tbuckley/cabot-search huggingface dataset:
Arginine (Arg) deprivation for the treatment of advanced melanoma: Clinical results/correlation with argininosuccinate synthetase (ASS) expression
Authors: N. Savaraj, M. You, C. Wu, A. Marini, M. T. Kuo, M. Wangpaichitr, J. Bomalaski, L. G. Feun
Journal: Journal of Clinical Oncology (2008)

20019 Background: Depletion of Arg using Arg deiminase results in cell death in melanoma cells. Lack of ASS, a key enzyme which can synthesize Arg from citrulline, explains why melanoma cells are sensitive to ADI-PEG20(Polaris Inc.). Our phase II trial of ADI-PEG20 showed activity in melanoma. With this clinical trial, we correlated ASS expression in tumor/primary culture (PC) before and at relapse. Methods: PC was established from biopsy prior or after treatment failure. ADI-PEG20 was given at 160 IU/m2 i.m weekly and escalated to 320 IU/m2 if Arg levels were detected. Tumor assessment was done every 8 wks. ASS was assayed by immunohistochemical (IH.) and/or real time PCR (RPCR.) The ratio of GADPH and ASS was calculated using sensitive/ resistant melanoma cell lines as control (efficiency of both primers sets are equal to 1). Results: 22 patients (pts) were accrued and were assessable for response. 4 pts (18%) had partial response (PR), 3 minor response, 3 mixed response and 1 stable disease. Thus, signs of antitumor activity were observed in 45% of pts (10/22). Duration of PR was 7, 12, 16 and 31 months. Toxicity was minimal. Tumor samples were available for ASS determination in 15 pts. PC were established in 8 pts and cell lines in 3 pts. Only 1 immunohistochemical staining (IH) showed slight positivity, however PC were tested positive in 5 pts by RRTPCR and negative by IH. Three of these pts were treated and showed no response while the other two were not treated. Two PC were established at the time of relapse; they were both ASS positive by RRT-PCR, however, IH was still negative. We have compiled the data from cell lines and PC. The best response to ADI-PEG20 occur in PC and cell line which have a ratio of 7000. The ratio of 200 indicates that cells can turn on ASS expression and become resistant. The ratio of 10 is indicative of no response to ADI-PEG20. At the ratio of 200, the IH is negative. Conclusions: ADI-PEG20 is an active drug for advanced melanoma and generally well tolerated. Response/relapse are governed by ASS expression. RRT-PCR appears to be more sensitive than IH for determining ASS expression. These results have clinical implication for selecting pts for clinical trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Polaris Inc. Polaris Inc. Polaris Inc.
Selective JAK inhibition proves efficacious in epithelial cancer models
Authors: K. Vaddi, E. Caulder, J. Li, X. Wen, L. Hall, J. Rodgers, A. Combs, R. C. Newton, S. Friedman, J. S. Fridman
Journal: Journal of Clinical Oncology (2008)

14592 Background: Signal transducers and activators of transcription (STATs) are a family of latent transcription factors that are aberrantly activated in a diverse spectrum of epithelial tumors. STATs can be activated through tyrosine phosyporylation by a number of kinases including Janus kinases (JAKs), Src, Abl, and EGFR. Phosphorylated STATs (pSTAT) contribute to oncogenesis by preventing apoptosis and stimulating proliferation and angiogenesis. With the evolution of novel targeted therapies, identification of the kinases responsible for STAT activation in cancer cells may help pinpoint sites of potential therapeutic intervention. Methods: A number of potent, selective, orally bioavailable JAK inhibitors were utilized to treat a series of human epithelial cancer cell lines and tumor xenografts derived from breast, head and neck, prostate, stomach, lung, and renal tumors. In doing so, the contribution of JAK signaling to STAT phosphorylation was investigated as were the sequela of such inhibition. Results: Selective JAK inhibition frequently reduced the basal and/or cytokine stimulated levels of phosphorylated STAT3/5 by > 90 %. Oral administration of JAK inhibitors was also sufficient to reduce phosphorylated STAT levels in tumor xenografts and impeded tumor growth, including tumor regression (e.g., BT-474 breast HER2+ breast cancer). Moreover, selective JAK inhibition dramatically improved the anti-tumor activities of various ancillary therapies including targeted and cytotoxic drugs. Conclusions: Aberrant STAT activation has been associated with epithelial cancers and contributes to oncogenesis. Here we utilized pharmacological tools to query the role of JAKs in STAT activation and demonstrated that selective JAK inhibition is sufficient to inhibit STAT phosphorylation in cell lines and xenograft tumors from a spectrum of human cancers. Selective JAK inhibition impeded the growth of xenograft tumors and markedly improved the anti-tumor activity of standard chemotherapies and molecularly targeted agents. As such, selective JAK inhibitors may prove to have clinical utility for the treatment of a number of common cancers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Incyte Incyte
Evaluation of quality measures for breast cancer care in a community setting
Authors: L. L. Dietrich, R. Ballandby, J. Lee, D. Sullivan, M. A. Mathiason, J. Landercasper
Journal: Journal of Clinical Oncology (2007)

