tbuckley/cabot-search huggingface dataset:
Correlation of effector and regulatory T cell responses with clinical outcome in metastatic renal cell carcinoma patients treated with MVA-5T4 vaccine and high-dose interleukin-2
Authors: H. L. Kaufman, S. Kim-Schulze, D. Kim, D. Moroziewicz, G. DeRaffele, J. Mitcham, W. H. Shingler, R. Harrop, S. Naylor
Journal: Journal of Clinical Oncology (2008)

3004 Background: The attenuated vaccinia virus MVA was engineered to deliver the tumor antigen 5T4 (MVA-5T4; TroVax). 5T4 is a glycoprotein expressed by nearly all RCCs. MVA-5T4 was tested in combination with HD IL-2 to determine the safety of the combination, clinical response rate and humoral and cellular immune responses. Methods: Patients with metastatic RCC who qualified for HD IL-2 were eligible to receive five TroVax vaccinations, which were administered i.m. every three weeks. Each vaccination was followed by a cycle of HD IL-2 (600,000 IU/kg). Blood was collected for analysis of 5T4-specific cellular and humoral responses. The frequency and functional characterization of regulatory T cells (Treg) was determined throughout the treatment time course. Results: 25 patients (mean age 58.4±10.07) were enrolled with a median follow-up of 22.8 months. There were no serious vaccine-related adverse events. The frequency of peripheral Tregs (pre-treatment) was found to be significantly higher than those detected in normal donors (6.44% vs 1.42%, P=0.00018) but cells had comparable suppressive capacity. Despite the presence of elevated levels of Tregs, 5T4-specific cellular and/or humoral responses were detected in all patients who had received ≥1 TroVax immunization (n=22). Two patients who presented with both primary tumors in place and metastases had complete responses of metastatic disease and underwent post-treatment nephrectomy. 10 patients (48%) were stable with a median overall survival that has not yet been reached, while median survival was 22 months for the 10 patients with PD (p=0.04). Patients with stable disease showed a significant increase in 5T4-specific T cell responses by direct ex vivo interferon-gamma ELISPOT assay (p=0.005) and a decrease in Tregs compared to those with PD (p=0.034) and the change in Treg frequency was independently associated with prolonged survival (P=0.006). Conclusions: Local vaccination with MVA-5T4 and HD IL-2 was safe and induced potent 5T4-specific cellular and humoral immune responses. Patients with SD demonstrated a significant increase in survival, reduced Treg frequency and enhanced 5T4-specific cellular responses relative to patients with PD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oxford Biomedica Oxford Biomedica
&lt;italic&gt;N&lt;/italic&gt;-Methyl-&lt;italic&gt;N&lt;/italic&gt;-nitrosourea and Saccharin: Effects on Epithelium of Normal Human Urinary Bladder In Vitro&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: S El-Gerzawi, B M Heatfield, B F Trump
Journal: JNCI Journal of the National Cancer Institute (1982)

The effects of N-methyl-N-nitrosourea (MNU) and saccharin on the histology of normal human bladder “urothelium” (i.e., the epithelium of the urinary bladder) were studied in long-term explant cultures. In MNU-treated cultures, a dose response was observed. Single doses of 1-100 γg MNU/ml induced atypical focal hyperplasia, which reverted to a single or a double cell layer as seen in controls. Exophytic, papillary-like hyperplastic structures were noted after a single dose of 10 or 100 γg MNU/ml. In contrast to single doses, multiple doses (given every 2 wk) of MNU at 5 or 10 γg/ml resulted in striking focal proliferation of dysplastic spindle cells in as little as 6 weeks (three doses of MNU). At 0.5% saccharin, urothelium on explant surfaces resembled that of controls, except in one instance in which mild focal hyperplasia persisted. In the presence of saccharin, hyperplasia induced by a single dose of MNU persisted. Following three multiple doses of MNU in the presence of saccharin, spindle cell hyperplasia was induced similar to that seen with multiple doses of MNU alone, although nuclei appeared more pleomorphic and hyperchromatic in the presence of saccharin.
Results of semimonthly 5-florouracil/leucovorin combined with paclitaxel and oxaliplatin in treatment of advanced gastric cancer (AGC)
Authors: R. Lin, N. Fan, Z. Guo, X. Wang, Q. Chen, J. Liu, J. Lin
Journal: Journal of Clinical Oncology (2007)

