tbuckley/cabot-search huggingface dataset:
Significance of <i>MTHFR</i> gene mutation with normal homocysteine level in vascular events
Authors: V. K. Gadiyaram, M. A. Khan, T. Hogan, R. Altaha, E. Crowell, G. Hobbs, P. Perrota
Journal: Journal of Clinical Oncology (2009)

e20520 Background: Hyperhomocysteinemia, due to a combination of genetic and environmental factors, is considered to be a risk factor for vascular disease. Two common variations of the MTHFR gene (C677T and A1298C) result in amino acid substitutions and enhanced thermolability of the enzyme. Individuals with MTHFR gene mutations appear to have raised plasma level of homocysteine which may lead to increased risk of vascular events. However, significance of MTHFR gene mutations with normal homocysteine levels is unknown. Objective: To assess the relation of MTHFR gene mutations with normal homocysteine level and risk of Vascular events (deep venous thrombosis (DVT), pulmonary embolism (PE), Ischemic Heart disease (IHD), cerebrovascular accidents (CVA),recurrent fetal loss). Methods: We reviewed the records of 90 patients referred to our benign hematology clinic for thrombophilia evaluation between 2006 and 2008. All available medical history for risk factors and laboratory test results, obtained from first vascular event through time of consultation, including genetic testing, were reviewed. Anti-cardiolipin antibody, MTHFR genotyping and Protein C and Protein S assays were performed at Warde Medical Laboratory, Ann Arbor, MI. Results: 61 patients with documented vascular events were tested for MTHFR gene mutations. Forty one of these patients also had homocysteine levels available. Thirty-eight of these 41 (92 %) patients had an MTHFR gene mutation with normal homocysteine levels. Eighteen (47%) of these 38 patients had only an MTHFR gene mutation with normal homocysteine level and no other congenital or acquired risk factors for vascular events identified. Conclusions: In our clinic population, many patients with documented vascular events had MTHFR gene polymorphisms with normal homocysteine levels with no other thrombophilia risk factors identified, raising the question of whether MTHFR gene polymorphisms alone, without hyperhomocysteinemia, may somehow contribute to thrombophilia. [Table: see text] No significant financial relationships to disclose.
Epithelial-mesenchymal transition and brain metastasis in non-small cell lung cancer
Authors: B. W. Goodgame, D. S. Young, J. Haley, W. Mark, R. Govindan
Journal: Journal of Clinical Oncology (2008)

19027 Background: Although brain metastases from lung cancer are the most common intracranial malignancy and contribute significantly to its mortality and morbidity, the underlying mechanisms are poorly understood. Epithelial-mesenchymal transition (EMT) is one proposed mechanism of metastasis and is associated with the loss of E-cadherin expression and the gain of vimentin expression. We hypothesized that these changes would be more common in resected NSCLC tumors that eventually relapsed in the brain and present here the preliminary analysis. Methods: From a large cohort of patients with completely resected stage I NSCLC, 21 patients were identified who later developed brain metastasis. These patients were matched by T classification and histology to two sets of controls: those with no relapse and those with relapse in other sites, for a total of 63 patients. A tissue microarray was constructed using two 0.8 mm cores per case from the original paraffin tumor block. Expression of E-cadherin and vimentin was evaluated by immunohistochemistry and was graded on a 0 - 3 scale based on the staining intensity and the percentage of tumor cells which stained. Low E-cadherin expression was defined as 0 or 1+ staining and vimentin expression was defined as 2 or 3+ staining. Chi-squared tests were used to compare groups. Results: The 21 patients with brain metastases, as compared to the combined 42 controls, were similar in age (median 63 vs 67) and gender (48% female vs 38%). Tumor stages were IA in 19% and IB in 81%, and histology was adenocarcinoma in 66% and squamous cell carcinoma in 33% for each cohort. Adequate immunohistochemical results were obtained in 59 of 63 cases. Only 2 specimens showed loss of E-cadherin, both in brain metastasis patients. Vimentin expression was seen in 8 patients, of whom 5 developed brain metastasis, including one who also had loss of E-cadherin. Patients with brain metastasis were more likely to have either loss of e-cadherin or gain of vimentin expression (30%) when compared to controls (8%, p=0.024). Conclusions: Markers of EMT may identify patients at risk of eventual brain metastasis. Confirmation in larger data sets could lead to a clinically useful tool to predict brain metastasis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Pharmaceuticals OSI Pharmaceuticals
Cyclin-dependent kinase (CDK) activity as a prognostic marker in primary epithelial ovarian cancer
Authors: J. A. de Souza, C. Wei, S. Noguchi, K. Lu, H. Ishihara, D. Aoki, N. T. Ueno
Journal: Journal of Clinical Oncology (2007)

