tbuckley/cabot-search huggingface dataset:
Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients.
Authors: R F Ozols, R E Cunnion, R W Klecker, T C Hamilton, Y Ostchega, J E Parrillo, R C Young
Journal: Journal of Clinical Oncology (1987)

Eight patients with refractory ovarian cancer were treated on a pilot protocol of verapamil plus Adriamycin (Adria Laboratories, Columbus, OH). This trial was based on our previous laboratory studies which demonstrated that Adriamycin resistance in human ovarian cancer cell lines could be partially reversed by exposure of the cells to high concentrations of verapamil (3,000 ng/mL). Patients were treated in an intensive care unit with continuous cardiovascular monitoring. The dose of verapamil was escalated in each patient until hypotension or heart block developed, and this dose was maintained for 72 hours. Adriamycin (50 mg/m2) was infused over 24 hours during the second day of the verapamil infusion and verapamil alone was administered on the third day in an effort to block efflux from drug-resistant cells. This intensive approach led to a median plasma verapamil level of 1,273 ng/mL (range, 720 to 2,767). However, the high infusion rates of verapamil (9 micrograms/kg/min) required to achieve these plasma levels produced an unacceptable degree of cardiac toxicity. Two patients developed transient atropine-responsive complete heart block and four patients developed transient congestive heart failure with increases in pulmonary capillary wedge pressure. There was no evidence that the noncardiac toxicities of Adriamycin were enhanced by verapamil. There were no objective responses to therapy. Future studies should use less cardiotoxic calcium channel blockers that can be safely administered to produce the plasma levels required for in vitro sensitization of drug resistant cells.
Quantitative Distribution of Virions in Virus-Induced Murine Leukemia&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Marvin A. Rich, Lewis W. Johns
Journal: JNCI Journal of the National Cancer Institute (1968)

Interpretation of studies on virions in the thymuses of leukemic mice has been complicated by morphologically similar virions in control mice. To determine the quantitative distribution and localization of leukemia virions in the thymuses of mice that would or would not develop leukemia, we examined the thymuses of 26 infected and control mice 1–4 days after inoculation of a murine leukemia virus (Rich). Large numbers of characteristic leukemia-like virions with similar localization and distribution were seen in both groups. At 70 days the thymuses of leukemic mice showed an increased number of virions in intercellular spaces. The virions proliferating and accumulating within the vacuoles of epithelial and lymphocytic cells were not significantly increased over those seen in normal controls. The larger number of virions in the thymuses of newborn control mice diminished in adult mice. The data suggest that the proliferation and accumulation of leukemia-like virions in the thymuses of newborn mice are not causally related to the subsequent proliferation of infectious virus and the development of leukemia that follows.
Interstitial fibrosis in radical prostatectomy specimen treated with neoadjuvant therapy and its relationship to biochemical outcome and castration-resistant status in high-risk prostate cancer.
Authors: Yasuhiro Hashimoto, Akiko Okamoto, Hayato Yamamoto, Atsushi Imai, Shingo Hatakeyama, Takahiro Yoneyama, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2014)

251 Background: Interstitial fibrosis (IF) have been known to occur in radical prostatectomy specimens treated with hormonal therapy. We previously reported that neoadjuvant therapy for high-risk prostate cancer (Pca) with luteinizing hormone-releasing hormone (LHRH) agonist and low-dose estramustine phosphate (EMP) (LHRH + EMP) significantly improved biochemical recurrence (BCR) free survival. In this study, we quantified IF in radical prostatectomy specimens treated with neoadjuvant LHRH + EMP, and we examined whether degree of IF has impact on BCR free survival or subsequent castration-resistant status. Methods: High-risk Pca was defined by the D’Amico stratification system. A total of 103 patients with high-risk Pca were enrolled in this study from July 2005 to August 2010. The LHRH + EMP therapy included the administration of the LHRH agonist and 280 mg/day of EMP for six months before the radical prostatectomy. BCR was defined as the prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after the prostatectomy. Castration-resistant prostate cancer (CRPC) is defined by PSA or radiographic progression in the castrate levels of testosterone (&lt; 50 ng/dL). A quantitative analysis of IF was performed using computer-assisted imaging. Results: The average patient age was 67.2 (49 to 78), and the median initial PSA level was 18.8 ng/mL (4.2–95.6). All patients completed six months of LHRH + EMP neoadjuvant therapy with no delays in the radical prostatectomy. At a median follow-up period of 64.0 months, BCR occurred in 41 patients (39.8%) and CRPC occurred in nine patients (8.7%). The average IF rate was 0.43 (0.33–0.55). The five year BCR-free survival rates for the groups with IF rates less than 0.42 and greater than 0.42 were 74.7% and 50.0%, respectively. The log-rank test was significantly different between the two groups (p = 0.010). We could not identify CRPC in the patients with IF rates less than 0.42. Conclusions: Although the present study was small and preliminary, the IF rate may have a predictive potential for biochemical outcome and the occurrence of CRPC after neoadjuvant therapy for high-risk Pca. Further study is warranted to elucidate its clinical significance.
Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study.
Authors: G Falkson, C Holcroft, R S Gelman, D C Tormey, J M Wolter, F J Cummings
Journal: Journal of Clinical Oncology (1995)

