tbuckley/cabot-search huggingface dataset:
A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients (pts) with advanced HER2+ breast cancer (BC)
Authors: S. N. Holden, M. Beeram, I. E. Krop, H. A. Burris, M. Birkner, S. Girish, J. Tibbitts, S. G. Lutzker, S. Modi
Journal: Journal of Clinical Oncology (2008)

1029 Background: T-DM1 is a first-in-class HER2 antibody-drug conjugate (ADC) in development for HER2-positive BC, and is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20–100 times more potently than vincristine. T-DM1 binds to HER2 without inducing downregulation with affinity similar to T. T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts; principal preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. In a phase I study of T-DM1 given every 3 weeks, the MTD was 3.6 mg/kg, with DLT of gr 4 thrombocytopenia (TCP); tumor responses were seen at doses at or below MTD. The effect of more frequent dosing of T-DM1 on its exposure and safety profile is unknown. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV once weekly to pts with advanced HER2+BC who have progressed on a T- containing regimen. Dose levels for successive cohorts are escalated if DLT is observed in <1/3 of pts within 21 days of first study treatment according to a 3+3 evaluation scheme. Results: Seven pts (median age 53 (range 44–63); all PS 0–1); median number prior metastatic chemo regimens 2 (range 1–4) have received 72 doses of T-DM1 at 3 dose levels (1.2 mg/kg, 3 pts; 1.6 mg/kg, 3 pts; 2.0 mg/kg, 1 pt) on a weekly schedule. Related mild-moderate AEs include fatigue (grade [gr] 1, 3 pts; gr 2, 1 pt), TA elevations gr 2, 1 pt), and headache (gr 2; 1 pt). Related gr >2 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt). No cardiac-specific toxicity has been observed. No DLTs have been observed. Concentration-time profiles appear consistent with predictions based on allometric scaling. Four pts have had partial responses (none confirmed as of the data cutoff date). Conclusions: Related gr ≥2 AEs have been infrequent and manageable, and objective tumor responses observed, on a weekly schedule of T-DM1. Dose escalation will continue until an MTD is identified. A phase II trial of T-DM1 on a q3-week schedule in advanced HER2+ BC is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech, Inc. Genentech™ BioOncology Genentech, Inc. Genentech, Inc.
Anticoagulation and cardiac tamponade: Is there a relationship?
Authors: B. Faller, J. Zhang, J. Picus
Journal: Journal of Clinical Oncology (2008)

9562 Background: A pervasive belief exists in medicine that anticoagulation increases the risk of cardiac tamponade in patients with known pericardial effusions, especially when the effusion is malignancy-related (MR). To our knowledge, there are no published data examining such an association. Methods: A retrospective, case-control trial was conducted using data from the medical records of consecutive patients diagnosed with non-iatrogenic pericardial effusions at Barnes Jewish Hospital (BJH) from January, 1998 to April, 2006. Comparative analysis using chi-square test was performed to identify differences between patients diagnosed with tamponade (cases) and those without tamponade (controls). The rate of “anticoagulated” patients (defined as INR > 1.6, treatment with therapeutic dosing of a heparin product, or a platelet count < 50K cells/ mm3) served as the primary risk factor. Results: Data were analyzed from 125 patients with cardiac tamponade (53 [42.4%] MR), and 60 who had pericardial effusions and no evidence of tamponade (30 [50%] MR). Primary malignancies in the MR group by decreasing frequency included: lung cancer, 43 patients (51.8%); esophageal cancer, 8 patients [9.6%]; and non-hodgkin's lymphoma, 6 patients (7.2%). Only 3 patients (3.6%) had breast cancer. There was no significant difference between the tamponade and non-tamponade patients in the proportion of patients defined as “anticoagulated” (37/125 [29.6%] for tamponade patients vs. 18/60 [30%] for non-tamponade patients; p= 0.96). Analysis of MR patients alone revealed similar results (14/53 [26.4%] vs. 11/30 [36.6%] for tamponade and non-tamponade patients, respectively; p= 0.33). Additionally, no significant differences were found between the MR tamponade and non-tamponade patients in the presence of metastatic disease (34/52 [63.5%] vs. 20/27 [74.1%], p=0.43); mediastinal involvement of tumor (36/52 [69.2%] vs. 21/27 [77.8%], p=0.420; or prior thoracic radiation therapy (33/52 [63.5%] vs. 15/27 [55.5%], p=0.50). Conclusions: In this retrospective trial of patients with non-iatrogenic pericardial effusions at BJH, the proportion of patients with cardiac tamponade who were anticoagulated did not differ from patients without tamponade, regardless of the effusion's relation to malignancy. No significant financial relationships to disclose.
Addition of temozolomide to radiotherapy for treatment of newly diagnosed anaplastic gliomas
Authors: M. Simonelli, G. Banna, P. Navarria, A. Di Ieva, P. Zucali, F. De Vincenzo, P. Gaetani, R. Condorelli, R. Rodriguez y Baena, M. Scorsetti, A. Santoro
Journal: Journal of Clinical Oncology (2009)

