tbuckley/cabot-search huggingface dataset:
FGFR1 amplification in squamous cell lung cancers.
Authors: Michele L Cote, Gerold Bepler, Susan Land, Aliccia Bollig-Fischer, Ann G. Schwartz, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2012)

7063 Background: Squamous cell carcinoma of the lung (SqCCL) is the second most common type of lung cancer. There are currently no established targeted therapies that take advantage of SqCCL-specific genetic abnormalities. Amplification of the fibroblast growth factor receptor type 1 gene (FGFR1) has been identified as a driver event in breast cancers and in SqCCL. The demographic characteristics and prognosis of patients with these tumors remains to be defined. Methods: DNA from 123 surgically resected, fresh frozen, and clinically annotated SqCCLs was extracted using a resin-based or phenol-based methodology. DNA quantity and quality was assessed using the Quantifiler kit (ABI). Specimen histology was validated, and the proportion of tumor cells was &gt;60%. Copy number variation (CNV) analysis was performed using quantitative PCR with primers specific for exons 12 and 16 of FGFR1 and data analysis using CopyCaller (ABI). Samples with a predicted CNV of at 2 or greater in at least one exon were scored as amplified. Chi-squared tests were used to examine clinical and demographic differences between patients with and without amplification of FGFR1. Survival differences were examined by Kaplan Meier and Cox regression models. Results: Men comprised the majority of the population (n=91, 74%) and most cases were pathological stage I (n=75, 61%) or stage II (n=32, 26%). Thirty (24.4%) tumors showed amplification of FGFR1. There was no association between amplification and sex (p=0.18) or stage (p=0.37). The majority of the patients were white (n=114, 92.7%), but the proportion of tumors that were amplified was higher among non-whites (5/9, 55.5%) than whites (25/114, 21.9%, p=0.02). Overall, median survival was 32.2 months. In univariate survival analysis, amplification was associated with an increased hazard of death (HR=1.55, Wilcoxon p=0.03). Tumor stage at diagnosis was also associated with increased risk of death (HR=1.67, p=0.0009). Only stage remained a significant predictor of death in the multivariate survival models (HR=1.65, p=0.004). Conclusions: Somatic amplification of FGFR1 is a relatively common event in SqCCL and may be associated with race and overall survival.
Association of hyaluronan accumulation with clinical-pathologic features in pancreatic ductal adenocarcinomas.
Authors: Brent K Larson, Dana Pan, Jasleen Khanuja, Rishi Patel, Jenny Zhou, Arsen Osipov, Maha Guindi, Thomas Müller, Quanlin Li, Ping Jiang, Richard Tuli, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2017)

322 Background: Pancreatic ductal adenocarcinoma (PDA) is characterized by marked stromal fibrosis and hyaluronan (HA) accumulation. Degradation of stromal HA using PEGylated recombinant human hyaluronidase (PEGPH20) in combination with anti-cancer therapeutics has demonstrated increased efficacy in preclinical models. This study used an exploratory prototype HA assay to assess HA and to explore the association of HA status with clinical and pathological variables. Methods: Sixty-four PDA samples from 49 patients treated with gemcitabine and nab-paclitaxel were stained for HA using a prototype histochemical binding assay. The tumor extracellular matrix staining for HA at any intensity above background as a proportion of the total tumor surface area was recorded. Cases were categorized as HA-high (HA score of ≥50%) or HA-low (HA score of &lt;50%). Subgroup analyses were also performed in paired pre- and post-chemotherapy samples. Results: Twenty-six of 49 (53%) patients were determined to be HA-high. HA-high status was significantly associated with pN1 (positive node) status (p&lt;0.001) and well/moderate differentiation (p&lt;0.001). No correlation of HA status was observed with sex, race, primary tumor location, pT (tumor) stage, lymph-vascular invasion, pathologic stage, or initial CA19-9 levels. No trend in HA status was observed comparing pre- and post-chemotherapy specimens (n=5). Conclusions: HA status was significantly associated with nodal stage and grade.
Phase Ib study of plitidepsin (APL) with gemcitabine (GEM) in refractory solid tumors and lymphoma patients.
Authors: Mark N. Stein, Vincent Ribrag, Carlos Alberto Gomez-Roca, Gilles A. Salles, Angelo Michele Carella, Emmanuel Gyan, Sergio A. Szyldergemajn, Carmen Maria Kahatt, Manuel Luque, Sonia Extremera, Bernardo De Miguel, Eva Fernandez-Garcia, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2012)

