadler, Seongjung Joo, Jenny Black-Shinn, Marley Boyd, Joseph Zhuo, Diana Romana Chirovsky
Journal: Journal of Clinical Oncology (2017)

6033 Background: Given the most recent FDA approval of cetuximab in 2008 for treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), the objective was to assess utilization of cetuximab and other treatments for R/M HNSCC in real world setting. Methods: Adult patients (pts) with R/M HNSCC who initiated systemic therapy between 9/1/2011-12/31/2014 were identified from iKnowMedelectronic health records database (McKesson Specialty Health) supplemented with chart abstraction. Pts were followed through 12/31/2015 to collect data on clinical characteristics, treatments and survival outcomes. Results: Among 325 pts with R/M HNSCC, median age was 62 yrs; 82% were male, and 67% had oropharyngeal cancer. The most common first line (1L) regimen consisted of platinum-based combinations (76%; Table 1); 63% received platinum+taxane +/-5FU and only 8% received platinum+cetuximab +/- 5FU. Median overall survival was 13.6 months (range 11.7-16.6). Following 1L therapy, 171 pts (53%) received a 2L regimen; 57 pts (18%) received platinum monotherapy and 8% received 2L platinum+taxane +/- 5FU, while only 12% received cetuximab mono- or platinum+cetuximab + /- 5FU. Among pts receiving 1L platinum combination, 32% were re-treated with platinum based therapy of which platinum monotherapy (23%) and platinum+taxane +/- 5FU (7%) were most common. Conclusions: Despite FDA approval and NCCN guidelines recommending use of cetuximab for palliative treatment of R/M HNSCC, our study demonstrates underutilization in both 1L and 2L settings, underscoring the need to understand reasons for underutilization and the need for newer efficacious treatments. [Table: see text]
ROR1-specific CAR for neuroblastoma using <i>sleeping beauty</i>-modified t cells.
Authors: Fiorela Natali Hernandez Tejada, Amer Najjar, Alan D Guerrero, Leo G Flores, Harjeet Singh
Journal: Journal of Clinical Oncology (2018)

10523 Background: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is predicted to provide a treatment option for advanced/refractory neuroblastoma. One potential target, receptor tyrosine kinase-like orphan receptor-1 (ROR1), is a cell surface protein that is aberrantly expressed on solid organ tumors including neuroblastoma. Methods: A ROR1-specific CAR was developed by linking a ROR1-specific scfv to a mutated IgG4-Fc stalk and co-stimulatory endodomains CD3-zeta and CD28 (ROR1R*CD28 CAR). Human T cells were genetically modified to express the ROR1-CAR by electro-transfer of DNA plasmids from Sleeping Beauty system and (i) directly injected the next day under technology designated as point-of-care (P-O-C) or (ii) numerically expanded for 14 days on ROR1+ activating and propagating cells (AaPC). Redirected specificity for ROR1 was assessed in vitro by chromium release assay and cytokine release. To demonstrate therapeutic potential, the ROR1R*CD28 CAR manufactured under the two conditions, were infused into NSG mice bearing disseminated CHLA 255 ROR1+ neuroblastoma cells expressing firefly luciferase. Results: The day after electroporation, T cells had 20-30% CAR expression from episomal and integrated transgene and by day 14, 90% of CD3+ T cells expressed CAR. CAR+ T cells were able to lyse neuroblastoma lines and produce IFN-gamma in a ROR1-specific manner. In vivo, POC and 2-stim manufactured CAR+ T cells both exhibited similar antitumor activity. This antitumor effect was confirmed by histological evaluation of metastatic liver lesions and correlated with the presence of circulating human CD3+ T cells. Conclusions: Genetically modified T cells with CAR infused after being manufactured under P-O-C or propagated on AaPC can specifically target and lyse neuroblastoma cells significantly reducing the tumor burden in mice. These data reveal that shortening the manufacturing time from 14 days to 1 day result in anti-tumor effects with CARs that signal via chimeric CD28. Shortening the manufacturing from 14 days to 1 day is predicted to broaden the application of CAR+ T cells as this avoids the need for ex vivo tissue culture and thus reduced the costs and expense of manufacture.
Overall survival after image guided thermal ablation of pathologically proven T1a RCC in cancer survivors.
Authors: Mohamed E. Abdelsalam, Sharjeel H Sabir, Bryan Fellman, Samuel B. Kusin, Christopher G. Wood, Surena F. Matin, Jose A. Karam, Kamran Ahrar
Journal: Journal of Clinical Oncology (2016)

