tbuckley/cabot-search huggingface dataset:
A phase I study of combretastatin A4 phosphate (CA4P) and bevacizumab in subjects with advanced solid tumors
Authors: P. D. Nathan, I. Judson, A. Padhani, A. Harris, C. P. Carden, J. Smythe, D. Collins, M. Leach, P. Walicke, G. J. Rustin
Journal: Journal of Clinical Oncology (2008)

3550 Background: The vascular disruptive agent (VDA) CA4P induces significant tumor necrosis as a single agent. Vascular shut down is reversible and tumors can re-grow due to vascularisation of the surviving tumor rim. Pre-clinical models have demonstrated that the addition of an anti-VEGF antibody to a VDA significantly increases anti-tumor activity. Methods: Patients with advanced solid malignancies received CA4P at 45mg/m2 (cohort 1), 54mg/m2 (cohort 2) or 63mg/m2 (cohort 3) every 14 days followed by bevacizumab 10mg/kg 4 hours later. Functional imaging with DCE-MRI was performed at baseline, after CA4P alone and after cycle 1 CA4P + bevacizumab. Results: 63mg/m2 CA4P + 10mg/kg bevacizumab q14 is the recommended phase II dose. Two grade 3/4 dose limiting toxicities possibly related to study medication were seen. One patient developed transient self-limiting asymptomatc atrial fibrillation after 54mg/m2 CA4P and was withdrawn from study. A patient with metastatic angiosarcoma and a history of haemorrhage experienced grade 3 haemorrhage 2 weeks post treatment. Most common grade 1/2 toxicities were headache, hypertension, pruritis, and pyrexia. Asymptomatic transient self-limiting ECG changes were seen in 3 patients with no evidence of myocardial damage. No partial responses were seen. 9/14 patients experienced disease stabilization for > 12 weeks. 3 patients experienced disease stabilization for > 24 weeks with 2 of these on- going at 47 and 29 weeks respectively at time of data cutoff. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34+ and CD133+ bone marrow progenitors increased following CA4P as did VEGF and GCSF levels. Conclusion: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule with early evidence of clinical activity. CA4P induced profound vascular changes which were maintained by the presence of bevacizumab. CA4P induced an acute rise in circulating bone marrow progenitors which may in part be mediated by GCSF and VEGF release. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oxigene Inc Oxigene Inc Oxigene Inc Oxigene Inc Oxigene Inc
A Gynecologic Oncology Group study of associations between polymorphisms in <i>ABC</i> transporter genes (<i>ABCB1</i>, <i>ABCC2</i>, and <i>ABCG2</i>) and outcome in advanced stage epithelial ovarian cancer treated with platinum and taxane chemotherapy
Authors: K. M. Darcy, C. Tian, C. B. Ambrosone, T. C. Krivak, D. K. Armstrong, M. A. Bookman, W. Davis, H. Zhao, K. Moysich, J. A. DeLoia
Journal: Journal of Clinical Oncology (2009)