e13037 Background: Anaplastic astrocytoma (AA), oligodendroglioma (AOD), and oligoastrocytoma (AOA) are rare tumors showing variable outcome due to their histological heterogeneity and different chemo- and radio-sensitivity. The presence of an oligodendroglial component is associated with LOH 1p/19 and a prolonged survival. Currently, the addition of chemotherapy to radiotherapy (RT) for newly diagnosed anaplastic gliomas is not sustained by available data. We evaluated the addition of temozolomide (TMZ) to radiotherapy for newly diagnosed anaplastic gliomas in terms of tolerability, progression-free survival (PFS), and overall survival (OS). Methods: Since September 2004, following initial surgery, patients (pts) with histologically confirmed anaplastic glioma, Karnofsky Performance Status (KPS) ≥40, adequate organ function, no prior chemotherapy, were treated with RT to limited fields once daily at 2 Gy per fraction, 5 days a week, for a total of 60 Gy with concomitant TMZ (75 mg/m 2 for 7 days a week) followed by 6 cycles of maintenance TMZ at 200 mg/m 2 on days 1–5 every 28 days. LOH 1p/19q was assessed by fluorescence in situ hybridization (FISH). Results: Twenty-eight pts were treated, 20 males, 8 females, median age 51 (range, 22–75), median KPS 90 (range, 40–100). Eleven pts had AOD (39%), 10 AA (36%), 6 AOA (21%), 1 pt gliosarcoma (4%). Nine pts (32%) underwent tumor complete resection, 10 partial resection (36%), and 9 (32%) tumor biopsy. In 1 patient with AOD RT and concomitant TMZ were interrupted at 44 Gy because of cerebral oedema, while in 1 patient with AA maintenance TMZ was suspended due to cumulative myelosuppression. Other severe toxicities included one spondilodiscitis, and a cutaneous G3 rush. Frequent mild toxicities were grade 1–2 nausea/vomiting (17 pts-63%), and grade 1–2 asthenia (8 pts-30%). With a median follow-up of 18 months (range, 4–53), median PFS, and 1-year PFS were 14.8 months and 72.6%, respectively; 1-year OS was 84.3%, median OS was not reached yet. Data on LOH 1p-19q available on 16 pts will be presented. Conclusions: The addition of temozolomide to radiation therapy for newly diagnosed anaplastic gliomas is well tolerated and seems active; efficacy needs confirmation in a randomized clinical trial. No significant financial relationships to disclose.
Increasing doses of cyclophosphamide suppress antigen-specific T helper-dependent immunity induced by a GM-CSF-secreting breast tumor vaccine
Authors: L. A. Emens, J. M. Asquith, J. M. Leatherman, M. M. Daphtary, S. Petrik, J. H. Fetting, M. L. Disis, S. Piantadosi, N. E. Davidson, E. M. Jaffee
Journal: Journal of Clinical Oncology (2008)

