tbuckley/cabot-search huggingface dataset:
Effect of CMP, carfilzomib (CFZ) plus melphalan-prednisone (MP), on response rates in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM): Results of a phase (Ph) I/II trial.
Authors: Cyrille Touzeau, Brigitte Kolb, Cyrille Hulin, Denis Caillot, Lotfi Benboubker, Mourad Tiab, Xavier Leleu, Murielle Roussel, Carine Chaleteix, Michel Attal, Thierry Facon, Philippe Moreau
Journal: Journal of Clinical Oncology (2013)

8513 Background: MP+thalidomide (MPT) and MP+bortezomib (MPV) have shown significant progression-free survival and overall survival (OS) benefits in NDMM pts &gt; 65 years (y) but are associated with peripheral neuropathy (PN). CFZ, a novel proteasome inhibitor, has shown promising activity and a favorable toxicity profile with low PN rates. Methods: This PhI/II study in NDMM &gt;65y was designed to determine maximum tolerated dose (MTD) of CMP and assess safety and efficacy. In PhI, CFZ was started at 20mg/m 2 , then escalated to 27, 36, and 45mg/m 2 , given IV in 42-day (D) cycles (C) on D1/2/8/9/22/23/29/30 for 9C. Melphalan 9mg/m² and prednisone 60mg/m² were given PO D1–4 of every 45-day cycle. MTD was based on dose-limiting toxicity (DLT) in C1 defined as any grade (G) 4 hematologic adverse event (AE), any hematologic AE preventing aministration of ