tbuckley/cabot-search huggingface dataset:
Expression profile of angiogenic factors in paired initial and recurrent glioblastoma.
Authors: Emeline Tabouret, Aurelie Tchoghandjian, Emilie Denicolai, Christine Delfino, Philippe Metellus, Laetitia Padovani, Isabelle Nanni, Maryline Barrie, Celine Boucard, L'houcine Ouafik, Dominique Figarella-Branger, Olivier L. Chinot
Journal: Journal of Clinical Oncology (2014)

2060 Background: Angiogenesis is one of the key features of Glioblastoma (GB). Our objective was to identify the changes in the expression of angiogenic factors in GB after radio-chemotherapy. Methods: Analysis of all patients with available frozen tumor material from initial and recurrent surgery for GB treated with chemo-radiotherapy (CTRT) in first line setting in our institution between 2003 and 2009. Molecular screening was realized using two types of RT²Profiler PCR arrays (Qiagen). The RNA expression profile of selected genes was validated using quantitative RT PCR. Protein expression was analyzed by immunohistochemistry (IHC). Explants of newly GB were treated with temozolomide, radiotherapy and anti-CXCR4 (AMD3100). Results: Twenty nine patients were included with median age of 57.1 years (37.2-74.1). The RT2Profiler PCR arrays results allowed a selection of seven genes: VEGFA, VEGFR2, VEGFR1, Adrenomedullin, SDF1, CXCR4, and HIF1α. The steady state levels of CXCR4 RNA at recurrence was significantly increased (p=0.029) while HIF1α RNA was significantly decreased (p=0.009). A trend for a decrease of VEGFR2 RNA (p=0.081) and an increase of SDF1 RNA (p=0.107) was observed. Changes of SDF1 RNA tended to be correlated to changes of CXCR4 RNA (p=0.077) and inversely correlated to changes of HIF1 α RNA (p=0.064). By IHC, VEGFR2 staining was significantly decreased at recurrence (p=0.004) while SDF1 expression tended to increased (p=.096). Medians initial and at recurrence overall survival (OSI and OSR) of this selected population were 25.5 (95% confidence interval (CI) 17-34) and 11.4 (95%CI 9-13.9) months respectively. By multivariate analysis, VEGFR2 RNA initial and at recurrence levels were significantly correlated to OSI (p=0.019, Hazard ratio (HR) =3.650) and OSR (p=0.024, HR=2.536) while HIF1 α RNA level at baseline was correlated to OSI (p=0.012, HR=0.300). In newly GB explants, a higher anti-tumoral effect was observed with the combination of AMD3100 and CTRT versus CTRT alone. Conclusions: Acquired resistance of GB to chemo-radiation could be associated with a switch of angiogenic pattern from VEGFR2-HIF1α to SDF1-CXCR4 pathway, leading to new perspectives in angiogenic modulation and GB treatment.
Constitutive single nucleotide polymorphisms (SNP) assessment for predicting tolerability and efficacy of triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-CET) in patients (pts) with liver metastases from colorectal cancer (LM-CRC) (European trial OPTILIV, NCT00852228).