3009 Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines have shown promise, but their activity is limited by immune tolerance. We tested the hypothesis that integrating vaccination with cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine activity. Methods: We conducted a 3-by-3 factorial dose-ranging study of CY and DOX with an allogeneic, HER-2+ GM-CSF-secreting breast tumor vaccine in patients with stable metastatic breast cancer. CY was given at doses of 200, 250, and 350 mg/m2, and DOX at 15, 25, and 35 mg/m2. Subjects received three monthly immunizations, and a boost 6 to 8 months later. CY was given Day -1, vaccination Day 0, and DOX Day +7. Vaccine-induced HER-2-specific immunity was measured by delayed type hypersensitivity (DTH) to the HER-2-derived MHC Class II peptide epitopes p369 and p776. HER-2-specific antibody was measured by ELISA. Results: Twenty-seven individuals received at least 1 immunization with vaccine alone (6 subjects), or combined with low dose chemotherapy (21 subjects); 14 individuals received 4 vaccinations. Four of 6 subjects (66%) receiving vaccine alone developed HER-2-specific DTH, whereas 4 of 7 (57%) subjects receiving it with 200 mg/m2 CY developed a post- vaccination DTH (p=0.587, 1-sided Fisher’s exact test). However, higher doses of CY (250 or 350 mg/m2) one day before vaccination completely suppressed vaccine-induced DTH compared to vaccine alone or with 200 mg/m2 CY (p=0.007). Significant HER-2-specific humoral immunity developed in 3 of 5 (60%) evaluated subjects who received vaccine with 200 mg/m2 CY, but only 1 subject receiving higher CY doses. DOX did not impact the development of DTH or humoral immunity. Conclusions: Vaccination with an allogeneic, GM-CSF-secreting tumor vaccine with or without CY and DOX induced HER-2-specific DTH in patients with metastatic breast cancer. CY at 200 mg/m2 was associated with the development of humoral immunity. Doses of CY higher than 200 mg/m2 suppressed vaccine-induced HER-2-specific DTH, whereas DOX had no influence. Further investigation of the impact of chemotherapy on distinct measures of vaccine-induced antigen-specific immunity is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cell Genesys, Incorporated
Mechanisms of E. Coli mediated lysis of cancer cells
Authors: M. L. Levitt, D. Morvinski, S. Zeligson, Y. Freudentahal, A. Karpetian, G. Tenne, N. Amariglio, G. Tenne, G. Rechavi
Journal: Journal of Clinical Oncology (2005)

9599 Background: We have previously reported (Proc ASCO 21:2325 [2002]) a new test for the detection of cancer based on the capability of colonic E. Coli and Enterococci obtained from patients with and without a diagnosis of cancer to differentially lyse cultured EMI-1000 cancer cells. In order to explain the biologic basis of this phenomenon and to develop a high-throughput screening test for cancer a number of investigations have been performed. Methods: Frozen stocks of E.Coli originally obtained from clinical trials performed at the Sheba Medical Center were inoculated into liquid media, expanded and plated on selective solid media. Individual colonies were selected and and co-incubated with with EMI-1000 cancer cell cultures. Cell count and viability were determined by fluorescence activated cell sorter (FACS) analysis. E.Coli serotyping was performed by the Ministry of Health serotyping facility. The E. Coli Gene Array gene chip (Affymetrix) was used for the differential genomics study. Sequence information for probes on the array correspond to the M49 version of the E. Coli Genome Project database at the University of Wisconsin. Results: Our new FACS-based assay for lysis determination demonstrated, based upon analysis of cell viability, that E. Coli from patients with a diagnosis of cancer were more likely to cause lysis of EMI-1000 cells than those without a diagnosis of cancer. We did not find a correlation between lysis of EMI-1000 cells and E. Coli serotype; in fact, different colonies of a single specific serotype could be either lytic or non-lytic. In addition, patients usually had multiple serotypes and the overall lytic capability in our current bioassay may thus be dependent upon the relative abundance of lytic strains. We have begun a comparative genomics pilot study to attempt to identify the gene(s) responsible for lysis. Using the Affymetrix algorithm MAS5, 128 probe sets have a t-test p-value less than 0.05, 87 upregulated and 41 downregulated in lytic relative to non-lytic samples. Conclusions: The differential lytic capability of colonic E. Coli is not related to standard serotype. Updated results from the comparative genomic study will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Era-Massis Era-Massis
Abstract 8993: Protective Effects of Glucagon-like Peptide-1 on Cardiac Microvessels Injury via cAMP/PKA/Rho Dependent Pathway in Diabetic Rats
Authors: Dongjuan Wang, Peng Luo, Haichang Wang, Nan Liu, Feng Cao
Journal: Circulation (2012)

