tbuckley/cabot-search huggingface dataset:
Analysis of cell surface erythropoietin receptor (EpoR) expression and function in human epithelial tumor tissues
Authors: J. Rossi, I. McCaffery, K. Paweletz, Y. Tudor, S. Elliott, V. D. Fitzpatrick, S. D. Patterson
Journal: Journal of Clinical Oncology (2009)

11104 Background: EpoR mRNA and protein expression have been reported at low levels in human tumors implying EpoR may be functional in tumor cells with inferred implications for the use of erythropoiesis stimulating agents in the Oncology setting. However, mRNA studies use bulk tumor tissue which ignores contribution from the stroma and IHC studies have all used Abs that have since been shown to not be specific for EpoR. Therefore this important question remains unresolved. Methods: EpoR expression and function was investigated in viable, non-apoptotic primary human tumor cells (using tumor specific Abs) that were disaggregated from at least 30 patients from each of the following tumor types: breast (incl. metastases), NSC lung, colorectal, and ovarian. Additional tumor types included head and neck, GBM, pancreatic and gastric. Analysis was performed under conditions that were shown to preserve EpoR expression and function in positive control tissues (primary human erythroid progenitors from bone marrow and UT-7 cells). Cell surface EpoR expression was evaluated by flow cytometry using novel EpoR-specific Abs. EpoR function was investigated by analysis of EpoR signaling using phospho-specific Abs specific for STAT5, Erk, Akt etc following ex vivo Epo stimulation (0U- 300U/mL; for 5 and 30 min). Results: No expression of cell surface EpoR was detected in tumor cells in any of the over 130 tumors. In contrast, high levels of expression were observed in positive controls analyzed in parallel. No induction of EpoR signaling was observed in tumor cells at any [Epo], whereas activation was readily detected in tumor cells treated in parallel with a cocktail of known tumor growth factors. Positive controls treated in parallel, showed robust Epo concentration-dependent signaling. No evidence of EpoR expression or function was observed in tumor endothelial cells. Conclusions: These data demonstrate that epithelial tumor cells do not express functional cell surface EpoR and are not responsive to physiological, therapeutic or indeed very high levels of Epo (300U/mL). No significant financial relationships to disclose.
Contribution of TP53 p.R337H mutation to breast cancer prevalence in Brazil.
Authors: Patricia Ashton-Prolla, Cynthia ABT Osorio, Patricia Koehler-Santos, Marcia S Graudenz, Edenir Inez Palmero, Gabriela Fernandes, Rodrigo Micheli, Ghyslaine Martel-Planche, Maria Isabel Achatz, Fernando Augusto Soares, Jose Roberto Goldim, Maira Caleffi, Pierre Hainaut, Suzi Alves Camey, Juliana Giacomazzi
Journal: Journal of Clinical Oncology (2012)

1522 Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni Syndrome, to the overall burden of cancer is still only partially known. Studies in Southern and Southeastern Brazil have shown that a specific germline mutation at codon 337 (c.1010G&gt;A; p.R337H), has incomplete penetrance and may be present in a significant number of subjects (estimated frequency at the populational level of 1:300 individuals). In an exploratory approach, the aim of the study is to assess the frequency of the p.R337H mutation in women from different Brazilian regions, diagnosed with breast cancer (BC) before 46 and after 55 years of age, and unselected for family history of cancer. Methods: Formalin-fixed paraffin-embedded (FFPE) non-tumoral tissue (lymph nodes or normal breast) of women diagnosed with BC between 2000 and 2010 in 3 pathology laboratories from the Brazilian cities of Porto Alegre, São Paulo and Barretos were obtained retrospectively and analyzed after anonimization. Genomic DNA was isolated with standard methods and genotyping performed in duplicates by qPCR (TaqMan assay). Confirmation of all mutation-positive and a sample of mutation-negative cases were done by TP53 exon 10 sequencing or by a second independent qPCR analysis. Results: Analysis of 515 BC-affected women identified the p.R337H mutation in the germline of 70 (8,6%) cases: 49/403 (12,1%) diagnosed before 46 years and 21/412 (5,1%) diagnosed after 55 years. BC occurred earlier in p.R337H mutation carriers than in non-carriers (p=0.001). Conclusions: Preliminary analysis in a sample of women with BC indicates that p.R337H founder mutation is present in a high proportion of cases, especially those diagnosed at a young age. Regional genetic background and recruitment strategies may account for the different mutation frequencies observed in the centers of study. The occurrence of this mutation at such a high frequency in a particular geographic region has important implications for disease management and cancer risk counseling for these patients and families. This mutation likely contributes to a significant proportion of the health burden associated with BC in Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline.
Dosimetric evaluation and comparison of small-field non-coplanar multi-arc radiotherapy (SMART) and intensity-modulated radiotherapy (IMRT) in treatment of tumor-related bronchial/superior vena cava (SVC) obstructions
Authors: A. T. Figura, J. Montebello, J. Wang, H. Zhang, N. Mayr, N. Gupta, J. Grecula
Journal: Journal of Clinical Oncology (2007)

