tbuckley/cabot-search huggingface dataset:
Enzastaurin (ENZ) versus lomustine (CCNU) in the treatment of recurrent, intracranial glioblastoma multiforme (GBM): A phase III study
Authors: H. A. Fine, V. K. Puduvalli, M. C. Chamberlain, A. F. Carpentier, L. Cher, W. P. Mason, M. J. van den Bent, S. Hong, D. Thornton, W. Wick
Journal: Journal of Clinical Oncology (2008)

2005 Background: ENZ, an oral serine/threonine kinase inhibitor, targets PKC and AKT pathways to induce tumor cell apoptosis and suppress proliferation and angiogenesis. This phase III, multicenter, open-label study compared efficacy and safety of ENZ vs. CCNU in patients (pts) with recurrent, intracranial GBM (WHO grade IV). Methods: Pts were stratified by age, KPS, and disease recurrence, and randomized 2:1 to receive 6-week cycles of 500 mg ENZ daily (1,125-mg loading dose day 1) or CCNU (100–130 mg/m2 on day 1). Treatment continued until disease progression or occurence of unacceptable toxicity. Assuming a 45% improvement in PFS of ENZ over CCNU, 397 pts were to be enrolled to provide 80% power to achieve statistical significance at a one-sided level of 0.025. Enrollment was terminated at 266 pts after a planned interim analysis for futility. Results: Pt (N=266) characteristics were balanced between arms. Median PFS [HR=1.28 (0.97, 1.70)], OS [HR=1.2 (0.88, 1.65)] and 6 month PFS rate were not different between arms. As of 12/18/07, 3 pts are on ENZ therapy for ≥1 year. Pts with KPS 90–100 had significantly better PFS and OS with CCNU compared to ENZ. The incidence of adverse events (AEs) was similar in both arms; however, 62% in the CCNU arm were drug-related vs 44% in the ENZ arm. Four pts discontinued ENZ due to drug-related serious AEs (erysipelas, aortic thrombosis, cerebral hemorrhage, and convulsion). Eleven (7%) pts on ENZ died (4 due to AEs, 1 of which was drug-related). In the CCNU arm, all 4 (5%) deaths were disease-related. Grade (Gr) 3–4 hematological toxicities were significantly higher for CCNU (p ≤0.001). No anemia, neutropenia, or leukopenia occurred on ENZ, and only 1 pt had thrombocytopenia vs. 21 on CCNU. There were no significant differences in grade 3–4 nonhematological toxicities between arms. Conclusions: ENZ had a better toxicity profile but was not superior to CCNU in pts with recurrent GBM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company, Schering-Plough, MGI Pharma, Pfizer Eli Lilly and Company Eli Lilly and Company, Merck & Co., Pfizer, MGI Pharma, Schering-Plough Schering-Plough
CD44 as a prognostic and predictive marker for GBM.