5567 Background: This study evaluated the relationship between known functional variants in three ATP-binding cassette (ABC) transporter genes (ABCB1 [MDR1], ABCC2 [MRP2], and ABCG2 [BCRP]) and clinical outcomes in epithelial ovarian cancer (EOC). These genes induce resistance to multiple anticancer drugs and some polymorphisms appear to affect expression, stability or activity of these transporters. Methods: Genotypes for common polymorphisms in ABCB1 (G2677T/A, A893S/T -RS2032582 and C3435T, synonymous-RS1045642), ABCC2 (G1249A, V417I-RS2273697), and ABCG2 (C421A, Q141K-RS2231138) were determined in normal blood DNA from 385 women with optimal stage III ECO who participated in a randomized phase III trial (GOG 172 or 182) and were treated with intravenous or intraperitoneal platinum+paclitaxel. Associations between polymorphisms and progression-free survival (PFS) and overall survival (OS) were examined using logrank test and adjusted Cox regression analysis. Results: The genotype distribution for the C421A polymorphism in ABCG2 was 80.7%, 18.5% and 0.8% for CC, CA and AA, respectively. Median time to disease progression or death for the CA+AA versus (vs.) CC genotype in ABCG2 was 30.3 vs. 18.1 months (p = 0.023), or 69.8 vs. 51.6 months (p = 0.172), respectively. After adjusting for clinical covariates, women with the CA+AA vs. CC genotype in ABCG2 had a significant reduction in the risk of disease progression (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.49–0.91, p = 0.01) but not death (HR = 0.77, 95% CI = 0.56–1.08, p = 0.125). The results were consistent across treatments. Adjusted Cox modeling demonstrated that polymorphisms in ABCB1 (G2677T/A or C3435T) and ABCC2 (G1249A) were not associated with PFS or OS. Conclusions: The ABCG2 C421A polymorphism, but not the ABCB1 G2677T/A, ABCB1 C3435T, or ABCC2 G1249A polymorphism, appears to be an independent prognostic factor for disease progression in optimal stage III EOC treated with platinum + paclitaxel therapy. No significant financial relationships to disclose.
Abstract 18536: Camkii-{delta} Splice Variants Exert Differential Effects on Heart Failure Development and Myocardial Ischemia / Reperfusion Injury
Authors: B. Daan Westenbrink, Charlie B Gray, Sunny Xiang, Shika Mishra, Jan Shilling, Hemal Patel, Joan H. Brown
Journal: Circulation (2012)

Background: Ca2+/calmodulin-dependent kinase II-δ (CaMKII-δ) has been implicated in heart failure development and ischemia / reperfusion injury. It has been suggested that the most abundant cardiac...
Autologous stem cell transplantation (ASCT) as consolidation therapy for patients with low-intermediate (LI) risk diffuse large B-cell lymphoma (DLBCL) and overexpression of bcl2 protein. Results of the first interim analysis of the GELA trial LNH98-B2
Authors: P. Morel, N. Mounier, J. Brière, C. Ferme, B. Coiffier, H. Tilly, P. Gaulard, P. Lederlin, F. Reyes, C. Gisselbrecht
Journal: Journal of Clinical Oncology (2004)

6505 Background: The anti-apoptotic protein bcl2 expression is associated with treatment failure in elderly patients (pts) with DLBCL (Blood 101:4279,2003). The ACVBP regimen with conventional consolidation therapy (JCO 18:3025,2000) yield a 2-year (yr) EFS at 71% in DLBCL pts aged 60 yrs or less with only 1 adverse age-adjusted International-Prognostic-Index factor (LI risk pts). To assess if ASCT reduces treatment failure in these pts, we initiated a trial stratified by bcl2 expression. Methods: Centralized staining for bcl2 was prospectively performed within 6 weeks after inclusion. Induction regimen consisted of 4 courses of ACVBP given every 2 weeks. In case of response, bcl2 negative pts received the conventional consolidation regimen, whereas bcl2 positive pts underwent peripheral blood stem cell collection after the 4th cycle, and ASCT (mitoxantrone 45 mg/m2, cyclophosphamide 1.5 g/m2 x 4d, etoposide 250 mg/m2 x 4d and carmustine 300 mg/m2) between d80 and d90. Results: From 1999 to 2002, 272 LI-risk pts aged 18 to 59 (median 46, M/F=1.4) presented with bcl2 overexpression (151) or without (121). There was no difference in initial characteristics, toxicity of induction and complete response (CR+CRu) rates between bcl2 positive and bcl2 negative pts (78% and 82%, respectively, p = 0.38). ASCT was not performed in 35 pts, mainly because of early failure (37%). Although bcl2 negative pts retained a better 2-yr survival than bcl2 positive pts (95% vs. 86%, p=0.01) with a median follow-up of 21 months, 2-yr EFS and 2-yr DFS did not differ significantly (84% vs. 79%, p=0.33, and 89% vs. 87%, p=0.94 respectively). Conclusions: This analysis demonstrates the feasibility of taking bcl2 expression into account for the design of multicentre protocol. The lack of difference in EFS and DFS between bcl2 positive pts who received ASCT and bcl2 negative pts treated with conventional consolidation suggested that ASCT may overcome the adverse prognostic value of bcl2 expression in LI-risk pts who achieve CR or CRu. No significant financial relationships to disclose.
Complement-Dependent Cytotoxic Antitumor Antibody. II. Quantitative Determination of Cell-Bound Immunoglobulin M
Authors: Michael D. P. Boyle, John J. Langone
Journal: JNCI Journal of the National Cancer Institute (1979)

