tbuckley/cabot-search huggingface dataset:
Macrophage polarization related gene variants to predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with bevacizumab (bev) in combination with FOLFIRI.
Authors: Yu Sunakawa, Sebastian Stintzing, Volker Heinemann, Fotios Loupakis, Chiara Cremolini, Shu Cao, Dongyun Yang, Wu Zhang, Anish Parekh, Shinichi Yamauchi, Yan Ning, Stefan Stremitzer, Satoshi Matsusaka, Angela Mendez, Rita Elie El-Khoueiry, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2015)

621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angiogenesis, acceleration of tumor invasion, and suppression of immunosurveillance. CCL2 promotes the polarization into M2 whereas histidine-rich glycoprotein (HRG) redirects M2 to M1. We hypothesized that single nucleotide polymorphisms (SNPs) in CCL2 and HRG may predict clinical outcome in mCRC pts treated with anti-VEGF drug in combination with chemotherapy. Methods: This study enrolled 4 pts cohorts treated with antibody drug plus FOLFIRI in prospective trials, A: KRAS exon 2 wild-type (KRAS wt) pts (n=84), B: mutant-type pts (n=89) from FOLFIRI-arm of TRIBE trial (NCT00719797), C: bev-arm (n=295), D: cetuximab-arm (n=297), served as negative control arm, from KRAS wt pts of FIRE3 trial (NCT00433927). Functionally significant SNPs, CCL2 rs4586, HRG rs9898, and HRGrs2228243, were analyzed by PCR-based direct sequencing for associations with response rate (RR), progression-free survival (PFS), and overall survival (OS) by uni- and multivariable analyses. Results: The minor G allele of HRG rs2228243 was significantly associated with better PFS, but not RR and OS, than the A/A genotype in both uni- and multivariable analyses (10.8 vs 9.3 months. HR: 0.62, p=0.048; HR: 0.57, p=0.040, respectively) in the cohort B while it was not associated in the other KRAS wt cohorts. In the cohort C, the minor C allele of CCL2 rs4586 correlated with significantly shorter OS, but not RR and PFS, in both uni- and multivariable analyses (22.3 vs 28.4 months. HR: 1.61, p=0.003; HR: 1.63, p=0.004, respectively). No significant association of CCL2 rs4586 was seen in the other cohorts although pts with the C allele of CCL2rs4586 had a negative marginal significant association in PFS and a shorter OS than pts with the T/T genotype (22.0 vs 30.8 months) in the cohort A. Conclusions: Our study provides evidence that SNPs in CCL2 and HRG may serve as a predictive or prognostic marker in mCRC pts treated with bev plus FOLFIRI. Our results also suggest that the impact of the SNPs on outcome may differ according to KRAS status. Prospective validation of this study is warranted.
Rituximab maintenance following a rituximab containing chemotherapy significantly prolongs the duration of response in patients with relapsed follicular and mantle cell lymphomas: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)
Authors: W. Hiddemann, R. Forstpointner, M. Dreyling, M. Gramatzki, H.-P. Böck, M. Haenel, J. F. Seymour, M. Unterhalt
Journal: Journal of Clinical Oncology (2005)

6527 Background: Rituximab (R) was shown to prolong the time to treatment failure (TTF) and response duration (RD) in follicular lymphoma (FL) when given either together with chemotherapy or as maintenance after a no R containing therapy. Methods: The current study investigated the impact of R maintenance on RD particularly after remission induction by an R-chemo combination. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The initial study design comprized a first randomization between 4 courses of chemotherapy with Fludarabine (25mg/m2/d days 1–3), Cyclophosphamide (200mg/m2/d days 1–3) and Mitoxantrone (8mg/m2/d day 1) (FCM) versus FCM plus Rituximab (375mg/m2/d on day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomzation for observation only versus R maintenance with 4 weekly doses of R (375mg/m2/d) to be given at three and nine month after end of therapy. Both randomizations were stratified for histology and preceding therapy. The first randomization was stopped after 147 patients demonstrating a significant improvement for the R-FCM therapy in initial response, progression free survival and even overall survival (OS). So all subsequent patients received R-FCM. Results: 184 patients underwent the second randomzation and 157 are currently evaluable. In Oct. 2004 the one sided sequential triangular test showed a significantly longer RD for the R maintenance arm. After R maintenance the median for RD is not reached at 3 years while it was 19 months for observation only (p=0.0171). This beneficial effect was also observed in patients receiving initially R-FCM (n=119) with the median not being reached in the R maintenance arm versus 19 months in the observation only group (p=0.0208). This improvement was seen both in FL and MCL although differences did not yet reach statistical significance. Conclusion: This study demonstrates that R maintenance after R chemotherapy is highly effective and may improve the outcome of patients with relapsed FL and MCL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche
Impact of symptomatic skeletal events on healthcare resource utilization, health-related quality of life and pain among patients with castration-resistant prostate cancer and bone metastases.
Authors: Rana R. McKay, Batool Haider, Mei Sheng Duh, Adriana Valdarrama, Mari Nakabayashi, Matthew Fiorillo, Ljubica Ristovska, Lonnie Kent Wen, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2016)