5575 Background: The unpredictable nature of primary epithelial ovarian cancer (EOC) response to treatment necessitates the identification of factors that predict long-term outcome. CDK activity is the core regulator of the cell-cycle checkpoint for cancer cells. We previously found that cell death induced by taxanes requires increased activity of CDK1 and CDK2- fundamental kinases in cell proliferation. Thus, we hypothesized that CDK1/2 activities can determine the prognosis of patients with primary EOC. Methods: We retrospectively analyzed frozen ovarian cancer specimens from 72 women treated with cytoreductive surgery and adjuvant chemotherapy for newly diagnosed EOC. Median patient age was 61 years (range, 38–80), 91% had FIGO stage III/IV disease, and 86% were treated with platinum- or taxane-based regimens. Median follow-up was 32 months; median time to treatment failure (TTF), defined as time from surgery to first relapse for patients who had achieved complete response or time to disease progression for those who had persistent disease, was 15 months. Enzymatic activity of CDK1/2 in the tumor tissues was determined by a modified in vitro kinase activity assay using a C2P device (Sysmex Inc.). Recursive partitioning and regression trees algorithm (RPART) was used to identify the cohorts based on CDK1/2 activities. Results: In the univariate analysis, disease stage (p=0.021), type of surgery (optimal vs. suboptimal) (p=0.004), presence of ascites (p=0.043), and CA125 after the adjuvant therapy (p=0.005) were significant predictors of TTF. The cohort with CDK2 activity = 87.3 had a significantly shorter TTF (p=0.014) and the cohort with CDK1 activity = 226.35 showed a trend toward longer TTF (p=0.094). Multivariate Cox proportional hazards regression analysis revealed CDK2 activity (&lt;87.3 vs. = 87.3) (p=0.012) and CA125 level at completion of the adjuvant chemotherapy regimen (p=0.02) to be independent predictors of TTF. Conclusion: Our data supports kinase activity of cell cycle as a clinically significant prognostic factor. To extend these findings, we plan to conduct a large prospective study to determine whether CDK1/2 profiling can predict long-term outcome in primary EOC. [Table: see text]
Multiparametric magnetic resonance imaging (MRI) of diffuse intrinsic pontine gliomas (DIPG) after radiation therapy (XRT)
Authors: K. E. Warren, D. Draper, J. A. Butman
Journal: Journal of Clinical Oncology (2006)

1579 Background: The diagnosis and treatment of DIPG are based on typical MRI findings because of the inherent risk of biopsy. The standard treatment for this tumor is XRT. The limited ability of standard MRI to distinguish tumor from treatment effect hampers the determination of tumor response and time to progression. The objective of this study is to measure biochemical and physiologic MRI markers in DIPG after XRT that may aid in assessment of response. Methods: Fifteen pediatric patients (5 y, range, 1.8–12) with DIPG involving &gt;50% of the pons and treated with XRT only were evaluated 12–64 days (median 38) following XRT (50.4–67.2 Gy, median 54 Gy) by MRI at 1.5 T. Standard T1, T2, and FLAIR MRI was performed in all cases. In addition, proton MR spectroscopy (MRS) was performed in 10 cases, MRS imaging ( 1 H-MRSI) in 12, dynamic contrast enhanced MRI (DCE-MRI) in 14, and dynamic susceptibility weighted MRI (DSC-MRI) in 9. K trans and rCBV were measured using ROIs on enhancing portions of the tumor from the DCE- and DSC-MRI data after kinetic modeling. Results: Tumor area changed following XRT by a median of −29% (range, −61 to +37; SD, 33) and −17% (range, −65 to +101; SD, 45) on T2 and FLAIR, respectively. Enhancement was identified in 15 of 15 patients following XRT, and in only 6 of 15 prior to XRT (P = 0.0039 McNemar’s test). Following XRT, Choline: N-Acetyl Aspartate (CHO:NAA) ratio was 3.2 ± 1.9 by single voxel MRS, and the “worst voxel” CHO:NAA ratio was 3.5 ± 1.5 by 1 H-MRSI. Overall, rCBV (1.98 ± 1.30) was elevated relative to normal cerebellum. However in 4 of these cases, rCBV was markedly elevated (&gt;2), 4 were normal (1.0–1.3), and one was markedly reduced (0.6).Similarly, disruption of the blood-tumor barrier was variable across the group. K trans , a measure of permeability, ranged from 0.000 to 0.026 s −1 , averaging 0.0086 ± 0.0085 s −1 . Conclusions: Although all patients had a structurally similar tumor on MRI prior to XRT, significant variability in physiologic and metabolic response to XRT as measured by multiparametric MRI are noted. Presumably this variability represents real biologic differences resulting from differential responses to therapy. Determination of the prognostic significance is ongoing. No significant financial relationships to disclose.
Endoscopic surveillance in patients with multiple (10–100) colorectal polyps
Authors: Fátima Valentín, Carla Guarinos, Miriam Juárez, María Rodríguez-Soler, Anna Serradesanferm, Francisco Rodriguez-Moranta, David Nicolas-Perez, Luis Bujanda, Maite Herraiz, Luisa De-Castro, Fernando Fernández-Bañares, Alberto Herreros-de-Tejada, Fernando Martínez, Elena Aguirre, Ángel Ferrández, José Díaz-Tasende, Virginia Piñol, Artemio Paya, Cecilia Egoavil, Cristina Alenda, Antoni Castells, Rodrigo Jover, Joaquín Cubiella
Journal: Endoscopy (2015)