Authors: Francis Levi, Abdoulaye Karaboué, Raphaël Saffroy, Elodie Peyric, Michel Ducreux, Denis Michel Smith, Mohamed Hebbar, Pasquale F. Innominato, Simon Pernot, Carlos Carvalho, Rosine Guimbaud, C. N. J. Focan, Mohamed Bouchahda, Rene Adam, Marie-Christine Etienne-Grimaldi, Gerard A. Milano, Antoinette Lemoine
Journal: Journal of Clinical Oncology (2014)

3593 Background: The combination of IV-CET and HAI of irinotecan , oxaliplatin and 5-fluorouracil displayed high activity as 2-4thchemotherapy line for initially unresectable wt KRAS LM-CRC, yielding a macroscopic complete resection rate (R0+R1) of 29.7% and an overall survival of 25.7 months (Ducreux, ASCO 2013). The purpose is to identify the pts whose constitutive SNPs predict for best outcomes on this neoadjuvant protocol. Methods: 192 constitutive SNPs from 36 pharmacogenetically-relevant genes were analysed in pt blood cells using the ADME PGx panel with the MassArray platform (Sequenom, USA). Relations between polymorphic genes with minor SNPs and grade distribution for main toxicities per pt over 6 courses, best tumor response, and R0+R1, were explored using Mann Whitney or Fisher Exact test. Results: Gene polymorphisms were assessed in 52/64 registered pts with unresectable LM-CRC (16F; 36M), aged 33-76 years with good PS (0-1: 98%) receiving IV-CET + IFO-HAI as 2nd line for 21 pts (40%) and 3rd-4thline for 31 pts (60%). Main grade 3-4 toxicities were neutropenia (40%), abdominal pain (29%), fatigue (21%), and diarrhea (17%). Objective response was achieved in 20 pts (39%). Secondary R0-R1 LM resection was performed in 14/52 pts (27%). None of the minor SNPs in the 36 genes studied was a potential predictor of LM resection, nor displayed any significant relation with pt characteristics except for Cyp2C19 and sex (p<0.05). Best objective response was associated with minor SNPs in SLC22A2 (p=0.049) and UGT2B15 (p=0.011). Neutropenia, fatigue and diarrhea were associated with minor SNPs in Cyp2C19 (p<0.05). Neutropenia was further related to minor SNPs in Cyp1A2 (p = 0.017) and SLC22A1 (p=0.027), while diarrhea was predicted by minor SNPs in Cyp2D6A (p<0.05). Conclusions: This selected pharmacogenetics analysis revealed six genes involved in drug metabolism and transport whose minor SNPs predicted safety and efficacy outcomes and could warrant treatment adjustment for pts on neoadjuvant triplet HAI and IV-CET for LM-CRC. Clinical trial information: NCT00852228.
The impact of chronic kidney disease in locally advanced rectal cancer patients treated with neoadjuvant chemoradiation.
Authors: Shaan Dudani, Horia Marginean, Joanna Gotfrit, Patricia A. Tang, Jose Gerard Monzon, Kristopher Dennis, Hagen F. Kennecke, Erin Diana Powell, Sam Babak, Winson Y. Cheung, Michael M. Vickers
Journal: Journal of Clinical Oncology (2018)

794 Background: Chronic kidney disease (CKD) and cancer are common with advancing age. CKD may influence drug tolerance/efficacy and is an independent prognostic factor in some cancers. The impact of CKD on outcomes in patients (pts) with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiation (nCRT) has not been previously studied. Methods: We reviewed pts with LARC undergoing nCRT prior to surgery with curative intent from 2005-2013 across 4 Canadian provinces. Data regarding demographics, staging, baseline renal function, treatments and outcome were collected. CKD was defined as having an estimated glomerular filtration rate (eGFR) (Cockroft-Gault) &lt; 60 ml/min. Primary endpoints were neoadjuvant treatment completion rate, disease-free survival (DFS), and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for an association between renal function and outcomes. Results: 1122 (71%) of 1580 pts were included for analysis. Median age was 61 (IQR 54-69), 70% male, 84% performance status 0-1. 28% and 68% had clinical stage II and III disease, respectively. Median eGFR was 93 ml/min (IQR 74-114), with 11% &lt; 60 ml/min (n = 120). 97% of all pts received ≥ 44 Gy (median 50 Gy [range 20-80]). 53% received 5-fluorouracil and 44% received capecitabine as neoadjuvant chemotherapy (nCT). 84% completed nCT, 95% completed neoadjuvant radiotherapy (nRT), and 76% received adjuvant chemotherapy (aCT). Pts with CKD were less likely to receive aCT (62% vs 78%; p &lt; 0.01). There was no significant difference in completion rate of nCT (80% vs 85%; p = 0.15) or nRT (93% vs 95%; p = 0.20) based on renal function. After a median follow up time of 62 months, 8% developed local recurrence, 21% developed distant recurrence and 21% have died. 5-year OS and DFS were 78% and 73%, respectively. Pts with CKD had decreased OS on univariate analysis (HR 1.59, 95% CI 1.11-2.28; p = 0.01), but not on multivariate analysis. DFS was not significantly different based on renal function (HR 1.27, 95% CI 0.89-1.81; p = 0.18). Conclusions: In LARC pts undergoing nCRT, CKD was associated with less use of aCT but did not have any independent association with nCT and nRT completion rate, DFS or OS.