Introduction: Impaired cardiac microvascular function contributes greatly to diabetes cardiovascular disease. Glucagon-like peptide-1 (GLP-1) was found to have multiple cardioprotective effects besides its glucose lowering properties. Hypothesis: To investigate the protective effects of GLP-1 on cardiac microvessels injury and the underlying mechanism in diabetic rats. Methods: STZ-induced diabetic rats were randomized to 12 weeks of treatment with vehicle, LAF237 or Exenatide. Cardiac function and energetics was examined by echocardiography and 18 F-FDG PET respectively. Lanthanum nitrate perfusion was applied to assess cardiac microvascular barrier function. Cardiac microvascular endothelial cells (CMECs) were cultured in medium alone or medium containing high glucose, GLP-1, high glucose plus GLP-1. Lucigenin-enhanced chemiluminescence assay and DHE staining were used to assess ROS production. The expression of Rho, ROCK, p47 phox and gp91 phox was examined by Western blot. Results: LAF237 or Exetinade treatment improved cardiac function and energetics as well as microvascular barrier function significantly compared with vehicle groups. Compared with vehicle groups, ROS production was markedly decreased in GLP-1 groups. There were also significant reductions in p47 phox and gp91 phox expression. The cAMP/PKA activity was increased and the Rho expression was decreased in high glucose-induced CMECs after treatment with GLP-1, which reproduced the same effects as PKA inhibitor. Conclusions: GLP-1 could protect the cardiac microvessels against oxidative stress injury and the resultant microvascular barrier dysfunction in diabetic rats, which contribute to the improvement of cardiac function. The protective effects of GLP-1 are dependent on downstream inhibition of Rho, which is through cAMP/PKA pathway, resulting in subsequent decreased production of NADPH oxidase.
Ramsete: A Single-Arm, Multicenter, Single-Stage Phase II Trial of Rad001 (EVEROLIMUS) in Advanced and Metastatic Silent Neuro-Endocrine Tumours in Europe: Analysis by Tumor Origin
Authors: M. Pavel, B. Wiedenmann, J. Capdevila, J.W. Valle, W.W. De Herder, C. Metzer, R. Salazar, D. Horsch, K. Oberg
Journal: Annals of Oncology (2012)
Results of a phase I study of fixed dose rate gemcitabine /irinotecan (FIGI)
Authors: T. Ryan, H. Hochster, J. Escalon, F. M. Muggia
Journal: Journal of Clinical Oncology (2004)

2112 Background: Based on the activity of combined gemcitabine (gem)/ irinotecan (irino), we performed a phase I/PK study using Fixed Dose Rate (FDR) Infusion gem. The primary objectives were DLT and RPTD of irino combined with FDR Infusion gem at 10mg/m2/min(FIGI). Secondary objectives included the evaluation of antitumor activity as well as the PK and pharmacodynamic interaction of this combination. Methods: Pts with advanced cancer, adequate organ function, and PS of 0–1 were eligible. Gem and irino were given on days 1 and 8 q21d according to the dose levels below. Gem was infused over the time noted. Pts were followed with weekly CBC's and CT scans q 2 cycles. Results: 17 pts with, med age 54 (34–67 yrs), and med 1 prior regimen were enrolled, including 6 pancreatic, 4 gastric/GEJ, 3 colorectal and 1 pt each with anal, cholangio, esophageal, and primary peritoneal carcinoma. All are evaluable for toxicity, 16 for response. 1 pt at DL4 is currently being treated. The MTD and RPTD have not yet been reached; however, many pts required dose reductions and delays. Pts were treated for a med of 6 cycles. Observed toxicity was gr 1–2 including fatigue, abd pain, muscleoskeletal pain, and nausea/vomiting. There were 12 episodes of gr3 and 2 gr4 non-heme toxicity. Gr 3/4 heme toxicities are listed below. DLT has not been observed with 2 deaths unrelated to protocol therapy. 6 pts have achieved a response; CR in 4 (2 gastric, 1 pancreatic and primary peritoneal cancer) and PR in 2 (G-E junction and pancreatic). 4 pts had stable disease. Conclusion: “FIGI” is a well-tolerated and effective regimen in pts with advanced GI malignancies. Gem by FDR infusion does not appear to substantially increase toxicity compared to “IrinoGem” (100mg/m2 & 1000mg/m2 over 30min). Although MTD has not been reached; a dose of Gem/Irino 900/90mg/m2 appears to be best tolerated in pre-treated pts. A phase II study to further evaluate the activity of this regimen in UGI cancer is planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly
Sites of recurrence in resected stage I non-small-cell lung cancer: a guide for future studies.
Authors: R Feld, L V Rubinstein, T H Weisenberger
Journal: Journal of Clinical Oncology (1984)

