tbuckley/cabot-search huggingface dataset:
Selective benefit of high-dose, platinum-containing, alkylating chemotherapy with stem cell rescue for patients with breast cancers with an expansive growth pattern on histology
Authors: S. C. Linn, M. A. Vollebergh, M. Hauptmann, L. F. Wessels, P. M. Nederlof, E. G. de Vries, S. Rodenhuis, J. Wesseling
Journal: Journal of Clinical Oncology (2009)

587 Background: Breast cancer (BC) cells lacking the DNA repair mechanism homologous recombination (HR), a feature of BRCA-deficient tumor cells, are hypersensitive to bifunctional alkylating agents. Metastatic BC patients whose tumors were scored as BRCA1-like with a BRCA1 Comparative Genomic Hybridization classifier had an impressive progression-free survival after platinum-containing (PC), high-dose alkylating (HDA) chemotherapy. BRCA1-like tumors showed an expansive growth (EG) pattern, were generally HER-2 negative and estrogen receptor (ER) negative (Vollebergh et al, Cancer Res. 2009, 69;[Suppl. 2]6050). To further investigate whether BRCA1-like tumors were chemosensitive in general, or were sensitive specifically to PC HDA chemotherapy, we studied outcome of stage III BC patients who had participated in a randomized trial of adjuvant 5 x FEC (5-fluorouracil, epirubicin, cyclophosphamide) versus 4 x FEC followed by high-dose CTC (cyclophosphamide, thiotepa, carboplatin) with autologous stem cell rescue (Rodenhuis et al, New Engl J Med. 2003). Methods: 162 Patients with an ER negative or low (&lt;25% of tumor cells positive) and HER-2-negative tumor were selected from abovementioned trial. EG was used as a surrogate for ‘BRCA1-like'. Currently available whole slides of n = 99 patients were scored for EG. An interaction term was fitted to a multivariate proportional hazards model to evaluate whether effect of CTC treatment in terms of recurrence-free survival (RFS) was modified by EG. Results: While RFS after 5 x FEC was similar for the 15 patients with EG as compared to 38 without EG (33%, and 31% 10-year RFS, respectively), 10-year RFS after high dose CTC was better for the 16 patients with EG (81% (multivariate hazard rate [HR] of CTC versus FEC 0.11 [95% CI 0.02–0.53]) as opposed to the 30 without EG (53% [multivariate HR of CTC versus FEC 0.58 (95% CI 0.3–1.12)]); multivariate test for interaction p = 0.056). Conclusions: Using histological information, by determining the presence of an expansive growth pattern, we were able to identify a group of stage III breast cancer patients who selectively benefited from PC HDA chemotherapy. No significant financial relationships to disclose.
Effect of ID1 expression change following chemotherapy on chemotherapy sensitivity.
Authors: T. M. Beer, B. L. Rademacher, H. Geng, J. Pittsenbarger, M. Garzotto, P. Nelson, C. S. Higano, D. Z. Qian
Journal: Journal of Clinical Oncology (2010)

4548 Background: To identify mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression in individual human prostate cancer specimens before and after chemotherapy collected from patients with high-risk, localized disease. Our prior results suggested that increased expression of Inhibitor of DNA Binding 1 (ID1) following chemotherapy may be associated with sensitivity to treatment. Methods: 57 high-risk prostate cancer patients were enrolled in a phase I/II study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 delivered weekly for 3 of every 4 weeks per cycle for 4 cycles over 16 weeks followed by radical prostatectomy. The primary end point was relapse-free survival (RFS) defined as a time until confirmed serum PSA > 0.4 ng/mL or the initiation of new therapy. Cells isolated using laser-capture microscopy from both cancer and adjacent benign tissue following a pretreatment biopsy, and from cancer tissue following a post-treatment prostatectomy. Kaplan-Meier and chi-square analyses were applied to a subset of patients from this population (n = 35) from whom cDNAs were available for analysis. Results: The overall RFS at 5 years was 50.0% (95% CI 32.9 to 67.1). The RFS function showed a trend for longer RFS in patients with ID1 upregulation. A chi-square analysis of risk of relapse showed a significantly lower risk at 12, 24, and 36 months (Fisher's exact test, p = 0.012, 0.009, and 0.036, respectively). To test the biologic relevance of this finding, we examined the effect of ID1 on docetaxel sensitivity in vitro. Docetaxel dose-dependently induced ID1 expression in the relatively low ID1 expressing LNCaP cell line. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted cell cycle progression through the G1 phase, and enhanced susceptibility to docetaxel. In contrast, ID1 knock-down in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity. The ID1-mediated chemosensitivity enhancement was in part due to the ID1-suppression of p21. Conclusions: ID1 upregulation after chemotherapy appears to modify chemotherapy sensitivity and deserves further study as a potential marker of chemotherapy activity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis
Abstract 1919: Warfarin-dependent gamma-carboxylation regulates androgen receptor activity
Authors: Ben Yi Tew, Teresa Hong, Sumanta K. Pal, Markus Kalkum, Jeremy Jones
Journal: Cancer Research (2015)