2539 Background: Combination chemotherapy (CT) regimens may improve the outcome of patients with advanced metastatic disease. APL (a marine-derived cyclodepsipeptide) is a cytotoxic agent that induces apoptosis by JNK-pathway activation and increased oxidative stress; it has also shown anti-angiogenic properties in vitro. GEM has a different mechanism of action and toxicity profile from APL, making this combination appropriate for clinical testing. Moreover, APL has been shown pre-clinically to potentiate the anti-tumor effect of GEM. Methods: Patients with ECOG-PS ≤ 1 received escalating doses of APL/GEM (1.8/750, 1.8/1000, 2.4/1000 and 3.0/1000 mg/m 2 ) on days 1, 8 and 15 every four weeks. The primary objective was to determine of the maximum tolerated dose (MTD) and the recommended dose (RD) for APL/GEM. Secondary objectives included characterization of safety profile, pharmacokinetics (PK) and anti-tumor activity of APL/GEM. Results: 34 patients were included and 33 treated (23 solid tumors and 11 lymphomas) with a median age of 59 years (r: 28–86), median prior CT lines 3 (r:1-7) and a median of 2 cycles (r:1-12). Relative dose intensity was 66.7% (r: 37.7-85.7%) and 80.9% (r: 56.1-100.6%) for APL and GEM, respectively. The MTD was 3.0/1000 mg/m 2 , as 2/6 patients experienced dose limiting toxicities (DLTs) [grade (G) 4 thrombocytopenia and 2 missed doses due to G2 ALT/AST]. The RD was 2.4/1000 mg/m 2 , with no patients experiencing DLTs. Adverse events (AEs) were mainly G 1-2 anemia, thrombocytopenia and ALT/AST increase. Six patients with solid tumors had stable disease (SD) ≥ 3 months, one patient with NK T-cell lymphoma had a complete response, a patient with Hodgkin disease (HD) had a partial response and three other patients with HD had SD ≥ 3 months with tumor decrease at the RD. No relevant drug-drug interaction was observed for the dose levels tested. Conclusions: APL/GEM at the RD can be safely combined. Objective responses were observed in patients with HD and NK T-Cell lymphoma. Further studies of this combination in lymphoma are warranted.
ATM/RB1 mutations to predict shorter overall survival (OS) in bladder cancer.
Authors: Ming Yin, Petros Grivas, Siraj Mahamed Ali, Joann Hsu, Monali K. Vasekar, Hamid Emamekhoo, Sumanta K. Pal, Sierra Min Li, Joseph J. Drabick, Monika Joshi
Journal: Journal of Clinical Oncology (2017)

393 Background: DNA repair defect plays an important role in tumorigenesis, progression and treatment outcomes of urothelial cancer. Somatic mutations of ATM/RB1 genes are frequently found in urothelial cancer and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, their prognostic value overall in urothelial cancer have not been determined. Methods: Exome sequencing data of 130 urothelial bladder cancer patients (pts) from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM and RB1 mutations. Results from discovery dataset were further validated by an independent cohort of 79 advanced urothelial cancer pts who received comprehensive genomic sequencing for urothelial cancer with FoundationOne. OS was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: In the discovery dataset, somatic mutations of ATM/RB1 genes were present in 24% of pts and were associated with significantly shorter OS [all stages: adjusted HR = 2.67, 95% CI, 1.45–4.92, P = 0.002; stage II-III only: adjHR = 2.76, 95% CI, 1.23–6.20, P = 0.014]. There was high mutation load in pts carrying ATM/RB1 mutations (median mutation count: 196 versus 160, P = 0.09). In the validation (stage IV) dataset, ATM/RB1 mutations were present in 31.7% of pts and tended to associate with shorter OS (adjHR = 1.97, 95% CI, 0.89–4.40, P = 0.094) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, P = 0.136), although statistical significance was not reached. Conclusions: These results suggest that ATM/RB1 mutations may be considered as a poor prognostic biomarker in unselected urothelial cancer pts and may correlate with higher mutational load. Further studies are required to determine patient characteristics that can further stratify prognosis based on ATM/RB1 mutation status, and evaluate the potential predictive role of ATM/RB1 mutation status in response to immunotherapy.
Defining the Impact of Adjuvant Therapy in Molecularly Defined Subsets of Gastrointestinal Stromal Tumor
Authors: Michael C. Heinrich, Christopher L. Corless, George D. Demetri
Journal: JAMA Oncology (2017)

