tbuckley/cabot-search huggingface dataset:
Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer.
Authors: Z U Rahman, D K Frye, A U Buzdar, T L Smith, L Asmar, R E Champlin, G N Hortobagyi
Journal: Journal of Clinical Oncology (1997)

PURPOSE Most of the data about high-dose chemotherapy (HDCT) for metastatic breast cancer are derived from phase II studies. The interpretation of these data depends on comparisons with data from properly selected historical control patients treated with standard therapy under similar circumstances. We report the long-term results of patients with metastatic breast cancer who were eligible for HDCT but were treated with doxorubicin-containing standard-dose chemotherapy. PATIENTS AND METHODS Prospectively collected data from 18 successive doxorubicin-containing protocols for the treatment of metastatic breast cancer were evaluated. Using common eligibility criteria for HDCT, we identified patients who would have been candidates for HDCT. We analyzed response rates, progression-free survival (PFS), and overall survival (OS) for all patients, potential HDCT candidates, and noncandidates. RESULTS A total of 1,581 patients was enrolled onto the 18 studies. Six hundred forty-five were HDCT candidates, and 936 were noncandidates. The complete response rate was 27% for HDCT candidates and 7% for noncandidates; median PFS was 16 and 8 months and median OS was 30 and 17 months, respectively. Survival rates for HDCT candidates and noncandidates, respectively, were 21% and 6% at 5 years and 7% and 2% at 10 years. CONCLUSION This study suggests that encouraging results of single-arm trials of HDCT could partially be due to selection of patients with better prognoses and further stresses the importance of completing ongoing randomized trials of HDCT to assess the relative efficacy of HDCT in patients with metastatic breast cancer.
Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis
Authors: Aaron D. Viny, Christopher J. Ott, Barbara Spitzer, Martin Rivas, Cem Meydan, Efthymia Papalexi, Dana Yelin, Kaitlyn Shank, Jaime Reyes, April Chiu, Yevgeniy Romin, Vitaly Boyko, Swapna Thota, Jaroslaw P. Maciejewski, Ari Melnick, James E. Bradner, Ross L. Levine
Journal: The Journal of Experimental Medicine (2015)

Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function.
A Familial C3GN Secondary to Defective C3 Regulation by Complement Receptor 1 and Complement Factor H
Authors: Sophie Chauvet, Lubka T. Roumenina, Sarah Bruneau, Maria Chiara Marinozzi, Tania Rybkine, Elizabeth C. Schramm, Anuja Java, John P. Atkinson, Jean Claude Aldigier, Frank Bridoux, Guy Touchard, Veronique Fremeaux-Bacchi
Journal: Journal of the American Society of Nephrology (2015)

C3 glomerulopathy is a recently described form of CKD. C3GN is a subtype of C3 glomerulopathy characterized by predominant C3 deposits in the glomeruli and is commonly the result of acquired or genetic abnormalities in the alternative pathway (AP) of the complement system. We identified and characterized the first mutation of the C3 gene (p. I734T) in two related individuals diagnosed with C3GN. Immunofluorescence and electron microscopy studies showed C3 deposits in the subendothelial space, associated with unusual deposits located near the complement receptor 1 (CR1)-expressing podocytes. In vitro, this C3 mutation exhibited decreased binding to CR1, resulting in less CR1-dependent cleavage of C3b by factor 1. Both patients had normal plasma C3 levels, and the mutant C3 interacted with factor B comparably to wild-type (WT) C3 to form a C3 convertase. Binding of mutant C3 to factor H was normal, but mutant C3 was less efficiently cleaved by factor I in the presence of factor H, leading to enhanced C3 fragment deposition on glomerular cells. In conclusion, our results reveal that a CR1 functional deficiency is a mechanism of intraglomerular AP dysregulation and could influence the localization of the glomerular C3 deposits.
Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry
Authors: J. Wagstaff, R. Jones, R. Hawkins, E. Porfiri, L. Pickering, A. Bahl, J. Brown, S. Buchan
Journal: Annals of Oncology (2015)