6545 Background: Compliance with National Initiative for Cancer Care Quality (NICCQ) quality indicators and National Comprehensive Cancer Network (NCCN) guidelines for breast cancer care are proposed measures of quality breast cancer care. Previously, we had determined NCCN guideline compliance rates for breast cancer care by physician review of electronic medical record (EMR). In the present study, we sought to compare NCCN guideline compliance and NICCQ adherence at our institution in regard to percent compliance, time taken to complete review, and comparison of physician reviewer (PR) versus non-physician reviewer (NPR). Methods: Review of the EMR was conducted for all 200 female patients who were newly diagnosed with breast cancer and treated at our multi-specialty institution in 2004. A PR and a NPR reviewed compliance with NICCQ quality indicators and NCCN guidelines for breast cancer care and time spent reviewing charts was recorded. Results: Adherence rate was less than 85% in only 7 of 36 NICCQ breast cancer quality measures for PR and only 6 of 36 for NPR. Patients overall received 91.5 % of NICCQ recommended care according to PR and 89.8% according to NPR. NICCQ measures were divided into categories to correspond with NCCN guideline categories and results are compared and summarized in the table below. Differences in observed compliance rates between PR and NPR were not significant for NCCN (except in pre-op workup where NPR was more accurate) or overall NICCQ audit, however differences were seen in individual NICCQ items with small numbers of patients. Average time for review of charts for NCCN guideline compliance vs. NICCQ adherence was not significantly different (6.8 vs. 6.3 minutes for PR and 8.3 vs. 8.9 minutes for the NPR). Conclusions: Our adherence rates for NICCQ and NCCN measures compare favorably with published values. Despite both being proposed quality measures, comparison of adherence rates for the two systems varied. PR is slightly faster than NPR but offset by PR's time value. A NPR performs as well, if not better, than a PR. No significant financial relationships to disclose. [Table: see text]
Immunotherapeutic role of mutant ras peptide-based vaccine as an adjuvant in pancreatic and colorectal cancer
Authors: A. Toubaji, M. S. Achtar, V. E. Herrin, M. Provenzano, S. Bernstein, T. Brent-Steel, F. Marincola, S. N. Khleif
Journal: Journal of Clinical Oncology (2005)