15045 Background: At present there is still no standard chemotherapy regimen for AGC, the progress of AGC exhibits a pessimistic result with a median survival of less than 9 months. The purpose of this trial was designed to enhance the treatment efficacy for AGC by using semimonthly FU/LV combined with paclitaxel and oxaliplatin. Methods: Patients chosen with histologically proven diagnosis of adenocarcinoma of the stomach or gastroesophageal junction, locally advanced (i.e., unresectable) or metastatic and measurable disease. The chemotherapy regimen was comprised of a 3-hour infusion of 135 mg/m 2 of paclitaxel followed by oxaliplatin 85 mg/m 2 and LV 400 mg/m 2 , administered simultaneously as a 2-hour infusion, then continued a 46-hour infusion of FU 2.4 g/m 2 using an ambulatory pump. Treatment was continued until disease progressed, unacceptable toxicity, or patient choice. The primary endpoint was response rate. Results: Twenty-seven patients were enrolled onto this study in our center between September 19, 2005 and December 25, 2006. The median patient age was 51 years (range, 28 to 66 years), 21 were males and 6 were females. All patients received the chemotherapy between at least two cycles and maximum eight cycles with a median of three. Four CRs of 27 enrolled patients, fifteen PRs and eight SDs were observed. Nineteen patients were chemonaive within enrolled patients: Four CRs, eleven PRs. At a median follow-up of 8.7 months, the median survival was 6.8 months. Frequent grade 3 to 4 toxicities were: neutropenia (37.0%), stomatitis (7.4%), nausea (7.4%), vomiting (7.4%), hepatic dysfunction (3.7%), paresthesia (18.5%). No treatment-related death occurred. Conclusion: Semimonthly FU/LV combined with paclitaxel and oxaliplatin appears to be of well efficacy and is well tolerated in patients with AGC. Currently, this regimen is being tested in the phase III trial involving patients with AGC on the basis of well result. No significant financial relationships to disclose.
HER2-positive early breast cancer (HER2EBC): An Australian pattern of care study.
Authors: Carole A. Harris, Sallie Pearson, Benjamin Daniels, Preeyaporn Srasuebkul, Robyn L. Ward
Journal: Journal of Clinical Oncology (2013)