To investigate the long-term survival of premenopausal women with previously untreated first recurrence or metastases of breast cancer entered on Eastern Cooperative Oncology Group (ECOG) study 2177 (EST 2177), which completed accrual in June 1983.One hundred forty-seven premenopausal women with metastatic breast cancer were entered onto the study. Eighty-nine patients with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide (CTX), doxorubicin (ADR), and fluorouracil (FU) (CAF) or surgical oophorectomy plus CAF (O+CAF). Fifty-eight patients with known ER-negative disease were treated with CAF. Survival time was measured from the time of study entry. Randomization was stratified by performance status (PS), dominant metastatic site, and ER status.One hundred thirty patients were eligible. The median survival time of randomized patients was 35 months (90% confidence interval, 28.9 to 54.3), with 28% alive at 5 years. The overall median survival duration, including ER-negative patients, was 30 months. There was no significant difference in survival time between the randomized treatments (median, 42 months for O+CAF and 30 months for CAF). In models of survival time, age > or = 45 years and last menstruation within 1 month were associated with significantly longer survival (P < .004 for each). There were also three significant interactions with treatment (even after correction for multiple comparisons): age (P = .00009; O+CAF associated with longer survival in patients < 45 years, CAF associated with longer survival in patients > 45 years), PS (P = .002; O+CAF associated with consistently better survival in PS O patients), and disease-free interval (DFI).Long-term follow-up data of premenopausal women with metastatic breast cancer show a longer than expected median survival time at 2.5 years overall and close to 5 years for patients treated with O+CAF who were ER-positive or had a good PS.
Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528
Authors: C. J. Hoban, A. Hoering, T. W. Synold, V. Chung, D. R. Gandara, A. F. Schott, L. Kingsbury, D. Lew, P. M. LoRusso, S. M. Gadgeel
Journal: Journal of Clinical Oncology (2009)

3553 Background: Anti-tumor activity of Her inhibitors including lapatinib, an oral inhibitor of Her1 and Her 2, appears to correlate with their ability to down regulate PI3/Akt pathway. Everolimus, an oral inhibitor of mTOR, a serine/threonine kinase downstream of Akt, has shown enhanced efficacy when combined with Her inhibitors in pre-clinical studies. This phase I study is being conducted to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of the combination of lapatinib and everolimus. Methods: Pts with advanced tumors, for which there was no effective therapy, were eligible. The study consists of two parts. In Part I dose escalation to define MTD was performed with both drugs being given together. MTD was defined by dose limiting toxicities (DLT) in the first cycle (each cycle is of 4 weeks duration). In Part II, PK of both drugs are being analyzed in patients treated at MTD and randomized to either cohort A- everolimus alone for a week followed by both drugs, or cohort B- lapatinib alone for a week followed by both drugs. 12 PK eligible pts will be accrued to each cohort to detect the influence of one drug over the other drug's PK. Results: 26 pts were enrolled in Part I of the study, 23 were evaluable for DLT. Median age- 63 (29–76); males/females- 20/6. Common tumors were breast (4), lung cancer (3), adenoid cystic (3). 79 cycles (median 2, range 1–15) have been administered to date. 6 pts developed DLTs: pneumonitis, rash, diarrhea, stomatitis (2), and fatigue (2). The MTD of the combination is lapatinib 1250mg and everolimus 5mg, daily. None of the pts had a response but 11 pts (2 liver, 1 breast, 1 renal, 1 sarcoma, 2 adenoid cystic, 1 melanoma, 1 bladder, 1 NSCLC, 1 colorectal) had stable disease for 8 weeks or longer. Conclusions: The MTD of the combination is lapatinib 1250 mg and everolimus 5 mg. The dose limiting toxicities observed were diarrhea, stomatitis and fatigue. Accrual to Part II is ongoing and pharmacokinetic analysis is pending. [Table: see text] [Table: see text]
OP25 Bacterial translocation and regulatory T lymphocytes in patients with liver cirrhosis
Authors: M Márquez, M Montes de Oca, C Rodríguez-Ramos, C Fernández-Gutiérrez, M J Blanco, S P Corchado, J A Girón
Journal: Gut (2010)