Disruption of NOTCH1-MYC-CD44 Axis Targets Leukemia Initiating Cells (LIC) in T-ALL
Authors: Sujan Piya, Seemana Bhattacharya, Hong Mu, Vivian Ruvolo, Natalia Baran, Teresa McQueen, R. Eric Davis, Yimin Qian, Kanak Raina, M. James You, Marina Y. Konopleva, Hagop M. Kantarjian, Michael Andreeff, Gautam Borthakur
Journal: Blood (2018)
Comprehensive Analysis of Chromatin States in Atypical Teratoid/Rhabdoid Tumor Identifies Diverging Roles for SWI/SNF and Polycomb in Gene Regulation
Authors: Serap Erkek, Pascal D. Johann, Martina A. Finetti, Yiannis Drosos, Hsien-Chao Chou, Marc Zapatka, Dominik Sturm, David T.W. Jones, Andrey Korshunov, Marina Rhyzova, Stephan Wolf, Jan-Philipp Mallm, Katja Beck, Olaf Witt, Andreas E. Kulozik, Michael C. Frühwald, Paul A. Northcott, Jan O. Korbel, Peter Lichter, Roland Eils, Amar Gajjar, Charles W.M. Roberts, Daniel Williamson, Martin Hasselblatt, Lukas Chavez, Stefan M. Pfister, Marcel Kool
Journal: Cancer Cell (2018)
Prognostic relevance of KRAS genotype and the prevalent C.35 G > a mutation in metastatic colorectal cancer (MCRC) patients fitting for intensive FIr-B/FOx triplet chemotherapy plus bevacizumab.
Authors: Gemma Bruera, Katia Cannita, Alessandra Tessitore, Alessio Cortellini, Jean Christophe Sabourin, Mario Tosi, Thierry Frébourg, Edoardo Alesse, Corrado Ficorella, Enrico Ricevuto
Journal: Journal of Clinical Oncology (2014)

e14575 Background: Bevacizumab (BEV) addiction to chemotherapy can predict increased efficacy in KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients. Codon 12 KRAS mutations differentially affect GTPase function, and confer worse clinical behaviour. Prognostic relevance of KRAS genotype and the prevalent c.35 G > A mutation were verified in patients fit for, and after progression to first line FIr-B/FOx. Methods: KRAS codon 12/13 mutations were screened. Activity and efficacy were evaluated and compared by log-rank. Results: Sixty-nine patients (45% overall MCRC) were treated with FIr-B/FOx: 32 KRAS wild-type, 17 c.35 G > A mutant, 20 other mutant. At median follow-up 24 months, objective response rate (ORR) was 77%, progression-free survival (PFS) 13 months, and overall survival (OS) 31 months. Among wild-type and mutant patients, respectively: ORR 91% and 64%, PFS 14 and 11 months, OS 38 and 20 months. KRAS mutant patients showed a significantly worse OS compared to wild-type (P = 0.031). c.35 G > A mutant confirmed significantly worse OS compared to wild-type and to wild-type plus other mutant patients. Post-progression to FIr-B/FOx, among 46 second line treated patients (67%), at median follow-up 13 months, ORR was 36%, PFS 8 months, OS 14 months. Among patients treated with re-challenge of triplet chemotherapy plus targeted agent, and triplet regimens, respectively: ORR 83% and 29%, PFS 11 and 8 months, OS 40 and 11 months. OS was significantly different in patients treated with triplet chemotherapy plus targeted agent compared to other treatments, and to triplet regimens. Among wild-type and mutant patients, respectively: ORR 48% and 25%, PFS 9 and 8 months, OS 23 and 12 months. KRAS wild-type compared with mutant patients did not show significantly different OS, while it was significantly worse in c.35 G > A mutant patients. Conclusions: KRAS mutant genotype and specifically the prevalent c.35 G > A mutation may significantly affect worse clinical outcome in patients fit for first line FIr-B/FOx intensive regimen. c.35 G > A mutation may also significantly affect worse OS after progression.