101 Background: Clinical trials have demonstrated the benefits of trastuzumab in treating HER2EBC. However, in routine care it is unclear which patients are recommended treatment, what chemotherapy partners are used and whether patients receive all of their intended treatments. In this study we describe the real world treatment patterns in HER2EBC patients. Methods: We undertook a clinical audit of patients diagnosed with HER2EBC (stage I-III) at four Sydney-based cancer centres between 2008 and 2011. We identified patients from pathology records and extracted information on patient and cancer characteristics, treatments planned and received from medical notes and medication charts. Results: 203 patients formed the study cohort; median age 55 years (range: 21-91), all but one patient was female. 77 patients had stage I disease, 84 stage II, and 42 stage III. 176 patients (86.7%) were recommended trastuzumab-based treatment and 168 patients initiated therapy. 96 were treated with anthracycline-based chemotherapy and 70 with taxane-based chemotherapy. 76.7% completed the planned number of taxane-based treatments compared with than the 60% receiving anthracycline-based therapies; toxicity being the main reason for not completing treatment. Younger patients (OR 0.89, 95%CI 0.84-0.93, p&lt;0.001) and those with grade 3 tumours compared to grade 1 and 2 combined (OR 3.99, 95%CI 1.31-12.08, p0.014) were more likely to be recommended trastuzumab-based treatment. Younger patients (OR 0.85, 95%CI 0.81-0.90, p &lt;0.001) with a high HER2 gene copy number (OR 4.10, 95%CI 1.06-15.81, p 0.041) multifocal disease (OR 3.53, 95%CI 1.06- 15.82 p 0.023) and stage II and III disease (OR 0.73, 95%CI 0.25-0.90 p 0.011) were more likely to be recommended anthracycline over taxane-based therapy. Conclusions: Trastuzumab-based therapy is standard of care for patients with HER2EBC regardless of patient or cancer characteristics. Whilst chemotherapy partners are determined by patient and cancer characteristics, treatment limiting toxicities also need to be considered in order to maximise patient benefit.
Analysis of exhaled breath with electronic nose and discrimination of lung cancer and COPD by logistic regression analysis
Authors: Gunta Strazda, Maris Bukovskis, Uldis Kopeika, Ainis Pirtnieks, Normunds Jurka, Liga Balode, Jevgenija Aprinceva, Agnese Kislina, Viesturs Silins, Immanuels Taivans
Journal: European Respiratory Journal (2013)

Background  Lung cancer and COPD are diseases associated with cigarette smoking and coexist in many patients.  Objective  We hypothesized that electronic nose can discriminate exhaled air of patients with lung cancer from patients with COPD and healthy controls.  Methods  Exhaled breath of morphologically verified lung cancer patients (cancer group), lung cancer patients with COPD (cancer COPD group), COPD patients without verified lung cancer (COPD group) and healthy volunteers (control group) was examined. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected that was sampled by electronic nose (Cyranose 320). Optimal detector parameter combination and mathematical model for discrimination of lung cancer were calculated by MLRA backward stepwise method. Age, smoking history (pack years) and ambient temperature °C were included as continuous predictors of the diagnosis. Percentage of correct prediction cases was calculated.  Results  93 patients with lung cancer, 128 with lung cancer and COPD, 27 patients with COPD and 88 volunteers were included in the study.  The main classification error occurred between cancer and cancer COPD group.  Conclusions  Exhaled breath analysis with electronic nose demonstrate good discrimination pattern between lung cancer, COPD patients and control, even in patients with combined disease.  Acknowledgements  Study was sponsored by ERAF activity 2.1.1.1.0 Project Nb. 2010/0303/2DP/2.1.1.1.0/10/APIA/VIAA/043/
Early immune reconstitution and abrogation of GvHD after infusion of HSV-TK engineered donor lymphocytes after haplo-identical hemopoietic stem cell transplantation
Authors: F. Ciceri, C. Bonini, A. Bondanza, Z. Magnani, M. Bernardi, J. Peccatori, F. Crippa, C. Gallo Stampino, M. Bregni, C. Bordignon
Journal: Journal of Clinical Oncology (2004)