Introduction  Increased prevalence of bacterial infectious diseases has been observed in cirrhotic patients, classically attributed to immunosuppression-associated liver cirrhosis. Conversely, advanced states of liver cirrhosis predispose to increased antigenic load. A possible role has been ascribed to the translocation of bacteria and endotoxins (lypopolysaccharide, LPS) from the gut. LPS increases the plasma levels of LPS-binding protein (LBP), the principal plasma protein responsible for transporting LPS to immune effector cells. High serum LBP has been proposed to identify a subset of cirrhotic patients with ascitis characterised by an activation of the immune cells to producer proinflammatory cytokines. Moreover, raised levels of circulating LBP or proinflammatory cytokines have been implicated in the endothelial activation and haemodynamic derangement observed in cirrhosis. A chronic antigenic stimulus will induce a monocyte and lymphocyte activation.  Aim  Intestinal permeability and bacterial translocation and their influence on T lymphocytes activation and differentiation in T reg were analysed in patients with compensated and decompensated liver cirrhosis. In particular, the regulation of T cell activation, mediated by co-stimulatory molecules, the expression of activation markers and the proportion of T CD4+ regulatory cells, as a function of bacterial translocation, were studied.  Method  40 patients with liver cirrhosis, 20 of them without previous decompensation (CC) and 20 with ascetic decompensation (DC), and 20 healthy controls (HC) were studied. Bacterial translocation was analysed by serum concentrations of lypopolysacharide-binding protein (LBP). Membrane expression of co-stimulatory molecules (CD28), activation markers (CD25 and CD122) and proportion of T regulatory cells (defined as those CD4+CD25highintracellular FoxP3+) were studied by flow cytometry with specific antibodies. Values of the variables were expressed as median (interquartile range). Comparisons between variables were made by the Mann–Whitney U test. Associations between variables were analysed by the Pearson9s correlation coefficient.  Results  Serum concentrations of LBP were significantly elevated in patients with compensated (7.7 (5.7–9.1 microg/ml) and decompensated (28.2 (10.7–40.6)) cirrhosis when compared with healthy controls (3.4 (2.7–4.2)) (p  Conclusion  Patients with liver cirrhosis, fundamentally those with previous decompensation, shows increased intestinal permeability and chronic systemic antigenic stimuli. As a response to those, T lymphocyte activation is detected. Probably as a mean to decrease the continuous antigenic stimuli, a diminution of co-stimulation and an expansion of suppressor populations are observed in them.
Epidermal growth factor receptor (EGFR)-activating mutations (mut) and response to gefitinib in lung adenocarcinoma
Authors: H. Cortes-Funes, C. Almanza, P. Valero, C. Garcia Giron, A. Velasco, R. Colomer, C. Camps, P. Diz, M. Taron, R. Rosell
Journal: Journal of Clinical Oncology (2005)