Abstract The anti-coagulant warfarin prevents the gamma-carboxylation (gla) of target proteins by interfering with the vitamin K cycle through its inhibition of the vitamin K epoxide reductase (VKOR). Most known gla proteins are found in the blood clotting cascade, but we demonstrate using immunoprecipitation and mass spectrometry that the androgen receptor (AR) can also be gamma-carboxylated. This modification occurs at amino acid 2E and can be prevented by warfarin treatment. This residue has been found to be mutated in partial androgen insensitivity syndrome patients. Warfarin, likely through its ability to control carboxylation, alters AR conformation and inhibits AR transcriptional activity, as does siRNA-mediated knockdown of VKOR, the target of warfarin. We further demonstrate that warfarin treatment reduces AR target gene expression in benign mouse prostate tissue in vivo. Interestingly, retrospective studies have shown that prolonged use of warfarin reduces the incidence of prostate cancer, an effect that is not observed for other cancers. In a small series of patients at our institution, we found that one allele of a functional SNP in VKOR is found at a significantly higher rate in prostate cancer patients than would be expected in the general population. We also found that VKOR is highly expressed in normal human prostate epithelia but is lost in cancerous tissue, a pattern of expression that appears to be unique to prostate cancer. We hypothesize that the lower prostate cancer incidence observed in men taking warfarin is due to the ability of warfarin to reduce AR activity, similar to the effect of 5-alpha reductase inhibitors. Importantly, we show for the first time that a nuclear receptor and transcription factor can be regulated by gamma-carboxylation. Citation Format: Ben Yi Tew, Teresa Hong, Sumanta K. Pal, Markus Kalkum, Jeremy Jones. Warfarin-dependent gamma-carboxylation regulates androgen receptor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2015-1919
Comparing immunogenicities of tumor-specific antigens administered as therapeutic vaccines in metastatic melanoma patients
Authors: J. Baurain, M. Stas, B. Neyns, G. Schuler, T. Velu, K. Thielemans, N. Van Baren, T. Dorval, M. Marchand, P. Coulie
Journal: Journal of Clinical Oncology (2007)