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Adjuvant chemoradiotherapy in patients (pts) with resectable gastric (GC) or gastroesophageal junction cancer (GEJC): A monoinstitutional experience.
Authors: Barbara Soini, Giuseppe Pani, Orazio Caffo, Michela Frisinghelli, Antonello Veccia, Sonia Brugnara, Alessia Caldara, MariaChiara DiPasquale, Antonella Ferro, Salvatore Mussari, Viviana Murgia, Lucianna Russo, Francesco Valduga, Salvatore Tumulo, Enzo Galligioni
Journal: Journal of Clinical Oncology (2012)

e14711 Background: Several studies have investigated the role of adjuvant chemotherapy ± radiotherapy showing conflicting results. In this retrospective study we report our monoinstitutional experience in pts with resectable GC or GEJC, treated with adjuvant chemoradiotherapy. Methods: Between January 2004 and August 2010 a consecutive series of 48 pts (34 male and 14 female) with a median age of 61 years (range 45-76) underwent a curative resection for GC or GEJC. All pts were treated with adjuvant chemoradiotherapy according to Mc Donald protocol (NEJM 2001;345:725-30). Thirty-three tumors (69%) were localized at the antrum or corpus level and 9 (19%) at the cardias. Thirty-one patients (64 %) had a T3-T4 tumor and 46 (95%) had nodal metastases.Treatment consisted of fluorouracil (5FU) 425 mg/m 2 per day plus leucovorin (L) 20 mg/m 2 per day, for 5 days, followed by radiotherapy 4500 cGy at 180 cGy per day, given 5 days per week for 5 weeks, with 5FU (400 mg/m 2 per day) and L (20 mg/m 2 per day) during the first four and the last three days of radiotherapy. One month after the completion of RT, two five-day cycles of 5FU (425 mg/m 2 per day) plus L (20 mg/m 2 per day) were given one month apart. Results: The treatment was completed in all but 4 pts: 2 pts stopped treatment due to chemotherapy side effects, 1 pt died due to intestinal perforation, and 1 pt declined radiotherapy. Major toxicities consisted of: grade 3/4 neutropenia in 6 pts (12%) and grade 3/4 gastrointestinal toxicity in 8 pts (16 %). At a median follow-up of 25.5 months (range 7 - 68), the median disease free-survival (DFS) was 41 months (2-y DFS 59%, 3-y DFS 53%) and the median overall survival (OS) was 57 months (2-y OS 77%, 3-y OS 68%). Conclusions: Concomitant chemo-radiotherapy appears in our experience a feasible adjuvant regimen in curatively resected node positive gastric cancer. Despite the short follow-up, local control and survival rates seem promising and comparable to those reported in the literature.
Broad, hybrid capture-based next generation sequencing of circulating tumor DNA identified actionable genetic alterations in advanced cancer with treatment resistance.
Authors: Xiaochun Zhang, Helei Hou, Lihua Deng, Chuantao Zhang, Xiaofeng Cheng, Yanfang Guan, Xiaomei Xu, Xiaofei Wang, Airong Tan, Congmin Liu, Wenjun Yu, Chun Yan, Chengye Guo, Dong Liu, Xiaonan Yang, Rongjiao Wang, Wenqi Liu, Zhuokun Li, Yi Xin
Journal: Journal of Clinical Oncology (2015)

