tbuckley/cabot-search huggingface dataset:
A next-generation sequencing approach to capturing CEBPA: A hematologic malignancy sequencing panel capturing clinically useful targets.
Authors: Jennifer J. Morrissette, Jianhua Zhao, Adam Bagg, Dale Frank, Selina M. Luger, Martin Carroll, Robert D Daber
Journal: Journal of Clinical Oncology (2014)

7096 Background: The use of next generation sequencing (NGS) for clinical diagnosis of cancer promises to improve diagnosis and lead to more precise cancer care. However, this methodology does not cover all regions of the genome uniformly, with some regions not sequenced with sufficient depth for accurate mutation detection. Here we describe the validation of a 34 gene hematological NGS panel, including one gene, CEBPA, which performed poorly and required an alternative NGS method due to GC–rich regions. Methods: Fifty five AML patient samples were obtained from the Stem Cell and Xenograft Core at the University of Pennsylvania and analyzed using an Illumina TrueSeq Custom Amplicon panel with subsequent sequencing on the Miseq. To capture CEBPA we developed a separate method using target amplification by a long range PCR followed by library preparation using the Nextera XT kit (Illumina Inc). Results: We found NGS of commonly mutated genes in hematologic malignancies is technically feasible and reliable in a clinical diagnostic laboratory, with >99% sensitivity and specificity on variant detection achieved when allele frequency of a given variant was 5% or higher over regions that met our sequencing QC threshold of 250x. The middle of the coding region for CEBPA demonstrated inefficient capture using amplicon or bead based approaches. Using a long range PCR approach followed by Nextera library preparation, 100% coverage of CEBPA was achieved. Given the high GC content a lower limit of detection for CEBPA, at a 10% allele frequency, allowed for 100% sensitivity and specificity in the samples analyzed. Conclusions: We have developed a clinical grade multi-gene test for hematologic malignancies using next generation sequencing technology that can reliably detect somatic mutations including single nucleotide variants, insertions and deletions. For most genes on the panel, a minimal allele frequency of 5% was detectable for indels and SNVs. With CEBPA, there was robust mutation detection at an allele frequency of 10% or greater. This combined approach allows for comprehensive mutation screening of the genes relevant to the prognosis of AML, including CEBPA, with a single approach, NGS.
Activity of a multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen in metastatic renal cell carcinoma (mRCC): A phase II study of sorafenib, gemcitabine (Gem), and metronomic capecitabine (Cap) in patients with advanced mRCC (SOGUG-02–06)
Authors: J. Bellmunt, J. Trigo, E. Calvo, J. Carles, J. Perez-Gracia, J. Rubió, J. Virizuela, R. López, M. Lázaro, J. Albanell
Journal: Journal of Clinical Oncology (2009)

5040 Background: Maximal tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses administered on a frequent schedule) acts on tumor vascular endothelial cells and enhances the antitumor effect of anti-angiogenic agents (Pietras et al. J Clin Oncol. 2007). This study investigated treatment of mRCC with Gem at MTD combined with metronomic Cap and the multikinase inhibitor sorafenib. Methods: Eligible patients had cytologically or histologically confirmed mRCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and no previous targeted therapy or chemotherapy, and were unsuitable for or intolerant to immunotherapy. Treatment consisted of six 3-week cycles of Gem 1000 mg/m 2 i.v. (days 1 and 8), oral Cap 500 mg/m 2 b.i.d. (days 1 to 14) and oral sorafenib 400 mg b.i.d. (every day), followed by sorafenib monotherapy (at the discretion of the investigator). Study endpoints included median progression-free survival (PFS, primary endpoint), disease control rate according to Response Evaluation Criteria in Solid Tumors, and safety. Results: Forty patients were enrolled and received at least one dose of treatment (median age 63 yrs, male n = 24, ECOG 0/1 n = 18/22, 1–2/&gt;2 metastatic sites n = 31/9). Median duration of treatment was 6 months. Among 36 evaluable patients, 17 (47%) had a partial response and 17 (47%) achieved stable disease. Median PFS was 10.2 months (95% CI 7.6, 20.5). The most common adverse events (AEs) were fatigue/asthenia (78%) hand-foot syndrome (75%) and mucositis (69%). Most AEs were grade1/2, no grade 4 toxicities occurred. One patient had grade 5 dyspnea; 6 patients discontinued treatment for AEs. Conclusions: PFS and objective responses in this study were greater than those observed in previous studies with Gem and Cap or sorafenib monotherapy in patients with mRCC, while AEs remained moderate in the majority of patients. These findings confirm the synergistic activity of the “chemo-switch” concept seen in preclinical models. The combination of sorafenib with MTD Gem and metronomic Cap warrants further investigation in mRCC. [Table: see text]
Characteristic and management of lung cancer as a secondary malignancy.
Authors: Adam Pluzanski, Pawel Badurak, Dariusz M Kowalski, Maciej Glogowski, Katarzyna Zajda, Maciej Jerzy Krzakowski
Journal: Journal of Clinical Oncology (2012)

