tbuckley/cabot-search huggingface dataset:
Abstract 18526: Catheter Ablation as a First-Line Therapy for Atrial Fibrillation - A Meta-Analysis
Authors: Ajay Vallakati, Madhu Y Reddy, Gopi C Ponnaganti, Vivek Yarlagadda, Donita Atkins, Sudharani Bommana, Pramod Janga, Arun Raghav Mahankali Sridhar, Ryan Maybrook, Rhea C Pimentel, Luigi DiBiase, Andrea Natale, Buddhadeb Dawn, Dhanunjaya Lakkireddy
Journal: Circulation (2013)

Introduction: Catheter ablation (CA) has been shown to be superior to anti-arrhythmic therapy (AAD) for drug-refractory atrial fibrillation (AF). Whether CA is superior to AAD as a first-line therapy for AF is not clear. We performed meta-analysis of all prospective studies assessing the efficacy of CA as first line therapy for paroxysmal AF. Methods: We searched PubMed, Cochrane library and Embase for observational studies and randomized control trials (RCT) assessing CA as first-line therapy for AF. Recurrence rates of AF after CA and AADs in these studies were extracted and analyzed. Random effects model with inverse variance weighting was used to calculate relative risk (RR) of AF recurrence after CA in comparison to AADs. Results: We identified 5 prospective trials (3 RCTs and 2 observational) (n=597) of which 3 RCTs compared the efficacy of CA with AADs and the other 2 observational studies evaluated AF recurrence after CA (no comparator group). Follow-up duration ranged from 12 to 24 months across the studies. In these 5 studies, 353 and 244 AF patients received CA and AADs as first line therapy respectively. Pooled data of 353 CA patients revealed AF recurrence rate of 0.28 (95% CI, 0.23 - 0.33). Pooled data of 244 patients who received AADs revealed AF recurrence of 0.44 (95% CI, 0.38 -0.51). Random effects model including the 3 RCTs demonstrated that catheter ablation was associated with a significantly lower AF recurrence rate when compared with AADs (RR: 0.5; 95% CI, 0.28 -0.89; p =0.02). Conclusion: As a first-line therapy strategy for paroxysmal AF, CA is associated with 50% lesser recurrence of AF when compared to AADs.
A phase I/II trial of fixed-dose docetaxel plus irinotecan and escalating doses of estramustine phosphate for first-line or greater treatment of selected advanced solid tumors
Authors: F. Nakhl, R. Elsoueidi, F. Forte, J. Lowry, J. Burton
Journal: Journal of Clinical Oncology (2008)

13522 Background: This phase I/II study evaluated the safety of the combination of irinotecan, docetaxel and estramustine phosphate (EMP) for selected advanced solid tumors and also obtained initial efficacy data. Methods: 22 patients (6 in phase I) were enrolled in the study. The regimen consisted of fixed doses of docetaxel, 30 mg/m2, and irinotecan, 60 mg/m2, on days 1 and 8 of a 21-day schedule in combination with escalating doses of estramustine phosphate (500 and 750 mg/m2 for 3 days starting on days −1 and 6) during phase I. After the appropriate phase II dose of EMP was found, additional patients were enrolled. Toxicity and efficacy data were collected. Results: 21 of the 22 patients were evaluable for toxicity and 19 for tumor response. The recommended phase II dose of EMP was found to be 750 mg/m2. Hematologic toxicity was fairly mild, with only one episode of grade 3 neutropenia during both phase I and II. Diarrhea was the most common non-hematologic toxicity with grade 3 toxicity occurring in 6 of 21 patients (28.5%). Only one episode of venous thrombosis was observed. The overall clinical benefit rate was 59% (including 1 PR, 2 major marker responses [1 PSA; 1 CA-125] and 10 stable disease). Conclusions: EMP in combination with the doublet of docetaxel and irinotecan is a well tolerated regimen with relatively mild hematologic toxicity and mild to moderate non-hematologic toxicity, and promising initial anti-tumor activity in previously treated patients with a broad range of advanced or metastatic solid tumors. No significant financial relationships to disclose.
Combination treatment of infusional 5-fluorouracil, low-dose leucovorin and docetaxel (FLT) for advanced gastric cancer
Authors: H. C. Chung, H. C. Jeung, S. Y. Rha, S. H. Noh, J. K. Roh
Journal: Journal of Clinical Oncology (2005)

4144 Background: We estimated the efficacy and the safety of continuous infusion of 5-FU with leucovorin and docetaxel for advanced gastric cancer. Methods: Patients with unresectable advanced gastric cancer received a 1-hour infusion of docetaxel 75 mg/m2 followed by IV bolus leucovorin 20 mg/m2 and a 24-hour infusion of 5-FU 1,000 mg/m2 on D1–3, which was repeated every 3 weeks. Prophylactic G-CSF was administered for 5 days on D4–8. The treatment was repeated until disease progression. Response was evaluated according to the RECIST criteria at every 2 cycles. Results: Sixty-six patients were enroled of whom 38 patients were chemonaive. A total of 260 cycles were administered, and the median number of cycles per patient was 4. The median relative dose intensity was 0.86. Of the 59 evaluable patients, the overall response rate was 25.7% and disease control rate was 60.5%. The response rate was higher for the chemotherapy-naïve group than for the previously treated group (34.2% vs. 14.2%, respectively). The median progression-free and the overall survival were 21 (range: 2 - 44+ weeks) and 40 weeks (range: 4 - 152 weeks) respectively, with no difference based on the previous treatment. The most frequent grade III-IV toxicities were leucopenia and neutropenia (34.9% and 48.8% per treatment cycle), which was the major cause of treatment delay. Febrile neutropenia was observed in 11.6% of the patients and in 5.3% of the the treatment cycle. Other hematological and non-hematological toxicities were exceptionally rare with only 1% of diarrhea and mucositis. Conclusions: Docetaxel in combination with infusional 5-FU and leucovorin showed a comparable efficacy with other second-generation regimens and a relatively low non-hematologic toxicity, suggesting a new alternative combination to the cisplatin-containing regimens for the treatment of advanced gastric cancer. No significant financial relationships to disclose.
Repetitive Administration of BeG in Prevention and Treatment of Spontaneous Leukemia of AKR Mice
Authors: Peter C. Ungaro, Walter P. Drake, Michael R. Mardiney
Journal: JNCI Journal of the National Cancer Institute (1973)

Female AKR mice were randomly grouped at 8 weeks of age and treated every 2d week thereafter until 42 weeks of age with intraperitoneal injections of BCG or saline. BCG treatment increased the survival time but did not prevent the eventual onset of leukemia. The responses were dose related.
Understanding premature discontinuation of aromatase inhibitor (AI) therapy in postmenopausal breast cancer survivors.
Authors: C. T. Stricker, S. C. Palmer, A. DeMichele, J. Mao
Journal: Journal of Clinical Oncology (2010)

6073 Background: Suboptimal adherence and premature discontinuation of AIs in breast cancer survivors (BCS) compromise treatment outcomes. While several studies report suboptimal adherence to AIs, few have examined rates and predictors of premature discontinuation, and none have evaluated patient-reported reasons for stopping early. Understanding reasons for prematurely stopping AIs are important as these offer opportunities for preventative intervention. Methods: We conducted a cross-sectional survey of 490 postmenopausal non-metastatic BCS prescribed AIs at an outpatient oncology clinic. The primary outcome was premature discontinuation of AIs, defined as stopping prior to end of prescribed therapy (self-report confirmed by chart review). Predictors included sociodemographic factors, health variables, treatment variables (e.g., prior tamoxifen, chemotherapy), and prior communication with a health care provider about difficulty taking AI therapy. Patients also self-reported reasons for stopping AIs. Results: 32 BCS (7%) had prematurely discontinued AI therapy after a mean of 15.7 months (range, 1 to 55 months). In univariate analyses, previously taking Tamoxifen, having inflammatory conditions (e.g., rheumatoid arthritis), never having been asked about difficulty taking AIs, and being married were significant predictors of stopping AIs early (all p ≤ 0.05). In multivariate analysis all remained significant (p ≤ 0.05). Patients reported side effects as the most frequent reason for stopping AIs early, with 17 (53%) reporting joint pain, 5 (16%) effects on bone, and 12 (32%) reporting other side effects, such as hot flashes and cognitive effects. Conclusions: BCS who prematurely stopped AIs did so an average of just over a year after treatment initiation. This is the first study to examine self-reported reasons for stopping AIs. These data suggest a profile of BCS at high risk for early discontinuation, and highlight the importance of provider communication and assessment and management of symptoms, including joint pain, in designing supportive interventions for these women. No significant financial relationships to disclose.
An update of phase II results from RTOG 0211: A phase I/II study of gefitinib with radiotherapy in newly diagnosed glioblastoma
Authors: A. Chakravarti, B. Berkey, H. I. Robins, A. Guha, W. J. Curran, D. Brachman, C. Shultz, M. Mehta
Journal: Journal of Clinical Oncology (2006)