e22078 Background: Circulating tumor DNA (ctDNA) is an optional specimen used to identify potentially targetable genetic alterations in solid tumors, particularly for those that developed treatment resistance and cancer tissue sample cannot be obtained. There are still few sensitive and clinically applicable ctDNA detection methods. In this study, we used a broad, hybrid capture-based next generation sequencing (NGS) assay to screen actionable genetic alterations in plasma ctDNA with diverse cancer patients. Methods: 147 cases of advanced tumor were enrolled, including 65 lung cancers, 39 breast cancers, 23 gastric cancers, and 20 colorectal cancers. 7708 exons of 508 tumor related genes and 78 introns of 19 frequently rearranged genes were assessed for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 940×. Results: Targetable genetic alterations were detected in 19 of 65 (29.2%) lung cancers, 15 of 39 (38.5%) breast cancers, and 6 of 20 (30%) colorectal cancers. Remarkably, these alterations were only found in 3 of 23 (13.0%) gastric cancers. Specifically, EGFR mutation was found in 8 of 65 (12.3%) lung cancers. HER2 gene amplification was detected in 8 of 39 (20.5%) breast cancers, and in 1 of 23 (4.3%) gastric cancers. Additionally, K-ras mutation was found in 4 of 20 (20.0%) colorectal cancers. The common actionable alterations found in various cancer types were in HER2 (n = 12), EGFR (n = 9), K-ras (n = 6), and PTEN (n = 4). Conclusions: 29.3% (43/147) of all ctDNA samples harbored at least one actionable genetic alteration identified by NGS testing. Noninvasive actionable genetic alterations detection in ctDNA by NGS assay might be an efficient strategy to guide personalized therapy for advanced cancer patients.
Construction of a frailty index for older adults with cancer using a geriatric assessment.
Authors: Emily Jean Guerard, Allison Mary Deal, Grant Richard Williams, Trevor Augustus Jolly, William Allen Wood, Hyman B. Muss
Journal: Journal of Clinical Oncology (2015)

9535 Background: Frailty is a state of increased vulnerability to adverse outcomes and can be defined by counting the number of health deficits an individual acquires. This study constructs a frailty index from a geriatric assessment (GA), defines the prevalence of frailty in older adults (65+) with cancer, and evaluates associations of frailty with sociodemographic and GA variables. Methods: The Carolina Senior Registry (CSR) is an institutional database (NCT01137825) that contains GA data on older adults with cancer. From the CSR, a 32-item frailty index (range 0-1) was developed by deficit counting as previously reported [Searle et al. BMC Geriatrics 2008] and categorized as robust (0-0.2), pre-frail (0.2-0.35), and frail ( > 0.35) based on prior studies. Fisher’s exact tests and linear regression were used to evaluate associations. Results: Of the 1179 total patients, the median age was 72, 87.7% Caucasian, 69.6% female, 90.7% had at least a high school education, 58.7% married, and 44.3% had a breast cancer diagnosis. Overall 59% were robust, 25.3% were pre-frail, and 15.7% were frail. Frailty and pre-frailty were more prevalent among lung cancer patients (54.6%) compared to patients with hematologic malignancies (46.5%) and breast cancer (34.1%). In a multivariable model, increasing age, African American race, lower education, increasing number of daily medications, and decreasing Karnofsky Performance Status were significantly associated with increased frailty (all p < 0.001). Gender, marital status, and cancer type were not associated with frailty in this model. Frailty status was also associated with measures of physical function such as falls and a Timed Up and Go of greater than 14 seconds (p < 0.001). Conclusions: We created a 32-item frailty index using GA data from a cohort of older adults with cancer. Frailty was prevalent and significantly associated with sociodemographic variables. Additional work will be focused on validating our frailty index by using outcomes data. Because frail older adults with cancer are at an increased risk for adverse outcomes, a frailty index constructed from a cancer-specific GA may provide a straightforward way to identify frail patients who should be targeted for further intervention.
A Multicenter Retrospective Analysis on Pentostatin As Salvage Therapy of Severe Steroid Refractory Intestinal Acute Graft Versus Host Disease
Authors: Stefan A. Klein, Thomas Schmitt, Gesine Bug, Johannes Schetelig, Rainer Schwerdtfeger, Kerstin Schaefer-Eckart, Christoph Schmid, Hannes Wandt, Wolf-Karsten Hofmann, Martin Bornhaeuser, Hans Martin, Peter Dreger
Journal: Blood (2011)
Functional profiling of clear cell ovarian cancer.
Authors: Rowan Miller, Rachel Brough, Ilirjana Bajrami, Stanley B. Kaye, Christopher J. Lord, Alan Ashworth
Journal: Journal of Clinical Oncology (2012)