e16134 Background: Although surgical excision remains the gold standard treatment for renal cell carcinoma ( RCC ), active surveillance and thermal ablation provide alternative options for patients at higher surgical risk.The purpose of our study is to investigate the effectiveness of image guided thermal ablation for pathologically proven T1a RCC in patients with other non-renal primary malignancies. Methods: We performed a retrospective review of our renal tumor ablation registry for the period of January 2005 to December 2013. We included patients with T1a renal tumors (< 4 cm). We excluded patients without histologically proven RCC, those with Von Hippel Lindau syndrome, and those with prior history of RCC. Two groups were created; (A) patients with RCC and history of other non-renal primary malignancy (in remission or active), (B) Patients with RCC only. Statistical analysis was performed to compare the two groups using Fisher’s exact and Kruskal-Wallis test for demographics (age, sex) and clinical characteristics (prior or current cancer history, renal tumor Size, and complications). Overall survival (OS) was estimated using the Kaplan-Meier product-limit estimator and we conducted a log-rank test to compare the two groups. OS was measured from the procedure date to the date of last contact or death. Results: Seventy four patients were included in the study, 37 patients (50%) has other non-renal primary. The average age at procedure was 68.8 years. There was no difference in age (68.6 vs. 68.9; p = 0.842), sex (15 women and 22 men vs. 13 men and 24 women; p = 0.811), or tumor size (2.3 vs. 2.5; p = 0.107).Complication rates did not differ between the groups (2.9 vs. 5.9; p = 0.614). Median survival time for the entire population was 8.39 years. The probability of 5-yr (10-yr) survival was 0.74 (0.48). There was no difference in survival between the two groups (p = 0.384). Conclusions: Minimally invasive therapy with image guided thermal ablation provides safe and effective treatment for T1a RCC in patients with other non-renal malignancies. In our study, Primary malignancies or their therapy did not have discernible impact on the thermal ablation effectiveness, complications, or overall survival rates.
Adverse events of special interest in the phase 3 COLUMBUS study.
Authors: Helen Gogas, Reinhard Dummer, Paolo Antonio Ascierto, Ana M. Arance, Mario Mandalà, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Vanna Chiarion-Sileni, Caroline Dutriaux, Jan Willem de Groot, Naoya Yamazaki, Carmen Loquai, Laure A. De Parseval, Michael D Pickard, Ashwin Gollerkeri, Caroline Robert, Keith Flaherty
Journal: Journal of Clinical Oncology (2018)