Authors: B. D. Vaillant, K. Bhat, E. P. Sulman, V. Balasubramaniyan, S. Wang, K. D. Aldape, H. Colman
Journal: Journal of Clinical Oncology (2011)

2049 Background: While GBM has a poor prognosis overall, molecular subsets of tumors exist with differential outcome to initial treatment. Finding biomarkers of outcome would be beneficial prognostically and help understand resistance mechanisms. Previous GBM molecular subtyping demonstrated that the mesenchymal GBM subtype has worse prognosis compared to tumors with a proneural signature. CD44 is a cell surface marker associated with cancer stem cell populations and treatment resistance in other tumors. Methods: We performed expression profiling analyses of multiple GBM stem cell (GSC) lines derived from individual human tumors. GSCs were subjected to in vitro radiation (2Gy) and invasion assayed by matrigel assay. We analyzed 3 GBM gene expression datasets (TCGA, Rembrandt, Erasmus) for CD44 correlation with other genes and survival. We performed semi-quantitative immunohistochemistry for CD44 on a retrospective set of GBM tumors. Results: CD44 expression was significantly higher in GSCs with a mesenchymal expression pattern versus those GSCs with a proneural pattern. Mesenchymal GSCs also had significantly lower expression of CD133 and OLIG2, previously identified GSC markers, compared to proneural GSCs. Mesenchymal GSCs were more resistant than proneural GSCs to radiation, and also demonstrated increased invasion in matrigel. In the TCGA dataset, the highest CD44 expression quartile was associated with worse survival when compared to the lowest expression quartile (logrank test, p=0.02). All three GBM datasets demonstrated that high CD44 expression was associated with increased STAT3 and CEBP-β, which have been identified as master regulators of the mesenchymal signature (p<0.006 for all, Wilcoxon signed-rank test). We found that high CD44 expression by IHC was associated with significantly worse survival (n=63, p=0.04, Welch two-sample t-test), and worse radiographic response to initial radiation therapy (n= 50, p=0.0003, Pearson's Chi-squared test). Conclusions: Overall, these results indicate that CD44 is a marker of mesenchymal GSCs and the mesenchymal GBM subtype, is a biomarker of worse prognosis, and a predictor of radiation resistance in human GBM tumors.
CYP3A phenotype-based individualized dosing of irinotecan to reduce interindividual variability in pharmacokinetics and toxicity: Results from a randomized trial
Authors: J. M. van der Bol, R. H. Mathijssen, J. Verweij, A. S. Planting, G. M. Creemers, A. Sparreboom, F. A. de Jong
Journal: Journal of Clinical Oncology (2008)

2506 Background: Irinotecan, a prodrug of SN-38, is mainly metabolized by CYP3A. Based on the known relationship between midazolam clearance, a measure of CYP3A activity, and irinotecan disposition (Mathijssen et al, JNCI 2004), a randomized trial was performed comparing the pharmacokinetics and toxicity of irinotecan following conventional BSA-based dosing and dosing based on a formula derived from midazolam clearance, γGT, and height. Methods: Forty patients were randomized 1:1 to receive irinotecan at a dose of 350 mg/m2 (arm A) or at a dose based on the formula (arm B). UGT1A1*28 status, blood samples for pharmacokinetics, and toxicities were obtained during the first course. Pharmacokinetic parameters were calculated using WinNonLin. Results: Patient characteristics (22 males/18 females; median age, 58 years) were balanced between both arms, including the UGT1A1*28 status (p = 0.87). Doses ranged from 480–780 mg (mean 645) in arm A and 380–1,060 mg (mean 698) in arm B. The mean area under the curve (AUC) of irinotecan (22.4 vs 21.1 μg×h/mL) and SN-38 (0.57 vs 0.51 μg×h/mL) did not differ significantly between both arms (p> 0.44). Although the variability in dose was higher in arm B (10 vs 26%), the interindividual variability in AUC was reduced by 19% for irinotecan (31 vs 25%) and 26% for SN-38 (46 vs 34%). In addition, a lower interindividual variability in the nadir of the absolute neutrophil count (ANC) was found (80 vs 55%). Compared to arm A, the incidence of grade 3–4 neutropenia decreased by 75% (42 vs 11%; p= 0.03), which was unrelated to UGT1A1*28 genotype status (p > 0.79). Similarly, the incidence of grade 4 neutropenia was reduced (26 vs 5%). The incidence of grade 3–4 diarrhea was equal in both arms (11%). Conclusions: Individualization of irinotecan dosage based on CYP3A phenotyping results in a substantially reduced interindividual pharmacokinetic variability for irinotecan and SN-38. The variability in nadir ANC and the incidence of severe neutropenia decline as well. In combination with UGT1A1*28 genotyping approaches to predict the extent of SN-38 inactivation, CYP3A phenotype-determination should be explored further as a strategy to identify patients that are at risk for experiencing severe side effects. No significant financial relationships to disclose.