A method for the quantitative determination of rabbit IgM bound to cell surfaces has been developed. This method was based on the ability of goat IgG specific for rabbit IgM heavy chains to bind 125I-labeled protein A when bound to the antigen. With the use of this technique the production of specific IgM antitumor antibodies in New Zealand White rabbits after immunization with guinea pig hepatoma cells line-1 and line-10 was followed. Differences in the production of IgM were observed between the different bleedings from rabbits immunized with line-1. No significant IgM antibody was produced following immunization of rabbits with line-10 tumor cells. This indirect method for determining IgM on the cell surfaces was objective, easy to perform, and detected complement-fixing and noncomplement-fixing antibodies. In addition, this technique could be applied to quantify other components on the cell surface for which a suitable specific antibody was available.
A study for establishment of individualized chemotherapy for colorectal cancer using the area under the concentration curve (AUC) based on the collagen gel droplet embedded culture-drug sensitivity test (CD-DST)
Authors: T. Ochiai, K. Nishimura, H. Noguchi, M. Kitajima, A. Tsukada, M. Watanabe, S. Futagawa, I. Nagaoka
Journal: Journal of Clinical Oncology (2006)

13560 Background: The drug sensitivity of tumor cells is one of the key issues to explore for individualized chemotherapy for cancer patients. We reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact duration. We also reported that growth inhibition rate (IR) and area under the concentration curve (AUC) approximated to logarithmic curve in ASCO 2003 (#1283). The aim of this study was to evaluate the individual 50% inhibitory AUC (AUC IR50 ) and research the usefulness of individual AUC IR50 for establishment of individualized chemotherapy. Methods: Surgical specimen was obtained from resectable 53 CRC patients without any preoperative chemotherapy during 2002 to 2005. CD-DST was performed under nine different conditions: concentration of 5-FU tested: 0.2, 1 and 10μg/ml; duration of exposure: 3, 24 and 120 hours. After converting drug concentration and contact time to AUC and plotting against growth IR, individual correlation between AUC and growth IR was evaluated. The histogram of individual AUC IR50 was also evaluated. Results: The curve between AUC and growth IR approximated to logarithmic curve in all of the patients (R 2 =0.69–0.96). We could calculate the individual AUC IR50 in all of the patients (AUC IR50 = 23.7–98796298.1μg*hr/ml). The histogram of the individual AUC IR50 (AUC IR50 &lt;2500μg*hr/ml) indicated CURT(X) pattern (SK=0.0076). Conclusions: We could obtain a position for each patient on the histogram of AUC IR50 . We could also indicate the potential for 5-FU sensitivity to each patient. Some patients demonstrating low 5-FU sensitivity could not be recommended for 5-FU based chemotherapy, and non-5-FU chemotherapy should be explored for them. This study demonstrated that the individual AUC IR50 is useful to distinguish the individualized chemotherapy of colorectal cancer patients. Utilization of CD-DST will facilitate establishment of individualized chemotherapy for colorectal cancer. No significant financial relationships to disclose.
Nipple areola skin-sparing mastectomy with TRAM flap reconstruction: Single-center study
Authors: H. Kim, E. Park, W. Lim, J. Sei, B. Koh, B. Son, S. Ahn
Journal: Journal of Clinical Oncology (2009)