9567 Background: Combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy is standard of care for BRAFV600-mutant metastatic melanoma. In COLUMBUS Part 1, encorafenib 450 mg once daily (QD) + binimetinib (BINI) 45 mg twice daily (BID) (COMBO450) reduced risk of progression or death vs encorafenib 300 mg QD (ENCO300) or vemurafenib 960 mg BID (VEM) in patients (pts) with advanced BRAFV600-mutant melanoma. Adverse events of special interest (AESIs) including pyrexia, serous retinopathy, photosensitivity, and rash are reported here. Methods: Pts were randomized 1:1:1 to receive COMBO450, ENCO300, or VEM. Pts had standard physical and laboratory assessments, and regular dermatologic, cardiac, and ophthalmologic evaluations. AESIs comprised known effects of available BRAFi and/or MEKi. Results: Safety was evaluated in 192, 192, and 186 pts in the COMBO450, ENCO300 and VEM arms, respectively. Median duration of exposure to treatment was 51 weeks for each component in the COMBO450 arm, 31 weeks in the ENCO300 arm, and 27 weeks in the VEM arm. Pyrexia incidence with COMBO450 was low (grade 1/2: 14%; grade 3: 4%) and led to treatment discontinuation in 1% of pts and to dose modification in 4%. Photosensitivity was infrequent with COMBO450 (grade 1/2: 4%; grade 3: 1%), required dose modification in 1% of cases, and did not lead to treatment discontinuation. Rash occurred in 22% of pts with COMBO450 (grade 1/2: 21%, grade 3: 1%, grade 4: 1%), led to discontinuation in 0.5%, and to dose modification in 2%. Serous retinopathy (grade 1/2: 17%; grade 3: 3%) and left ventricular dysfunction (grade 1/2: 6%; grade 3: 2%) with COMBO450 did not lead to discontinuation and were generally reversible (in 89% and 93% of pts, respectively). Conclusions: Common BRAFi/MEKi toxicities were generally manageable and reversible and were infrequently associated with treatment discontinuation. Pyrexia and photosensitivity were uncommon with COMBO450. The observed safety profile suggests COMBO450 may provide a meaningfully differentiated treatment option for patients with BRAFV600-mutant melanoma. SPONSOR: Array BioPharma Inc. Clinical trial information: NCT01909453.
Tackling "big data" for accelerating cancer research.
Authors: Jennifer Brooke Goldstein, Hannah Beird, Jianjun Zhang, Chris Belmont, Bryan Lari, Mark Mynhier, Dhiraj Pathak, Prabal Basu, Jeff Jin, Gregory Barbosa, Trey Kell, Vamshi Punugoti, Edward Suh, Brett Smith, Lynda Chin, Andrew Futreal
Journal: Journal of Clinical Oncology (2016)

e23160 Background: The University of Texas MD Anderson Cancer Center (MDACC) is a freestanding, NCI-designated comprehensive cancer center. Since its inception, MDACC has cared for over 900,000 patients and had over 1.3 million ambulatory care visits. MDACC seeks to leverage its considerable clinical and research enterprise by developing a Translational Research Accelerator (TRA) platform, purpose built to integrate longitudinal patient clinical and research data. The goal of this initiative is to implement a scalable, extensible, secure and compliant TRA within the MDACC data center in the first instance. To accelerate cancer research we have implemented a technology platform to aggregate patient clinical and research data and enable access to researchers through simple visualization and search tools. Methods: Clinical Data, Natural Language Processing (NLP) data and structured research data for patients seen at MDACC from 2012 to the present are securely incorporated into TRA. Results: TRA includes allergies, blood supply, care plans, conditions, demographics, transcribed, pathology and radiology reports, medications, laboratory results, patient registration survey and treatment protocols. Research data includes genomic mutations and Immunotherapy results were also ingested. NLP data includes reports from bone marrow, cytogenetics, diagnostic imaging, flow cytometry, molecular studies, solid tumor diagnoses, surgical procedures, chemotherapy plans, family history and adverse events. Researchers have the ability to upload their curated data. Conclusions: TRA is a new way to transform and integrate clinical and research data in a short time period. Data is continuously aggregated in real time from numerous source systems to accelerate hypothesis testing in a purpose-built framework for query, cohorting and analytics. Simple visualization and search tools provide simple interfaces to researchers seeking to quickly identify and analyze data sets of interest. Further work is ongoing to develop a data governance program for the platform to ensure that the data in the platform is well-characterized, controlled for quality, and managed for intended use in research. This technology may be expanded to other areas of medical practice and industries.
Clinical and morphological characterization for detection of hypermutation in colorectal cancer.
Authors: Yoshifumi Shimada, Yosuke Tajima, Masayuki Nagahashi, Hiroshi Ichikawa, Kizuki Yuza, Kohei Miura, Kana Tanaka, Takuya Ando, Daiki Soma, Yuki Hirose, Junko Tsuchida, Masato Nakano, Hitoshi Kameyama, Jun Sakata, Takashi Kobayashi, Yasumasa Takii, Stephen Lyle, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2018)