Inhibition of telomerase in ovarian cancer using siRNA technology
Authors: S. J. Tebes, N. C. Johnson, J. V. Fiorica, P. A. Kruk
Journal: Journal of Clinical Oncology (2005)

3182 Background: Clinically, platinum-resistance predicts a poor prognosis for ovarian cancer patients with second line chemotherapeutic agents having poor response rates. Methods to improve platinum sensitively might ultimately improve patients’ response to chemotherapy and long term survival. Telomerase adds telomeric repeats to chromosome ends. This process stabilizes chromosomal DNA and prevents apoptosis in malignant cells, including ovarian cancer. Since telomerase activity is not found in somatic cells, it is an attractive target for cancer therapy. By inhibiting telomerase in platinum-resistant ovarian cancer cell lines one increases the sensitivity to cisplatin. RNA interference offers a new mode for efficient and selective inhibition of specific gene expression in cancer. The current study addresses the feasibility of RNA interference for telomerase inhibition in ovarian cancer cell lines. Methods: We used siRNA (short-interfering RNA) designed to interact with the catalytic subunit of telomerase (hTERT) as well as a synthetic telomerase inhibitor 2’-O-MeRNA to establish optimal conditions for telomerase inhibition. Ovarian cancer cell lines sensitive to cisplatin and resistant daughter cell lines were transfected with siRNA or 2’O-MeRNA using lipofectamine, oligofectamine and electroporation. The reduction in telomerase activity was quantified using the telomerase polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA). Results: Telomerase inhibition using 2’O-MeRNA generally reduced telomerase activity in cisplatin-sensitive and resistant cells by 47–71% and 32–80%, respectively. In contrast, telomerase activity was optimally decreased by 99% in the platinum sensitive group and by 100% in the resistant group when transfected with siRNA using lipofectamine (p<0.01). Conclusion: Inhibitory RNA technology can be used to effectively decrease telomerase activity and potentially improve cisplatin sensitivity. This method of telomerase inhibition warrants further investigation to identify telomerase-dependent genes for therapeutic intervention. No significant financial relationships to disclose.
Randomized Trial of Adjuvant Therapy in Colon Carcinoma: 10-Year Results of NSABP Protocol C-01
Authors: R. E. Smith, L. Colangelo, H. S. Wieand, M. Begovic, N. Wolmark
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: The National Surgical Adjuvant Breast and Bowel Project C-01 trial reported in 1988 that, for patients with adenocarcinoma of the colon, compared with surgery alone, 1) postoperative chemotherapy with 1-(2-chloroethyl)-3-(4- trans -methylcyclohexyl)-1-nitrosourea (i.e., MeCCNU or semustine), vincristine, and 5-fluorouracil was associated with better 5-year disease-free and overall survival and 2) postoperative immunotherapy with bacillus Calmette-Guérin was associated with better 5-year overall, but not disease-free, survival. We now provide a 10-year update of this trial. Methods: Between November 11, 1977, and February 28, 1983, 1166 patients with resected Dukes' stage B and C adenocarcinoma of the colon were stratified by Dukes' stage, sex, and age (<65 years or ≥65 years) and then randomly assigned to receive no further treatment (surgery alone; 394 patients), adjuvant chemotherapy (379 patients), or adjuvant immunotherapy (393 patients). Those eligible for follow-up included 375 (95.2%) patients in the surgery-alone group, 349 (92.1%) patients in the adjuvant-chemotherapy group, and 372 (94.7%) patients in the adjuvant-immunotherapy group. All statistical tests were two-sided. Results: No difference was observed between patients in the chemotherapy group and those in the surgery-alone group in 10-year disease-free survival (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 0.94 to 1.39; P = .17) or overall survival (HR = 1.12, 95% CI = 0.91 to 1.38; P = .27). Immunotherapy did not appear to prevent tumor relapse after 10 years (for surgery alone versus immunotherapy, relative risk [RR] = 0.99, 95% CI = 0.78 to 1.25; P = .93) but had a beneficial effect on 10-year overall survival (for surgery alone versus immunotherapy, RR = 1.27, 95% CI = 1.03 to 1.56; P = .02) that apparently results from a reduction in deaths associated with comorbidities in the immunotherapy group. Conclusion: The disease-free and overall survival benefit associated with chemotherapy in this patient population is of limited duration, disappearing after 10 years.
