tbuckley/cabot-search huggingface dataset:
Hsa-miR-31-3p expression in FFPE tumor samples as a predictor of anti-EGFR response in patients with metastatic colorectal cancer.
Authors: Gilles Manceau, Jean-Baptiste Bachet, Benoist Chibaudel, Francois Liebaert, Raphaële Thiébaut, Pieter Demetter, Jean-Luc Van Laethem, Karen Leroy, Olivier Bouche, Frederique Penault-Llorca, Marie Danielle Diebold, Thierry André, Sandrine Imbeaud, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2013)

3562 Background: In metastatic colorectal cancer (mCRC), KRAS mutations are associated with resistance to anti-EGFR antibodies. To identify, in wild-type KRAS mCRC patients, markers that predict response to anti-EGFR antibodies, we focused on miRNAs. Methods: Expression profile of 1145 miRNAs was done on 84 colorectal tumors and 5 normal colon mucosae. Correlations between miRNAs expression level and survival were based on frozen samples of a training set from a retrospective series of 33 patients treated by cetuximab and irinotecan and of two validation set from prospective collections of 38 patients treated by cetuximab or panitumumab based chemotherapy or by panitumumab and irinotecan as third-line, using an adjusted Cox proportional hazards model. Validation on FFPE samples was done on 39 patients treated with panitumumab and irinotecan as third-line. Results: A predictive signature of 11 miRNA linked to the PFS was identified (p&lt;0.01) but only one, hsa-miR-31-3p, exhibited significant different expression level between tumor from bad prognosis and good prognosis from the training set. We tested expression of this miRNA on the training set, and found a HR of 1.9 CI95% [1.1-2.9]. In validation set, the prognostic impact of hsa-miR-31-3p the HR was estimated to 1.9 CI95% [1.1-3.1]. Using multivariate model obtained from the training set to the two validation set, we predict the PFS of the patients (accuracy of prediction: AUC = 0.77). We classified the validation set according to a free PFS score (P=0.005) with a specificity of 62% CI95% [38%-82%] and a sensitivity of 82% CI95% [56%-96%] for the prediction model. A nomogram, established taking into account hsa-miR-31-3p expression level, predicted the progression risk (P&lt;0.0001). Confirmation of the predictive value of hsa-miR-31-3p expression on survival risk progression was done on FFPE sample (p=0.0006). Conclusions: This is the first tool to select individual patients with a wild-type KRAS tumor for anti-EGFR therapy from frozen or FFPE samples.
EORTC-ETOP randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab versus placebo for patients with early stage non-small cell lung cancer (NSCLC) after resection and standard adjuvant chemotherapy: PEARLS (NCT02504372).
Authors: Mary E.R. O'Brien, Baktiar Hasan, Urania Dafni, Jessica Menis, Solange Peters, Michele De Waele, Rolf A. Stahel, Paul Van Schil, George Coukos, Sylvie Lantuejoul, Keith M. Kerr, Ignacio Melero, Benjamin Besse, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2016)

TPS8571 Background: The benefit of adjuvant chemotherapy in NSCLC has plateaued at around 5.4% improvement in 5 year overall survival and is hampered by toxicities having a major impact on treatment compliance. Anti PD-1 inhibitors have proven efficacy, favorable safety, and have been registered for the treatment of advanced NSCLC. Immunotherapy approaches are hypothesized to work best in the context of minimal residual disease, making the adjuvant setting the ideal clinical scenario, potentially improving the cure rate after surgery. The objective of this trial is to prospectively investigate whether adjuvant treatment with pembrolizumab after completion of radical surgery and standard adjuvant chemotherapy as appropriate for stage IB (T ≥ 4 cm) -II-IIIA NSCLC patients improves outcome compared to placebo in the PD-L1high positive subgroup and overall population. Methods: Adaptive Study Design PEARLS is an international, triple-blinded, placebo-controlled, randomized (1:1) phase III trial. Previous studies suggest that pembrolizumab works better in patients with stronger PD-L1 expression. PEARLS is designed to consider potential heterogeneity of treatment effect across subgroups of PD-L1 status (-: 0 staining; low: 1-49% staining and high: ≥ 50% staining). Co-primary endpoints, disease-free survival (DFS) in the whole population and DFS in 'high' are used to address potential efficacy in all comers and in patients with high expression. In addition, futility interim analysis for PD-L1 – patients is integrated to allow stopping the study in those patients, if needed. Overall, an improvement of 13.5 months(m) in median DFS (from 48 m to 61.5 m, hazard ratio (HR) = 0.78) is aimed for the whole population. Assuming 15% of DFS events at the final analysis will be in the high subgroup, an improvement of 39.3 m in median DFS (HR = 0.55) is the effect targeted in this subgroup. With a total of 640 required DFS events the study has 90% power to detect the target treatment effects in either the overall population or high subgroup. A sample size of 1380 randomized patients is planned. Clinical trial information: NCT02504372.
Total Body Water predicts 5-FU plasma concentration after the first cure of chemotherapy
Authors: V. Berger, S. Dupuis, M. Boisdron-Celle, E. Gamelin, P. Ritz
Journal: Journal of Clinical Oncology (2004)