The aim of the RECCORD registry was to gather real-world UK data on the use of targeted therapies in renal cell carcinoma (RCC) and assess clinical outcomes. Here, demographic and outcome data are presented with the treatment patterns and demographic profile of patients on the registry.Patients were retrospectively identified at seven UK hospitals with large cancer centres in England (5), Scotland (1) and Wales (1). Anonymised data were collected through an online registry covering demographics, treatments and outcomes. Five hundred and fourteen UK adult patients with metastatic RCC were included in the study for analysis. Patients were included if they were treated for metastatic RCC at one of the seven centres, and started systemic anti-cancer treatment from March 2009 to November 2012 inclusive. In addition to demographic factors, the principal outcome measures were overall survival (OS), time to disease progression and toxicity.The majority of first-line treatment was with sunitinib; first-line use of pazopanib increased as the study progressed. 15.8% of patients received second-line treatment, half of whom were prescribed everolimus. Median OS (from initiation of first-line treatment) was 23.9 months (95% confidence interval [CI] 18.6-29.1 months), similar to that reported for clinical trials of targeted RCC therapies [Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615-621; Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013; 20: 944-955; Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590]. OS was significantly longer for those who received second-line treatment after disease progression (33.0 months; 95% CI 30.8-35.2 months) than those who did not (20.9 months; 95% CI 16.4-25.3 months; P = 0.008).RECCORD is a large 'real-world' database assessing metastatic RCC treatment patterns and outcomes. Treatment patterns changed over time as targeted therapies were approved and became widely available; survival data in RECCORD are consistent with those reported for systemic treatments in clinical trials. Kaplan-Meier analysis of results demonstrated that receiving second-line therapy was a major prognostic factor for longer OS.
Effect of continuous deep sedation on survival in patients with advanced cancer (J-Proval): a propensity score-weighted analysis of a prospective cohort study
Authors: Isseki Maeda, Tatsuya Morita, Takuhiro Yamaguchi, Satoshi Inoue, Masayuki Ikenaga, Yoshihisa Matsumoto, Ryuichi Sekine, Takashi Yamaguchi, Takeshi Hirohashi, Tsukasa Tajima, Ryohei Tatara, Hiroaki Watanabe, Hiroyuki Otani, Chizuko Takigawa, Yoshinobu Matsuda, Hiroka Nagaoka, Masanori Mori, Yo Tei, Ayako Kikuchi, Mika Baba, Hiroya Kinoshita
Journal: The Lancet Oncology (2015)
Pfizer and Allergan agree $160bn merger deal
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

<h3>Introduction</h3> Lung clearance index (LCI) is a sensitive measure of lung disease in infants, with potential applications in clinical practice and research. However, measuring LCI in infants is technically challenging and there is no simple method of assessing LCI outside of specialist research laboratories in this population. We have previously described an alternative method of measuring LCI, in which expired gas is collected and analysed to derive functional residual capacity (FRC) and LCI without directly measuring flow. This eliminates one of the major technical challenges, whilst also reducing the system’s dead space. This method is highly accurate <i>in vitro</i>, with a mean accuracy of FRC measurement to within 1%, down to FRC of 100ml.<sup>1</sup> The method does not require large external gas tanks, and washout is performed breathing room air, making the system fully portable. <h3>Aim</h3> To assess the performance of this method <i>in vivo.</i> <h3>Method</h3> Healthy controls and infants with CF are currently being recruited to undergo LCI measurement using this method. Practical applicability of the system is determined by the number of successful tests and within-subject repeatability, defined as coefficient of variation (CV%) of same-visit repeats. Comparison will be made with LCI measurements obtained using a respiratory mass spectrometer, currently considered the gold standard for infant LCI measurement. <h3>Results</h3> To date, 10 healthy controls (mean age 53 weeks) and 2 infants with CF (mean age 55 weeks) have successfully undergone LCI measurement using this method. Mean LCI in controls was 6.62 (range 5.79–7.91). Mean within-subject CV% was 5.9%. Mean LCI in infants with CF was 7.63 (CV 5%). <h3>Conclusion</h3> Preliminary data suggest this is a feasible and reproducible method of performing LCI in infants. Results in both infants with CF and controls fall within ranges predicted by the respiratory mass spectrometer<sup>2</sup> and within accuracy limits set by international guidelines. This could provide a more accessible alternative to current technologies, enabling this test to be offered in more centres. <h3>References</h3> Shawcross, <i>et al</i>. <i>Ped Pulmonol</i> 2016;<b>51</b>:491–497. Lum, <i>et al</i>. <i>Eur Respir J</i> 2013;<b>41</b>:1371–7.
Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy.
Authors: G L Phillips, J D Shepherd, M J Barnett, P M Lansdorp, H G Klingemann, J J Spinelli, T J Nevill, K W Chan, D E Reece
Journal: Journal of Clinical Oncology (1991)