The Queensland Lung Cancer Screening Study: risk stratification using participant data and lung function tests can significantly increase screening effectiveness
Authors: H. M. Marshall, R. Bowman, J. Crossin, M. A. Lau, R. E. Slaughter, J. Ayres, L. H. Passmore, E. M. McCaul, S. C. Leong, D. A. Courtney, M. N. Windsor, I. A. Yang, Zimmerman, P., V., T. J. Hayes, S. J. Redmond, S. C. Lam, M. C. Tammemagi, K. M. Fong
Journal: Journal of Thoracic Oncology (2012)
A randomized, double-blind, placebo-controlled phase II study of testosterone replacement in men with asymptomatic castrate-resistant prostate cancer (PC).
Authors: R. Z. Szmulewitz, E. M. Posadas, B. Manchen, W. M. Stadler
Journal: Journal of Clinical Oncology (2010)

TPS241 Background: Although androgen deprivation (ADT) is highly effective treatment for prostate cancer, eventual progression to a castrate-resistant state (CRPC) occurs in most patients (pts). CRPC has been characterized by increased androgen receptor (AR) expression, alterations in AR regulation, and other AR related mechanisms (Scher, JCO, 2005). Preclinical studies have shown that PC cell lines and tumor xenografts adapted to ADT are inhibited by re-administration of androgen, recapitulating the known growth inhibitory effects of testosterone on fetal prostate development (Chuu, Can Res, 2005; Joly-Pharaboz, J Ster Biochem Mol Bio, 2000). Phase I studies of testosterone replacement in men with asymptomatic CRPC have demonstrated the safety of this approach and suggest that disease stabilization may be observed in a subset of pts (Morris, Euro Uro, 2009; Szmulewitz, Euro Uro, 2009). Methods: The current study is a 1:1 randomized double-blind study of daily 1% testosterone gel (10g) versus matched placebo. Key selection criteria include progressive CRPC (progressive disease on radiographs or rising PSA, with testosterone <50 ng/dl, post anti-androgen withdrawal), baseline PSA ≥ 3 ng/ml and ≤30 ng/ml, PSA doubling time > 3 months, and lack of symptomatic metastatic disease (e.g. requiring analgesics or radiation). he primary endpoint of the study is to determine the effect of testosterone replacement on PC progression by radiographic assessment or PSA. Because of the known effect of testosterone on PSA secretion, PSA progression is arbitrarily defined as a 3-fold rise above nadir or an absolute value of > 50 ng/ml. The secondary objectives are to explore the value of AR expression in circulating tumor cells as a marker of treatment benefit and to determine the effect of testosterone administration on quality of life (FACT-P, FACT-fatigue, and Expanded Prostate Cancer Index) and grip strength. Planned accrual is 120 pts, which will provide 87% power to detect a hazard ratio of 1.75 on time to progression with a one sided t-test at 5% significance. Safety monitoring includes stopping rules for tumor flair and an interim analysis after the first 60 pts are enrolled. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Solvay Pharmaceuticals
Predictive factors and prognostic significance of tumor regression grade in rectal cancer.