3003 Background: Therapeutic vaccination of metastatic melanoma patients with detectable disease is followed by some tumor regression in only about 10% of the patients, with no clear difference observed between studies carried out with various tumor-specific antigens and vaccination modalities. For antigenic peptide MAGE-A3 168–176 , presented by HLA-A1 molecules and administered as peptide alone or recombinant ALVAC poxvirus, anti-vaccine T lymphocyte (CTL) responses have been observed in no progressor patient and in only half of the regressors, suggesting a poor immunogenicity of these vaccines. Methods and Results: We compiled anti-vaccine CTL responses measured in the blood of 202 metastatic melanoma patients vaccinated with various associations of 10 different tumor antigens administered as peptides, alone or with adjuvant, recombinant ALVAC poxvirus, or peptide-pulsed dendritic cells. Blood lymphocytes collected before and after vaccination were all analyzed with the same method involving in vitro restimulation in limiting dilution condition followed by labeling with tetramers for each antigen. A CTL response was deemed to have occurred if the CTL frequency increased by at least 10 times, and if the pre-vaccination frequency was lower than 2 x 10 -6 of the CD8 cells. No responses were detected against peptides MAGE- A4 230–239 (0/26) and MAGE-C2 336–344 (0/22). Some were observed against MAGE-A3 168–176 (11/81), MAGE-A1 278–286 (2/22), MAGE-A3 112–120 (2/55), and MAGE-A10 254–262 (2/35). Responses were frequently found against NY-ESO-1 157–165 (10/19), GnTV VLPDVFIRC (18/73), gp100 209–217 (21/33), or Tyrosinase 369–377 (11/59). For the latter four antigens, there was no correlation between the occurrence of CTL responses and that of tumor regressions. Neither did we find a correlation between the CTL responses and the expression of the antigen-encoding genes in pre- vaccination tumor samples. Conclusions: These results suggest that some of the antigenic peptides that are commonly used in melanoma vaccines are more immunogenic than others but do not induce more tumor regressions. Therefore, inducing strong CTL responses against these immunogenic peptides is probably not the most appropriate endpoint of future vaccine trials. No significant financial relationships to disclose.
Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma
Authors: James E. McDonald, Marcus M. Kessler, Michael W. Gardner, Amy F. Buros, James A. Ntambi, Sarah Waheed, Frits van Rhee, Maurizio Zangari, Christoph J. Heuck, Nathan Petty, Carolina Schinke, Sharmilan Thanendrarajan, Alan Mitchell, Antje Hoering, Bart Barlogie, Gareth J. Morgan, Faith E. Davies
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Fluorine-18 fluorodeoxyglucose positron emission tomography with CT attenuation correction (18F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semiquantitative characterization of metabolic activity (glycolytic phenotype) by calculation of glucose uptake. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have the potential to improve the value of this approach and enhance the prognostic value of disease burden measures. This study aims to determine whether TLG and MTV are associated with progression-free survival (PFS) and overall survival (OS), and whether they improve risk assessments such as International Staging System (ISS) stage and GEP70 risk. Experimental Design: 192 patients underwent whole body PET/CT in the Total Therapy 3A (TT3A) trial and were evaluated using three-dimensional region-of-interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal. Results: In multivariate analysis, baseline TLG &amp;gt; 620 g and MTV &amp;gt; 210 cm3 remained a significant factor of poor PFS and OS after adjusting for baseline myeloma variables. Combined with the GEP70 risk score, TLG &amp;gt; 205 g identifies a high-risk–behaving subgroup with poor expected survival. In addition, TLG &amp;gt; 205 g accurately divides ISS stage II patients into two subgroups with similar outcomes to ISS stage I and ISS stage III, respectively. Conclusions: TLG and MTV have significant survival implications at baseline and offer a more precise quantitation of the glycolytic phenotype of active disease. These measures can be assessed more readily than before using FDA-approved software and should be standardized and incorporated into clinical trials moving forward. Clin Cancer Res; 23(8); 1981–7. ©2016 AACR.
Prognostic significance of the cyclin D3 and the Ki-67 expression for predicting clinical outcome in diffuse large B-cell lymphoma
Authors: H.-J. Shin, J. Chung, D. Y. Park, G. J. Cho
Journal: Journal of Clinical Oncology (2004)