e12011 Background: New diagnostic and therapeutic strategies increase survival in cancer patients. Etiology and management of primary lung cancer (LC) are well established, but little is known about incidence of LC as a secondary neoplasm. The study analyzes the clinical characteristic, pathology and management of LC as a secondary neoplasm. Methods: We reviewed medical records of patients (pts) treated in our institution from Feb.1998 to Aug.2011 with diagnosis of LC as a second malignancy. The analysis included median age at the time of diagnosis of primary cancer, histology, type of treatment and time until diagnosis of LC. Results: 84 pts were analyzed – median age at the time of diagnosis of primary cancer was 62 years (range 35-79) (65 years in men and 58 years in women p&lt;0,05). The most frequent primary was: breast -21 pts (25%), larynx -19 pts (23%), colon - 9 pts (11%). According to etiology, tobacco-related primary cancers occurred in 37 (44%) pts. Radiotherapy/chemoradiotherapy was the treatment for primary cancer in 42 (50%) pts, surgery alone in 31 (37%) and chemotherapy in 11 (13%) pts. Adenocarcinoma as a secondary LC was diagnosed in 43 pts (51%), squamos-cell carcinoma in 30 pts (36%), small-cell lung cancer or carcinoid in 6 pts (7%), other types of non-small cell lung cancer in 5 pts (6%). Median time between diagnosis of primary cancer and LC was 50 months (range 0-354). Stage I or II LC was found in 56 pts (67%) and stage of III or IV in 26 (31%) pts (contrary to staging observed in pts diagnosed with LC as a primary malignancy in our institution concurrently). After diagnosis of LC radical and palliative treatment was offered in 65 (77%) pts and 19 (23%) pts respectively. After median follow-up of 84 months, progression of LC was noted in 27 pts (32%) and median time to progression was 16 months (range 2-89). Conclusions: Patients after treatment of tobacco-related cancers are at risk of developing LC as a second malignancy. LC as a secondary cancer is observed also after treatment of breast cancer and radiotherapy use. Close surveillance after treatment of primary malignancy allows detection of LC at early stage with a chance of radical treatment.
Population survey to assess the knowledge of smoking habit and its consequences on women (w) in Spain.
Authors: Margarita Majem, Angel Artal, Javier De Castro, Enriqueta Felip, Pilar Garrido Lopez, Dolores Isla, Juan Ramon Bujosa, Rosana Cajal, Nuria Vinolas
Journal: Journal of Clinical Oncology (2012)

e12000 Background: Lung cancer (LC) w has reached epidemic proportions with a 600% increase in w’s death rate for LC. LC is the leading cause of cancer death in w in USA and the second in Spain. However, Spanish population is not aware of the significant increase in smoking and LC incidence in w. We performed a population survey to know the smokers’ characteristics and to assess the knowledge about smoking and its consequences especially in w. Methods: We conducted 1000 telephone interviews in Spanish population &gt;18 years (y). Sample was distributed in proportion to the population by region with age and gender quotas: 48% were men (m), 52% w. Age distribution: 18-29y 16%; 30-44y 30%; 45-64y 32%; &gt; 65y 22%. Results: The 17% and 25% of w were current and former smokers, respectively. The 27% and 38% of m were current and former smokers, respectively. People of 18-29y were the most current smokers (26%), and w smokers rate was higher than m. The 58% of w and 52% of m started smoking between 14-18y. Among students, 43% of w and 23% of m smoke. The 70% of smokers of 30-44y have tried to quit smoking, and having a relative with LC increased by 47% the possibility of quitting smoking as a young. Only 1/10 people had ever asked for their own LC risk, even if they had ever smoked or had a relative with LC. LC was the first disease named as smoking-related disease (58%). The 78% believed that nowadays more w smoke. The 60% believed that LC in w is increasing. Additionally, &gt;40% belief that &gt;75% of w LC have ever smoked. The 24% believed that tobacco hurts w more than m and the 55% that LC affects w more or equal than m. The 65% believed that breast cancer is the leading cause of cancer death in w in Spain and 13% that it is LC. 9/10 is aware about direct relation between tobacco and LC and the 50% believed that &gt;50% of smokers will develop LC. The 97% believed that never smokers might also develop LC. Conclusions: Although the relation between tobacco and LC is overestimated, the 17% of w and 27% of m smoke. A large % of surveyed is aware that nowadays more w smoke, although only the 60% believed that LC in w is increasing. The highest rate of smoker w are those of 18-29y, especially among students, and &gt;50% started smoking between 14-18y. Anti-tobacco campaigns are needed especially those targeting young w.
CD133 expression in circulating tumor cells (CTCs) from metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rosa Ana Marcos, Sara Alfonso, Rebeca Lozano, Ignacio Matos, Blanca Espinet, Rocio Garcia, Jesus Maria Hernandez, Francisco Gomez-Veiga, Juan Luis Hernandez, Juan J. Cruz
Journal: Journal of Clinical Oncology (2015)

