tbuckley/cabot-search huggingface dataset:
Combined treatment with immunotherapy and chemotherapy using endoscopic ultrasonography guided injection for locally advanced pancreatic carcinoma
Authors: K. Nonogaki, Y. Hirooka, A. Itoh, H. Kawashima, N. Ohmiya, Y. Niwa, H. Goto, K. Yamamoto, J. Takamatsu, K. Yokokawa
Journal: Journal of Clinical Oncology (2007)

13503 Background: Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity. Usually, mature DCs were cultured using resected tumor tissue, but for inoperable cases, this method is impractical. The injection of immature DCs into the tumor after appropriate chemotherapy is reasonable, if DCs come to maturity capturing the specific cancer antigen . The aim of this study is to assess the toxicity and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic carcinoma. Methods: Five patients with pathologically confirmed pancreatic ductal carcinoma using EUS-FNA were enrolled, median age 56 years (range, 46–70 years). All cases without distant metastasis were diagnosed as surgically unresectable . Patients underwent leukapheresis, immature DCs were prepared from peripheral blood by a culture with granulocyte macrophage colony-stimulating factor and interleukin 4. Lymphokine-activated killer (LAK) were also prepared from peripheral blood. Immature DCs were injected biweekly in the mass by endoscopic ultrasound-guided fine needle injection (EUS-FNI), LAK were administered intravenously. Patients received the treatment of gemcitabine 1000 mg / m 2 by intravenous injection 3 days before the immunotherapy. One course with 6 times combined therapy was continued until the judgment of progressive diseases (PD) was given. The toxicity and efficacy of this treatment were assessed. We also assessed whether tumor associated antigen (TAA)-specific IFN-?producing cells increase after treatment. Results: Hematological toxicity occurred in one case, leucopenia of grade 2. No severe toxicities of grade 3 to 4 occurred. One had a partial response (PR), stable disease (SD) was observed in 2 patients for more than 6 months (long-term SD). PR patient could undergo curative operation after this therapy. The number of TAA-specific IFN-?producing cells in PR patient increased 12-fold higher than that seen before treatments. Conclusions: These results support the safety and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic ductal carcinoma. This treatment may be a useful for the treatment of pancreatic ductal carcinoma. No significant financial relationships to disclose.
Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma
Authors: Giedre Krenciute, Simone Krebs, David Torres, Meng-Fen Wu, Hao Liu, Gianpietro Dotti, Xiao-Nan Li, Maciej S Lesniak, Irina V Balyasnikova, Stephen Gottschalk
Journal: Molecular Therapy (2015)

Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies.
A phase II pilot study of valproic acid in relapsed/refractory chronic lymphocytic leukemia
Authors: P. Ganesan, V. Raina, R. Kumar
Journal: Journal of Clinical Oncology (2009)

7081 Background: Valproic acid (VA) has demonstrated cell-kill by triggering pro-apoptotic pathways in chronic lymphocytic leukemia (CLL) in preclinical studies. We studied the safety and efficacy of VA in patients with relapsed and refractory CLL. Methods: Adult patients with CLL diagnosed by the NCI-WG criteria who had received at least one previous fludarabine-based therapy and subsequently progressed or relapsed with ECOG performance status (PS) ≤3 and normal organ functions were included. Patients were started on VA 10 mg/kg which was gradually increased to 20 mg/kg. Efficacy (NCI-WG criteria) and safety (NCI common toxicity criteria) were assessed at 3 months. Responding patients were continued on the study medication. Results: Five patients have so far been included, age 48–70 years (mean 62 years); sex: 3 males/ 2 females; disease duration: 2–16 years (mean 5.4 years). Previous therapies included fludarabine/alkylators in all patients; in addition rituximab was given in one and lenalidomide in two. Three patients have completed three months of therapy and are evaluable. One patient had partial response and one had stable disease. In the third patient the total leucocyte count continued to rise but there was response in other parameters like decrease in lymphadenopathy by 50%, stabilization of hemoglobin, increase in absolute neutrophil (ANC) and platelet counts. Two of these patients who were requiring 2–3 blood transfusions per month and frequent admissions for infectious complications have not required further transfusions or hospital admissions since starting VA. Significant improvements were also seen in their ECOG PS from 3 to 0–1, 61% and 230 % rise in ANC and 50% and 83% rise in platelet counts. Grade 3 hypersensitivity skin rashes developed in one patient at one month and the therapy was discontinued. Most patients had mild drowsiness and two patients had significant weight gain of grade 2. Conclusions: VA produces very impressive palliation in advanced/ refractory CLL in terms of improvement of hemoglobin, ANC, platelets, PS, and a reduction in the number of infective episodes –apparently a sequel to significant rise in neutrophils. We are encouraged by these results and are continuing the study. No significant financial relationships to disclose.
The TGF-beta1 antisense oligonucleotide AP 11014 for the treatment of non-small cell lung, colorectal and prostate cancer: Preclinical studies
Authors: K.-H. Schlingensiepen, A. Bischof, T. Egger, M. Hafner, H. Herrmuth, P. Jachimczak, M. Kielmanowicz, M. Niewel, E. Zavadova, G. Stauder
Journal: Journal of Clinical Oncology (2004)