6714 Background: Cyclin D3 expression is associated with cell proliferation in lymphoid tissues, and high cyclin D3 expression in tumor cells of patients with diffuse large B-cell lymphoma (DLBCL) predicted poor response to chemotherapy and shorter overall survival in one study. However, cyclin D3 expression may sensitize cells to apoptosis induced by caspase 2 overexpression by increasing the absolute amount of cleaved caspase 2. The purpose of this study was to evaluate the clinical utility of the cyclin D3 monoclonal antibody for predicting clinical outcome and the correlation between cyclin D3 expression and the proliferation marker Ki-67 in patients with DLBCL. Methods: Thirty-six previously untreated patients with DLBCL who had been treated between May, 1994 and April, 2003 and from whom paraffin blocks were available were included in this study. Immunostaining was performed by means of monoclonal antibodies against cyclin D3, and Ki-67 expression. Results: Patients with high cyclin D3 expression had a more clinical stage I or II disease (p=0.04) and more often had low risk, low-intermediate risk according to the International Prognostic Index (p=0.07) than patients with low cyclin D3 expression. Patients with high cyclin D3 expression had a more low Ki-67 expression associated with proliferation in tumor tissue (p=0.019). The complete remission rate was 82.4% for patients with high cyclin D3 expression and 50% for those with low cyclin D3 expression (p=0.049). Furthermore, high cyclin D3 expression was associated significantly with better overall survival (p=0.028), disease free survival (p=0.009) and event free survival (p=0.008). Conclusions: This study shows that better response for chemotherapy may be related to the cell cycle regulatory protein cyclin D3 overexpression, which can be predictive and prognostic factor associated with longer overall survival and disease free survival in DLBCL. No significant financial relationships to disclose.
Thiotepa + Total Body Irradiation vs Melphalan vs MT as Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
Authors: Arvinder Bir, Theresa Hahn, Allison M. Miller, Tariq Islam, Joanne Becker, Myron Czuczman, Asher A. Chanan Khan, Arif R. Alam, Philip L. Mccarthy
Journal: Blood (2002)
Gabapentin for the management of hot flashes in prostate cancer survivors: A longitudinal continuation study—NCCTG trial N00CB.
Authors: A. R. Moraska, P. J. Atherton, D. W. Szydlo, D. L. Barton, P. J. Stella, K. M. Rowland, P. L. Schaefer, J. E. Krook, J. Bearden, C. L. Loprinzi
Journal: Journal of Clinical Oncology (2010)

9139 Background: Hot flashes are a common, undesirable complication of androgen-deprivation therapy in men with prostate cancer. A previous randomized trial indicated that gabapentin (900 mg/day) was well-tolerated and moderately decreased hot flashes for 4 weeks, leading to increased quality of life and satisfaction with hot flash control (Loprinzi et al; Ann Oncol 2009, 20; 542-9). Methods: In this open-label continuation study, men from the above trial were studied. Men were allowed to start or continue gabapentin, titrating the dose to maximum efficacy, up to 900 mg/day. They completed a hot flash diary daily and weekly logs of toxicity, satisfaction with hot flash control, and effect on quality of life, over the course of eight additional weeks. Hot flash frequencies, scores and changes from baseline in patient reported side effects were calculated. Kruskal-Wallis methodology, ANOVA and Bonferoni techniques, frequency counts, and chi-square tests were employed, as appropriate, to compare study endpoints. Results: Of 214 evaluable men from the randomized trial, 147 (69%) registered to remain on the continuation phase. Data were provided by 80% of them: 34, 32, 21, and 30 from the placebo, 300 mg/d, 600 mg/d, and 900 mg/d target dose arms, respectively. Demographic characteristics of men in the continuation phase were representative of those in the double blind study. The moderate reduction in hot flash frequency and severity observed in the randomized trial appeared to be maintained during the continuation phase. Those originally on placebo or lowest dose (300 mg/d) had improved hot flash control as they increased dosage during this open-label study. Using the last week of the randomized trial as a baseline for this continuation study period, median hot flash scores decreased by 57%, 39%, 19%, and 4% in the original placebo and gabapentin 300 mg/d, 600 mg/d, and 900 mg/d target dose arms, respectively. Gabapentin continued to be well tolerated, with minimal toxicities reported. Conclusions: Gabapentin appears to provide moderate efficacy as a nonhormonal option for longer-term treatment of hot flashes in men undergoing androgen ablation for prostate cancer and seems to be well tolerated. No significant financial relationships to disclose.
Cisplatin plus capecitabine (CisCape) and concurrent pelvic radiotheapy for the neoadjuvant treatment of rectal cancer (RC)
Authors: V. Formica, L. Martano, A. Nardecchia, M. Benassi, G. Del Vecchio Blanco, E. Giudice, E. Mannisi, P. Sileri, L. Franceschilli, P. Rossi, I. Portarena, S. Pellicori, E. Krasniqi, R. Adamo, S. Riondino, R. Santoni, M. Roselli
Journal: Annals of Oncology (2015)
Targeted Inhibition of the MLL Transcriptional Complex By Proteosome Inhibitors Elicits a High Response Rate in Relapsed/Refractory MLL Rearranged Leukemia
Authors: Cary Koss, Stephanie Nance, Michele Connelly, Jing Ma, Anang Shelat, Anitria Cotton, Qi An, Cheng Cheng, Monika L. Metzger, Sima Jeha, Jeffrey E Rubnitz, James R Downing, R. Kiplin Guy, Tanja A Gruber
Journal: Blood (2014)
Acarbose and acetaminophen: A dangerous combination?
Authors: Hans J. Ahr, Ernst Bomhard, Ulrich Schmidt, Gerhard Schlüter
Journal: Hepatology (1999)