Endoscopic surveillance in patients with multiple colorectal polyps aims to reduce colorectal cancer (CRC) incidence and mortality, as well as the need for colorectal surgery. The aim of this study was to determine the risk of developing CRC or the need for surgery during endoscopic surveillance in a cohort of patients with multiple (10 - 100) colorectal polyps.This was a multicentrer, longitudinal, observational study in 15 CRC high risk clinics in Spain, carried out between January 2009 and December 2010. Patients who were included in the EPIPOLIP trial and had at least 1 year of follow-up were included in the study. The primary outcome of interest was the incidence of CRC at least 1 year following the initial colonoscopy. The secondary outcome was the need for colorectal surgery.A total of 265 patients were followed for a median of 3.8 years. Patients underwent a median of 5 colonoscopies, and 17 patients (6.4 %) were diagnosed with CRC. A total of 32 patients (12.1 %) underwent surgery, including 15 (5.7 %) for prophylaxis without a diagnosis of CRC. The corresponding incidence density rates for CRC and colorectal surgery were 1.4 (95 % confidence interval [CI] 0.7 to 2.1) and 2.7 (95 %CI 1.7 to 3.6) per 100 patient-years, respectively. Only the presence of symptoms at first colonoscopy was independently associated with CRC diagnosis (hazard ratio [HR] 7.7, 95 %CI 1.1 to 59.3) and colorectal surgery (HR 4.6, 95 %CI 1.02 to 20.6).Patients with more than 10 neoplastic polyps required frequent colonoscopies within a short follow-up period. More than 10 % of patients required colorectal surgery within 4 years, more than half for incident CRC.
Analyses of the transcriptome and metabolome to elucidate the role of HIF1α in clear cell renal cell carcinoma metabolism.
Authors: Denise R. Minton, Leiping Fu, Qiuying Chen, Brian D. Robinson, Steven S. Gross, Maria M. Shevchuk, David M. Nanus, Lorraine J. Gudas.
Journal: Journal of Clinical Oncology (2015)

493 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by altered metabolism, including a shift from oxidative phosphorylation to glycolysis and lactate production (the Warburg effect). Here we evaluate human ccRCC tissue samples and kidney samples from the TRACK transgenic mouse model of ccRCC (that express constitutively active HIF1α in proximal tubule cells) [1] to characterize the effect of HIF1α on the renal cancer metabolome. Methods: We performed untargeted metabolomics analyses of 12 primary human ccRCCs and 10 TRACK kidney samples. In addition, we analyzed human ccRCC mRNA expression (Oncomine database) and performed RNA sequencing (RNAseq) on six TRACK kidney samples for expression of HIF1α target genes that regulate metabolism. Results: Analysis of RNA expression of HIF1α target genes in human ccRCCs and TRACK kidneys identified significantly increased transcript levels of genes responsible for mediating glucose uptake and glycolysis and suppressing the activity of the TCA cycle and mitochondrial respiration, including glucose transporter 1 (SLC2A1), glycolytic enzyme phosphofructokinase (PFKP), TCA cycle inhibitor pyruvate dehydrogenase kinase (PDK1), oxidative phosphorylation inhibitor NADH dehydrogenase 1 alpha subcomplex, 4-like 2 (NDUFA4L2), and lactate transporter (SLC16A3). Metabolomics analysis similarly demonstrated a significant increase in glycolytic intermediates and lactate, in association with a decrease in metabolites of the TCA cycle. Conclusions: These studies show that in both human ccRCC and TRACK mice HIF1α mediates a metabolic switch to aerobic glycolysis, implicating HIF1α in RCC tumorigenesis. Additionally, these data suggest that targeting the metabolic pathway (or inhibition of HIF1α) is a novel approach to treat ccRCCs.
A Phase 1 dose-escalation study of the safety and pharmacokinetics (PK) of the oral Hsp90 inhibitor SNX-5422
Authors: J. C. Bryson, J. R. Infante, R. K. Ramanathan, S. F. Jones, D. D. Von Hoff, H. A. Burris
Journal: Journal of Clinical Oncology (2008)