19668 Background: Rapid and cost-effective palliation is of great importance in patients with complications from lung cancer progression. To offer immediate treatment for a tumor-related obstructed bronchus or SVC, we have implemented the SMART technique which has been shown to be effective and safe in the primary and re-treatment of malignant bronchial/SVC obstructions. The purpose of this study was to determine if the dose coverage to the obstructed bronchus/SVC and normal tissue sparing achieved by SMART compare favorably to the lengthier and more expensive IMRT technique. Methods: Treatment planning CT’s from 9 patients with a bronchial obstruction and 1 with SVC were studied. The planning target volume (PTV) consisted of the clinical target volume (CTV = obstructed bronchus or SVC) plus a 1 cm margin. For SMART, a dose of 10 Gy in a single treatment to the target was computed using 18 MV photons with 5 to 8 non-coplanar arcs with field sizes ranging from 4 cm 2 to 8 cm 2 . For a dosimetric comparison using the same planning CT, an IMRT plan with 5 to 9 fields using 6 MV photons with 95% CTV coverage was computed to deliver the same dose. Dose volume histograms (DVH), treatment delivery time based on monitor units (MUs), and mean doses to the CTV, PTV, heart, lungs, spinal cord, and total body dose were compared using Student’s t-test. Results: Pooled DVH analysis of SMART and IMRT showed that SMART provided slightly better, but not statistically significant, coverage of the CTV (97±1.1 vs. 92±5%) and PTV (94±2 vs. 89±5%). There was no difference in normal tissue sparing between SMART and IMRT with respect to the mean lung dose (9±7 vs. 9±7%), heart dose (7±10 vs. 3±5%), cord dose (37±13 vs.30±13%), and total body dose (8±4 vs.7±4 Joules). However, SMART delivery was faster requiring significantly less MUs compared to IMRT (1,284±65 vs.1984±90, p&lt;0.002). Conclusions: IMRT showed no advantage over SMART in dose coverage of the CTV/PTV and sparing of critical normal tissues. Therefore, less complex planning and faster treatment delivery of SMART maybe clinically preferable for rapid palliation of critically ill patients with an obstructed bronchus/SVC. No significant financial relationships to disclose.
A phase II study of oral vinorelbine concurrent to thoracic radiotherapy (TRT) in elderly locally advanced (LA) stage NSCLC: Preliminary results
Authors: G. Silvano, G. Lazzari, M. Soloperto
Journal: Journal of Clinical Oncology (2008)