632 Background: Cosmetic aspect of breast cancer treatment becomes important. The originally described technique of Skin sparing mastectomy (SSM) included the removal of gland, nipple areola complex (NAC), and biopsy scar. However, the risk of tumor involvement of NAC in patients with breast cancer has been overestimated. The purpose of this study is to evaluate the oncological safety and technical outcomes of nipple areola skin sparing mastectomy (NA-SSM) compared with SSM. Methods: This retrospective study includes 522 patients who underwent immediate breast reconstruction using pedicled transverse rectus abdominis musculocutaneous (TRAM) flap between July 2001 and December 2006. The indication of NA-SSM in this study was defined as being for any stage, any tumor size and any tumor areola distance. Briefly, NAC was preserved when palpation and the outlook of the nipple was normal. 364 patients underwent SSM with immediate TRAM flap reconstruction and 152 underwent NA-SSM with immediate TRAM flap reconstruction. We compared complication rate, local recurrence rate (LRR), disease-free survival (DFS), and overall survival (OS) Between NA-SSM and SSM with immediate TRAM reconstruction cases. Results: Median follow up of NA-SSM and SSM was 60 and 67 months respectively. Complete or partial nipple areola necrosis developed in 26 (17.1%; complete, partial 15). The 5 year DFS was 89% for NA SSM and 87.4% for SSM (log rank p = 0.20), The 5 year OS was 99.3% for NA SSM and 98.3 % (log rank p = 0.33) The local failure occurred in 3 (2%) of 152 underwent NA SSM, 3 (0.8%) of 364 patients underwent SSM (p = 0.27). There were 2 (1.3%) nipple areola recurrence. Cosmetic outcome of NA SSM was better than that of SSM in the majority of patients. Conclusions: Our study demonstrates that NA-SSM with immediate TRAM reconstruction is oncologically as safe as SSM with immediate TRAM reconstruction and provides a good cosmetic outcome. No significant financial relationships to disclose.
The Kinetic Of Bone Marrow Fibrosis Regression Predicts Outcome In Myelofibrosis Patients After Allogeneic SCT
Authors: Nicolaus Kröger, Haefaa Alchalby, Tatjana Zabelina, Hans-Michael Kvasnicka, Juergen Thiele, Guntram Büsche, Hans Kreipe
Journal: Blood (2013)
Phase I Evaluation of ISIS 3521, an Antisense Oligodeoxynucleotide to Protein Kinase C-Alpha, in Patients With Advanced Cancer
Authors: J. Nemunaitis, J. T. Holmlund, M. Kraynak, D. Richards, J. Bruce, N. Ognoskie, T. J. Kwoh, R. Geary, A. Dorr, D. Von Hoff, S. G. Eckhardt
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha. PATIENTS AND METHODS: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites. RESULTS: Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C max ), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C max , AUC, and elimination half-life. CONCLUSION: No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.
Preliminary results of a phase 2 study of ABT-751 in patients (pts) with taxane-refractory non-small cell lung carcinoma (NSCLC)
Authors: A. M. Mauer, L. Szeto, R. J. Belt, L. S. Schwartzberg, A. Hagey, A. I. Coates, K. A. Meek, P. Cernohous, G. B. Gordon
Journal: Journal of Clinical Oncology (2005)