e15647 Background: Hypermutation, which is a molecular subtype with high tumor mutation burden (TMB), has been recognized as a biomarker of anti-PD-1 therapy in many cancers. Hypermutation can be detected using next-generation sequencing (NGS) technology, and, to maximize medical economic effects, it is required to select the patients who needs NGS for detection of hypermutation. Thus, we aimed to clarify the clinicopathological characteristics associated with hypermutation in colorectal cancer. Methods: Two-hundred-one patients with Stage I-IV colorectal cancer were analyzed. We investigated genetic alterations using NGS of a 415-gene panel. Hypermutation was defined as a tumor with microsatellite instability-high (MSI-H) and/or high TMB, and the threshold of TMB was set as the lowest TMB observed in tumors with MSI-H. Univariate and multivariate analyses were conducted to investigate the association between clinicopathological characteristics and hypermutation. Results: Seventeen of 201 patients (8%) had hypermutation; 15 and 2 patients had MSI-H and POLE mutation, respectively. Univariate analysis revealed that hypermutation was significantly associated with right-sided tumor (P = 0.008), medullary type (P = 0.005), venous invasion (P = 0.033), absence of nodal metastasis (P = 0,047), absence of distant metastasis (P < 0.001), tumor-infiltrating lymphocytes (P < 0.001), Crohn-like lymphoid reaction (P = 0.029), and peritumoral lymphocytes (P = 0.042). Multivariate analysis revealed that right-sided tumor (P = 0.004), absence of distant metastasis (P = 0.013), and tumor-infiltrating lymphocytes (P < 0.001) were independent predictors of hypermutation. Eight of 201 (4%) patients had all the 3 factors, and all the 8 patients showed hypermutation. Conclusions: Right-sided tumor, absence of distant metastasis, and tumor-infiltrating lymphocytes are associated with hypermutation in colorectal cancer. The clinicopathological characteristics has potential to select the patients who needs NGS for detection of hypermutation.
Abstract IA09: Early, highly specific risk stratification for lethal prostate cancer using a prespecified statistical model based on four kallikrein markers in blood
Authors: Hans Lilja
Journal: Cancer Research (2018)

Abstract Prostate-specific antigen (PSA) and human kallikrein-related peptidase 2 (hK2) are 237-aa single chain glycoproteins with uniquely different serine proteinase activity and products of two highly homologous primate-lineage specific, androgen receptor-regulated genes (KLK3 and KLK2) with abundant prostate-restricted expression. In blood from healthy middle-aged men not subject to PSA testing, million-fold lower levels of multiple noncatalytic forms of PSA and hK2 are very strongly associated with 20+ year- risk of metastasis or death from prostate cancer (PC), whereas prospective randomized trials in Europe show that early detection by systematic PSA testing reduces PC-specific deaths but remains controversial due to harm from overdiagnosis and overtreatment. Population-based findings of longer lead time at Gleason Grade Group ≥2 (GGG2) versus GGG1 at PC diagnosis provide evidence of grade progression over time. However, our estimates of a ≤6% risk of ≥GGG2-PC by a predefined statistical model based on four kallikrein markers in blood in middle-aged men with modestly elevated PSA is strongly associated with 15-20-year risk of PC death or metastasis below population average. By contrast, a smaller subset of these middle-aged men with modestly elevated PSA and a ≥6% four kallikrein risk-score have 15-20-year risk of PC death or metastasis that is multiple folds higher than the population average. Although evidence exists that mutations in germline DNA are associated with PC-death or metastasis, it is currently unclear how we could integrate these findings in programs aimed at early specific detection of lethal PC. Citation Format: Hans Lilja. Early, highly specific risk stratification for lethal prostate cancer using a prespecified statistical model based on four kallikrein markers in blood [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA09.
TCT-770 Contemporary Trends, Readmission Rates, and Costs of Same-Day Discharge Among Patients Undergoing Elective Percutaneous Coronary Intervention: Department of Veterans Affairs, 2008-2016
Authors: Jennifer Rymer, Colin O'Donnell, Paul Hess, Mark Donahue, Paul Hebert, Adhir Shroff, Rajesh Swaminathan, Stephen Waldo, Arnold Seto, Christian Helfrich, Sunil Rao
Journal: Journal of the American College of Cardiology (2018)
Fully automated and sensitive detection of EGFR exon 18, 19, 20 and 21 mutational status in <2.5 hrs from a single FFPE slice.
Authors: Erwin Sablon, Martin Reijans, Genevieve Vandercruyssen, Inge Keuleers, Kenny Helsens, Charlotte Vandesteene, Natasja Elsen, Natania Peelman, Ina Vandenbroucke, Geert G. Maertens
Journal: Journal of Clinical Oncology (2017)