entered the clinical trial in 1989.Therefore, there were only 4 untreated and 7 treated patients at the end of ''10 years of follow-up.''These numbers are indeed small, but those at the end of 8 years or less are adequate (Table 1).Furthermore, the opportunity for relatively long-term follow-up of this number of untreated patients might be possible only in countries like Taiwan in which the only licensed drug is expensive and not covered by health insurance.As to patients with HBV/HCV dual infection, studies have shown that such patients react differently, including response to interferon therapy, than patients with chronic HBV infec-tion alone. 4 It seems reasonable to exclude patients with dual infection from the analysis.
Abandoning personalization to get to precision in the pharmacotherapy of depression
Authors: Roy H. Perlis
Journal: World Psychiatry (2016)

Effectiveness studies and analyses of naturalistic cohorts demonstrate that many patients with major depressive disorder do not experience symptomatic remission with antidepressant treatments. In an effort to better match patients with effective treatments, numerous investigations of predictors or moderators of treatment response have been reported over the past five decades, including clinical features as well as biological measures. However, none of these have entered routine clinical practice; instead, clinicians typically personalize treatment on the basis of patient preferences as well as their own. Here, we review the reasons why it has been challenging to identify and deploy treatment-specific predictors of response, and suggest strategies that may be required to achieve true precision in the pharmacotherapy of depression. We emphasize the need for changes in how depression care is delivered, measured, and used to inform future practice.
Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models
Authors: Nicolas A Menzies, Gabriela B Gomez, Fiammetta Bozzani, Susmita Chatterjee, Nicola Foster, Ines Garcia Baena, Yoko V Laurence, Sun Qiang, Andrew Siroka, Sedona Sweeney, Stéphane Verguet, Nimalan Arinaminpathy, Andrew S Azman, Eran Bendavid, Stewart T Chang, Ted Cohen, Justin T Denholm, David W Dowdy, Philip A Eckhoff, Jeremy D Goldhaber-Fiebert, Andreas Handel, Grace H Huynh, Marek Lalli, Hsien-Ho Lin, Sandip Mandal, Emma S McBryde, Surabhi Pandey, Joshua A Salomon, Sze-chuan Suen, Tom Sumner, James M Trauer, Bradley G Wagner, Christopher C Whalen, Chieh-Yin Wu, Delia Boccia, Vineet K Chadha, Salome Charalambous, Daniel P Chin, Gavin Churchyard, Colleen Daniels, Puneet Dewan, Lucica Ditiu, Jeffrey W Eaton, Alison D Grant, Piotr Hippner, Mehran Hosseini, David Mametja, Carel Pretorius, Yogan Pillay, Kiran Rade, Suvanand Sahu, Lixia Wang, Rein M G J Houben, Michael E Kimerling, Richard G White, Anna Vassall
Journal: The Lancet Global Health (2016)

BackgroundThe post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa.MethodsWe examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016–35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice.FindingsIncremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective.InterpretationExpansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary.FundingBill & Melinda Gates Foundation.
A Multicentre Study of Environmental Factors on the Severity of Sickle Cell Disease
Authors: Sanjay Tewari, Fred Piel, Valentine Brousse, Baba PD Inusa, Paul Telfer, Stephan Menzel, Mariane De Montalembert, Kate Gardner, Gary Fuller, Swee Lay Thein, David Rees
Journal: Blood (2014)