3132 Background: Tumor derived transforming growth factor beta (TGF-β) is a pivotal factor for malignant progression by inducing metastasis, angiogenesis and tumor cell proliferation and by mediating the tumors' escape from immunosurveillance. In colorectal, non-small cell lung and prostate cancer in particular expression of the TGF-β1 isoform has been correlated with tumor progression and poor clinical prognosis. Significantly elevated TGF-β1 plasma levels to more than 3fold in colon cancer (median control: 6,200 pg/ml, range: 1,977 - 17,515 pg/ml; median patients: 19,948 pg/ml, range: 5,014 - 38,900 pg/ml) and NSCLC (median control: 3,482 pg/ml, range: 747 - 9,984 pg/ml; median patients: 11,572 pg/ml, range: 4,952 - 30,985 pg/ml) and to more than 4fold in prostate cancer (median control: 2,152 pg/ml, range: 1,275 - 3,958 pg/ml; median patients: 10,066 pg/ml, range: 3,435 - 41,574 pg/ml) further support the role of TGF-β1 as a key tumor promoter. Methods: The in vitro effects of AP 11014, a TGF-β1 specific phosphorothioate antisense oligonucleotide, on TGF-β1 secretion, proliferation, migration of and immunosuppression by various cancer cell lines were determined. Results: AP 11014 significantly reduced TGF-β1 secretion by 43 - 100% in different NSCLC (A549, NCI-H661, SW 900), colon cancer (HCT-116) and prostate cancer (DU-145, PC-3) cell lines. Tumor cell proliferation was inhibited in a dose-dependent manner in all cell lines. In a scratch assay AP 11014 reduced migration of a NSCLC (SW 900) and prostate cancer (PC-3) cell line by max. 65% after 24h. Additionally, AP 11014 reversed immunosuppression mediated by NSCLC (NCI-H661, A-549) and colon cancer (HCT-116) cell derived TGF-β1 by increasing LAK cell cytotoxicity up to 368% of the untreated control (effector/target ratio 5:1). Conclusion: These preclinical data clearly indicate antisense mediated suppression of TGF-β1 by AP 11014 as a highly promising approach for the therapy of non-small cell lung, colorectal and prostate cancer in humans. Based on these data a clinical trial with AP 11014 in TGF-β1 overexpressing tumors is planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma GmbH Antisense Pharma GmbH
A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors
Authors: Haihong Zhong, April Davis, Maria Ouzounova, Rosa A. Carrasco, Cui Chen, Shannon Breen, Yong S. Chang, Jiaqi Huang, Zheng Liu, Yihong Yao, Elaine Hurt, Jacques Moisan, Michael Fung, David A. Tice, Shawn G. Clouthier, Zhan Xiao, Max S. Wicha, Hasan Korkaya, Robert E. Hollingsworth
Journal: Cancer Research (2016)

Abstract Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2+ tumor cells by targeting the CD44+CD24− cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of IL6 in tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance. Cancer Res; 76(2); 480–90. ©2016 AACR.
Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies.
Authors: A F Ratliff, J Wilson, M Hum, M Marling-Cason, K Rose, N Winick, B A Kamen
Journal: Journal of Clinical Oncology (1998)

PURPOSE Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT. PATIENTS AND METHODS Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration. RESULTS Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with endometrial adenocarcinoma achieved a complete response (CR) and remains on therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or greater, which included one patient with a metastatic nerve sheath tumor who was stable for 9 months. CONCLUSION We conclude that AMT has good oral bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.
Abstract 12563: Variation in Referral for Specialist Follow-Up and 30-Day Mortality in Patients Hospitalized With Heart Failure in England and Wales
Authors: Kazem Rahimi, Connor A Emdin, John G Cleland, Henry Dargie, Reza Korshidi, Suzanna Hardman, Mark Woodward, Stephen MacMahon, Polly Mitchell, Theresa McDonagh
Journal: Circulation (2014)