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.
Waldenström's macroglobulinemia: a clinical perspective in the era of novel therapeutics
Authors: M.A. Dimopoulos, E. Kastritis, I.M. Ghobrial
Journal: Annals of Oncology (2015)

Waldenström's macroglobulinemia (WM) is a rare, low-grade malignancy with no established standard of care. Rituximab regimens are most commonly used, supported by their efficacy in hematologic malignancies, including WM. A growing number of investigational regimens for WM have been evaluated in phase II clinical trials, including single-agent and combination strategies that include newer-generation monoclonal antibodies (ofatumumab and alemtuzumab), proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory agents (thalidomide and lenalidomide), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), a Bruton's tyrosine kinase inhibitor (ibrutinib), and a histone deacetylase inhibitor (panobinostat). Other novel agents are in early-stage development for WM. International treatment guidelines for WM suggest suitable regimens in the newly diagnosed and relapsed/refractory settings, in accordance with patient age, disease presentation, and efficacy and safety profiles of particular drugs. These factors must be considered when choosing appropriate therapy for individual patients with WM, to maximize response and prolong survival, while minimizing the risk of adverse events. This review article provides a clinical perspective of the modern management of patients with WM, in the context of available trial data for novel regimens and recently updated treatment guidelines.
A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes
Authors: Tiffany C. Scharschmidt, Kimberly S. Vasquez, Hong-An Truong, Sofia V. Gearty, Mariela L. Pauli, Audrey Nosbaum, Iris K. Gratz, Michael Otto, James J. Moon, Jan Liese, Abul K. Abbas, Michael A. Fischbach, Michael D. Rosenblum
Journal: Immunity (2015)
Screening for recurrent breast cancer--its effectiveness and prognostic value.
Authors: R Tomin, W L Donegan
Journal: Journal of Clinical Oncology (1987)

Performance of periodic follow-up examinations after mastectomy for breast cancer is standard practice, primarily for early detection and treatment of recurrence. This study was designed to determine whether this routine screening resulted in significant survival benefit for the patient. The medical records of 1,230 women treated for cure of invasive carcinoma of the breast were reviewed, and 248 cases of recurrence were identified for analysis. Only 36% of recurrences were discovered asymptomatically. Asymptomatic recurrence was associated with favorable biologic factors, ie, more frequent estrogen receptor (ER) positivity and initial node negative status, and survival was superior to that of others. This was particularly true for occult local recurrence. However, compliance with a present schedule of examinations did not confer superior survival. It was concluded that (1) routine screening after mastectomy detects few recurrences that are not already symptomatic, and (2) the superior survival associated with discovery of occult recurrence may result from the influences of lead time and length bias.
Trends in Modifiable Risk Factors Are Associated With Declining Incidence of Hospitalized and Nonhospitalized Acute Coronary Heart Disease in a Population
Authors: Jan Mannsverk, Tom Wilsgaard, Ellisiv B. Mathiesen, Maja-Lisa Løchen, Knut Rasmussen, Dag S. Thelle, Inger Njølstad, Laila Arnesdatter Hopstock, Kaare Harald Bønaa
Journal: Circulation (2015)

Few studies have used individual person data to study whether contemporary trends in the incidence of coronary heart disease are associated with changes in modifiable coronary risk factors.We identified 29 582 healthy men and women ≥25 years of age who participated in 3 population surveys conducted between 1994 and 2008 in Tromsø, Norway. Age- and sex-adjusted incidence rates were calculated for coronary heart disease overall, out-of-hospital sudden death, and hospitalized ST-segment-elevation and non-ST-segment-elevation myocardial infarction. We measured coronary risk factors at each survey and estimated the relationship between changes in risk factors and changes in incidence trends. A total of 1845 participants had an incident acute coronary heart disease event during 375 064 person-years of follow-up from 1994 to 2010. The age- and sex-adjusted incidence of total coronary heart disease decreased by 3% (95% confidence interval, 2.0-4.0; P<0.001) each year. This decline was driven by decreases in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in coronary risk factors accounted for 66% (95% confidence interval, 48-97; P<0.001) of the decline in total coronary heart disease. Favorable changes in cholesterol contributed 32% to the decline, whereas blood pressure, smoking, and physical activity each contributed 14%, 13%, and 9%, respectively.We observed a substantial decline in the incidence of coronary heart disease that was driven by reductions in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in modifiable coronary risk factors accounted for 66% of the decline in coronary heart disease events.
Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression
Authors: Brygida Bisikirska, Mukesh Bansal, Yao Shen, Julie Teruya-Feldstein, Raju Chaganti, Andrea Califano
Journal: Cancer Research (2015)