247 Background: Prostate cancer patients frequently develop bone metastases (BM), leading to symptomatic skeletal events (SSE). Given the real-world data on SSE are lacking, this study evaluated the impact of SSE on healthcare resource utilization (HRU), health-related quality of life (HRQoL), and pain in patients with castration-resistant prostate cancer (CRPC) and BM. Methods: Electronic medical records (EMR) and clinical database of a tertiary oncology center were used to identify CRPC patients with BM. SSE, including pathologic fracture, radiation to bone, spinal cord compression, and bone surgery, were extracted from medical charts. HRU, such as emergency room (ER), outpatient and inpatient visits, was determined from the EMR. A subset of patients who were alive and had clinic visits from 11/2014-7/2015 completed HRQoL (FACT-P) and pain (BPI-SF) surveys. The impact of SSE on HRU was evaluated using multivariate negative binomial regression. Survey scores were compared using Rank-Sum test and standardized effect sizes (ES); an ES ≥ 0.33 corresponds to meaningful differences between SSE and non-SSE groups. Lower FACT-P and BPI-SF scores suggest reduced HRQoL and less pain, respectively. Results: Of 832 patients, 207 developed ≥ 1 SSE (mean 1.5±0.8); 84% had radiation to bone. The median age at CRPC with BM diagnosis was 68 yrs. and follow-up after diagnosis was 2.1 yrs. Adjusting for baseline factors, the SSE group had significantly higher ER (incidence rate ratio (IRR) = 1.48; 95% confidence interval (CI) = 1.12, 1.95), outpatient (IRR = 1.17; 95% CI = 1.05, 1.30), and inpatient (IRR = 1.74; 95% CI = 1.34, 2.26) visits. Of 107 patients eligible for surveys, 103 responded. The mean FACT-P functional well-being score was 17.5 in SSE and 19.8 in non-SSE group (p = 0.16) with an ES of 0.36. Mean BPI-SF pain severity score was 2.5 in SSE and 1.6 in non-SSE group (p = 0.05) with an ES of 0.47, and that for worst pain was 3.6 and 2.3, respectively, (p = 0.03) with an ES of 0.5. Conclusions: The economic and quality of life burden of SSE amongst CRPC patients with BM is high, underscoring the need for preventive treatments for SSE in this population.
Symptoms of endocrine treatment and outcome: A retrospective analysis of the monotherapy arms of the BIG 1-98 trial.
Authors: J. B. Huober, B. F. Cole, J. Wu, A. Giobbie-Hurder, M. Rabaglio, H. T. Mouridsen, L. Mauriac, J. F. Forbes, R. Paridaens, I. Lang, I. E. Smith, A. M. Wardley, K. N. Price, A. Goldhirsch, A. S. Coates, B. J. K. Thurlimann
Journal: Journal of Clinical Oncology (2011)