20698 Background: Novel drugs as vinorelbine (VNR) have shown a radiation enhancing effect; in elderly VNR has shown a good response rate on clinical benefit. Aim of this study is to explore if oral VNR concurrent to TRT is feasible and effective in unfavorable patients > 65 years old with LA NSCLC as first line chemoradiotherapy (CRT). Methods: Patients ≥ 65 years with LA NSCLC and at least one of the following: ECOG ≤ 2, weight loss > 5%, creatinine clearance < 60 ml/min, comorbidities, received TRT total mean dose 45 Gy (30–50) as palliative (arm A) or 60 Gy (50–66) as curative (arm B) intent concurrent to oral VNR 20 mg/m2/twice weekly. Results: From January 2003 to December 2006 25 naivepatientswere treated: 15 patients in arm A and 10 pts in arm B. Median age was 72 (65–80), male 95%, stage IIIA 30%, stage IIIB 70%, ECOG 2 35%, weight loss > 5% 30%, comorbidity 60%. More than one poor risk inclusion criteria: 60%. Compliance to the entire treatement was 87% and 80% respectively. Early RTOG G3 oesophagitis was the most acute side effect to require the suspension of the CRT. RTOG G4 oesophagitis occurred at the end of CRT in one patient with diabetes and tumor in the posterior mediastinum. No grade 3–4 hematological toxicity was recorded. In the A arm ECOG PS ameliorated in 65% of pts. No survivors are in the A arm. In the B arm there were 4 CR, mean age 73 years (70–81), 3 PR and 2 PD. Brain and bones were the most common site of systemic progression. At a 2 years mean follow-up the 4 CR patients in the B arm are alive and disease free; one patients developed late RTOG G3 pneumonitis. Conclusions: Concurrent TRT with oral VNR is feasible and effective. Survival profile need further follow up. No significant financial relationships to disclose.
Role of Runx2 in transcriptional regulation of MMP9 in bone metastatic cancer cells and the control of cell invasion
Authors: Jitesh Pratap, Lucia Languino, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian
Journal: Cancer Research (2005)

6122  Matrix metalloproteinase-9 (MMP9) is a key regulator in the development of the growth plate during endochondral bone formation. The transcription factor runt-related gene 2, (RUNX2, CBFA1/AML3) is essential for maturation of the growth plate and bone formation. Up regulation of MMP9 expression has been implicated in invasion and metastasis of breast and prostate tumors, and Runx2 is ectopically expressed in breast (MDA-MB-231) and prostate (PC3) cancer cells that metastasize to bone. By cDNA expression array, we identified MMP9 as a novel downstream target of Runx2 using total RNA from wild type and Runx2ΔC /ΔC mutant mouse. MMP9 expression, like MMP13 but not MMP2, is nearly depleted in Runx2 deficient mice. In vivo analysis by chromatin immunoprecipitation assay and in vitro by EMSA revealed recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter activity in both osteoblastic cells (MC3T3- E1) and non-osseous (HeLa) cells. Runx2 regulation of MMP9 was examined relative to the invasive properties of tumor cells. We find that over-expression of Runx2 by adenovirus delivery in both primary and bone metastatic cancer cell lines significantly increases endogenous levels of MMP9. Furthermore, knockdown of Runx2 by RNA interference results in decreased MMP9 expression. Importantly, we have demonstrated using a cell migration assay that Runx2 regulated MMP9 levels are functionally related to the invasion properties of cancer cells. In conclusion, our findings demonstrate the role of Runx2 in transcriptional regulation of MMP9 and that modulation of MMP9 expression by Runx2 influences cell migration .We suggest that Runx2 is a primary initiator for expression of genes that contribute to the metastatic properties of cancer cells and their activity in the bone environment.
Abstract 3238: Synergy Between Severe LV Systolic Dysfunction and LVH for Risk of Sudden Cardiac Death
Authors: Sumeet S Chugh, Celia Dervan, Kyndaron Reinier, Carmen Socoteanu, Audrey Uy, Ronald Mariani, Karen Gunson, Jonathan Jui
Journal: Circulation (2007)