14613 Background: SNX-5422 is an oral pro-drug of SNX-2112, a potent and highly selective small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). SNX-2112 potently inhibits solid and hematological tumor cell proliferation with IC50 values of 1–10 nM, and is more potent than 17-AAG and 17-DMAG in a majority of the cell lines tested. Due to its involvement in the maturation and maintenance of numerous proteins critical for tumor cell viability and growth, Hsp90 is an exciting therapeutic target for a broad range of solid tumor and hematological malignancies. Methods: Eligibility included patients (pt) with refractory solid tumors or lymphomas, Karnofsky performance status ≥60, adequate organ function, and no known CNS involvement, primary or metastatic. SNX-5422 was given orally every other day daily for 21 days followed by 7 days of rest. Dose escalation is proceeding at 100% with standard 3 pt cohorts until a grade (gr) 2 adverse event (AE) occurs, then escalation decreases to 33%. The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, and PK of SNX-5422. Results: 11 patients have been dosed to date; 3 in cohort 1 (4 mg/m2); 3 in cohort 2 (5.32 mg/m2); 4 in cohort 3 (10.64 mg/m2); and 1 in cohort 4 (21.28 mg/m2) for a total of 20 cycles. Tumor types included: 3 melanoma; 2 breast cancer; 1 anal; 1 prostate; 1 adrenal; 1 adenocystic; 1 NSCLC; and 1 squamous cell carcinoma of unknown primary. SNX-5422 has been well tolerated with no DLTs observed. All drug related toxicities have been gr 1 (nausea 3 pt and fatigue 2 pt). The predicted effective human dosing range based on animal models is approximately13–53 mg/m2. PK results of the first two cohorts demonstrate dose proportional increases in Cmax and AUC and a half-life of ∼ 8–10 hours. Proof of mechanism will be supported by PBMC evaluation of multiple biomarkers including p-Erk and p-S6. Conclusions: SNX-5422 has been well tolerated through the first three dose levels and is enrolling at 21.28 mg/m2, which is within the effective human dose range predicted by pre-clinical studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Serenex, Inc. Serenex, Inc. Serenex, Inc. Serenex, Inc.
Retrospective analysis of treatment practices for elderly cancer patients (Pts) in Ontario, Canada
Authors: C. A. Townsley, G. R. Pond, W. Melnick, B. Peloza, J. Kok, D. Dale, C. Herbert, E. Holowaty, S. Straus, L. L. Siu
Journal: Journal of Clinical Oncology (2004)

8168 Background: Older patients are underrepresented in many areas of cancer services utilization and in clinical trial enrollment. This study evaluates whether age, when adjusted for potential confounders is predictive of cancer management. Methods: First, we utilized the Ontario Cancer Registry (OCR) to examine for any differences in treatment practices between older (≥ 70 yrs) and younger pts in the past 3 decades. Specifically, the proportions of older versus younger pts who received surgery, chemotherapy or radiotherapy in 3 common tumor sites (lung, breast and colorectal) were compared. Second, we planned a chart review of 1,800 randomly selected patients with these cancers, seen either at an urban or rural centre in 1977 or 1997. Results: The proportions of elderly pts who received treatment for some conditions (e.g. chemotherapy in colorectal cancer) were lower than that of younger pts. From the first 860 charts reviewed, univariate analyses of predictive factors for pts receiving any cancer treatment and for clinical trial discussion, are listed below. Multivariate analysis showed that older age remained a statistically significant predictor of treatment practice and of clinical trial discussion, after adjusting for all univariately significant variables. Conclusions: Regardless of other factors, age is consistently a barrier in cancer treatment practice and in clinical trial discussion. No significant financial relationships to disclose.
The role of serum chromogranin A (CgA) in patients with small cell lung cancer
Authors: T. Ibrahim, A. Riccobon, M. Petrini, M. Stefanelli, C. Tison, R. Ridolfi, D. Amadori
Journal: Journal of Clinical Oncology (2004)