RANIDO: A phase III clinical trial of racotumomab-alum or nimotuzumab versus docetaxel in advanced non-small cell lung cancer patients.
Authors: Maurenis Hernandez, Eduardo Rafael Santiesteban, Ramon Alberto Ortiz, Elia Neninger, Soraida Acosta, Yoana Flores, Rosa Maria Amador, Mayte Robaina, Ivis Mendoza, Pedro Pablo Guerra, Anet Valdes, Ana Maria Vazquez, Amparo Macias, Tania Crombet
Journal: Journal of Clinical Oncology (2014)

TPS3111 Background: Despite extensive research in NSCLC treatment, overall survival remains insufficient. Immunotherapy has become a viable treatment to help the immune system to control or eliminate cancer.Racotumomab-alum is an anti-idiotypic vaccine that induce an inmunological response against N-glycolilated gangliosides in NSCLC patients. Several studies have demonstrated its antitumoral effect and safety. Nimotuzumab is an anti-EGFR monoclonal antibody that has shown promising activity in NSCLC patients without skin toxicity. The aim of this study is to evaluate safety and efficacy of racotumomab-alum or nimotuzumab versus docetaxel as second line or switch maintenance therapy for advanced NSCLC. Methods: This phase III, randomized clinical trial will include 670 patients with histologically confirmed stage III-IV NSCLC, after first line therapy, with PS 0-2,aged>18 years, with written informed consent. The primary endpoint will be overall survival, and also we will assess quality of life, safety and immunological response. Patient will be randomized with 2:2:1 ratio to 3 arms: racotumomab-alum, nimotuzumab or docetaxel, in 2 strata: progressive patients that will receive the treatment as second line, and non-progressive patients that will receive it as switch maintenance. Racotumomab-alum treatment consists in 5 bi-weekly intradermal immunizations and re-immunizations every 4 weeks. Nimotuzumab arm will receive 6 weekly infusions followed by bi-weekly doses .Both drugs will be given until severe worsening of PS or toxicity. Treatment will not be interrupted at disease progression, even when other therapy line will be administered concomitantly. Docetaxel will be used at 75 mg/m2 for six cycles, if no progressive disease after 3rd cycle. In the progressive setting racotumomab-alum and nimotuzumab will be considered as non-inferior to docetaxel if 1- year OS rate is 23.1% (HR 0.75) considering a 10 % non-inferiority margin. As switch maintenance therapy both drugs will be equivalent to docetaxel, if 1- year OS rate is 36% (HR 0.62) using a 15% non- inferiority margin. An interim analysis will be done when half the patients in each arm has completed 1 year follow-up.
Extra-gastrointestinal stromal tumors (eGISTs): Experience of a cooperative group.