e16077 Background: CTCs are emerging as a source of material for therapy-resistant prostate cancer, a so-called “liquid biopsy” that could serve as a therapeutic biomarker. CTCs can be obtained through non-invasive means, opening the door to serial assessments of the disease state and examine the response to different therapies. CTCs enumeration has been extensively studied and validated as a prognostic tool and received FDA clearance for use in monitoring advanced disease. The main objective of this study was to investigate the expression of CD133 in CTCs, and analyze genomic alteration by fluorescence in situ hybridization (FISH) for Androgen Receptor gene (AR), PTEN and TMPRSS2-ERG in patients with metastatic prostate cancer (mPCa) Methods: Ten milliliter of whole blood was collected from patients with mPCa. The fresh cells were subjected to erythrocyte lysis using NH4CL, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate the expression of CD133 in CTCs using the following murine-anti-human antibodies: CD45-FITC, CD34-PerCP, CD16 PECy7 and CD133 APC. In the CD133 enriched fraction, FISH analysis was performed for AR gene (Xq12), PTEN (PTEN/CEP10) and for TMPRSS2-ERG Results: In this preliminary analysis, a total of 38 samples were obtained. All of them were patients with mPCa, but 8 were receiving only Androgen Deprivation Therapy (ADT), and 30 patients were mCRPC, of which 20 were classified as post-DocetaxelmCRPC and 10 as Pre-DocetaxelmCRPC. The presence of CD133+ in CTCs was observed in 97% of samples analyzed. The median of this cell fraction was 4.5 (range 1-26). In 20 cases (53%) the number of CD133+ CTC was ≥ 5. In patients underwent ADT, the median of CD133+ CTC was 3.5 (range 0-9), while in mCRPC the median was higher: 7 per case (range 2-23). Genomic changes in AR were observed in 68% of cases, and PTEN deletion was observed in 78% of samples. This alteration was more frequently observed in patients with mCRPC than in patients treated with ADT. The traslocation TMPRSS2-ERG was detected in 23% of samples Conclusions: The quantifying and genomic characterization of CD133+in CTCs might help to develop new therapeutic approaches for targeting and monitoring in patients with mCRPC
Plasma cytokine concentrations and quality of life in patients with non-small cell lung cancer in a phase II trial of first-line treatment with carboplatin-paclitaxel and/or vandetanib
Authors: E. O. Hanrahan, F. Kim, H. Y. Lin, H. T. Tran, A. J. Ryan, A. D. Krebs, J. J. Lee, B. E. Johnson, J. V. Heymach, E. S. Kim
Journal: Journal of Clinical Oncology (2009)