7076 Background: The potential relevance of EGFR mut to non-small-cell lung cancer (NSCLC) treatment has recently been identified. We have examined the presence of EGFR mut in Spanish chemoresistant gefitinib-treated NSCLC patients (p). Methods: A total of 83 p were selected on the basis of availability of tumor specimens. EGFR exons 19 and 21 were amplified from genomic DNA and automatic sequencing was performed. Results: EGFR somatic mut in the tyrosine kinase domain were found in 10 of 83 p (12%). 8 mut were deletions in or near E746-A750, 3 of which carried insertions. The 2 remaining mut were L858R. Mut were more frequently observed in women (70%), adenocarcinomas (90%) and non-smokers (60%). p had received a median of 2 prior chemotherapy regimens. Median follow-up was 5 months (m) (range, 4.7–28.2). Duration of gefitinib: p with mut, 8.5 m, p with wild-type (wt), 3.1 m (P<0.001). Response: p with mut, 80%; p with wt, 8.8% (P<0.001). Time to progression from the start of gefitinib: all p, 3.9 m; p with mut, 12.3 m (95%CI, 6.4–18.3); p with wt, 3.6 m (95%CI, 2.6–4.7) (P=0.002). Median survival: all p, 5.7 m; p with mut, 13 m (95%CI, 6.5–19.4); p with wt, 4.9 m (95%CI, 3.8–5.9) (P=0.02). The Cox model indicated a 3.7 times higher risk of progression for p with wt, even adjusted for covariates, including gender and number of prior chemotherapy lines (P=0.005). Relative risk of death was 3.1 times higher for p with wt (P=0.03). Conclusions: This first study of its kind in Spain confirms that the presence of EGFR mutations is a major determinant of gefitinib response. Based on these results, a clinical trial of first-line gefitinib in lung adenocarcinomas harboring EGFR mut will be performed. No significant financial relationships to disclose.
Insulin-like growth factor-I (IGF-1), IGF binding protein-3 (IGFBP-3), and outcome in metastatic colorectal cancer (CRC): Results from Intergroup Trial N9741
Authors: C. Fuchs, M. Pollak, D. J. Sargent, J. A. Meyerhardt, R. K. Ramanathan, S. Williamson, B. Findlay, E. Green, R. M. Goldberg
Journal: Journal of Clinical Oncology (2004)

3521 Background: IGF-1 has been shown to stimulate neoplastic cell growth and inhibit apoptosis, whereas IGFBP-3 inhibits the bioavailability of IGF-1 and has independent proapoptotic activity. In epidemiologic studies, higher levels of plasma IGF-1 increase the risk of CRC whereas higher levels of IGFBP-3 have been associated with decreased risk. Methods: We examined plasma levels of IGF-1, IGFBP-3, and C-peptide among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic CRC (Intergroup trial N9741). Three chemotherapy arms were evaluated in this multicenter study: 5-FU/leucovorin/CPT-11, 5-FU/leucovorin/oxaliplatin, and oxaliplatin/CPT-11. Data on prognostic factors and body size as well as plasma specimens were collected at baseline. Results: Controlling for IGF-1 levels, treatment arm, and other prognostic factors, increasing IGFBP-3 levels were associated with a higher response rate (RR) to chemotherapy (P = 0.01; RR = 51% vs. 34% comparing highest to lowest quartiles). Compared to subjects in the lowest quartile of IGFBP-3, the hazard ratio (HR) for tumor progression for those in the highest quartile was 0.71 (95% CI, 0.53–0.95) (median TTP = 302 vs. 218 days, comparing highest to lowest quartiles; P for trend = 0.003). Neither IGF-1 nor C-peptide were significantly related to RR or TTP after adjusting for other covariates. Moreover, there was no statistical interaction between IGFBP-3 levels and treatment assignment. In preliminary analyses, higher plasma IGFBP-3 was positively associated with overall survival with an over 6 month difference in median survival comparing highest to lowest quartiles (HR = 0.50, 95% CI, 0.35–0.73). Mature data on TTP and overall survival will be available for presentation. Conclusions: Higher baseline levels of circulating IGFBP-3 predict an improved outcome among patients with metastatic CRC. The IGF pathway may represent an important target for future treatment strategies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology Pharmacia, Inc. (now Pfizer)
Abstract 13404: Lps Improves Msc-mediated Cardioprotection in a Mouse Model of Cardiac Ischemia/reperfusion Injury via Myd88 and Stat3 Signaling
Authors: Bing Xu, Yunlong Liu, Baiyan Li, Yue Wang
Journal: Circulation (2014)

Background: Bone marrow-derived mesenchymal cells (MSCs) improve cardiac function following ischemia/reperfusion injury, in part due to the release of paracrine factors such as VEGF, HGF and SDF-1. Toll-like receptor 4 (TLR4) is expressed in MSCs to regulate the expression of cytoprotective factors, cytokines, and chemokines. Upon stimulation by its ligand such as LPS, TLR4 activates two distinct signaling pathways that are either MyD88-dependent or MyD88-independent/TRIF-dependent. While it was reported previously that LPS treatment improved MSC-mediated cardioprotection, the mechanism underlying such improved effect remains unknown. Methods and Results: To study a mechanism for LPS in MSC cardioprotective activity, both WT and MyD88-/- MSCs were treated with or without LPS (200 ng/ml) for 24 h. WT-MSCs, MyD88-/- MSCs, LPS-MSCs and LPS-MyD88-/- MSCs (1x10^5 each) were infused into the coronary circulation of isolated mouse hearts (Langendorff model) and then subjected to ischemia (25 min) and reperfusion...
A phase I trial of G3139 (Bcl-2 Antisense) combined with cytotoxic chemotherapy in relapsed pediatric solid tumors - A Children’s Oncology Group Study
Authors: S. Rheingold, M. Krailo, S. Blaney, M. Hogarty, L. Mascarenhas, K. Adlard, M. Barnich, J. Murphy, R. Chandula, P. Adamson
Journal: Journal of Clinical Oncology (2005)