2107 Background: Plasma concentrations of cytostatic drugs ranging within a narrow therapeutic index should be obtained to ensure maximal efficacy and minimal toxicity. The aim of this study was to demonstrate that plasma 5-FU (an hydrophilic drug) concentrations could be predicted from estimates of body water spaces. Methods: Body composition was assessed in 35 patients suffering from digestive cancer after the first cure of chemotherapy using 5-FU. 5-FU was administered as FOLFOX, FOLFIRI or De Gramont (LV5-FU2) protocols. Initial doses were adapted to body surface area. Body composition was estimated from Total Body Water (TBW), Extra Cellular Water (ECW) or Intra Cellular Water (ICW) (multifrequency bioelectrical impedance analysis), Fat Free Mass (FFM) (combination of TBW and body density measured by plethysmography ). 5-FU plasma concentrations were determined by HPLC. Results: Pharmacokinetics parameters (steady state plasmatic concentration, AUC) of 5-FU did not differ between chemotherapy protocols. Plasma 5-FU concentration was correlated with body weight, BMI, TBW, ECW, and FFM. It did not correlate with fat mass. After stepwise multiple regression, only TBW was correlated with 5-FU plasma concentration (p = 0.031; Concentration (ng/ml) = -6.082 x TBW (kg) +666). Similarly clairance of 5-FU was correlated to TBW, ECW, ICW, FFM. After stepwise regression, only TBW predicted clairance. Conclusions: Despite an initial adaptation of 5-FU doses, plasma concentrations were correlated to TBW which could be used as an easy indicator to adapt the doses. Performing BIA is easy. It takes only a few minutes to measure impedances from surface electrodes attached to right hand and foot. Supported by Comité Départemental de Maine et Loire et de la Mayenne, la Ligue Nationale Contre le Cancer. No significant financial relationships to disclose.
Generation of CMV Specific T Cells From CMV Seronegative Donors by T Cell Receptor RNA Transfer.
Authors: Simone Thomas, Sebastian Klobuch, Mirjam H.M. Heemskerk, Diana Stolle, Katrin Besold, Bodo Plachter, Niels Schaft, Matthias Theobald, Ralf H Voss, Wolfgang Herr
Journal: Blood (2009)
Genetic landscape of ALK+ non-small cell lung cancer (NSCLC) patients (pts) and response to ceritinib in ASCEND-1.
Authors: Daniel Shao-Weng Tan, Dong-Wan Kim, Michael Thomas, Serafino Pantano, Ying Wang, Sebastian Lukasz Szpakowski, Alejandro Javier Yovine, Ranee Mehra, Laura Q. Chow, Sunil Sharma, Benjamin J. Solomon, Enriqueta Felip, D. Ross Camidge, Johan F. Vansteenkiste, Hans Bitter, Lilli M. Petruzzelli, Margaret Han Dugan, Alice T. Shaw
Journal: Journal of Clinical Oncology (2016)