9596 Background: A randomized phase II trial (JCO 26:5407–15, 2008) compared carboplatin-paclitaxel (CP) with vandetanib (VEGFR-EGFR inhibitor) monotherapy (V) and V plus CP (VCP) 1st-line for advanced NSCLC (N=181). PFS was superior for VCP vs CP (HR 0.76). We performed analyses of quality of life (QOL) and its correlations with plasma concentrations of cytokines and angiogenic factors (CAF) among the participants in this trial. Methods: QOL was serially measured by Functional Assessment of Cancer Therapy-Lung (FACT-L) and Trial Outcome Index (TOI) scores. Concentrations of 35 plasma CAFs were measured at baseline and multiple timepoints during treatment with multiplexed bead suspension arrays and ELISAs. We performed exploratory analyses for the following associations: (1) QOL with plasma CAF levels at baseline; (2) changes in QOL with changes in plasma CAF levels. Spearman correlation coefficient, log-rank test and mixed linear models were applied in the analyses. P-value &lt; 0.05 was considered significant. Results: Baseline QOL and plasma samples were both available for 120 patients. Lower baseline FACT-L scores (inferior QOL) were associated with higher pre-treatment plasma levels of INF-γ, IL-1RA, IL-6, IL-12, IL-15, TNF-α, RANTES, MIG, MIP-1β, MMP-9, bFGF, VEGF and sVEGFR-2 (all P&lt;0.05). Lower baseline TOI scores (inferior QOL) were also associated with higher pre-treatment plasma levels of multiple CAFs, including GCSF, HGF, INF-α, INF-γ, IL-2, IL-6, IL-8, IL-12, IL-15, TNF-α, bFGF, sVEGFR-2 and VEGF (all P&lt;0.05). Among all patients, decreasing TOI scores post cycle 2 (HR=2.57 [1.28,5.17], P=0.008) and cycle 4 (HR=2.58 [1.01,6.56], P=0.049) were associated with increased progression risk. Trends for FACT-L were similar, but did not reach statistical significance. Rises in GCSF, HGF, IL-2, IL-8, IL-15, MCP-1, MIP-1β, and VEGF from baseline to post cycle 2 were associated with decreased FACT-L and/or TOI scores (all P&lt;0.05). Conclusions: High plasma concentrations of multiple CAFs pre-treatment in patients with NSCLC correlated with inferior QOL, and rises in these factors during treatment were associated with worsening QOL. This work was funded in part by grant from ACS (FK). [Table: see text]
Abstract 241: Cardiac-Specific Overexpression of Runx2 Mediates Cardiac Hypertrophy and Dysfunction in Mice
Authors: Hiroyuki Nakayama, Tatsuto Hamatani, Shohei Kumagai, Kota Tonegawa, Tomomi Yamashita, Yasushi Fujio
Journal: Circulation Research (2012)

Backgrounds: Recent studies demonstrated that the osteopontin (OPN), an acid phosphoprotein plays pivotal roles in cardiac hypertrophy and failure. An osteogenic transcription factor Runx2 regulates the expression of OPN in osteoblasts. In the present study, we examined the pathological role of Runx2 in cardiac hypertrophy and failure. Methods and Results: Runx2 expression was detected in neonatal cardiomyocytes and upregulated in heart 14 days after myocardial infarction (MI) as well as 7days after transverse aortic constriction (TAC) procedures. To determine the functional role of Runx2 in heart, we generated transgenic mice (TG) with inducible cardiac-specific overexpression of Runx2. Two TG lines (low and high) were obtained and high-expressing TG (HE-TG) showed premature death within 8 weeks of age specifically in male mice. At two months of age, the survived male and female HE-TG displayed significant increases in heart weight/body weight ratio (mg/g) compared to controls (control; 4.95±0.26, n=6 vs HE-TG; 6.63±0.12, n=5, p&lt;.05). Consistent with those results, the expression of hypertrophic marker genes such as atrial natriuretic factor (ANF) and αskeletal actin significantly increased in HE-TG heart assessed by real-time RT-PCR analysis. In addition, HE-TG mice demonstrated decreased fractional shortening assessed by echocardiography (control; 44.1±1.89%, n=9 vs HE-TG; 23.9±3.48%, n=7, p&lt;.05). HE-TG mice demonstrated significantly lower heart rate (control; 630±18 bpm, vs HE-TG; 350±74 bpm, n=3 each, p&lt;.05) and complete atrioventricular block by telemetry analysis. In response to pressure overload, low expressing TG (LE-TG) demonstrated higher mortality and enhanced cardiac hypertrophic response after TAC (control; 6.20±0.23, n=6 vs LE-TG; 6.90±0.26, n=4, p&lt;.05). Conclusions: Targeted expression of Runx2 in heart mediates cardiac dysfunction and hypertrophy in mice. Thus, Runx2 could be a novel therapeutic target for heart failure.
Patterns of progression in patients (pts) with V600 BRAF-mutated melanoma metastatic to the brain treated with dabrafenib (GSK2118436).
Authors: Mary W. F. Azer, Alexander M. Menzies, Lauren Haydu, Richard Kefford, Georgina V. Long
Journal: Journal of Clinical Oncology (2012)