Background : The Framingham Heart Study reported an association between increased LV mass/hypertrophy (LVH) and sudden death that was independent of coronary risk factors. Severely decreased LV systolic dysfunction (LVEF ≤ 35%) is an established predictor of SCD risk, but the potential for enhancement of SCD risk in combination with LVH has not been evaluated. Methods : In an ongoing population-based study, adult residents of a metro area (population 1,000,000) who suffered SCD in association with coronary artery disease (CAD) were identified prospectively (2002–2005). The subgroup of consecutive SCDs that had a cardiac echo performed prior to, and remote from cardiac arrest was identified. Echocardio-graphic findings were evaluated and LV mass normalized for body surface area calculated (American Society of Echocardiography modified equation). Comparisons were conducted with a geographically matched control group of subjects with known CAD, but no history of SCD. Results : LV mass was available for 99 SCD cases with established CAD (mean age 71, 29% female), as well as 100 controls (mean age 68, 32% female). Patients with severe aortic stenosis or hypertrophic cardiomyopathy were excluded (6 SCDs, 2 controls). LV mass was significantly greater in cases vs controls and this was consistent for unadjusted LV mass (247 vs. 215 g, p=0.02) as well as LV mass adjusted for body surface area (124 g/m 2 vs. 108 g/m 2 , p=0.008). Among SCD cases, 40% had LVH vs. 22% in controls (p=0.01). In a logistic regression model controlling for age, LVH was independently associated with SCD (OR 2.3, 95% CI 1.2 – 4.4, p=0.009). In a logistic regression model including both age and LV dysfunction, there was an interaction between LVH and severe LV dysfunction (p =0.05). In the presence of severe LV dysfunction, LVH increased the odds of SCD by 8-fold (OR 8.1, 95% CI 2.4 –28.2). Conclusions : LVH and severe LV systolic dysfunction combined appear to substantially increase risk for SCD (8-fold). These findings have implications for refinement of SCD risk stratification.
Abstract 18392: Latent Myopathy is More Pronounced in Low Flow Versus Normal Flow Aortic Stenosis Pre- and Post-aortic Valve Replacement in Patients with Normal Left Ventricular Ejection Fraction
Authors: Monica Sanchez-Ross, Daniel Marrero, Valentin Suma, Amit K Correa, Bani M Azari, Sameh Mohareb, Daniel Swistel, Sandhya Balaram, Suraj Sookhu, Farooq A Chaudhry
Journal: Circulation (2012)

Background: Strain assessment using speckle tracking echocardiography (STE) is more sensitive than 2D echocardiography to detect subtle changes in left ventricular (LV) function. Mid cavity fibrosis on MRI and low indexed stroke volume are independent predictors of mortality in severe AS with preserved LV ejection fraction (LVEF). The role of 2D STE to identify latent myopathy (fibrosis) in AVR and normal LVEF is limited. Methods: Demographic, 2D echocardiographic, and STE data were analyzed in patients with severe AS and preserved LVEF who underwent tissue AVR. Velocity vector imaging (VVI) 2D STE was used to assess global and regional peak systolic longitudinal strain and strain rate in both pre- and post-AVR echocardiograms. Basal and mid segment averages were compared to normal reference values. Low flow (LF) was defined as an indexed LV stroke volume &lt;35ml/m2. Results: Between July 2009 to May 2012, 47 patients (76 ± 10 yrs, 42% male) who underwent tissue AVR had both a pre- and post-AVR echo within 6.3 ± 6.7 months of surgery. Compared with pre-AVR values, global longitudinal strain (-6.6 ± 4.9% vs. -10.3 ± 3.7%; p=0.002) and strain rate (-0.8 ± 0.3 1/s vs. -0.9 ± 0.3 1/s; p=0.03) improved within 3.2 ± 2.3 months post-AVR. Pre-AVR mid segments showed a worse myopathy than basal segments, with a decrement of -10.1 ± 1.6% vs. -8.8 ± 1.6% (p=0.0009) from reference values. Although, improvement was seen in both mid (-8.6 ± 5.6 % vs. -10.6 ± 4.3%; p= 0.04) and basal (-8.2 ± 5.5% vs. -10.8 ± 5.0%; p=0.02) segments post-AVR, the myopathy remained more pronounced in the mid segments. Overall, 21 (46%) patients were classified as LF with significant improvement in pre- vs. post-AVR strain (-5.3 ± 4.6% vs. -9.4 ± 4.1%; p=0.003). However, compared with normal flow (-8.6 ± 5.7%) LF had lower pre-AVR (-5.3 ± 4.6%; p=0.05) and post-AVR (-12.4 ± 3.4% vs. -9.4 ± 4.1%; p=0.02) longitudinal strain. Conclusions: STE VVI can identify both global and regional latent myopathy in patients with severe AS and preserved LVEF undergoing AVR. The myopathy is more pronounced in low indexed stroke volume pre and post-AVR. Furthermore, the myopathy in normal flow and low flow patients is more pronounced in the mid segments both pre- and post-AVR.
Recovery from delirium and survival of patients with advanced cancer.
Authors: M. S. Boddaert, T. C. Versteegde, J. Berkhof, A. T. Beekman, H. Verheul
Journal: Journal of Clinical Oncology (2010)