Authors: Matias Chacon, Guillermo Ariel Mendez, Andres Sebastian Guercovich, Luisina Bruno, Anabella Llanos, Mariano Diocca, Carmen Puparelli, Martin Angel
Journal: Journal of Clinical Oncology (2014)

10558 Background: eGIST occurs in regions such as omentum, mesentery, retroperitoneum and undefined abdominal and pelvis locations. Some authors hypothesized that the origin are Cajal interstitial cells from the abdominal cavity or the tumors are mural GISTs with extramural growth. Clinical, pathology and molecular profile of eGIST is similar to GISTs. Some publications show higher size and mitotic index than GIST. eGISTs are not consider in risk stratification consensus. Differential diagnosis of abdominal or pelvis mass with other tumors requires expert pathologist. The aim of the study is to evaluate clinical characteristics and mutation profile of consecutive eGISTs from a prospective database. Methods: Data from patients (pts) with histologic diagnosis of GIST with no evidence of gastric or intestinal involvement was analyzed. Demographics and medical information was obtained from an Argentinean GIST prospective database. Mutation analysis was performed with HPLCA. Descriptive statistical analysis was used. Results: Between 2004 and December 2013, 63 pts with eGISTs were included. Median age was 56 years old (16-87). Thirty three (52%) pts were female. Primary sites were: retroperitoneum 13 pts (21%), mesentery and omentum, 22 pts (35%), pelvis 17 (27%), peritoneum 9 pts, thoracic wall and pleura in two pts. Complete surgical resection was performed in 14 pts (35%). Initial pathology report was other than eGIST in 19 pts (30%). Median size tumor was 8 cm (1-39) and 47% had >10 mitoses/50 HPF. Positive C-KIT was in all pts. Median time to recurrence in pts was 11 months (1-12). Liver was the most frequent site of relapsed (9 pts). Exon 9,11,13, 17 KIT and 12, 14, 18 PDGFR mutations were evaluated in 24 pts. Exon 11 KIT deletion was the most frequent mutation (5 pts) and 12 (50%) were Wild type KIT and PDGFR. Imatinib was the systemic in 42 pts. Objective clinical benefit was 60%. Conclusions: eGISTs is a rare entity. In our series there was a female predominance located mostly in mesentery and omentum. Higher size and mitotic index was observed. One third of pts were complete resected and pathologic misdiagnosis. Better pre-operative approach should be required in this group of pts and more knowledge is necessary to improve outcome.
The impact of place on health-related quality of life among U.S. cancer survivors.
Authors: Sherri Sheinfeld Gorin, Paul Robinson, Paul Juarez, Deyu Pan, Ron Hays
Journal: Journal of Clinical Oncology (2014)

e17642 Background:Place of residence is marked by variations in land use, spatial distribution and socio-economic status (SES).Place influences healthy life expectancy.The aim of this study was to examine the associations among indicators of place and HRQoL among Medicare managed care beneficiaries diagnosed with 4 major cancers.To our knowledge, this is the first US population-based study to quantify the impact of place on HRQoL among cancer survivors. Methods:The Surveillance, Epidemiology, and End Results cancer registry data were linked with the Medicare Health Outcomes Survey (SEER_MHOS) over 1998-2007, among enrollees aged 65 years and older. SF-36 and SF-12 physical(PCS) and mental health(MCS) component summary scores were collected after first diagnosis (n = 39,040) of prostate, breast, colorectal, and lung cancers. Land use data were collected by the satellite-based Landsat Program, and categorized by % green space.We created an index of SES from census tract data, grouped at the county level as a class variable.We estimated random effects models of place on HRQOL. Results: Overall, scores for MCS (51.70 ([1.52] and PCS, (42.31 [2.36]) were comparable to the age-adjusted general US population 1998 norms. Participants diagnosed with breast, colorectal, and lung cancer had significantly lower PCS scores than those with prostate cancer.There was a trend toward lower MCS among those with lung cancer relative to other cancers.There were no significant interactions between type of cancer and PCS scores, but the association of SES with MCS was greater for persons with lung cancer than other cancers.In addition, we found significant negative effects of green space and farmland on PCS and a significant positive effect of farmland on MCS.Green space and farmland were more frequent in rural areas. While more open land enhanced perceived mental health, limited health care access reduced physical functioning among survivors. Conclusions:These findings indicate that place of residence is related to HRQOL among cancer survivors.Targeting specific locations in the US where the impact is most strong may improve the quality of community-based cancer care.
FGFR and FGF ligand overexpression in lung cancer: Implications for targeted therapy.