3102 Background: Dysregulated bcl-2 expression has been observed in a variety of pediatric solid tumors. G3139 downregulates bcl-2 expression and, when administered with cytotoxic chemotherapy, may enhance tumor cell apoptosis. The objectives of this study were to determine the recommended phase 2 dose, dose-limiting toxicity (DLT), and pharmacokinetic profile of G3139 when used in combination with doxorubicin (DOX) and cyclophosphamide (CTX). Methods: Patients with refractory solid tumors received a 7-day continuous infusion (CI) of G3139. DOX (30mg/m2/day), dexrazoxane, and CTX (500mg/m2/day) were administered on days 5 and 6. Cycles could be repeated every 21 days. Cohorts of 3–6 patients were studied at 3, 5, and 7 mg/kg/day. Results: To date, 28 patients (13 female), median age 16 (range 1–19 years), have completed at least one cycle of therapy of whom 23 were evaluable for toxicity. At the initial G3139 dose of 3 mg/kg/day, 2/3 pts had Gr 4 neutropenia lasting > 7 days; this led to a 30% dose reduction of DOX/CTX. 2/3 pts again had dose limiting neutropenia that led to the addition of G-CSF. With reduced cytotoxic doses and G-CSF, 0/3, 1/6 (Gr 3 creatinine), and 0/6 pts experienced DLT at 3, 5, and 7 mg/kg/day dose levels, respectively. Non-DLTs included infection, fever, thrombocytopenia, anemia, and mild electrolyte abnormalities. At the 7 mg/kg/day dose level the median Css of G3139 was 2.2±1.4 μg/mL, a concentration associated with biologic activity in animal models. Conclusions: A G3139 dose of 7 mg/kg/day as a 7-day CI was well tolerated in children and is the recommended phase 2 dose. G3139 accentuates the myelosuppressive effects of DOX/CTX in heavily pretreated pediatric patients. This effect appears to be readily overcome with G-CSF; re-escalation of the DOX/CTX doses with G-CSF is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genta
Imatinib mesylate in thymic epithelial malignancies.
Authors: C. Buonerba, M. Marino, S. Sioletic, S. Conti, L. Petillo, P. Federico, V. Damiano, G. Merola, A. Evoli, M. Lalle, A. Ceribelli, M. Milella, G. Palmieri
Journal: Journal of Clinical Oncology (2011)

7091 Background: Study supported by Agenzia Italiana del Farmaco(AIFA code: FARM6HJ7CA). Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Histologic types, defined by the WHO (A, AB, B1, B2, B3 and Thymic carcinoma-TC), carry a variable prognosis, with TC being associated to the most aggressive clinical behavior. Anthracycline- and platinum-based chemotherapy is active in these tumors, but novel therapeutic options are still needed. Imatinib (Novartis Pharma) is a competitive inhibitor of BCR-ABL, KIT, PDGFRA, and PDGFRB tyrosine kinases. The rationale for its use in TETs lies in the high levels of expression of c-KIT reported in TC and for the reported efficacy of Imatinib in one case of TC (Stroebel, 2004). Methods: Phase II trial was initiated to deliver imatinib at 400 mg to a population of patients affected by TETs. Due to the low predicted accrual of patients with TC, patients with all histologic types of TETs were eligible for the trial. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the CTC of the NCI, version 3.0. 15 patients with advanced TETs (most of them B2 or B3 thymoma, some of them with a squamous component) , who had been pretreated with at least one chemotherapeutic agent, were enrolled at the Department of Molecular and Clinical Oncology and Endocrinology of University ‘Federico II of Naples’ from March, 2008 to July 2010. Results: One third of patients presented with thymic carcinomas. C-Kit was expressed only in some cases of TC, as revealed by immunohistochemistry. No mutations in the C-kit gene (exons 9-11-13 and 17) were found in the TC cases by mutational analysis. Imatinib was overall well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (range, 2.75-4). Median overall survival was not reached. Conclusions: The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. Imatinib seems to be not efficacy to treat TET.