tbuckley/cabot-search huggingface dataset:
Adjusted indirect comparison of everolimus and sorafenib in sunitinib-refractory mRCC patients using a robust matching technique.
Authors: G. Di Lorenzo, R. Casciano, E. Malangone, C. Buonerba, S. Sherman, J. Wang, Z. Liu, S. De Placido
Journal: Journal of Clinical Oncology (2011)

378 Background: Vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib (SU) and sorafenib (SO) are approved for first- and second-line (after cytokines) use in metastatic renal cell carcinoma (mRCC). Because most patients progress after first-line VEGFr-TKI, the need for an effective second-line treatment is compelling. Although SO is frequently considered after SU failure, no randomized controlled trials have established clinical benefit in this scenario. Results from the RECORD-1 phase III trial suggest that second-line everolimus (EVE) therapy leads to improved overall survival (OS) vs. placebo. No trial data exist comparing treatment outcomes for EVE vs SO in the second-line setting. Thus, the current analysis provides a robust estimate from an indirect comparison examining the OS benefit of EVE and SO as second-line treatment options after SU failure. Methods: The single-arm SO study was selected as a basis by which to match an EVE SU-refractory subpopulation of the RECORD-1 trial. Patients were limited to those with clear cell histology. An adjusted matching approach was taken in which 1,000 repeated random samples matched to the SO population on risk score distribution were produced. These data were used to generate a distribution of survival outcomes and infer a 95% CI around the mean of all sampled median OS estimates. Results: After adjusted matching, the estimated median OS benefit, based on SO patients with clear cell histology (n = 45) and 1000 random samples of n = 41 from the 127 SU-refractory EVE patients, was 82 weeks (95% CI: 78, 86) and 32 weeks (95% CI: 22, 64) for EVE and SO, respectively. Conclusions: These indirect comparison results suggest that SU-refractory mRCC patients treated with EVE may experience significantly improved OS outcomes compared with patients treated with SO. [Table: see text]
Germline single-nucleotide polymorphisms (SNPs) associated with response of urothelial carcinoma (UC) to platinum-based therapy: The role of the host.
Authors: D. Gallagher, V. Joseph, I. R. Garcia-Grossman, J. A. Przybylo, J. C. Riches, I. Ostrovnaya, R. Hamilton, M. I. Milowsky, K. Offit, D. F. Bajorin
Journal: Journal of Clinical Oncology (2011)

236 Background: Platinum-based therapy improves outcome in neoadjuvant and metastatic UC. Since cell-line and human subject studies in other cancers show germline associations with platinum response, we hypothesized that germline variation also identifies genes that determine UC response to platinum-based therapy. Methods: Saliva or blood was prospectively collected from 651 UC patients (pts) diagnosed between 1984 and 2010. SNPs (n=80) were selected based on previously reported associations with UC and/or platinum response and genotyped using Sequenom MassArray iPLEX system. Samples and SNPs were filtered for genotyping rate (&lt;0.8), minor allele frequency (&lt;0.05) and departures from Hardy-Weinberg equilibrium (&lt;1E-03). Clinical data were ascertained and linked with the genomic data in an anonymized manner. This analysis focused on 199 pts who received cisplatin or carboplatin and were eligible for response assessment (RES=partial response or complete response, n=90). Associations between SNPs and RES were tested using one and two degree of freedom tests. Results: Sixty-nine pts received neoadjuvant therapy (RES=54%), 126 chemo-naive pts received first-line metastatic treatment (RES=37%) and 4 received systemic treatment after prior chemoradiotherapy (RES=25%). We expected 4 associations due to chance alone at p &lt; 0.05. However, on univariate analysis using a 2 degree of freedom test, 9 SNPs were associated (p &lt; 0.05) with RES. Individual odds ratios (ORs) ranged from 0.32 to 3.29 with p-values ranging from 0.006 to 0.05. In analysis of rs9344 (CCND1) in all treated pts, 75/148 (51%) responded with AG/GG compared to 12/44 (27%) with AA [p=0.005312, OR 2.74 (CI 1.34, 5.92)]. In neoadjuvant pts treated with cisplatin, rs9344 analysis showed 29/48 (60%) responses in AG/GG pts compared to 5/17 (29%) with AA [p=0.026, OR 3.66 (CI 1.16, 13.1)]. Conclusions: We identified associations between 9 SNPs and response of UC to platinum-based therapy that are biologically and clinically relevant. A larger study will be required to independently validate these findings. Additional investigation of associations with time to metastasis and overall survival is ongoing. [Table: see text]
Accelerated Gray and White Matter Deterioration With Age in Schizophrenia
Authors: Vanessa L. Cropley, Paul Klauser, Rhoshel K. Lenroot, Jason Bruggemann, Suresh Sundram, Chad Bousman, Avril Pereira, Maria A. Di Biase, Thomas W. Weickert, Cynthia Shannon Weickert, Christos Pantelis, Andrew Zalesky
Journal: American Journal of Psychiatry (2016)

Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age.Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference.Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident.The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.
Incidence, Risk Factors and Clinical Outcome Of Leukemia Relapses Due To Loss Of The Mismatched HLA Haplotype After Partially-Incompatible Hematopoietic Stem Cell Transplantation
Authors: Lara Crucitti, Roberto Crocchiolo, Cristina Toffalori, Maria Teresa Lupo Stanghellini, Andrea Assanelli, Matteo Carrabba, Benedetta Mazzi, Elisabetta Zino, Sarah Marktel, Magda Marcatti, Consuelo Corti, Massimo Bernardi, Jacopo Peccatori, Claudio Bordignon, Chiara Bonini, Katharina Fleischhauer, Fabio Ciceri, Luca Vago
Journal: Blood (2013)
Haemostasis Impairment in Patients with Myelodysplastic Syndromes with Normal Platelet Counts
Authors: Nora Butta, Monica Martín Salces, Raquel De Paz, Ihosvany Fernandez Bello, María Teresa Álvarez Román, María Isabel Rivas Pollmar, Miguel Canales, Victor Jiménez Yuste
Journal: Blood (2015)
Genomic patterns resembling BRCA-mutated breast cancers and benefit of intensified carboplatin-based chemotherapy in HER2-negative breast cancer.
Authors: S. C. Linn, E. H. Lips, P. M. Nederlof, L. F. Wessels, J. Wesseling, M. van de Vijver, E. De Vries, H. van Tinteren, J. Jonkers, M. Hauptmann, S. Rodenhuis, M. A. Vollebergh
Journal: Journal of Clinical Oncology (2011)

10505 Background: The inability of breast cancer (BC) cells deficient in homologous recombination to repair DNA double strand breaks (DSBs), such as BRCA1/-2-mutated cells, offers a target for DNA crosslinking agents, e.g. bifunctional alkylating agents or platinum compounds. Our group previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of breast cancers with loss of BRCA1- or BRCA2. We hypothesized that these patterns might be present in some sporadic BCs as well and might predict sensitivity to DNA crosslinking agents. Methods: BRCA-likeCGH status, defined as positive when the previously published BRCA1-likeCGH and/or BRCA2-likeCGH pattern was present, was assessed in 249 stage-III BC patients, who had participated in a randomized controlled trial studying adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus conventional 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. We evaluated whether the effect on recurrence-free and overall survival (RFS, OS) of HD-CTC compared to conventional FE90C differed by BRCA-likeCGH status, stratified for number of lymph nodes and triple negative status, and adjusted for tumor size and grade. Results: 81 patients (81/249, 32%) were shown to have BRCA-likeCGH tumors and had a significant benefit of HD-CTC compared to conventional FE90C regarding OS (adjusted HR 0.19, 95%CI: 0.08-0.48), while HD-CTC was not superior among patients with a Non-BRCA-likeCGH tumor (adjusted HR 0.90, 95%CI: 0.53-1.54). The difference was statistically significant (p-interaction: 0.004). Similar results were found for RFS. Sensitivity analyses showed that the aCGH test was robust and not dependent on small changes in tumor percentage or thresholds. Half of all BRCA-like tumors were ER-positive; 14% of BRCA1-like ones and 69% of the BRCA2-like ones. Twelve cases were both BRCA1- and BRCA2-like. Conclusions: aCGH genomic patterns identify both ER-positive and triple negative BC patients who derive a marked survival benefit from intensified DNA crosslinking chemotherapy.
Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction
Authors: Payman Zamani, Victor Tan, Haideliza Soto-Calderon, Melissa Beraun, Jeffrey A. Brandimarto, Lien Trieu, Swapna Varakantam, Paschalis-Thomas Doulias, Raymond R. Townsend, Jesse Chittams, Kenneth B. Margulies, Thomas P. Cappola, David C. Poole, Harry Ischiropoulos, Julio A. Chirinos
Journal: Circulation Research (2016)

Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking.To determine (1) the dose-response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in heart failure with preserved ejection fraction.We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO3 (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (visit 1: 9.87, 95% confidence interval [CI] 9.31-10.43 minutes; visit 2: 10.73, 95% CI 10.13-11.33 minute; visit 3: 11.61, 95% CI 11.05-12.17 minutes; P=0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire total symptom (visit 1: 58.0, 95% CI 52.5-63.5; visit 2: 66.8, 95% CI 61.3-72.3; visit 3: 70.8, 95% CI 65.3-76.3; P=0.016) and functional status scores (visit 1: 62.2, 95% CI 58.5-66.0; visit 2: 68.6, 95% CI 64.9-72.3; visit 3: 71.1, 95% CI 67.3-74.8; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO3 (visit 2: 199.5, 95% CI 98.7-300.2 μmol/L; visit 3: 471.8, 95% CI 377.8-565.8 μmol/L) versus baseline (visit 1: 38.0, 95% CI 0.00-132.0 μmol/L; P<0.001). KNO3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95% CI -28.3 to -7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2-342.4) μmol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4-232.0) minutes.KNO3 is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345.
High toxicity in patients receiving adjuvant docetaxel plus hormone treatment after radical radiotherapy for high-risk prostate cancer: A preplanned safety report of SPCG 13 trial.
Authors: P. Kellokumpu-Lehtinen, M. Hjelm-Eriksson, C. Thellenberg-Karlsson, L. Astrom, L. Franzen, T. Marttila, M. Taalikka, C. Ginman
Journal: Journal of Clinical Oncology (2011)