Authors: Melody Xuan Lu Qu, Ravi Ramjeesingh, Oluwabunmi Ogundimu, Kevin Ren, David Hurlbut, James Joseph Biagi, Aamer Mahmud
Journal: Journal of Clinical Oncology (2015)

e14628 Background: Tumor regression grade (TRG) after neo-adjuvant chemo-radiotherapy (nCRT) for rectal cancer is described by multiple pathologic scoring systems. There is a lack of consensus in TRG assessment and data on clinical and pathologic factors predicting TRG. Methods: We undertook a retrospective chart review of 187 patients (pt) diagnosed with rectal cancer from 2005 to 2011, managed at our institution. Eligible patients were identified as clinical T3 or T4 and/or node positive adenocarcinoma completing nCRT. Assessment of TRG post-nCRT in 104 pt was determined using College of American Pathologists (CAP) and Modified Rectal Cancer Regression Grade (mRCRG) scoring systems. Logistic regression model was used to identify factors associated with TRG. Kaplan-Meier method, log-rank test and Cox proportional hazard model were used for survival analysis. Results: Median age of 102 eligible pts was 64.5 with 70% being male. Median pre nCRT tumor size was 4 cm. 61% tumors were distal. Radiation dose (RD) was >54 Gy in 58%, 50.4 Gy in 39%, and 45 Gy in 3% patients. Concomitant chemotherapy regimens included 5-Fluorouracil (71%), capecitabine (12%) and clinical trials (17%). Median follow-up was 5.0 years. Five year overall survival (OS) was 77% for CAP 0 and 1 vs. 59% for CAP 2 and 3 (p=0.042, HR2.8); mRCRG 1 and 2 OS was 75% vs 54% for mRCRG 3 (p= 0.014, HR2.6). 67% non-complete responders (CAP 1-3) had a significant cytoreduction post nCRT. Multivariate analysis showed age (<65 yr), higher RD and lower pre-op CEA were associated with favorable TRG (p=0.034, 0.042, and 0.076 respectively). Tumor size, location, grade, type of chemotherapy, or gender were not predictive of TRG. Pathology review of additional cases is ongoing. Conclusions: Favorable TRG post-nCRT is associated with a statistically significant OS advantage. Younger age and RD escalation are associated with favorable TRG. CAP and mRCRG scoring systems of TRG were comparable for prognosis. nCRT leads to a significant cytoreduction in 2/3rd of non-complete responders. 5-year OS based on tumor regression grade (TRG). CAP mRCRG TRG N (%) 5-yr OS N (%) 5-yr OS 0 20 (19.6) 77% n/a n/a 1 8 (7.8) 31 (30.4) 75% 2 19 (18.6) 59% 22 (21.6) 3 55 (53.9) 49 (48.0) 54% Log-rank p-value 0.042 0.014
A phase I study of nab-paclitaxel (nab-P) with carboplatin (C) and thoracic radiation (RT) in patients with locally advanced NSCLC.
Authors: V. L. Keedy, B. Lu, Y. Shyr, L. Horn, D. P. Carbone, A. Sandler, D. H. Johnson
Journal: Journal of Clinical Oncology (2010)

e17504 Background: One third of patients (pts) with NSCLC present with localized, unresectable disease. Concurrent chemoradiotherapy (e.g. weekly paclitaxel + C) is well established with median survival ≈14 mo. Nanoparticle albumin-bound (nab) paclitaxel is a cremophor-free formulation of paclitaxel designed to improve solubility and intratumor delivery of active drug. This phase I trial evaluates weekly nab-P + C + concurrent TRT in pts with unresectable stage III NSCLC. Methods: Pts entered escalating dose cohorts in a 3+3 design of nab- P weekly, beginning at 40 mg/m2 and increasing by 20 mg/m2, in combination with C (AUC 2) weekly for 7 weeks and concurrent RT 66Gy/33 fractions. Pts received 2 cycles of consolidation therapy with full dose nab-P (100 mg/m2 weekly for 3 weeks) and C (AUC 6 on day one of each cycle) every 21d. The DLT period is defined as the concurrent chemoradiation period. Results: Eight pts have been treated at 2 dose levels of nab-P, 40mg/m2 and 60mg/m2. One pt signed consent and then withdrew. Seven pts have completed all cycles of therapy. Three pts were treated at 40 mg/m2 with no DLT. Four pts were treated at 60 mg/m2 with 2 DLT of G3 radiation dermatitis and G3 esophagitis. The 40 mg/m2 cohort is expanded and 1 pt