e20519 Background: Current molecular testing for mutations and indels in EGFRexons 18, 19, 20 and 21 is still laborious and often requires &gt; 5 days in specialized labs. Multiple slices of FFPE tissue are often needed. Lack of experience, time or tissue for molecular testing are among the reasons why patients are often deprived of the proper targeted therapies. Therefore, a fast and fully automated assay with minimal hands-on time which can handle small samples should allow laboratories to quickly generate EGFR testing results as part of their precision medicine report. Methods: Idylla is a fully integrated MDx platform that combines speed and ease of use with high sensitivity and high multiplexing capabilities. For EGFR testing, it overcomes the current problem of lack of tissue and the time-consuming step of processing FFPE tissue samples. After insertion of a single 5 µm FFPE slice containing ≥10% neoplastic cells into the cartridge, the complete process of liquefication, extraction, rtPCR, data analysis and reporting is fully automated and takes &lt; 2.5 hours. The Idylla EGFR Mutation Assay (RUO) allows the sensitive detection of 50+ mutations including indels in exons 18, 19, 20 and 21. Results: The Idylla EGFR Mutation Assay (RUO) was tested with single FFPE slices from 280 clinical NSCLC samples with known mutations as analyzed by NGS and digital droplet PCR. It demonstrated excellent specificity and sensitivity with an overall percentage agreement of &gt; 96% and a positive and negative percentage agreement of &gt; 97% and &gt; 95%, respectively. Analytical sensitivity was assessed using cell line derived materials embedded in paraffin containing defined ratios of mutants and dilutions thereof in a WT background. Allelic frequencies ranging from 1 to 10% were tested in 6-fold and showed analytical sensitivities of 1% for all except one target which showed a sensitivity of 5%. Turnaround time of a run was &lt; 2.5 hours and hands-on time was &lt; 2 min. Conclusions:The new and fully automated Idylla EGFR Mutation Assay (RUO) demonstrates excellent specificity, high sensitivity, ease of use combined with a fast turnaround time for complete testing of more than 50 relevant EGFR mutations on FFPE samples from NSCLC patients.
Ipilimumab real-world efficacy and safety in Asian melanoma patients from the Korean Named-Patient Program cohort.
Authors: Minkyu Jung, Jeeyun Lee, Tae Min Kim, Dae Ho Lee, Jin Hyoung Kang, Sung Yong Oh, Soo Jung Lee, Sang Joon Shin
Journal: Journal of Clinical Oncology (2016)

e21002 Background: Ipilimumab improved survival in advanced melanoma patients. However, the efficacy and safety of impilimumab has not been evaluated in Asian melanoma patient who have high frequency of mucosal and acral melanoma subtypes. Methods: An advanced melanoma patients treated with 3mg/kg ipilimumab in a Korean multicenter NPP were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes Results: A total 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26.3%), cutaneous (25.9%), uveal (1.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median PFS was 2.73 months (95% CI, 2.67-2.85 months), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR ( ≥ 5) were independent poor prognostic factors by multivariate analysis Conclusions: In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared with Western patients, and regardless of subtypes. All subtypes should benefit from ipilimumab with consideration to performance status, liver metastasis, and NLR.