Authors: Krishna Maddula, Eva Wang, Vijay Modur
Journal: Journal of Clinical Oncology (2014)

11080 Background: Fibroblast growth factor receptors (FGFR) have been shown to be frequently dysregulated in non-small cell lung cell carcinoma (NSCLC). To determine the impact of dysregulation of FGFR pathway in NSCLC, we profiled 100 samples using a sensitive gene expression assay for FGFR and its ligands. Methods: FGFR and FGF gene expression in formalin fixed paraffin embedded (FFPE) samples was performed using a sensitive quantitative nuclease protection assay. This gene expression panel includes all four FGFRs, all 22 FGF ligands and known FGF interacting proteins KLOTHO and KLOTHO beta. Using this array we profiled 100 NSCLC samples (45 squamous, 55 non-squamous). Results: Gene expression analysis of the FGFR family in lung cancer showed overexpression by 3X over median levels of FGFR2 and FGFR3 predominantly in squamous subtype (28% and 19% respectively), FGFR4 overexpresion mainly in non-squamous subtype (25%) and FGFR1 overexpression evenly distributed between squamous and non-squamous subtypes (9 %). There were rare instances of joint overexpression of more than one FGFR, FGFR 1 and 2 together (6%), FGFR 1 and 3 together (2%) and FGFR 3 and 4 together (2%). Overexpression of FGFs was seen in ~35% of all NSCLC samples with FGF19 overexpression being the most common, with increases seen in 20 % of all NSCLC samples. Conclusions: We report for the first time a sensitive and comprehensive FGF and FGFR gene expression analysis of 100 lung cancers. Our expression profiling did not confirm frequent overexpression of FGFR1 in squamous NSCLC in contradiction to frequent gene amplification at this locus suggesting that DNA amplification may not result in transcriptional alteration in many cases. Additionally, we detected frequent overexpression of FGFR2 and 3 in squamous NSCLC and FGFR4 overexpression in adenocarcinoma subtype of NSCLC. The receptor overexpression is frequently associated with overexpression of FGF ligands suggesting a paracrine effect. Expression profiling data support frequent FGFR pathway dysregulation in lung cancer and highlight that gene expression profiling is an important modality for identifying potential responders to novel anti-FGFR therapies.
Potentiation of crizotinib activity by fasting cycles in an ALK+ lung cancer model.
Authors: Alessio Nencioni, Irene Caffa, Lizzia Raffaghello, Fabrizio Montecucco, Michele Cea, Fiammetta Monacelli, Francesco Grossi, Franco Patrone, Patrizio Odetti, Alberto Ballestrero, Valter Longo
Journal: Journal of Clinical Oncology (2014)

e13511 Background: The ALK inhibitor crizotinib is the standard of care of patients with ALK+, advanced NSCLC. However, its clinical benefit is limited by the development of resistance. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are explored in oncological clinical trials. Whether combining fasting with molecularly targeted agents, such as crizotinib, is going to be potentially beneficial remains unknown. Methods: H3122 (ALK+) NSCLC cells were treated in vitro with crizotinib (80-400 nM) in regular culture conditions or in fasting-mimicking conditions (FMCs: 1% FBS, 0.5g/L glucose). Viability was assessed in sulforodhamine B assays. P-Erk and total Erk levels were assessed by WB. H3122 cells were engineered to overexpress HRAS, HRASV12 or a control plasmid. Subcutaneous H3122 xenografts were established in nude mice. Mice were given 25 mg/kg crizotinib (or vehicle) daily for five days a week (Mon-Fri) for a total of three weeks. Fasting cycles of two days (water only; Sun, Mon) were done in animals treated with crizotinib or with vehicle. Tumor size and mouse weight were monitored daily. Results: In vitro, FMCs synergistically increased the activity of crizotinib in H3122 cells. Crizotinib administration in FMCs inhibited Erk activation to a higher extent compared to its administratin in standard conditions. HRAS or HRASV12 overexpression induced resistance to crizotinib, FMCs or their combination, consistent with inhibition of the MAPK pathway playing a key role in the anticancer activity of these treatments. Both fasting cycles and crizotinib effectively reduced the growth of H3122 xenografts in vivo with no difference in terms of efficacy between the two approaches. The combination crizotinib+fasting was more active than either type of treatment alone (p<0.05). Fasted mice exhibited transient weight losses, but fully recovered their weight between one cycle and the next. Conclusions: In an ALK+ NSCLC model, fasting cycles have similar anticancer activity compared to crizotinib and potentiate its activity when used in combination. Fasting cycles (or fasting-mimicking diets) could improve the efficacy of crizotinib in suitable patients.