remains on concurrent treatment. Grade 2-3 toxicities during concurrent treatment include: neutropenia, neutropenic fever, anemia, thrombocytopenia, fatigue, esophagitis, nausea, dermatitis, hypoxia, and dehydration. No grade 4 toxicities have been seen during concurrent treatment. Seven pts are evaluable for response with 7 partial responses. Three patients have progressed 5, 7, and 8 mo after enrollment, and 4 patients remain stable 5, 7, 13, and 18 mo. Conclusions: Weekly nab-P at 60 mg/m2 exceeds the maximally tolerated dose, but appears to be safe and well tolerated at 40 mg/m2 when used in combination with weekly C and RT and enrollment in this cohort continues. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience Abraxis BioScience Abraxis BioScience
OBSERVATIONS ON THE EFFECT OF AN ANIMAL PROTEIN FACTOR CONCENTRATE ON PERSONS WITH THE MACROCYTIC ANEMIA OF PERNICIOUS ANEMIA, OF NUTRITIONAL MACROCYTIC ANEMIA AND OF SPRUE, AND ON PERSONS WITH NUTRITIONAL GLOSSITIS
Authors: TOM D. SPIES, GUILLERMO GARCIA LOPEZ, FERNANDO MILANES, ROBERT E. STONE, RUBEN LOPEZ TOCA, TOMAS ARAMBURU, SAM KARTUS
Journal: Blood (1949)
Construction of tissue micro array from prostate needle biopsies using vertical clustering re-arrangement technique
Authors: J. H. Pinthus, D. Daya, J. Srigley, G. Singh, N. Kleinmann, E. Fridman
Journal: Journal of Clinical Oncology (2008)

22205 Background: Prostate cancer is heterogenic with variable natural history. Biomarkers defining prognosis and response to therapy at diagnosis are needed. Studies using highly sensitive genome-wide micro array highlighted some potential markers. However, as biomarkers, the value of these candidates must be validated on the protein rather than the gene level, and their predictive value should be tested on prostate biopsy material taken at diagnosis before treatment. Tissue microarray (TMA) is useful for profiling protein expression in a large number of samples simultaneously avoiding observer bias, providing standards for quality control and the potential for high-throughput analysis. In contrast to the relatively large amount of material available from Radical Prostatectomy (RP), prostate needle biopsies contains only very limited amount of tumor arranged within a very thin tissue core that limits TMA construction. Methods: Archival prostate needle biopsies from 48 patients with variable Gleason scores (6–10) were used. The paraffin blocks were melted. Each core, typically measured 0.5 mm and 1.5cm (diameter and length), was sectioned into equal parts of 3–4 mm. For each case, a group of fragments was then re- embedded in a vertical orientation. Using the Beecher Instruments' Manual TMA Apparatus, 2mm cores from each of the vertically rearranged fragments were harvested. Lung, kidney and RP specimens were inserted to the TMA block as negative and positive internal controls. Sections (4μ) from the TMA block were stained with H&E and anti-HMWCK, PIN-cocktail, and PSA stains. Results: A TMA from prostate needle biopsies was constructed. In all patients the same tumor and neighboring tissue (like HGPIN) morphology was evident with identical Gleason score. All tumors preserved their IHC phenotype and there was no loss of tissue. 50 serial sections of 4μ were performed with remaining capacity of 30. Conclusions: The Vertical Clustering Re-arrangement (VCR) technique developed by us is suitable for large scale construction of TMA blocks from prostate biopsies maintaining the morphological and imunohistochemical characteristics of the original samples. This method is promising both in terms of archival tissue preservation and biomarkers research. No significant financial relationships to disclose.
Human liver-derived leucocytes express FasL and immunomodulatory cytokines and induce apoptosis of activated allogeneic T cells
Authors: J. R. Jonsson, C. J. Edwards-Smith, P. G. Hogan, Y. Morotomi, A. D. Clouston, S. V. Lynch, R. W. Strong, E. E. Powell
Journal: Hepatology (1998)