6515 Background: Haplo-identical stem cell transplantation (haplo-SCT) is a therapeutic option for patients with high risk hematologic malignancies lacking an HLA matched donor. The full exploitation of haplo-SCT is limited by delayed immune recovery, resulting in prolonged risk of life-threatening infections. Infusion of small numbers of donor T cells, aimed at providing immune reconstitution, results in severe forms of graft-versus-host-disease (GvHD). We previously showed that infusion of donor lymphocytes (DLI) expressing the herpes simplex virus thymidine kinase (Tk) is an efficient tool for controlling GvHD and preserving anti-tumor activity. Methods: We designed a dose-finding clinical protocol of Tk-DLI for immune reconstitution and relapse prevention after haplo-SCT. Eight pts with high risk hematologic malignancies who underwent haplo-SCT received escalating doses (10e6–10e7/kg) of Tk-DLI from day +42. Results: Transduced cells were documented ex vivo in all evaluable pts. While no CD3+ cells were observed after infusion of 10e6/kg, the majority of pts who received 10e7/kg Tk-DLI reached 50 CD3+/μl by day 50, increasing steadily thereafter. Analysis on ex vivo PBLs showed Th1/Tc1 cells with a wide TCR repertoire able to proliferate, lyse and produce IFN-γ after stimulation with viral and allogeneic antigens. Immune reconstitution resulted in complete control of viral infections and complete remission of leukemia in the majority of patients. In 1 pt a grade II biopsy-proven acute GvHD, involving skin and liver was observed. Multiple doses of ganciclovir (10 mg/kg/die), in the absence of immunosuppressive drugs, quickly resulted in the complete resolution of all signs of GvHD. Ganciclovir-mediated abrogation of alloreactive T cells was confirmed by ex vivo ELISPOT analysis of host-reactivity. Conclusions: Tk-DLI at a dose of 10e7/kg is a promising tool for preventing disease relapse and promoting immune reconstitution after haplo-SCT while providing an effective and selective treatment for GvHD. A multicentric study aimed confirming these results on a larger cohort of patients recently started. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Molmed s.p.a.
Meta-analyses of randomized trials assessing the influence of chemotherapy and prognostic factor in advanced/recurrent gastric cancer
Authors: C. Pozzo, Y. Ohashi
Journal: Journal of Clinical Oncology (2009)

4550 Background: Advanced or recurrent stomach cancer remains an incurable disease. Several drugs and different combinations of chemotherapy have been investigated but very often with small sample sizes making definitive conclusions difficult. The GASTRIC project is an individual-patient-data (IPD) based meta-analysis in the advanced disease setting to quantify the potential benefit of various chemotherapies. We used this large database to study the role of various prognostic factors and potential interactions with chemotherapy. Methods: All randomized clinical trials (RCT) closed to patient accrual at the end of 2004 were eligible. Radiotherapy, intraperitoneal chemotherapy, or immunotherapy was excluded. The primary endpoint was overall survival (OS). Baseline variables included sex, age, performance status (PS), diseases status at entry, prior surgery, number of organs involved at entry, location of metastasis, TNM stages, histology, operative procedures, and geographic area. The hazard ratio (HR) and 95% confidence interval (CI) was calculated by the multivariate Cox analysis to assess of the prognostic factors for their relationship to OS. Results: Fourty-nine eligible RCTs (7,120 patients) were identified. As of December 2008, IPD from 21 trials (3,619 patients) with a median follow- up of 7.3 months were available for OS. There was no statistically significant difference between 5FU-based, anthracycline-based, platinum-based, taxane-based, or irinotecan-based regimens versus any other CT. In the multivariate Cox regression analysis stratified by trial and treatment arm, PS of 2 (HR, 2.43; 95%CI, 2.02 to 2.94) compared to PS of 0, metastatic (HR, 1.29; 95%CI, 1.01 to 1.64) compared to local advanced, many number of organs, and location of metastasis (especially with peritorium; HR, 1.75; 95%CI, 1.23 to 2.48) compared to none were strongly associated with lower survival. Conclusions: Our interim results could not show an overall survival benefit in favour of 5FU-, anthracycline-, platinum-, taxane-, or irinotecan-based regimens compared with a regimen without the specific chemotherapy. We confirm the impact of PS, diseases status at entry, number of organs involved, and location of metastasis on OS. No significant financial relationships to disclose.
The FDA Division of Oncology Initiative with the NCI SBIR/ STTR Programs
Authors: H. Saber-Mahloogi, W. C. Timmer, S.-L. Lee, J. Leighton, R. C. Kane, A. Pilaro, A. Rahman, G. Johnson, R. Pazdur
Journal: Journal of Clinical Oncology (2005)