9064 Background: To better understand genetic determinants of response to ceritinib, tumor biopsies from NSCLC pts treated with ceritinib in ASCEND-1 (NCT01283516) were analyzed by next-generation sequencing (NGS). Methods: Biopsies were assayed by NGS using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14 Apr 2014). Results: NGS data were generated for 85 pts (ALK inhibitor [ALKi]-pretreated [n=54]; ALKi-naïve [n=31]). Baseline (BL) biopsy collection times differed among pts. The most frequent ALK rearrangements detected were EML4-ALK variant 1 (26/85) and variant 3 (23/85); 6 pts did not carry an EML4-ALK fusion but had an ALK rearrangement with another gene (HIP1 [n=2]; CLTC, CRIM1, STRN and TFG [n=1 each]). Comprehensive analysis correlating genetic landscape with ceritinib efficacy will be presented, including for 2 pts with ceritinib BL and post-progression biopsies. Of 28 pts with biopsies collected during or after prior ALKi treatment (Tx), 10 harbored an ALK tyrosine kinase domain mutation. Among these 10 pts, 8 had BL biopsies collected after (or less than 7 days before) the last day of prior ALKi Tx. All but one of these 8 pts benefited from ceritinib Tx (Table 1). One pt ALKi-naïve had a MET amplification in a ceritinib post-progression biopsy (among other somatic mutations) but not in BL biopsy. Conclusions: This analysis increases our knowledge of the mechanisms of resistance to ALK inhibition and their impact on ceritinib Tx, including the potential role of MET amplification. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated pts. Ceritinib efficacy in pts with ALK mutations in biopsies collected after (or close to) last day of prior ALKi Tx. Pt ALK mutation(s) BOR PFS, days 1 E1129V PR 337 2 L1196M PR 267 3 I1171T, F1174V PR 250 4b C1156Y SD 246+ 5 L1196M PR 213 6c C1156Y PR 174 7 L1196M PR 163 8 G1202R Unknown 26 aEfficacy per blinded independent review committee. bBiopsy 5 days before end of crizotinib Tx; + pt ongoing without event cBiopsy on last day of crizotinib Tx. BOR, best overall response; PFS, progression-free survival; PR, partial response; SD, stable disease.
Use of protein pathway activation mapping of NSCLC to identify distinct molecular subtypes and a prognostic signature for aggressive node-negative tumors.
Authors: A. Zupa, G. Improta, J. Deng, M. Aieta, P. Musto, L. A. Liotta, C. Belluco, E. Mammano, J. D. Wulfkuhle, E. Petricoin
Journal: Journal of Clinical Oncology (2010)

10594 Background: Lung cancer is the primary cause of cancer-related mortality world-wide, and the systematic analysis of protein signaling pathway activation could help to find new molecular targets for individualized therapy along with pathway biomarkers for patient stratification and enrichment. Of critical importance is the identification of patients with aggressive tumor subtypes, especially in node negative disease. Methods: Highly enriched tumor epithelial cells from 47 frozen NSCLC tumors (26 N0, and 21 N1-2) from patients taken prior to any therapy, were procured by laser capture microdissection. Reverse phase protein microarrays were used to quantitatively evaluate the activation/phopshorylation levels of 128 key signaling proteins, known to be involved in tumorigenesis and metastasis. Correlations between protein activation, histologic type, nodal status, and clinical outcome were performed. Results: Unsupervised hierarchical clustering analysis revealed the presence of five different and distinct subgroups of NSCLC tumors based on signal pathway activation patterns. Some of these subgroups appeared enriched for either adeno or squamous carcinoma while other groups were populated with either histological type. In group of patients with node-negative tumors, pathway activation mapping revealed broad-scale activation of the ErbB3-EGFR-AKT signaling network along with many members of LKB1 and FAK signaling pathways in cases with short-term survival (median 9 months) compared to cases with long-term survival (median 68 months) (p < 0.05). Members of this specific signature were also elevated in an independent set of N1-2 tumors. Conclusions: Protein activation analysis of NSCLC revealed the presence of distinct molecular subtypes of disease based on specific pathway activation portraits. Moreover, we identified a unique prognostic signature that correlated with survival in patients regardless of nodal status. This finding suggests the presence of an aggressive molecular subtype of NCSLC that can be identified even in the early stage node-negative setting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Theranostics Health Theranostics Health Theranostics Health
Phase II trial of personalized chemotherapy in stage IV NSCLC: Clinical application of functional profiling in first-line therapy.
Authors: R. A. Nagourney, J. B. Blitzer, E. A. Deo, R. Nandan, R. Shuman, T. Asciuto, D. Mc Connell, M. Paulsen, S. S. Evans
Journal: Journal of Clinical Oncology (2010)