63 Background: In two randomized trials a survival benefit has been shown for docetaxel (T) in metastatic, hormone refractory prostate cancer PrCa). In order to increase the recurrence-free survival and overall survival with adjuvant treatment we conducted a randomized trial using T in patients (pts) with high risk PrCa after radical radiotherapy (RT). Methods: Between May 2007 and April 2009 100 pts with PrCa Gleason score (GS) 7 (4+3) and cT2 tumors with PSA &gt;10 to &lt;70 ng/mL or cT2 tumors with GS 8-10 or any cT3 tumors without metastases were randomized between surveillance (S) or six courses of T 75 mg/m 2 q21d at the end of RT. Neoadjuvant + adjuvant LHRH-treatment for 9 mo was mandatory. The defined end-point is PSA relapse (ASTRO-RTOG guidelines). The groups were well balanced; mean age 65 vs 66 years, ECOG (0/1, %) 90/10 vs 90/10; time from diagnosis 262 vs 270 days, GS (6-7/8-10, %) 60/40 vs 44/56; tumor stage (T2/T3, %) 26/74 vs 28/72 in groups T vs S, respectively. The mean PSA of the 100 pts at the time of diagnosis was 21.9 ng/mL and the nadir PSA after RT was 0.25 ng/mL. By September 2010 227 out of 378 pts have been randomized to this SPCG 13 trial, NTC 006653848. Results: During T treatment Grade (G) 3 adverse event (AEs) occurred in 15 pts (30%) and G 4 AEs in 30 pts (60%) mainly due to bone marrow toxicity, which was higher than expected; neutropenia G 3-4 in 72% of the pts. Febrile neutropenia in 24% of the pts, neutropenic infection in 10% the pts and G3 infection without neutropenia in 4% of pts was recorded. Nonhematological G 3 AEs (pts) were rare; anorexia (1), diarrhea (3), fatigue (5), mucositis (1), nausea (1) and pain (1). Other severe SAEs related to T were pulmonary embolism and renal failure. However, only three pts stopped T before 6 cycles were completed due to toxicity. No deaths have occurred. In the S arm only one patient experienced G 3 toxicity (pain) 12 weeks after the randomization. Conclusions: Adjuvant T chemotherapy after RT has a higher frequency of neutropenia than previous studies on pts with metastatic disease, but very similar to the SPCG 12 trial of adjuvant T after surgery. Otherwise the treatment was quite well tolerated. [Table: see text]
Prognostic Factors Identified Via a Cox Proportional Hazard Cure Model Explain Survival Differences After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Chronic Myeloid Leukemia (CML) Between Two Consecutive Patient Cohorts
Authors: Markus Pfirrmann, Susanne Saussele, Andreas Hochhaus, Andreas Reiter, Ute Berger, Dieter K. Hossfeld, Christoph Nerl, Christof Scheid, Karsten Spiekermann, Jiri Mayer, Christiane Falge, Herbert G. Sayer, Donald Bunjes, Arnold Ganser, Dietrich W. Beelen, Helen Baldomero, Urs Schanz, Hermann Heimpel, Joerg Hasford, Hans-Jochem Kolb, Alois Gratwohl, Rüdiger Hehlmann
Journal: Blood (2012)
LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells
Authors: Benjamin N. Ediger, Hee-Woong Lim, Christine Juliana, David N. Groff, LaQueena T. Williams, Giselle Dominguez, Jin-Hua Liu, Brandon L. Taylor, Erik R. Walp, Vasumathi Kameswaran, Juxiang Yang, Chengyang Liu, Chad S. Hunter, Klaus H. Kaestner, Ali Naji, Changhong Li, Maike Sander, Roland Stein, Lori Sussel, Kyoung-Jae Won, Catherine Lee May, Doris A. Stoffers
Journal: Journal of Clinical Investigation (2016)

The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells. Inducible ablation of LDB1 in mature β cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted β cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of β cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative β cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) - factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of β cells and is a component of active enhancers in both murine and human islets.
Prior Rituximab (RTX) Administration Might Adversely Affect Stem Cell Harvest in Patients with Aggressive B-Cell Lymphomas.
Authors: Panagiotis Kaloyiannidis, Charalambos Kartsios, Ioanna Sakellari, Chrisanthi Vadikolia, Maria Marantidou, Achilles Anagnostopoulos, Athanasios Fassas
Journal: Blood (2004)
Targeting Aberrant Non-Homologous End Joining in Multiple Myeloma: Role of the Classical and Alternative Pathways in Genomic Instability
Authors: Teresa Calimeri, Daniele Caracciolo, Nicola Amodio, Mehmet Kemal Samur, Marzia Leotta, Mariateresa Fulciniti, Marco Rossi, Stephane Minvielle, Herve Avet-Loiseau, Pierosandro Tagliaferri, Masood Shammas, Kenneth C. Anderson, Pierfrancesco Tassone, Nikhil C. Munshi
Journal: Blood (2014)
Foxp3 expression in breast cancer cells: A new predictor of response to anthracycline versus docetaxel in primary breast cancer treated with adjuvant chemotherapy in the phase III trial FNCLCC/PACS-01.
Authors: F. Ghiringhelli, P. Fumoleau, L. Arnould, G. Mignot, C. Dalban, F. Bonnetain, H. H. Roche, M. Spielmann, C. Levy, A. Lortholary, F. Eichler, C. Mesleard, S. Ladoire
Journal: Journal of Clinical Oncology (2011)