The Lung Cancer Study Group recently completed a double-blind adjuvant immunotherapy study, in which 473 patients with resected stage I non-small-cell lung cancer were randomized to either intrapleural BCG or placebo. The study showed no significant difference in time to first recurrence for the two treatment arms. The present report analyzes the distribution of the anatomic site of first relapse and relates this to TN staging, histology, and other appropriate risk factors. The overall rate of recurrence is significantly higher for increasing TN status and for nonsquamous as compared to squamous-cell type. However, the distribution of site of recurrence does not, in general, change with increasing TN status or with histology. Approximately 65% to 75% of the first recurrences involve distant sites, with the brain being by far the most common, regardless of TN staging or histology. The implications of this for planning future studies is discussed.
Clinical outcomes with high-dose image guided radiotherapy (IGRT) compared with non-IGRT for the treatment of clinically localized prostate cancer.
Authors: Michael J. Zelefsky, Marisa Kollmeier, Brett Wayne Cox, Xin Pei, Margie Hunt
Journal: Journal of Clinical Oncology (2012)

12 Background: To compare toxicity profiles and biochemical tumor control outcomes between patients treated with high-dose image-guided radiotherapy (IGRT) and high-dose intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer. Methods: 186 patients with prostate cancer were treated with IGRT to a dose of 86.4 Gy with daily correction of the target position based upon kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated with IMRT to the same prescription dose without, implanted fiducial markers in place (non-IGRT). In both groups the margins used for the prostate were the same. The median follow-up time was 2.8 years (range, 2-4 years). Results: A significant reduction in late urinary toxicity was observed for IGRT patients compared with the non-IGRT patients. The 3-year likelihood of urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p=0.02).Multivariate analysis identifying predictors for late urinary toxicity demonstrated that, in addition to the baseline IPSS, IGRT was associated with significantly less late urinary toxicity compared with non-IGRT. The incidence of late rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; p = 0.81). No differences in prostate-specific antigen relapse–free survival outcomes were observed for low- and intermediate-risk patients when treated with IGRT and non-IGRT. For high-risk patients a significant improvement was observed at 3-years for patients treated with IGRT compared with non-IGRT. Conclusions: IGRT is associated with a reduction in late urinary toxicity and improvement in biochemical tumor control after definitive high-dose external beam radiotherapy compared with high-dose IMRT. These data suggest that, for definitive radiotherapy, the placement of fiducial markers and daily tracking of target positioning should be the preferred mode of external beam radiotherapy delivery for the treatment of prostate cancer.
Predictive value of D-dimer and LDH levels in response to chemotherapy in metastatic colorectal cancer patients
Authors: O. Er, M. Inanc, M. Ozkan, G. G. Dogu, M. Dikilitas, A. Ozturk
Journal: Journal of Clinical Oncology (2007)

14568 Background: Hemostatic activation is known to occur in malignant diseases and this may be associated with tumor progression and angiogenesis. D-dimer levels are elevated in lung, uterine cervix, prostate and colorectal cancer patients. We aimed to evaluate the association and predictive value of LDH and D-Dimer levels with chemotherapy response in metastatic colorectal cancer (MCRC) patients. Patients and Methods: Twenty-five chemotherapy-naive MCRC patients were enrolled into this study. Plasma CEA, CA19–9, D-Dimer and LDH levels were measured before and after 3 cycles of capecitabine + oxaliplatin combination chemotherapy. The comparison between groups were done by Wilcoxon W and Mann-Whitney U tests. Results: Median age was 58 years in 15 female, 10 male patients. All patients received Capecitabine 2,000 mg/m2/day orally on days 1- 14 + Oxaliplatin 130 mg/m2 intravenously on day 1 every 21 days. The chemotherapy response after 3 cycles of treatment were 2 complete response, 7 partial response, 8 stable disease and progressive disease in 8 patients. Plasma CEA, CA19–9, LDH and D-Dimer levels were not significantly different between two groups before chemotherapy (table). Plasma LDH and D-Dimer levels were significantly higher in progressive disease patients than patients with complete, partial or stable response after 3 cycles of chemotherapy, but plasma CEA and CA19–9 were not significantly different between these groups (table). Conclusion: We found that D-dimer and LDH levels dropped in responders while they increased in patients with disease progression. D- Dimer and LDH plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the clinical outcome of the disease. [Table: see text] No significant financial relationships to disclose.