1527 Background: The epidermal growth factor receptor (EGFR) pathway is commonly deregulated in GBMs and its activity has been associated with treatment resistance in preclinical models. Accordingly, the Radiation Therapy Oncology Group (RTOG) recently conducted a Phase I/II study of Gefitinib, an EGFR tyrosine kinase inhibitor, in combination with radiotherapy for newly-diagnosed glioblastoma (GBM) patients. Methods: 178 GBM patients were entered on RTOG 0211 (Phase I: 31 patients and Phase II: 147 patients). The maximum tolerated dose (MTD) of Gefitinib was determined to be 500mg in non-EIACD patients, and the Phase II component of RTOG 0211 was continued at this dose level during radiation and as maintenance for 18 months afterward or until disease progression. Results: 119/147 patients completed treatment per protocol and/or with acceptable deviation. The median survival time for all patients in the study was 11.0 months. Progression-free survival was 5.1 months for all patients. When considering only patients who were treated per protocol, the median survival of RTOG 0211 patients was 11.5 months, compared to 11.0 months for historical controls treated in previous RTOG studies (p=0.14). RPA Class IV patients appeared to derive the greatest benefit from Gefitinib when combined with radiotherapy compared to historical controls, although not reaching statistical significance. Molecular and genetic profiling efforts are underway to determine which GBM patients derive greatest benefit from Gefitinib in the upfront setting, which will be reported at the time of the annual meeting. These include markers such as EGFRvIII and PTEN, which have been recently reported to be associated with response to anti-EGFR agents in the recurrent setting, and members of key signal transduction pathways regulated by EGFR. Conclusions: The observed survival advantage of newly-diagnosed GBM patients treated with Gefitinib in combination with radiotherapy compared to historical controls treated on previous RTOG studies does not reach statistical significance. Molecular and genetic profiling efforts are underway to identify subsets of GBM patients who might derive the greatest benefit from Gefitinib in the upfront setting. No significant financial relationships to disclose.
Effect of CD34<sup>+</sup> Cell Dose on Resource Utilization in Patients After High-Dose Chemotherapy With Peripheral-Blood Stem-Cell Support
Authors: Kevin A. Schulman, Robert Birch, Bo Zhen, Neelima Pania, Charles H. Weaver
Journal: Journal of Clinical Oncology (1999)