2573 Background: The ras oncogene is one of the best characterized oncogenes in human cancers; it is frequently mutated by a single amino acid substitution of codon 12. Those mutations are prevalent in many types of cancer including pancreatic adenocarcinoma (∼90%), colorectal adenocarcinoma (∼50%), and are associated with the malignant transformation and production of proteins that are unique for cancer cells. Methods: in a previous phase I study we concluded that a dose up to 5000 micrograms of peptide reflecting the patient mutant ras was well tolerated. Same dose was used in this phase II clinical trial were 12 cancer patients (5 fully resected pancreatic and 7 Dukes C or D colorectal) were vaccinated subcutaneously with the 13 mer mutant ras peptide, corresponding to their tumor’s ras mutation, admixed with DETOXTM adjuvant. Vaccinations are given every four weeks, up to total six cycles. Results: We didn’t see any serious systemic side effects and no delayed toxicities have occurred to date. We detected specific immune response to the relevant mutant ras peptide by measuring IFN-gamma mRNA expression by Quantitative real-time PCR. Five out of eleven patients showed a 1.5 folds or more increase in IFN-gamma copies accumulation in PBMCs after 3 cycles of vaccination. Furthermore, the 5 pancreatic cancer patients have shown a mean Disease-Free Survival (DFS) of 35.2+ months and a mean Post-Vaccination Survival (PVS) of 44.4+ months. The 7 colorectal patients have shown a mean Disease-Free Survival (DFS) of 27.2+ months and a mean Post-Vaccination Survival of 41.5+ months. Conclusions: mutant ras is an attractive target for vaccine therapy of cancer patients who carry the ras mutation in their cancer and it warrants further investigations No significant financial relationships to disclose.
Plasma heparanase as a significant marker of treatment response in pediatric malignancies: Pilot study
Authors: M. W. Ben Arush, I. Shafat, A. Ben Barak, S. Postovsky, R. Elhasid, I. Vlodavsky, N. Ilan
Journal: Journal of Clinical Oncology (2007)

9540 Introduction: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. Patients and Methods: Heparanase plasma levels of 45 consecutive pediatric patients (pts) with various types of cancer were assayed at diagnosis and at restaging. Mean age: 10.3 years (y) (0.5y-21y), 20 females, 25 males. Levels of heparanase were determined using a commercially available ELISA anti-human heparanase immunoassay kit. According to diagnosis, bone marrow aspiration, CAT scan, MRI, technetium bone scan, PET-CT fusion were performed to assess response to treatment after the first month of induction for leukemia patients, 2 to 3 courses of chemotherapy for other malignancies. Results: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1,539 pg/mL (range, 55 pg/mL-6,567 pg/mL) and decreased at restaging to 943 pg/mL (range, 0 pg/mL -3,682 pg/mL) (p=0.0133). At diagnosis, the average HP of the 37 patients in CR or VGPR was 1,692 pg/mL and at restaging decreased to 928 pg/mL (p=0.0071). At diagnosis, the average HP level for the 5 pts with TP or PR was 1,873 pg/mL and increased to 2,633 pg/mL at restaging (p=0.4223). Due to the small number of patients we did not observe any correlation with diagnosis or any other clinical prognostic factor. Conclusions: Changes in plasma heparanase levels correlated with response to treatment for all of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies. No significant financial relationships to disclose.
Abstract 19717: Cardiac Structural and Sarcomere Genes Associated with Cardiomyopathy Exhibit Marked Intolerance of Genetic Variation
Authors: Stephen Pan, Colleen A Caleshu, Kyla E Dunn, Marcia J Foti, Maura Moran, Oretunlewa Soyinka, Euan A Ashley
Journal: Circulation (2012)

Background - The clinical significance of variants in genes associated with inherited cardiomyopathies can be hard to determine as a result of uncertainty regarding population genetic variation and the recent finding of a surprising amount of tolerance in the genome even to loss of function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation. Methods and Results - We analyzed the rate of single nucleotide genetic variation in the coding regions of all known genes sequenced from the exomes of over 5,000 individuals from the National Heart, Lung, and Blood Institute’s Exome Sequencing Project (ESP), as well as the rates of structural variation from the Database of Genomic Variants (DGV). Most variants were rare, with over half being found in only one individual. Cardiomyopathy associated genes exhibited very low rates of variation. Nonsense variants in particular were extremely rare in these genes, appearing at a rate 96.1% lower than in other Mendelian disease genes, and 98.7% lower than genes without Mendelian disease association. We tested the utility of in-silico algorithms to predict variant pathogenicity using a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for disease causality compared with variants from the ESP data. Algorithms based on conservation at the nucleotide level (GERP, PhastCons) did not perform as well as amino acid level prediction algorithms (Polyphen-2, SIFT). Variants previously judged causal for disease were found in the ESP data at a prevalence higher than expected. Conclusion - Genes previously associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants previously held to be causal suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the ‘single gene’ causality model.
Combination therapy with alemtuzumab and pentostatin is effective and has acceptable toxicity in patients with T-lymphoid neoplasms
Authors: A. Aribi, H. Kantarjian, S. O'Brien, C. Koller, S. Verstovsek, S. Faderl, M. Keating, F. Ravandi-Kashani
Journal: Journal of Clinical Oncology (2007)