5035 Background: Clear cell ovarian cancer represents up to 15% of epithelial ovarian cancers. In comparison to other subtypes, clear cell ovarian carcinomas have a poorer prognosis and are relatively resistant to standard platinum based chemotherapy. Recently, loss of function mutations in the tumour suppressor gene ARID1A were identified in up to 50% of ovarian clear cell carcinomas. We have adopted an integral functional and molecular profiling approach as a route to identify new genetic dependencies and therapeutic targets for this disease. Methods: Clear cell ovarian cancer cell lines were functionally profiled using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and transcriptome sequencing to aid the discovery of novel targets. Results: Using functional screens we have now identified critical gene dependencies and potential therapeutics in a series of clear cell ovarian cancer models. The comparison of functional viability profiles for models characterized by ARID1A loss of function mutations is now enabling an analysis of synthetic lethal effects that could be used to target clear cell ovarian cancers carrying these mutations. Conclusions: The work undertaken so far provides the framework for the discovery of therapeutic targets for clear cell ovarian cancer using an integrated approach. Revalidation of these preliminary results is now underway to characterize new genetic dependencies for this disease.
Prediction of right ventricular failure after ventricular assist device implant: systematic review and meta‐analysis of observational studies
Authors: Diego Bellavia, Attilio Iacovoni, Cesare Scardulla, Lorenzo Moja, Michele Pilato, Sudhir S. Kushwaha, Michele Senni, Francesco Clemenza, Valentina Agnese, Calogero Falletta, Giuseppe Romano, Joseph Maalouf, Michael Dandel
Journal: European Journal of Heart Failure (2017)
Review of the current status of <i>KRAS </i>mutation testing in France in 2011: The Flash-<i>KRAS </i>study.
Authors: Pascal Artru, Michel Ducreux, Astrid Lièvre, Michel Guiu, Jean-Louis Merlin, Jean-Christophe Sabourin, Jérôme Viguier, Anne Bastie, Audrey Seronde, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2012)

e14129 Background: KRAS testing is required before treatment initiation of cetuximab in the management of metastatic colorectal cancer (mCRC). The objective of the study was to examine the current situation in 2011 regarding KRAS testing in the initial management of mCRC. Methods: This observational, retrospective, national study was carried out between March 28th and April 8th 2011. During this period 538 patients with mCRC were included across 160 french hospitals. The main objective was to assess the rate of KRAS testing in patients who had started first line (L1) treatment for mCRC. The secondary objectives were to describe the time taken and techniques used for KRAS testing, the possible reasons this test was not requested, to describe and analyse the clinical characteristics of the patients and the planned L1 treatments and those finally received. Results: KRAS testing was carried out for 433 patients (81.1%) and not carried out for 101 patients (18.9%). The main reasons for not requesting the KRAS status were (several answers possible): anti-EGFR not prescribed (n=58), candidate for surgery (n=8), samples not useable (n=5), age of the patient (n=3), other (n=24), data missing (n=13). The genotyping results were available after a mean delay of 23.6 ± 28.2 days. The KRAS testing was requested by an oncologist (45.5%), a gastroenterologist (31%), a surgeon (11.2%), a pathologist (7.2%) or a multidisciplinary group (5.1%) approximately 15 days (-66.5;33.6) median (min ; max) after the diagnosis of metastases, and 15 days (-66.9;3.7) median (min ; max) before the start of L1 treatment. Result of KRAS status had not been received before the L1 treatment was chosen in 56.6% of the patients. For patients with wild-type KRAS status whose therapeutic management was modified after the result of KRAS testing (n=108), this change was a prescription of an anti-EGFR in 77.8% of the cases. Conclusions: The Flash-KRAS study is the first one to assess the current modalities of KRAS genotyping in France. It shows that in 2011 the KRAS test is an integral part of the management of patients with mCRC. Nonetheless, it shows disparities between regions in terms of time to obtain results, which need to be improved to be compatible with the therapeutic management.