522 Background: Conflicting data exist regarding the association of side effects related to estrogen manipulation with prognosis. We evaluated the outcome of patients (pts) according to the early incidence of vasomotor and arthralgia/myalgia symptoms. Methods: In the BIG 1-98 trial 8010 postmenopausal pts with hormone receptor-positive early breast cancer were randomized to a 5-year regimen of tamoxifen (T), letrozole (L), T followed by L, or the reverse. This evaluation included pts randomized to T or L alone who received at least one dose of trial therapy, had no disease-free survival (DFS) event during the first 3 months (mos), and had no known vasomotor or arthralgia/myalgia symptoms prior to treatment (N=4,798 of 4,922). Vasomotor symptoms included hot flushes, night sweats and vaginal dryness. Arthralgia/myalgia symptoms included arthralgia, myalgia and carpal tunnel syndrome. Symptoms occurring within 3 mos of treatment initiation were considered for landmark analyses of DFS from 3 mos. Results: Median follow-up was 77 months. Incidence rates were 18.8%, 8.5%, 0.5%, 3.0%, 1.4% and 0.1% for hot flushes, night sweats, vaginal dryness, arthralgia, myalgia, and carpal tunnel syndrome, respectively. Rates of any vasomotor and arthralgia/myalgia symptoms reported within 3 mos were 21.2% and 4.1%, respectively. Unadjusted (log-rank) tests, showed significant associations between increased DFS and occurrence of hot flushes (p=.03), arthralgia (p=.005), myalgia (p=.07), any vasomotor symptoms (p=.05), and arthralgia/myalgia symptoms (p=.001). Following adjustment (Cox model) for age, BMI, prior HRT use, nodal status, tumor grade, tumor size and treatment group, occurrence of arthralgia/myalgia symptoms remained significantly associated with increased DFS (hazard ratio=0.64, p=0.05). No significant interactions were found between the occurrence of these AEs and treatment group. Conclusions: Arthralgia/myalgia, but not vasomotor early symptoms, were associated with improved DFS, irrespective of endocrine treatment.
Discrimination between Von Hippel-Lindau gene and hypoxia-regulated alterations in the metabolism and protein expression in renal cell carcinoma using ome-based strategies.
Authors: Barbara Seliger, Sandra Leisz, Kristin Schulz, Susanne Erb, Ena Wang, Francesco Marincola, Franziska Stehle
Journal: Journal of Clinical Oncology (2014)

447 Background: The objective of this project is to dissect the von Hippel-Lindau- and hypoxia-regulated alterations in human renal cell carcinoma to define both novel prognostic markers as well as therapeutic targets. Methods: For this, the VHL-negative RCC cell line 786-O next to recently established gain of function VHL transfectants thereof were used as a model system and subsequently cultured under normoxic or hypoxic conditions. Whereas direct effects on the altered energy metabolism were determined by lactate, pyruvate and pH measurements. the resulting effects at the gene/protein expression profiles were determined by comparative cDNA micro array analysis/ 2DE-based proteome analyses, respectively. Some of the differentially expressed genes/proteins were verified by qPCR and/or Western blot analysis in a panel of RCC cell lines. Results: By employing the VHL - /VHL + RCC model system VHL-dependent, HIF-dependent as well as VHL/HIF-independent alterations in the gene and protein expression pattern were found. Some of the differentially expressed genes/proteins were either associated with the loss of VHL function, the hypoxic conditions or both. The genes/proteins defined as differentially expressed under these conditions are mainly involved in the cellular metabolism and predominantly localized in the cytoplasm or mitochondrion. The verification of the differentially expressed genes/proteins by qPCR and Western blot analysis revealed a heterogeneous expression in RCC cells and lesions. One such gene/protein is represented by the glutamine gamma glutamyl transferase (TGM2). Its expression was associated with the loss of VHL and induction of hypoxia. Furthermore, TGM2 might be an important marker for both VHL-independent and/or hypoxia-induced responses. Conclusions: The data demonstrate that VHL functionality and/or hypoxia induce distinct effects on the metabolic switch of RCC.
Phase II clinical trial assessing the impact of an oral immunonutrition during concomitant chemoradiotherapy in advanced local-regional squamous cell carcinomas of the head and neck
Authors: F. Portales, E. Assenat, M. Latournerie, S. Thezenas, A. Serre, R. Garrel, L. Vercambre, R. Altweg, D. Azria, P. Senesse
Journal: Journal of Clinical Oncology (2008)