Introduction: Current US and European guidelines recommend that patients hospitalized with heart failure (HF) are followed up after discharge, but do not specify whether or not this should be with HF specialist services. We investigated referral patterns to specialist services amongst hospitals in England and Wales and assessed whether these differences were associated with 30-day mortality. Methods: We used data from the National Heart Failure Audit, which included 84647 HF patients from 176 hospitals. Vital status was obtained from the UK national death registry. Using hierarchical statistical models and instrumental variable analysis, we estimated whether different types of follow-up (cardiologist, HF nurse or geriatrician) were associated with 30-day mortality, adjusting for case mix. Results: At the hospital level, rates of referral to cardiologists for follow up varied from 4% to 94%, to HF nurses from 0% to 97% and to geriatricians from 0% to 65%. When heart failure patients were referred for follow-up to a heart failure nurse, to a geriatrician, or to a cardiologist, they were 15%, 15% and 47% less likely to die than patients who were not referred to these specialists (odds ratio [OR] = 0.85, p&lt;0.001; OR = 0.85, p&lt;0.001; OR = 0.53, p&lt;0.001). A patient admitted to one randomly selected UK hospital would have, on average, 2.1-fold odds of receiving referral to a cardiologist for follow up than a second similar patient admitted to another randomly selected hospital (95% confidence interval [CI]: 1.9, 2.3) Use of quintile of hospital preference as an instrumental variable for cardiology referral resulted in a consistent estimate for the effect of cardiology referral on 30-day mortality (OR=0.65, CI: 0.40, 0.90, p=0.005). Conclusion: Referral at discharge to cardiology services for follow-up varies considerably amongst UK hospitals. At both an individual patient and at a hospital level, referral to cardiology for follow-up is a major determinant of 30-day mortality.
Abstract 14278: Autonomic Nerve Activity and Blood Pressure Fluctuation in Ambulatory Dogs
Authors: Jessica Hellyer, A Akingba, Kyoung-Suk Rhee, Alex Tan, Kathleen Lane, Changyu S Shen, Jheel Patel, Michael Fishbein, Shien-Fong Lin, Peng-Sheng Chen
Journal: Circulation (2013)

Background: Orthostatic hypotension is a common phenomenon that can occur briefly in any individual. We hypothesize that orthostatic hypotension is caused by an abrupt simultaneous termination of s...
Vascular endothelial growth factor gene polymorphisms and risk of colorectal cancer
Authors: Y. Cho, Y. Chae, J. Kim, S. Shon, J. Moon, S. Jeon, J. Park, I. Lee, I. Lee, G. Choi, S. Jun
Journal: Journal of Clinical Oncology (2007)

4123 Background: Angiogenesis is closely related to the development, growth, and metastasis of solid tumors, including colorectal cancer (CRC), and the vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor. Accordingly, the present study was conducted to evaluate the potential association between two VEGF polymorphisms (+405G &gt; C, and 936C &gt; T) and the risk of CRC. Methods: The VEGF genotypes were determined using fresh colorectal tumor tissue from 477 patients with CRC who underwent surgical resection and peripheral blood lymphocytes from 413 healthy controls based on a polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/DHPLC) assay. The incidence of genotypes and haplotypes of two VEGF polymorphisms was compared between the patients with CRC and the controls. Results: The distribution of genotypes and allele frequencies of the 936C &gt; T polymorphism in the CRC group did not differ from those in the control group. However, compared with the combined GC and CC genotype, the GG genotype of +405G &gt; C polymorphism was significantly associated with an increased risk of CRC [odds ratio (OR), 1.575; 95% confidence interval (CI), 1.178–2.104; P = 0.002]. In the haplotype analyses, haplotype +405G / 936C was also associated with a significantly increased risk of CRC (OR, 1.264; 95% CI, 1.043–1.531; P = 0.017), whereas haplotype +405C / 936C was associated with a decreased risk of CRC (OR, 0.818; 95% CI, 0.677–0.989; P = 0.038). None of the VEGF polymorphisms studied significantly influenced the clinical or pathologic features of CRC. Conclusions: These findings suggest that the VEGF +405G &gt; C polymorphism may be associated with the risk of CRC in the Korean population. No significant financial relationships to disclose.
Implementing an oncology-specific health care IT portal to enhance patient-provider communication.
Authors: Debra A. Patt, Jennifer Trageser, Jeffrey A. Howard, Max Rush, Cara Heiman, Rajesh Yalamanchili, Daniel Lodder, Julie Neiman, Hk Khang, Lucy R. Langer, Rowena Schwartz, Asif Ahmad
Journal: Journal of Clinical Oncology (2013)