PURPOSE: The mean time to neutrophil and platelet recovery for patients receiving high-dose chemotherapy (HDC) supported with peripheral-blood stem cells (PBSCs) is related to the dose of CD34 + cells infused. The effect of cell dose on resource utilization after transplantation has not been previously reported. MATERIALS AND METHODS: We assessed CD34 + cell dose and resource utilization for 1,317 patients undergoing transplantation with PBSCs from April 1991 to June 1997. PBSCs were collected after mobilization with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). Daily measurement of the CD34 + content of the PBSC collection was performed by a central laboratory using a single CD34 + analysis technique. Resource utilization included engraftment parameters, length of stay, and transfusion requirements for 100 days posttransplantation. Analysis included descriptive statistics and multiple regression. RESULTS: Mean patient age was 47 years, and 86% of patients were female. Median cell dose was 3.6 × 10 6 /kg and 13.2 × 10 6 /kg for patients receiving less than 5.0 × 10 6 CD34 + cells/kg and 5.0 × 10 6 or more CD34 + cells/kg, respectively. Patients receiving less than 5.0 × 10 6 CD34 + cells/kg were more likely to have metastatic breast cancer or non-Hodgkin's lymphoma and required more platelet and RBC transfusions, 3.3 more hospital days, and increased antibiotic and antifungal use. In univariate analysis, the cost of care was $41,516 (±$20,876 SD) and $32,382 (±$16,353 SD) for patients with less than 5.0 × 10 6 CD34 + cells/kg and 5.0 × 10 6 or more CD34 + cells/kg, respectively. In multivariate analysis, patients with less than 5.0 × 10 6 CD34 + cells/kg had an increase in costs of $5,062 (± $1,262 SE). CONCLUSION: Infusion of more than 5.0 × 10 6 CD34 + cells/kg was associated with a reduction in resource utilization. Achieving a target of 5.0 × 10 6 CD34 + cells/kg should have important clinical and economic benefits for patients.
Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma
Authors: David J. Kwiatkowski, Toni K. Choueiri, André P. Fay, Brian I. Rini, Aaron R. Thorner, Guillermo de Velasco, Magdalena E. Tyburczy, Lana Hamieh, Laurence Albiges, Neeraj Agarwal, Thai H. Ho, Jiaxi Song, Jean-Christophe Pignon, Pablo M. Barrios, M. Dror Michaelson, Eliezer M. Van Allen, Katherine M. Krajewski, Camillo Porta, Sumanta Kumar Pal, Joaquim Bellmunt, David F. McDermott, Daniel Y.C. Heng, Kathryn P. Gray, Sabina Signoretti
Journal: Clinical Cancer Research (2016)

We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445-52. ©2016 AACRSee related commentary by Voss and Hsieh, p. 2320.
Synovial fluid hyaluronan mediates MSC attachment to cartilage, a potential novel mechanism contributing to cartilage repair in osteoarthritis using knee joint distraction
Authors: Thomas G Baboolal, Simon C Mastbergen, Elena Jones, Stuart J Calder, Floris P J G Lafeber, Dennis McGonagle
Journal: Annals of the Rheumatic Diseases (2015)

Knee joint distraction (KJD) is a novel, but poorly understood, treatment for osteoarthritis (OA) associated with remarkable 'spontaneous' cartilage repair in which resident synovial fluid (SF) multipotential mesenchymal stromal cells (MSCs) may play a role. We hypothesised that SF hyaluronic acid (HA) inhibited the initial interaction between MSCs and cartilage, a key first step to integration, and postulate that KJD environment favoured MSC/cartilage interactions.Attachment of dual-labelled SF-MSCs were assessed in a novel in vitro human cartilage model using OA and rheumatoid arthritic (RA) SF. SF was digested with hyaluronidase (hyase) and its effect on adhesion was observed using confocal microscopy. MRI and microscopy were used to image autologous dual-labelled MSCs in an in vivo canine model of KJD. SF-HA was investigated using gel electrophoresis and densitometry.Osteoarthritic-synovial fluid (OA-SF) and purified high molecular weight (MW) HA inhibited SF-MSC adhesion to plastic, while hyase treatment of OA-SF but not RA-SF significantly increased MSC adhesion to cartilage (3.7-fold, p<0.05) These differences were linked to the SF mediated HA-coat which was larger in OA-SF than in RA-SF. OA-SF contained >9 MDa HA and this correlated with increases in adhesion (r=0.880). In the canine KJD model, MSC adhesion to cartilage was evident and also dependent on HA MW.These findings highlight an unappreciated role of SF-HA on MSC interactions and provide proof of concept that endogenous SF-MSCs are capable of adhering to cartilage in a favourable biochemical and biomechanical environment in OA distracted joints, offering novel one-stage strategies towards joint repair.
Negative correlation between respiratory drive and SNIP in amyotrophic lateral sclerosis
Authors: Vitaliano Quaranta, Lorenzo Marra, Pierluigi Carratù, Vito Falcone, Anna Cassano, Silvano Dragonieri, Onofrio Resta
Journal: European Respiratory Journal (2014)