9629 Background: Locally advanced stage III or IV squamous cell carcinomas of head and neck warrant treatment concurrent chemoradiotherapy. In 45–50% of cases, mucositis grade NCI 3 or 4 underwent and required an artificial nutritional support. The aim of this study was to examine the impact of an oral immunonutrition (Oral IMPACT) on the occurrence of severe mucositis. Methods: This study is a prospective non-randomized phase II trial. The main criteria for inclusion were as follows: non-metastatic grade III or IV head and neck tumours treated by concomitant chemoradiotherapy (in curative or adjuvant setting) and prophylactic gastrostomy before any treatment. An informed consent was given by each patient. Oral IMPACT was administered 3 times a day, for the 5 days prior to each chemotherapy treatment (3 cycles of cysplatil during radiotherapy). A dietician was specifically recruited for the study and assured the toxicity and nutritional status. Results: Between October 2005 and July 2007, 45 patients were included. 39 patients were analysable (3 patients were found metastatic (TEPscan) after signing the informed consent and 3 others withdrew their consent after inclusion). Any patients were malnourished (Nutrition risk index > 83.5) and the change in median weight to the inclusion was −1.5% [−25% +5.7%]. 69.2% of patients had received surgery first. A perfect compliance (Oral IMPACT) was observed in 78.4% of courses. 33 patients (85%) had at least one unexpected interruption in their protocol of radiotherapy. Among these 33 patients, 9 (27%) had unexpected interruption for toxicity whose median duration was 5.0 days [1,0–18, 0]. During the treatment, only 5 patients (12.8%) had a severe mucosal toxicity (grade NCI 3 or 4). Depending on the compliance in taking the solution studied, the rate of severe mucosal toxicities was 6.8% when the compliance was 100% and 30% with a compliance less than 75% of the dose. Conclusions: The use of an oral immunonutrition reduces significantly the rate of severe mucosal toxicity during concomitant chemoradiotherapy for advanced local-regional squamous cell carcinomas of the head and neck. This protective effect must be confirmed in an ongoing phase III prospective randomized trial. No significant financial relationships to disclose.
Compliance to select quality measures in a non-QOPI subspecialty academic practice: A pilot quality improvement initiative.
Authors: Sonia Reichert, Paola DeGregorio, Lauren Bilotti, Fabienne Ulysse, Max Sung, Randall F. Holcombe
Journal: Journal of Clinical Oncology (2012)

261 Background: ASCO’s Quality Oncology Practice Initiative (QOPI) includes core, disease and domain-specific quality measures. QOPI Certification requires an overall score of 72.62% in 24 core and 80% in adjuvant quality measures. There are currently 137 oncology practices with only 10 in New York State having achieved QOPI certification. At Mount Sinai Medical Center (MSMC), the large hematology and oncology practice is subdivided into disease-specific groups functioning semi-autonomously. The practice is not QOPI certified. With no prior measures of quality adherence in the overall or subspecialty groups we aimed to determine the baseline compliance to QOPI disease specific measures. Methods: All colorectal patient charts seen in the GI oncology group at MSMC over a four-month period from February 2012 to May 2012 were retrospectively reviewed. The team included two GI oncology physicians, one physician assistant and one registered nurse. Each member was assigned roles to meet the defined quality measures prior to project initiation. A separate auditor reviewed medical records during the study period. 17 quality measures were evaluated including 10 core and one adjuvant colorectal disease-specific measure. Results: The average compliance with the QOPI measures tested was 96%, 98%, 92%, and 97% (February to May respectively). The measures with the lowest compliance were not required for certification but included for internal review after recent practice changes. Despite the high compliance rate, compliance for an individual patient in all 17 categories was achieved in only 48% of patients. Conclusions: This study highlights that adherence to quality benchmarks in a disease-specific subset of a larger oncology program can be achieved by identifying staff, assigning roles and defining practice structure. The GI Oncology group attained a level of compliance with quality measures that would result in QOPI certification if maintained practice-wide. This study serves as the basis for a larger internal audit of quality measures across other subspecialty disease-specific areas of hematology and oncology at MSMC.
Aberrant Expression in Human Epithelial Cancers of the P2X5-Encoded Minor Histocompatibility Antigen LRH-1: Implications for Graft-Versus-Tumor Immunity Against Solid Tumors.
Authors: Harry Dolstra, Henriette Levenga, Ingrid Overes, Johanna C.M. Vos, Agnes van Horssen-Zoetbrood, Robbert van der Voort, Pieter de Mulder, T.M. de Witte
Journal: Blood (2007)
Transforming growth factor β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease
Authors: Mickael Derangeon, Jérôme Montnach, Cynthia Ore Cerpa, Benoit Jagu, Justine Patin, Gilles Toumaniantz, Aurore Girardeau, Christopher L.H. Huang, William H. Colledge, Andrew A. Grace, Isabelle Baró, Flavien Charpentier
Journal: Cardiovascular Research (2017)