3173 Small businesses normally do not have a complete range of expertise and resources necessary to bring products to market from initial discovery through the expensive development phases. The NCI and other federal institutions support the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs to help fill this need. The SBIR and STTR programs are granting programs for small business and provide a mechanism for small business to collaborate with research institutions to engage in federally funded research and development. The goal of these programs is to provide resources for innovative research for discovery and early-stage development to ensure that interested commercial partners will continue product development and, ultimately, bring a new product to market. The CDER Division of Oncology Drug Products (DODP) has collaborated with the NCI to establish educational and training resources for the NIH SBIR/STTR program grantees. Grantees’ lack of regulatory knowledge necessary to file Investigational New Drug Applications (INDs), for product development may lead to inefficient use of resources, lost opportunities, and potentially to premature termination of development. The DODP team has been working with the NCI SBIR/STTR program managers to identify specific issues leading to these inefficiencies and to develop novel solutions. DODP reviewers presented an overview of the regulatory requirements for submitting INDs for oncology drug products at the annual NIH SBIR/STTR conference (http://grants.nih.gov/grants/funding/SBIRConf2004/presentations.htm). We will present an overview of the DODP-SBIR/STTR interaction and discuss the chemistry, pharmacology/ toxicology, and clinical regulatory requirements for submitting an IND. No significant financial relationships to disclose.
Sequential Homoharringtonine and Interferon- in the Treatment of Early Chronic Phase Chronic Myelogenous Leukemia
Authors: Susan O’Brien, Hagop Kantarjian, Charles Koller, Eric Feldman, Miloslav Beran, Michael Andreeff, Sergio Giralt, Bruce Cheson, Michael Keating, Emil Freireich, Mary Beth Rios, Moshe Talpaz
Journal: Blood (1999)
Effectiveness of TB diagnostics with microbiological methods in TB service and general health care institutions
Authors: Larisa Rusakova, Punga Victor, Gergert Vladislav
Journal: European Respiratory Journal (2011)

Objective:  To evaluate the effectiveness of TB diagnostics with microbiological methods in 41 574 newly detected TB patients.   Materials and methods:  The effectiveness of TB diagnostics with microbiological methods in newly detected TB patients in 2007-2009 in clinicodiagnostic laboratories (CDL) of general health care (GHC) and TB service institutions was analyzed according to official applied-research data and the results obtained by the institute staff during supervisory visits. Analysis of TB diagnostics was assessed according to the indicators established by the Federal Target Programme (FTP), World Bank and GFATM projects.   Results:  In 2007-2009 the proportion of SS+ among TB suspect patients examined by microscopy in CDL of GHC institutions increased by 33,3%. The indicator (1-5%) in 2009 was achieved in 7 out of 15 Russian regions. The proportion of newly detected pulmonary TB patients, SS+ by microscopy, among all registered SS+ by microscopy new cases of pulmonary TB has increased by 11,6% (2007 - 24,3%, 2008 - 28, 3%, 2009 - 27,5%). The proportion of newly detected patients, SS+ by microscopy, examined in CDL of TB service institutions, increased by 1,0% (48,8% and 49,3% accordingly).   Conclusion:  In general, thanks to funding from different sources (FTP, World bank and GFATM) during 2005 - 2009 all doctors and laboratory technicians of TB service and GHC institutions were trained to detect TB with microbiological methods, the laboratory equipment and supplies were received and put to use and that resulted in improving performance quality of laboratory service.
Phase 2 dose multi-center, open-label study of ARQ 501, a checkpoint activator, in adult patients with persistent, recurrent or metastatic leiomyosarcoma (LMS)
Authors: L. P. Hartner, L. Rosen, M. Hensley, D. Mendelson, A. P. Staddon, W. Chow, O. Kovalyov, W. Ruka, K. Skladowski, A. Jagiello-Gruszfeld, M. Byakhov
Journal: Journal of Clinical Oncology (2007)