e19588 Background: Since delirium is a frequent and serious complication in patients with advanced cancer, we studied the impact of delirium on the outcome of patients with advanced cancer admitted to an oncology ward. Methods: From 2006 to 2008 162 patients with advanced malignancies were prescribed the neuroleptics haloperidol or olanzapine while admitted to our academic oncology ward. These patients were included in this historical cohort study and their medical records were analyzed for diagnosis and cause of delirium, baseline characteristics, treatment of delirium and outcome. Results: Out of these 162 patients, 76 patients were diagnosed with a delirium according to their medical records. Forty of these 76 patients recovered from their delirium. While baseline characteristics were similar between patients who recovered and patients who did not recover, survival of patients who recovered from a delirium significantly increased by (hazard ratio = 2.5, P = 0,003, 95% CI 1.35782 – 4.61422). None of the baseline characteristics or the treatment strategy significantly influenced survival. However, patients younger than 70 years of age and patients with a ‘single cause' delirium had a significantly higher chance of recovery than patients older than 70 years of age and patients with ‘multifactorial cause' delirium, respectively. Conclusions: Recovery from a delirium of patients with advanced cancer admitted to an oncology ward is significantly associated with increased survival. Based on this finding we advocate early recognition and adequate treatment of delirium. No significant financial relationships to disclose.
IL-21 enhancement of rituximab-mediated B cell depletion
Authors: S. D. Hughes, C. Krejsa, F. Wagner, J. Heffernan, K. Henderson, R. Roque, R. Ponce, W. Kindsvogel, E. Sievers, M. Rogge
Journal: Journal of Clinical Oncology (2005)

2568 Background: IL-21 is a cytokine produced by activated CD4+ T cells that affects the growth, survival, and activation of several hematopoietic cell types. Because IL-21 augments antibody dependent cellular cytotoxicity (ADCC) in vitro, we evaluated its effects on rituximab-mediated B cell depletion in vivo. Methods: Four groups of cynomolgus monkeys were injected IV with vehicle, rIL-21 (0.5 mg/kg, Days 1–3, 8–10 and 22–24), rituximab (0.05 mg/kg, Days 1, 8 and 22), or a combination of the two agents. Peripheral B cells were enumerated by flow cytometry using antibodies to CD21, CD40 and CD20. The number and activation state of T cells, NK cells, and monocytes were also characterized. Results: Sub-clinical doses of rituximab reduced the number of circulating B cells to a nadir 70% below baseline within 6 hr of dosing. Treatment with rIL-21 alone initially reduced circulating B cells, T cells and NK cells, followed by a sustained increase and resolution prior to the next dosing cycle. Based on the rapid reversal of lymphopenia and previous observations of lymphoid follicle depletion with rIL-21, this effect was interpreted as transient margination of activated lymphocytes combined with increased recirculation from lymphoid tissues to blood. The increase in peripheral B cells was largely mitigated in animals treated with both rIL-21 and rituximab, and a consistently lower B cell nadir was observed, relative to groups treated with rituximab or rIL-21 alone. These findings suggest that rIL-21 enhanced B cell depletion by rituximab and that many B cells activated by rIL-21 were susceptible to depletion. Changes in other lymphocyte subsets induced by rIL-21 were not altered by rituximab treatment. Increased numbers of NK cells and phagocytic cells expressing FcγRI and FcγIII were also observed with rIL-21 treatment, consistent with enhanced ADCC activity in ex vivo assays (Krejsa, et al., ASCO submitted). Conclusions: Treatment with rIL-21 increased both lymphocytes and ADCC effector cells in circulation. Combined treatment with rituximab and rIL-21 resulted in depletion of greater numbers of B cells compared to rituximab alone. Thus, rIL-21 may potentially improve rituximab efficacy through dual actions of enhanced ADCC and B cell depletion in lymphoid tissues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ZymoGenetics ZymoGenetics
Phase I Clinical and Pharmacogenetic Trial of Irinotecan and Raltitrexed Administered Every 21 Days to Patients With Cancer
Authors: James P. Stevenson, Maryann Redlinger, Leo A.J. Kluijtmans, Weijing Sun, Kenneth Algazy, Bruce Giantonio, Daniel G. Haller, Christine Hardy, Alexander S. Whitehead, Peter J. O’Dwyer
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity. PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle. RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m 2 , and raltitrexed, 1.0 to 4.0 mg/m 2 . Raltitrexed doses of more than 3.0 mg/m 2 were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m 2 were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity. CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m 2 are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.