Loss-of-function mutations in SCN5A, the gene encoding NaV1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scn5a heterozygous knock-out (Scn5a+/-) mice, which are characterized by ventricular fibrotic remodelling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation.Our study shows that myocardial interstitial fibrosis occurred in Scn5a+/- mice only after 45 weeks of age. Fibrosis was triggered by transforming growth factor β (TGF-β) pathway activation. Younger Scn5a+/- mice were characterized by a higher connexin 43 expression than wild-type (WT) mice. After the age of 45 weeks, connexin 43 expression decreased in both WT and Scn5a+/- mice, although the decrease was larger in Scn5a+/- mice. Chronic inhibition of cardiac sodium current with flecainide (50 mg/kg/day p.o) in WT mice from the age of 6 weeks to the age of 60 weeks did not lead to TGF-β pathway activation and fibrosis. Chronic inhibition of TGF-β receptors with GW788388 (5 mg/kg/day p.o.) in Scn5a+/- mice from the age of 45 weeks to the age of 60 weeks prevented the occurrence of fibrosis. However, current data could not detect reduction in QRS duration with GW788388.Myocardial fibrosis secondary to a loss of NaV1.5 is triggered by TGF-β signalling pathway. Those events are more likely secondary to the decreased NaV1.5 sarcolemmal expression rather than the decreased Na+ current per se. TGF-β receptor inhibition prevents age-dependent development of ventricular fibrosis in Scn5a+/- mouse.
Velcade™ Plus Melphalan, Prednisone, and Thalidomide (V-MPT) for Advanced Multiple Myeloma.
Authors: Antonio Palumbo, Maria Teresa Ambrosini, Patrizia Pregno, Norbert Pescosta, Vincenzo Callea, Clotilde Cangialosi, Tommaso Caravita, Fortunato Morabito, Paola Omedè, Francesca Gay, Ilaria Avonto, Patrizia Falco, Sara Bringhen, Mario Boccadoro
Journal: Blood (2005)
ICORG 06-41: A phase II trial of single-agent sorafenib in the treatment of platinum-pretreated relapsed gastroesophageal adenocarcinoma (GECa).
Authors: Louise Catherine Connell, Seamus O'Reilly, Glenn Webb, Brian Moulton, Imelda Parker, Raymond McDermott, John McCaffrey, William Grogan, Gregory Leonard, Derek Gerard Power, Anne M. Horgan, Brian Bird, Kenneth John O'Byrne
Journal: Journal of Clinical Oncology (2014)

88 Background: Over 1 million individuals worldwide annually are diagnosed with GECa. The majority of patients(pts) present with inoperable locally advanced or metastatic disease(dx). Even with resectable dx 5 year survival is low at ~40% with current best treatment (tx). Following initial platinum based therapy there is no established standard 2 nd line tx. Besides HER2-directed therapy there has been little progress with targeted biologic agents. ICORG, the all-Ireland Cooperative Oncology Research Group investigated the utility of the tyrosine kinase inhibitor sorafenib in a multicentre trial. Methods: A prospective Phase II, nonrandomised, open label, one arm study of single agent sorafenib in the tx of platinum pre-treated relapsed GECa was conducted. Primary objective was dx control rate (DCR) post 4 months of tx. Secondary endpoints were OS, PFS, TTP, ORR, tolerability/toxicity and biomarkers of tx response/resistance. The protocol allowed for an interim analysis to be performed if clinically indicated. A sample size of 54 pts was identified using the single stage Fleming design approach to test whether the proportion responding, P, is ≤ 0.35 or ≥ 0.50. Pts received Sorafenib 400mg bid p.o. continuously q28days until dx progression or intolerable toxicity. Response by RECIST was evaluated by CT q8weeks. For pts with sufficient tumour samples translational studies were done. Results: An interim review performed in Nov 2012 (35 months post study opening) indicated that 33/41 evaluable pts recruited to date had progressed before completing 4 months of tx. Therefore, the number of evaluable pts with dx control could not reach the pre-specified figure of 22, &amp; the hypothesis P &gt;= 0.50 was rejected. Fifteen pts had just 1 cycle of tx, 5 of whom completed ≤ 2 weeks. A further 14 pts had 2 cycles. Median survival time to progression was 56 days (95% CI 53 – 59 days).Median OS was 120 days (95% CI 91 – 149 days). Safety data analyses and translational studies are ongoing and will be available for presentation at the meeting. Conclusions: Sorafenib as monotherapy is inactive in platinum pretreated pts with relapsed GECa. A significant unmet clinical need for novel effective therapies remains. Clinical trial information: 2008-005062-31.