7617 Background: Personalized chemotherapy is an important advance for NSCLC pts. While genomic platforms have identified prognostic and predictive factors e.g., ERCC1 and RRM1/2, proteomic platforms are now identifying novel phosphoprotein targets. To address the complexity and redundancy of cell-death pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R. Curr Treat Opt Oncol. 2006) to select therapy for chemo-naïve pts with stage IV NSCLC. Methods: Using morphologic and metabolic endpoints EVA/PCD gauges cellular response to drugs and signal transduction inhibitors in human tumor micro-spheroids isolated from surgical biopsies. Modified Z-scores and synergy analyses (median-effect) then select ex vivo best regimens (EVBR) from FDA-approved NSCLC drugs. Trial powered to improve ORR by 2-fold and median TTP by 50% (p=.05). All pts sign informed consent. Results: 26/32 (81%) pts are evaluable with CR = 3/26 (11.5%); PR = 15/26 (57.6%); SD = 6/26 (23%) and PD = 2/26 (7.6%) for an ORR = 18/26 (69%) and CBR = 24/26 (92.3%). Selected EVBR were CDDP/gemcitabine 12/26 (46%); CDDP/taxane 7/26 (27%); erlotinib 5/26 (19%); CDDP/vinorelbine 1/26 (4%); CDDP/pemetrexed1/25 (4%). Nine of 26 (36.6%) pts were converted to surgical/radiation candidates. All first-line erlotinib pts responded (100%). Conclusions: At ORR = 69%, the trial has met response criteria and with current TTP up to 46 months and OS up to 60 months, accrual will be completed to allow formal TTP and OS analyses. The EVA/PCD platform, by examining drug-induced events in native-state micro-spheroids, has shown the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, known crucial for clinical response prediction. Results support applications of personalized NSCLC therapy and warrant further evaluation. Supported by Memorial Medical Center Foundation, Long Beach. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Rational Therapeutics Rational Therapeutics
Early variations of circulating IL-6 and IL-10 during thoracic irradiation are predictive for incidence of radiation pneumonitis in patients with non small cell lung cancer: Results from a prospective study
Authors: M. Perol, D. Perol, D. Arpin, J. Y. Blay, L. Falchero, M. Vincent, B. Mastroianni, L. Alberti, C. Carrie
Journal: Journal of Clinical Oncology (2004)

7079 Background: Radiation pneumonitis (RP) is the toxicity of 3D-CRT in irradiated patients. The goals of this study were to evaluate the predictive value of circulating cytokines levels before, during and after 3D-CRT for the risk of radiation pneumonitis (RP) in patients (pts) with NSCLC. Methods: 96 pts receiving 3D-CRT for stage IA-IIIB were evaluated. Serum IL-6, IL-10, TNFα and TGFβ1 levels were measured using specific ELISAs before, every 2 weeks (w.) and 2 months (m.) after 3D-CRT. RP was diagnosed 2 m. after 3D-CRT using Lent-Soma score. All were reviewed by independent panel. A repeated measures analysis of variance was used to analyze the variations of cytokines levels during and after 3D-RCT. In addition, AUC was calculated during RT for each cytokine using the trapezoid rule. Non parametric Mann-Whitney's exact test was used to test the impact of cytokines levels at baseline and during 3D-CRT on RP. Results: 6 pts could not be evaluated for RP 2 m. after RT. Of the 90 remaining pts, 40 had a RP (grade ≥ 1) including 7 pts with severe RP (grade ≥ 2). At baseline, increased IL-6 (>20 pg/mL), IL-10 (>50 pg/mL) and TNFα (>20 pg/mL) were observed in 4, 16 and 32 respectively. Median TGFβ1 was 36 ng/mL (r: 0–76 ng/mL). Initial IL-6, IL-10, TNFα and TGFβ1 levels were not correlated to clinical characteristics or incidence of RP. During RT, mean serum TGFβ1 decreased in the whole group (mean 38 vs 32 ng/mL, p<0.001), while values remained stable for others cytokines. IL-6 and IL-10 levels showed opposite evolution: during RT, the AUC of IL-6 p was found to be significantly > in pts with RP compared to pts who did not. (1570 vs 246, p=0.03). Difference reached significance at 2 w. of treatment (Tt.) with a peak of IL-6 in RP pts (53.2 vs 3.4 pg/mL, p=0.025). In contrast, the chronological changes in serial serum IL-10 levels showed a peak at 2 w. of Tt. in pts who did not developed RP compared to pts with RP (82.3 vs 29.0 pg/mL). TNFα and TGFβ1 were not correlated with the risk of RP. Conclusions: Variations of IL-6 and IL-10 levels during 3D-CRT are strongly predictive for development of RP after RT. No significant financial relationships to disclose.
Focal 22q11.22 Loss Combined with IKZF1 Alterations Predict Very Poor Outcome in Childhood Acute Lymphoblastic Leukemia
Authors: D. Spencer Mangum, Soheil Shams, Jonathan M. Downie, Uta von Schwedler, Vladimir Rodic, Michael Engel, Phillip Barnette, J. Kimble Frazer, Nikolaus Trede, Dequing Pei, Cheng Cheng, Ching-Hon Pui, Stephen P Hunger, Jun J. Yang, Rodney R. Miles, Charles G Mullighan, Joshua D. Schiffman
Journal: Blood (2011)
Allogeneic Stem Cell Transplant Versus Tandem High-Dose Melphalan for Front-Line Treatment of Deletion 13q14 Myeloma – An Interim Analysis of the German DSMM V Trial.
Authors: Stefan Knop, Peter Liebisch, Holger Hebart, Ernst Holler, Monika Engelhardt, Ralf C Bargou, Bernd Metzner, Dietrich Peest, Walter E. Aulitzky, Hannes Wandt, Orhan Sezer, Markus Hentrich, Helmut Ostermann, Christian Peschel, Georg Hess, Bernd Hertenstein, Mathias Freund, Martin H Kropff, Hans-Heinrich Wolf, Wolfram Jung, Norbert Frickhofen, Georg Maschmeyer, Hans-Guenther Mergenthaler, Else Heidemann, Nicolaus Kröger, Christian Straka, Corinna Engel, Lothar Kanz, Christoph Meisner, Hermann Einsele
Journal: Blood (2009)
Enhancing Local Resources in Low- and Middle-Income Countries Through Education
Authors: George P. Yang, Sherry M. Wren
Journal: JAMA Surgery (2016)