Abstract Follicular lymphoma, the most common indolent subtype of non-Hodgkin lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from the time of diagnosis. However, in 20% to 60% of follicular lymphoma patients, transformation to aggressive diffuse large B-cell lymphoma (DLBCL) reduces median survival to only 1.2 years. The specific functional and genetic determinants of follicular lymphoma transformation remain elusive, and genomic alterations underlying disease advancement have only been identified for a subset of cases. Therefore, to identify candidate drivers of follicular lymphoma transformation, we performed systematic analysis of a B-cell–specific regulatory model exhibiting follicular lymphoma transformation signatures using the Master Regulator Inference algorithm (MARINa). This analysis revealed FOXM1, TFDP1, ATF5, HMGA1, and NFYB to be candidate master regulators (MR) contributing to disease progression. Accordingly, validation was achieved through synthetic lethality assays in which RNAi-mediated silencing of MRs individually or in combination reduced the viability of (14;18)-positive DLBCL (t-DLBCL) cells. Furthermore, specific combinations of small-molecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCL cells. Collectively, our findings indicate that MR analysis is a valuable method for identifying bona fide contributors to follicular lymphoma transformation and may therefore guide the selection of compounds to be used in combinatorial treatment strategies. Cancer Res; 76(3); 664–74. ©2015 AACR.
Women and tobacco: Edited by C Chollat-Traquet. (Pp 128; $23.40.) Geneva: WHO, 1992. ISBN 92-4-156147-5
Authors: J. D Folts, H. S Demrow
Journal: Cardiovascular Research (1995)

Journal Article Women and tobacco: Edited by C Chollat-Traquet. (Pp 128; $23.40.) Geneva: WHO, 1992. ISBN 92-4-156147-5 Get access Women and Tobacco. Edited by Chollat-Traquet C. (Pp 128; $23.40.) Geneva: WHO, 1992. ISBN 92-4-156147-5. John D Folts, John D Folts Madion, WI, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Heather S Demrow Heather S Demrow Madion, WI, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 2, February 1995, Pages 292–293, https://doi.org/10.1016/S0008-6363(95)90018-7 Published: 01 February 1995
Cricket injuries: a longitudinal study of the nature of injuries to South African cricketers
Authors: R A Stretch
Journal: British Journal of Sports Medicine (2003)

To determine the incidence and nature of injuries sustained by elite cricketers during a three season period in order to identify possible injury patterns.Thirty six physiotherapists and 13 doctors working with 11 provincial and the South African national teams completed a questionnaire for each cricketer who presented with an injury during each season to determine anatomical site of injury, month of injury during the season, diagnosis, mechanism of injury, whether it was a recurrence of a previous injury, whether the injury had recurred again during the season, and biographical data.A total of 436 cricketers sustained 812 injuries. Bowling (41.3%), fielding and wicketkeeping (28.6%), and batting (17.1%) accounted for most of the injuries. The lower limbs (49.8%), upper limbs (23.3%), and back and trunk (22.8%) were most commonly injured. The injuries occurred primarily during first class matches (27.0%), limited overs matches (26.9%), and practices (26.8%) during the early part of the season. Acute injuries made up 64.8% of the injuries. The younger players (up to 24 years) sustained 57% of the first time injuries, and the players over 24 years of age sustained 58.7% of the injuries that recurred from a previous season. The injuries were mainly soft tissue injuries predominantly to muscle (41.0%), joint (22.2%), tendon (13.2%), and ligament (6.2%). The primary mechanism of injury was the delivery and follow through of the fast bowler (25.6%), overuse (18.3%), and fielding (21.4%).The results indicate a pattern of cause of injury, with the young fast bowler most likely to sustain an acute injury to the soft tissues of the lower limb while participating in matches and practices during the early part of the season.
Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies
Authors: Jinal N Bhiman, Colin Anthony, Nicole A Doria-Rose, Owen Karimanzira, Chaim A Schramm, Thandeka Khoza, Dale Kitchin, Gordon Botha, Jason Gorman, Nigel J Garrett, Salim S Abdool Karim, Lawrence Shapiro, Carolyn Williamson, Peter D Kwong, John R Mascola, Lynn Morris, Penny L Moore
Journal: Nature Medicine (2015)