1026 Background: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Preclinical data suggest that breast cancer cells that loose expression of Foxp3 gene develop resistance to anthracyclines but not to taxane. However, only few conflicting clinical data are available. Using Foxp3 labelling we tested the hypothesis that adjuvant chemotherapy incorporating docetaxel confers an overall survival (OS) benefit over anthracyclines in Foxp3-negative tumors while anthracycline and docetaxel are equivalent in Foxp3 expressing tumors. Methods: We obtained breast tumor tissue from patients included in breast cancer adjuvant trial PACS-01. This study compared 3 cycles of anthacycline followed by 3 cycles of docetaxel versus 6 cycles of anthracycline. Tumor sections were labeled with anti Foxp3 antibody using immunochemistry. Foxp3 expression was determined blinded to data. Cox models were used to estimated HR for OS with 95%CI of Foxp3 expression according to chemotherapy adjusted for clinical characteristics (tumor grade, tumor size and number of lymph node involved). Results: Foxp3 status was assessable in 1097 patients. The median age was 50 years old. The median follow up was 96 months. 405 tumors were found to express Foxp3 (36.9%). Using multivariate analysis, using patients treated with anthracycline alone and without Foxp3 expression as a control group, we observed that adjuvant regimen incorporating docetaxel was associated with a significant reduction in the risk of death (HR=0.62; 95%CI: 0.43−0.88, p=0.008). By contrast, in patients with tumor expressing Foxp3, regimen with or without docetaxel gave similar benefit, and adjunction of docetaxel did not improve the risk of death compared to patients treated with anthracycline alone (HR=0.62; 95%CI: 0.4−0.97, p=0.035 and HR=0.57; 95%CI: 0.36−0.90, p=0.16 compared to control group). Conclusions: Foxp3 expression by breast tumor cells predicts resistance to anthracycline regimen, and may be used for the selection of patients that benefit from adjunction of docetaxel in adjuvant chemotherapy for localized breast cancer.
Predictors for response to chemotherapy and survival in locally advanced breast cancer.
Authors: A. Pinto, A. Redondo, P. Zamora, B. Castelo, E. Espinosa
Journal: Journal of Clinical Oncology (2011)

e11561 Background: Neoadjuvant therapy is considered the standard of care for locally advanced breast cancer. Nowadays, there are few established clinicopathological predictors to individualize therapy, apart from hormone receptor expression and Her-2/neu overexpression and/or amplification. Although several molecular factors are being studies, no one is widely accepted as a prognostic or predictive factor in this situation. Methods: We selected consecutive patients with locally advanced breast cancer, treated in our institution from 1999 to 2009, that had received chemotherapy as neoadjuvant treatment. Data regarding age, tumor size, nodal status, grade, hormone receptor expression, Her-2/neu status, Ki67, type of chemotherapy, treatment with hormonal therapy and/or radiotherapy, clinical and pathological response, relapse and survival were collected. Results: A total of 94 patients were included. 60 patients (63.8%) were hormone-receptor positive, and 34 (36.2%) hormone-receptor negative. 64 patients (68.1%) were considered Her2-negative, 25 (26.6%) Her2-positive, and 5 (5.3%) unknown. After a median follow-up of 48.5 months, 28 patients (29.2%) have relapsed and 18 (18.8%) have died. 16 patients (16.6%) achieved a pathological complete response (pCR) both in breast and axilla after chemotherapy. For the whole group, median progression-free survival (PFS) was 72 months, and overall survival (OS) 40.5 months. Up to now, no patient with a pCR has relapsed or died (median overall survival in the pCR group not reached vs. 86 months in the non-pCR group, p=0.154). There was a strong correlation between an increased probability of achieving pCR and a Ki67 index above 20% (chi-square = 0.006), negative expression of hormone receptors (chi-square = 0.001) and Her-2/neu overexpression and/or amplification (chi-square = 0.031). None of these factors seemed to influence by itself PFS or OS. Conclusions: In our set of patients, Ki67 index > 20%, negative hormone receptors and Her-2/neu overexpression and/or amplification correlated with a higher probability of achieving a pCR; this was also associated with better OS, not statistically significant probably due to small study size and short follow-up.