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Metalworking fluids: a new cause of occupational non-asthmatic eosinophilic bronchitis
Authors: R E Wiggans, C M Barber
Journal: Thorax (2016)

Ruth E Wiggans (REW): A 52-year-old man was referred with chronic cough of increasing severity over the last 4 years. The cough was productive of green sputum and he experienced coughing attacks weekly. He reported no other respiratory symptoms. He had a sore throat following coughing bouts but denied other upper airway complaints. He was otherwise well with no systemic symptoms. His cough had improved following a 2-week summer holiday, and subsequently deteriorated following his return to work.

A chest X-ray organised in primary care was normal. Three years earlier, his general practitioner increased his lansoprazole from 15 to 30 mg once daily for cough. This had not helped although treatment continued. His past medical history included treated obstructive sleep apnoea and hypertension for which he took bendroflumethiazide and losartan; the latter substituted for his ACE inhibitor 3 years earlier. He recalled no personal or family history of asthma or atopy and was a lifelong non-smoker. He had kept budgerigars until 6 months previously when the last bird died.

He had worked for 12 years as a computer numerical control (CNC) machine setter and operator, machining metal parts used to make tools for woodworking. He machined bronze, brass, leaded mild steel, high-speed steel and aluminium pieces to the desired specification. He operated five machines in a single area of the factory, adjacent to where ash handles were turned. He was the sole CNC operator turning metal components in the factory and was not aware of any colleagues reporting respiratory symptoms.

Water-based metalworking fluids (MWFs) were used on all five machines. Each machine collected and recirculated MWFs via its own sump. For the last 4 years, the fluids had occasionally become ‘foul smelling’ and sometimes changed colour from a translucent blue to a chocolate brown. The worksite did not perform dip-slide fluid analysis or use biocide contrary …
The relationships between golf and health: a scoping review
Authors: A D Murray, L Daines, D Archibald, R A Hawkes, C Schiphorst, P Kelly, L Grant, N Mutrie
Journal: British Journal of Sports Medicine (2016)

Objective To assess the relationships between golf and health. Design Scoping review. Data sources Published and unpublished reports of any age or language, identified by searching electronic databases, platforms, reference lists, websites and from consulting experts. Review methods A 3-step search strategy identified relevant published primary and secondary studies as well as grey literature. Identified studies were screened for final inclusion. Data were extracted using a standardised tool, to form (1) a descriptive analysis and (2) a thematic summary. Results and discussion 4944 records were identified with an initial search. 301 studies met criteria for the scoping review. Golf can provide moderate intensity physical activity and is associated with physical health benefits that include improved cardiovascular, respiratory and metabolic profiles, and improved wellness. There is limited evidence related to golf and mental health. The incidence of golfing injury is moderate, with back injuries the most frequent. Accidental head injuries are rare, but can have serious consequences. Conclusions Practitioners and policymakers can be encouraged to support more people to play golf, due to associated improved physical health and mental well-being, and a potential contribution to increased life expectancy. Injuries and illnesses associated with golf have been identified, and risk reduction strategies are warranted. Further research priorities include systematic reviews to further explore the cause and effect nature of the relationships described. Research characterising golf's contribution to muscular strengthening, balance and falls prevention as well as further assessing the associations and effects between golf and mental health are also indicated.