8558 Background: Dabrafenib has shown efficacy in pts with previously untreated brain metastases (BM) but most will progress. We report the pattern of disease progression (PD) in pts with either previously treated (surgery (Sx), SRS, WBRT) or untreated BM on dabrafenib. Methods: Clinicopathologic parameters were collected on 23 pts enrolled in the brain cohort of the BRF112680 phase I and BRF113929 phase II BM study of dabrafenib at Westmead Hospital between Sept 2009 and June 2011. Pts with RECIST PD but ongoing clinical benefit were allowed to continue dabrafenib. Results: 12 pts (52%) had previously untreated BM and 11 (48%) were previously treated with evidence of progression prior to dabrafenib. Median OS from study entry (8.4 mo, 95% CI 5.0-11.8), diagnosis of first BM (11.0 mo, 95% CI 9.1-13.0), and stage IV diagnosis (17.5 mo, 95% CI 12.1-23.0) were not different between the two groups. Similarly, PFS did not differ between groups. Of the 19 pts who had RECIST PD at datacut, 13 pts had intracranial (IC) PD with no pts progressing in new brain lesions alone (see table). At IC PD, 3/13 underwent SRS/Sx, 5/13 WBRT and 5/13 had no salvage local therapy to BM. 8 pts continued dabrafenib beyond IC PD, median 36 days; range 28-273. All measures of baseline disease burden correlated with worse OS; elevated LDH (HR 1.003, 95% CI 1.0-1.007, P=0.044), increased number (no.) metastatic sites (HR 1.32, 95% CI 0.97-1.81, P=0.08), increased no. of IC lesions (HR 1.04, 95%CI 1.00-1.09, P=0.04), increased no. extracranial (EC) lesions (HR 1.07, 95%CI 1.02-1.12, P&lt;0.01) and increased RECIST sum of diameters (SoD) (HR 1.012, 95% CI 1.003-1.021, P=0.007). High baseline SoD was the only factor that predicted worse RECIST response. Conclusions: Clinical benefit from dabrafenib does not appear to be influenced by prior local therapies to BM. There was no dominant pattern of progression in pts with BM on dabrafenib, but PD due to new lesions alone is rare. Pts with IC PD may benefit from salvage local therapy and continued dabrafenib. [Table: see text]
Results of the randomized phase III trial of trabectedin (T) versus doxorubicin-based chemotherapy (DXCT) as first-line therapy in patients (pts) with translocation-related sarcoma (TRS).
Authors: Andrew Eugene Hendifar, Sant P. Chawla, Michael Gordon Leahy, Antoine Italiano, Shreyaskumar Patel, Armando Santoro, Arthur P. Staddon, Nicolas Penel, Sophie Piperno-Neumann, George D. Demetri, Larry Hayward, Jeff White, Launce G. Gouw, Bernardo De Miguel, Pilar Lardelli, Arturo Soto, Antonio Nieto, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2013)

10517 Background: T is the first of a new class of anticancer agents with a transcription-targeted mechanism of action. In vitro,T interferes with the aberrant transcription factors binding to DNA promoters in TRS. Methods: Pts with advanced TRS of the subtypes: myxoid liposarcoma (ML), alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma, myxoid chondrosarcoma and synovial sarcoma, stratified by performance status (0 vs 1-2) and subtype (ML vs other TRS) were randomized (1:1 ratio) to T (1.5 mg/m 2 in 24h iv infusion q3wk) or doxorubicin, either single agent 75 mg/m 2 q3wk, or 60 mg/m 2 combined with ifosfamide (6-9 g/m 2 q3wk) as 1st line treatment. Primary endpoint: efficacy of T vs DXCT by comparing progression-free survival (PFS). Secondary: PFS at 6 months (PFS6), response rate (RR), PFS/RR by subtype (ML vs other TRS); overall survival (OS), safety. Results: 121 pts enrolled from 22 centers, 88 were confirmed by central pathology review and evaluable for the primary efficacy endpoint by independent review assessment (IR), and all 121 pts randomized were evaluable by investigators’ assessment (IA). The main limitation of the study analyses in both arms was high censoring rate (70% IR; 61% IA) mostly due to surgery (~30%) or chemotherapy/ radiotherapy (~30%). PFS results are shown in the Table. PFS6 was not different between arms (IR: 66.4% vs 80.8% p=0.18/IA: 60.7% vs 62.4% p=0.88). Current median OS:not reached (NR) for T (24.1-NR) and 21.7 mo. for DXCT (21.2-NR).Safety: Most frequent AEs in both arms were nausea (70% vs 65%), vomiting (44% vs 26%) and fatigue (64% vs 63%). ALT increase G4 occurred in 10% pts treated with T and neutropenia G4 in 25% of pts in the T arm vs 52% in the DXCT arm. Conclusions: Although with a high censoring rate, this prospective study suggests thatPFS/OS with trabectedin are not significantly different from DXCT in first-line treatment. Clinical trial information: NCT00796120. [Table: see text]