20521 Background: ARQ 501 selectively induces apoptosis in cancer cells by inducing a rapid and sustained increase of the pro- apoptotic protein E2F-1. ARQ 501 has been studied in three phase 1 studies, demonstrating acceptable toxicity and encouraging signs of efficacy. A 54 y/o female with metastatic LMS who failed 7 previous therapies achieved a prolonged PR on ARQ 501 monotherapy. This was consistent with preclinical data, where induction of E2F-1 and corresponding efficacy in human leiomyosarcoma xenografts was observed. Methods: A phase 2 study in adult LMS patients (&gt;3 prior systemic therapies) was initiated to assess ORR, TTP and further characterize the safety of ARQ 501. ORR included CR, PR and SD=4 mo. Four week cycles (ARQ 501 450mg/m2) were repeated until progression, unacceptable toxicity, or another discontinuation criterion. Results: 49 patients were enrolled and 45 received ARQ 501. Data is available for 43 patients (4M/39F, median age, 54). Of the 43, 10 did not reach a protocol defined tumor assessment (4 deaths, 5 PD and 1 lost to follow-up prior to week 8), 19 have been assessed for response per RECIST at eight weeks (7 SD of 8–28+ weeks, 1 PR, 11 PD) and 14 active patients yet to reach first tumor assessment. The most common AEs were: anemia (68%, 21%=G3), hyperbilirubinemia (35%, 6%=G3), fatigue (35%, 0%=G3), nausea (30%, 0%=G3), constipation (24%), hemolysis (21%, 6%=G3), dyspnea (21%), and vomiting (21%). One treatment related death was reported in a 47 y/o Asian male with severe hemolysis following a single infusion of ARQ 501 at 450 mg/m2. The pt was hospitalized, but severe hemolysis led to acute renal failure and the patient expired after 4 days. Conclusions: ARQ 501 was administered to 45 patients with advanced, recurrent or persistent leiomyosarcoma. Several patients have achieved some clinical benefit (1 PR, 3 prolonged SD), further analysis of efficacy data is warranted prior to additional clinical investigation. No significant financial relationships to disclose.
Enhanced expression of interleukin 8 (CXCL8) in cystic fibrosis (CF) airway epithelial (AE) cells
Authors: Anna Poghosyan, R.L. Clifford, W.R. Coward, L. Pang, A.J. Knox
Journal: European Respiratory Journal (2013)

Background: CF is characterised by neutrophil-dominated airway inflammation with excessive production of pro-inflammatory chemokine CXCL8. CXCL8 is regulated at the gene transcription level by transcription factors including NF-κB, AP-1, and C/EBPβ.  The Aim of the study was to investigate the transcriptional mechanisms of basal and IL-1β-induced CXCL8 production in CFTR-deficient AE (CFTR-AE) cells and their corrected counterparts.  Methods: CXCL8 secretion/expression was measured by ELISA/RT-PCR accordingly. Transcriptional regulation was assessed by transient transfection of wild type (WT) CXCL8 promoter constructs. Involvement of transcription factors was evaluated using CXCL8 promoter luciferase constructs with mutated binding sites for NF-κB, AP-1, and C/EBPβ. Chromatin immunoprecipitation (ChIP) measured binding of transcription factors to the CXCL8 promoter.  Results: CFTR-AE cells secreted higher levels of CXCL8 compared to their corrected counterparts both basally and after stimulation. CFTR-AE cells expressed increased levels of CXCL8 transcript and WT CXCL8 promoter luciferase activity. Mutation of NF-κB, AP-1, and C/EBPβ binding sites abolished CXCL8 promoter luciferase activity suggesting that all 3 factors are vital for CXCL8 expression. ChIP assay showed increased C/EBPβ binding to the CXCL8 promoter in CFTR-AE cells.  Conclusions: These data suggest CFTR-AE cells produce increased levels of CXCL8 due to higher binding of C/EBPβ to the CXCL8 promoter. Current studies focus on the underlying epigenetic mechanisms responsible for increased transcription factors binding.