7037 Background: The development of effective therapeutic strategies for T-lymphoid neoplasms has been difficult partly due to the paucity of clinical trials. These neoplasms are generally refractory to traditional chemotherapy regimens. Alemtuzumab and pentostatin have response rates of 50% to 65% when used individually to treat various T-cell leukemias and lymphomas. However, most responses are partial and of limited duration. Methods: We have treated 20 patients (pts) with T-lymphoid malignancies (11 T-PLL, 1 ATL, 1 PTCL, 2 T- ALL, 3 γd-T cell hepatosplenic lymphoma, 2 T-LGL) with a combination of alemtuzumab 30 mg IV, 3 times weekly for up to 3 months and pentostatin 4 mg/m 2 weekly×4 followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics were administered during the treatment and for 2 months after its completion. Results: The median age of pts was 57 yrs (range, 22 –79 yrs), median WBC was 43.9×10 9 /L (range 0.6 –279.5 x10 9 /L), and median serum β2M was 4.1 mg/L (range, 1.7 –10.8 mg/L). Four pts had splenomegaly, and 6 lymphadenopathy. Thirteen had prior therapy (median 2). Twelve pts have responded (10 CR, 2 PR) for an overall response rate of 60% (including 8 of 11 T-PLL, 1 of 1 ATL, 0 of 2 T-ALL, 2 of 3γd-T cell hepatosplenic lymphoma, 0 of 1 PTCL and 1 of 2 T-LGL). Monoclonal T-cell receptor chain gene rearrangements were detected by PCR in 18 pts and became negative in 5 of 7 evaluable pts in CR. Median response duration has not been reached (range, 0 to 78 weeks). 3 pts have proceeded to allogeneic stem cell transplant, 4 (1 with ATL, 2 with T-PLL, and 1 with T-LGL) have died from disease progression after a response, and 8 were refractory to therapy. Opportunistic infections included reactivation of CMV in 7 pts, reactivation of HSV in 1 pt, recurrence of pre-existing Serratia pneumonia in 1 pt and Aspergillus pneumonia in 2 pts. Unexplained, marked and sustained pancytopenia occurred in 2 pts. Other toxicities were mainly grade 1 and 2 and included nausea, fever, edema, and shortness of breath. Conclusions: The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections including CMV reactivation are a concern, they may be minimized with adequate prophylactic antibiotic therapy. No significant financial relationships to disclose.
Treatment related changes of the serum epidermal growth factor receptor in advanced colorectal cancer
Authors: K. G. Spindler, D. Olsen, I. Brandslund, A. Jakobsen
Journal: Journal of Clinical Oncology (2009)