7253 Background: Small cell lung cancer (SCLC) accounts for 20–25% of all lung cancers and often presents neuroendocrine characteristics. Neuron-specific enolase (NSE) is the most widely used marker in this pathology and CgA, which belongs to the chromogranin-secretogranin family, is considered a multifunctional pro-hormone and is used for the diagnosis and follow up of neuroendrocrine tumors. The aim of the present study was to define the prognostic role of CgA in SCLC and to assess its predictivity on response to therapy. Patients and Methods: CgA serum levels were determined in 26 healthy individuals (12 males, 14 females) and 26 patients (20 males, 6 females), and NSE was determined in the same healthy individuals and in 19 patients using the ELISA method. Median age was 45 years in healthy individuals (range 20–70 years) and 64 years in patients (range 51–87 years). Results: In the 26 healthy individuals, the median CgA and NSE values were 10 U/l (range 2–18 U/l) and 6.25 U/l (range 0–12.5 U/l), respectively. In the 26 SCLC patients, the median values of CgA and NSE were 23 U/l (range 0–421 U/l) and 29.9 U/l (range 5–134.5 U/l), respectively. Correlation analysis between the two markers in patients showed a weak direct relation (rs = 0.35, p = 0.14). Subgroup analysis as a function of stage and response to chemotherapy showed that median CgA values were similar in the 13 patients with limited disease (23 U/l, range 0–20 U/l) and in those with extended disease (14 U/l, range 0–421 U/l). Lower CgA values were observed in chemotherapy-refractory patients than in responders (median 7 vs. 33 U/l). Conclusions: Our preliminary results seem to indicate that there is no correlation between serum levels of CgA and NSE, and stage of disease. Recruitment is ongoing to verify the potential role of CgA in predicting response to chemotherapy. No significant financial relationships to disclose.
A phase I study of CS-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tumors or lymphomas
Authors: M. N. Saleh, I. Percent, T. E. Wood, J. Posey, J. Shah, R. Carlisle, S. Wojtowicz-Praga, A. Forero-Torres
Journal: Journal of Clinical Oncology (2008)

3537 Background: CS-1008 is an IgG1 agonistic humanized monoclonal antibody targeting the human death receptor 5 (DR5). CS- 1008 triggers apoptosis after binding to DR5 resulting in death of targeted cells; it has demonstrated cytotoxic activity against DR5-positive human tumor cell lines in vitro, and in vivo it has shown significant anti-tumor activity against human tumor xenografts in nude mice. Methods: A phase I trial in patients with relapsed/refractory solid tumors and lymphomas was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety profile of CS-1008 administered intravenously every week (a cycle was defined as 3 consecutive weeks). Three to six patients were enrolled in successive dose escalating cohorts at doses from 1 to 8 mg/kg weekly (1, 2, 4 and 8). The MTD was defined as the highest dose at which 0/3 or 1/6 patients experience dose limiting toxicities (DLT). Results: Seventeen patients were enrolled, with a median age of 57 years (range, 31–88 years). Nine patients were enrolled in the 1, 2, and 4 mg/kg dose cohorts (3 in each one) and 8 patients in the 8m/kg dose cohort. CS-1008 was well tolerated, with no DLTs observed and the MTD was not reached. There were no infusion related toxicities, grade 3 or 4 toxicities related with CS-1008, or renal/ hepatic/hematological toxicities. Nine non-related severe adverse events were reported, all of them related to the primary tumor or disease progression. PK results demonstrated a half-life of 8 to 16 days. Seven patients had stable disease: 2 in the 1 mg/kg dose cohort (hepatocellular carcinoma 497+ days, head and neck cancer 225 days), 1 in the 2 mg/kg cohort (colon cancer 77 days), 2 in the 4 mg/kg dose cohort (colon cancer 78 days, cholangiocarcinoma 155 days), and 2 in the 8 mg/kg dose cohort (colon cancer 79 days, hepatocellular carcinoma 78 days). Conclusions: CS-1008 is well tolerated, and the MTD was not reached. The high number of patients with stable disease in this phase I trial suggests anti-tumor activity. Clinical trials of CS-1008 in combination with chemotherapy for the treatment of DR5 positive epithelial tumors have been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Daiichi Sankyo Pharma Daiichi Sankyo Pharma Daiichi Sankyo Pharma