7137 Background: ABT-751, an oral antimitotic agent that binds to the colchicine site of β-tubulin and prevents microtubule polymerization, has shown antitumor activity in various human xenograft models, including lung models. Methods: This multi-center, phase 2 study evaluated the safety and efficacy of ABT-751 in pts with stage IIIB/IV NSCLC refractory to taxane therapy (paclitaxel, docetaxel). Eligibility required ECOG performance status 0–2, no more than 2 prior chemotherapy regimens (including EGFR inhibitors). Pts received 200 mg ABT-751 orally once daily for 21 consecutive days followed by a 7-day break. Cycles were repeated until pts developed disease progression or toxicity. Tumor response was assessed every 2 cycles using RECIST. Time to progression (TTP) was analyzed using Kaplan-Meier methods. Results: Thirty-five pts have been enrolled and treated. Pt characteristics were: median age 65 (range 29–84); 43% female, 57% male; and 44% received 1, 48% received 2, and 11% received ≥ 3 prior chemotherapy regimens. The median duration of therapy was 2 cycles (range 1 - 12). The most commonly reported adverse events (AEs) were asthenia, constipation, anorexia, and nausea. Serious adverse events (SAEs) were reported in 5/24 (21%) pts. Five pts experienced Grade 3 or 4 AEs that were considered probably or possibly related to study drug [asthenia (3 events), constipation, neuropathy, and paresthesia]. The only SAE considered probably or possibly related to study drug was constipation. The median TTP was 1.9 months (95% CI = 1.8 - 4.1). One partial response was observed. One subject experienced a minor response (17% reduction in target lesions maintained through Cycle 10). 14 pts (40%) had stable disease and 17% continued therapy for 6 or more cycles including 3 pts ongoing beyond Cycle 10. Sufficient data are not yet available for estimation of overall survival. Conclusions: The observed antitumor activity in pts with taxane-refractory disease, including long term stabilization of disease, and the favorable safety profile of ABT-751 support further development of this drug for advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories
Hierarchical clustering analysis of tissue microarray immunostaining data identifies prognostically significant subsets of stage IIIA N2 non-small cell lung cancer patients. An Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 014)
Authors: F. Grossi, D. Bordo, R. Spizzo, C. Consiglieri, M. Aita, A. Morelli, S. Di Terlizzi, T. Ceschia, C. A. Beltrami, O. Belvedere
Journal: Journal of Clinical Oncology (2006)

10085 Background: Based on gene expression profiling, prognostically relevant cluster groups of patients have been recently identified for breast cancer, lung cancer, and lymphoma. The development of tissue microarray (TMA) technology provides methodology for the concomitant analysis of multiple proteins on large numbers of tumor samples. Methods: Here, we report the hierarchical clustering analysis of TMA immunostaining data from 87 patients with stage IIIA pN2 non-small cell lung cancer (NSCLC), treated with surgery alone between 1985 and 1997. A panel of 10 markers was tested by immunohistochemistry: EGFR, ErbB-2, c-kit, COX-2, survivin, bcl-2, cyclin D1, cyclin B1, MMP-2 and MMP-9. Univariate, multivariate analyses and unsupervised hierarchical clustering analysis by using these 10 markers were performed. Results: Bcl-2 (p&lt;0.0001) and cyclin D1 (p=0.0036) are more expressed in squamous cell carcinoma (SCC), while MMP-2 (p=0.0115), MMP-9 (p=0.0075) and survivin (p=0.02) show increased expression levels in other histological subtypes. In univariate analysis, only squamous cell histology, bcl-2 and cyclin D1 expression were favorable prognostic factors (p=0.0149, p=0.0013, p&lt;0.0001, respectively), while MMP-2 expression showed a significant correlation with poor outcome (p=0.013). In multivariate analysis, cyclin D1 and MMP-2 were the only positive and negative prognostic factors, respectively (p&lt;0.0001, p=0.06). Unsupervised hierarchical clustering analysis produced 5 distinct cluster groups and the deduced dendrogram identified 2 prognostically significant subsets of patients, with a median survival of 51 (groups 1–2) and 10 (groups 3–4-5) months, respectively (p&lt;0.0001). Notably, groups 1–2 were mostly composed of SCC (80%). Conclusions: This study suggests that hierarchical clustering of TMA immunostaining data by using a limited set of markers might provide a useful tool for the identification of radically resected NSCLC patients at high risk of recurrence, likely to benefit from more aggressive treatment. No significant financial relationships to disclose.
A phase I trial of surgical resection with biodegradable carmustine (BCNU) wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma
Authors: J. D. Rudnick, S. Phuphanich, R. Chu, M. Mazer, H. Wang, N. Serrano, M. Francisco, K. L. Black, C. Wheeler, J. Yu
Journal: Journal of Clinical Oncology (2009)

2033 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy. No significant financial relationships to disclose.