e22096 Background: The epidermal growth factor receptor (EGFR) is an established target for therapy in colorectal cancer. The extracellular domain of the receptor is shed into circulation and detectable by ELISA. We investigated the changes in sEGFR levels during preoperative chemoradiation (CRT) in rectal cancer patients and third-line treatment with cetuximab and irinotecan (CETIRI) in advanced disease, to elucidate the predictive or prognostic value in these settings. Methods: We included 126 healthy controls and 118 patients with chemorefractory mCRC treated with cetuximab (initial 400/m 2 mg followed by weekly 250mg/m 2 ) and irinotecan (350 mg/m 2 q3w). Response was evaluated according to RECIST. Furthermore, 114 patients with locally advanced rectal tumours were treated with CRT (60 Gy/30 fractions and concomitant uftoral (300 mg/m 2 )/leukovorin (22.5 mg) on treatment days, followed by surgery 8 weeks post-treatment and pathological tumour regression evaluation. Pre-treatment and consecutive samples were drawn at each visit. sEGFR was measured by ELISA. Median statistics and Kaplain-Mayer curves with log-rank testing for comparison of survival rates were performed. Results: There were significant differences between the median pre-treatment sEGFR levels in controls, rectal cancer and mCRC (58 ng/ml(56–59 95% C-I), 53 ng/ml(51–55 95% C-I) and 51 ng/ml(49–53 95% C-I), respectively, p&lt;0.000). We detected a rapid increase in sEGFR by the first on- treatment values during CETIRI (p&lt;0.001), and a correlation between the magnitude of increase and a higher degree of skin toxicity, a well known indicator of clinical benefit to EGFR inhibitors. sEGFR in rectal cancer patients displayed a decreasing tendency during CRT (p&lt;0.001), but no correlation to local tumour response. Patients with baseline pre-treatment level &gt; 43.4 ng/ml (mean sEGFR of control group-2xSD) had a significantly higher OS rate than patients with low baseline levels (93% and 59% respectively, HR 0.15, P=0.002). Conclusions: We report a rapid increase in sEGFR by the onset of CETIRI, which may indicate development of skin toxicity and thereby a better change of response. Furthermore, we suggest a potential prognostic value of sEGFR measurement during CRT in locally advanced rectal cancer. No significant financial relationships to disclose.
Six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III (Dukes' C) colon cancer: Initial safety report for the open-label randomized phase III study (JFMC37-0801).
Authors: Katsuyuki Kunieda, Sotaro Sadahiro, Hideyuki Mishima, Chikuma Hamada, Shigetoyo Saji, Junichi Sakamoto, Toshihiko Sato, Takashi Hirai, Atsuyuki Maeda, Kazuhiro Yoshida, Hiroki Akamatsu, Masayuki Ohue, Naohiro Ohta, Yusuke Kinugasa, Shoichi Fujii, Junichi Hasegawa, Koji Tamagawa, Shigeki Yamaguchi, Naohiro Tomita
Journal: Journal of Clinical Oncology (2012)

3607 Background: The standard treatment duration of adjuvant chemotherapy (CT) in patients (pts) with stage III colon cancer is 6 months. On the other hand, no clinical trial showed the optimal treatment duration of oral chemotherapeutic agents in adjuvant setting for colon cancer. Sargent et al have reported that 83% of recurrences in stage II and III pts have occurred within the first 3 years after surgery and peak was observed around one year after surgery. Therefore, to clarify the benefit of 12 months administration of Capecitabine, we designed randomized phase III trial for a comparison of 6 months treatment and 12 months treatment of capecitabine as adjuvant CT for stage III colon cancer. Methods: JFMC37 is a multicenter, randomized Phase III trial. Patients with fully resected Stage III colon or recto sigmoid cancer were eligible. Capecitabine was administered orally as tablets, 2,500 mg/m²/day for 14 days followed by a 7-days rest. Treatment is continued to 8 cycles (6 months) in arm A (A) or 16 cycles (12 months) in arm B (B). Patients were randomized 1:1 to A or B. Data size was estimated by disease free survival as primary endpoint. The statistical design is based on superiority hypothesis; 5-yrs DFS is 60% in arm A, 67% in arm B ;unilateral α=0.05, 1-β=0.8;and planed accrual is 1200 pts. Results: Between September 2008 to December 2009, 1304 patients were enrolled and then randomized. Both arms were well balanced for mean age: (A) 64.1, (B) 63.8; ECOG PS (%0/1): (A) 95.0/5.0, (B) 97.1/2.9; involvement of lymph nodes (%N0/N1/N2): (A) 77.1/19.9/3.1, (B) 76.6/19.7/3.7. Treatment completion rate for A and B were 68.2% and 43.4%. Incidences of serious adverse events (SAEs) over 1% were neutropenia: (A) 2.6%, (B) 3.8%, diarrhea: (A) 2.9%, (B) 2.1%, loss of appetite: (A) 1.3%, (B) 1.0%, fatigue: (A) 1.8%, (B) 1.2%, hand-hoot syndrome: (A) 16.4%, (B) 22.1%. Conclusions: There were no obvious differences in SAEs between arm A and arm B. Although twelve months of capecitabine showed a tendency to increase G3/4 hand-foot syndrome, we concluded that incidence of SAEs were acceptable and comparable to previously report.