31 Background: Our large network of oncology practices (PRs) launched a health IT (HIT) patient portal (PP) to improve patient (PT) access to clinical information (CI) and serve as a platform to enhance PR-to-PT communication (C). Methods: A team of HIT specialists and oncologists engaged in development of the PP to develop a platform to facilitate PR-to-PT C, satisfy meaningful use (MU) requirements, and have brand identification (ID) for PRs. Workflow planning for implementation was conducted including ID and education of key participants at PRs. Educational signage was posted at PRs during initiation partnered with information at check-in at clinic visits to inform PTs about PP benefits and registration steps. After consent was obtained, pts were invited by email to the PP and could access their PP and view and download their secure CI. A review of support calls from both PR personnel and pts highlighted opportunities for enhanced PP engagement. Enrollment (E) was captured monthly. Results: From April 2012 to June 2013 more than 34,000 pts have enrolled in the PP across over 47 PRs (Table). In addition, inclusion of the PR brand and removing extraneous data capture during E are critical to success. Comparing E data from April 2012 to April 2013 after increased PR brand ID and reduction of pt validation changes were implemented, there was an increase of 13% of opened Is and 22% increase in Es. Conclusions: By engaging a development team, and strategically planning content dissemination and education around initiation, implementation of the PP was widely utilized throughout the PRs. By monitoring adoption rates and capturing the PT feedback, incremental enhancements can positively affect PT engagement with PRs. This functional mechanism can now serve as a platform to facilitate C between PRs and PTs, fulfill MU requirements, and plan future dissemination of educational content. [Table: see text]
A nonrandomized, multicenter, phase II study of S-1 with cisplatin as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC).
Authors: D. V. Jones, C. Zergebel, K. Saito, A. Sandler
Journal: Journal of Clinical Oncology (2010)

7602 Background: Platinum analogs form the backbone of most regimens for NSCLC, but the optimal regimen is unknown. S-1 is an oral agent which combines the 5-FU prodrug tegafur, with gimeracil and oteracil, which inhibit 5-FU phosphorylation in the GI tract, to increase antineoplastic activity while reducing toxicity. S-1 has therapeutic benefit in a variety of malignancies, including NSCLC, in East Asian populations. We investigated the activity and toxicity of S-1 + cisplatin in patients with advanced NSCLC. Methods: Patients with previously untreated measurable stage III-B/IV NSCLC, ECOG performance status 0-1, and adequate end-organ function were eligible for this study. Cisplatin, 75 mg/m2, was administered IV on Day 1, with S-1, 25 mg/m2 PO BID, Days 1-14, every 21 days. Tumor assessments were obtained every other cycle. Results: A total of 58 patients received at least one cycle of protocol-specified therapy. Most patients were male (64%) and White (79%). More than half of the patients (44, 76%) received at least four of the six planned cycles, while 28% received all six cycles. There were 13 (23.2%) partial responses, and 25 (44.6%) patients with stable disease. The median progression-free survival was 4.0 months. There did not appear to be any relationship between response to therapy and tumor histology. Thirty-four patients experienced at least 1 serious adverse event (SAE); 8 discontinued study treatment due to adverse events. The most frequently reported adverse events of G3 or more (> = 10%) were neutropenia (28%), hyponatraemia (19%), diarrhea (17%), hypokalaemia (12%), fatigue (10%), dehydration (10%) and deep vein thrombosis (10%). Seven patients died due to SAEs that occurred during the study; 3 died due to treatment-related SAEs (neutropenic sepsis, multi-organ failure or renal failure). Conclusions: The regimen of S-1 + cisplatin demonstrated antitumor activity in advanced NSCLC with an expected and tolerable toxicity profile. Therefore, further evaluation should be considered in advanced NSCLC to determine the optimal S-1-based regimen in the western countries. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Taiho Pharmaceutical