Respiratory Drive is a neurogenic stimulus for physiologic respiratory activity. It has been shown increased or decreased in different pathological conditions. Aim of this study was to evaluate the respiratory drive in Amyotrophic Lateral Sclerosis (ALS), compared to a healthy population, and to examine possible correlations with arterial blood gas (ABG), or with functional parameters.  We enrolled twenty-three (17 males) consecutive patients affected by ALS, and eighteen (13 males) healthy controls. Both groups were compared with rergard to anthropometrics, ABG, functional parameters, and respiratory drive [mouth occlusion pressure (P0.1), VT/Ti, Ti/Ttot].  In patients affected by ALS, we found an increased level of respiratory drive parameters compared to the control group (P0.1 1.64±1.01 vs. 1.21±0.32; p=0.05. VT/Ti 0.46±0.15 vs. 0.38±0.09; p=0.039). SNIP values higher than 20 cmH2O inversely correlated with mouth occlusion pressure (P0.1) (p=0.016; r 2 =-0.328) and with VT/Ti (p=0.044, r 2 =-0.243). It has been also observed a correlation tendency between lower FVC values and increased respiratory drive (p=0.08).  In conclusion, in ALS patients with SNIP higher than 20 cmH2O, we found an augmented respiratory drive activity compared to healthy controls, probably due to a significative reduction of muscular actvity.
Proteins with Highly Evolvable Domain Architectures Are Nonessential but Highly Retained
Authors: Chia-Hsin Hsu, Austin W. T. Chiang, Ming-Jing Hwang, Ben-Yang Liao
Journal: Molecular Biology and Evolution (2016)

The functions of proteins are usually determined by domains, and the sequential order in which domains are connected to make up a protein chain is known as the domain architecture. Here, we constructed evolutionary networks of protein domain architectures in species from three major life lineages (bacteria, fungi, and metazoans) by connecting any two architectures between which an evolutionary event could be inferred by a model that assumes maximum parsimony. We found that proteins with domain architectures with a higher level of evolvability, indicated by a greater number of connections in the evolutionary network, are present in a wider range of species. However, these proteins tend to be less essential to the organism, are duplicated more often during evolution, have more isoforms, and, intriguingly, tend to be associated with functional categories important for organismal adaptation. These results reveal the presence, in many genomes, of genes coding for a core set of nonessential proteins that have a highly evolvable domain architecture and thus a repertoire of genetic materials accessible for organismal adaptation.
Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4–Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus
Authors: Katalin Kis‐Toth, Denis Comte, Maria P. Karampetsou, Vasileios C. Kyttaris, Lakshmi Kannan, Cox Terhorst, George C. Tsokos
Journal: Arthritis & Rheumatology (2015)

Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4; CD244, 2B4) by its ligand SLAMF2 (CD48) modulates the function and expansion of both natural killer cells and a subset of cytotoxic CD8+ T cells. Because the cytotoxicity of CD8+ T lymphocytes isolated from patients with systemic lupus erythematosus (SLE) is known to be impaired, the aim of this study was to assess whether the expression and function of the checkpoint regulator SLAMF4 are altered on CD8+ T cells from patients with SLE.The expression of SLAMF4 by T cells from healthy donors and patients with SLE was determined by quantitative polymerase chain reaction and flow cytometry. T cells were activated with anti-CD3 antibody, and degranulation activity was monitored by the surface expression of lysosome-associated membrane protein 1 (LAMP-1; CD107a). The SLAMF4+ and SLAMF4- CD8+ T cell subpopulations were characterized by LAMP-1, perforin, and granzyme B expression and viral peptide-induced proliferation.SLAMF4 gene and surface protein expression was down-regulated in CD8+ T cells from SLE patients compared with that in cells obtained from healthy donors. Importantly, SLE patients had significantly fewer SLAMF4+ CD8+ T cells compared with healthy donors. SLAMF4- CD8+ T cells from SLE patients had a decreased cytotoxic capacity and decreased proliferative responses to viral peptides. The loss of memory SLAMF4+ CD8+ T cells in SLE patients was linked to the fact that these cells have an increased propensity to lose CD8 expression and become double-negative T cells.A selective loss of SLAMF4+ CD8+ T cells contributes to the compromised ability of T cells from patients with SLE to fight infection.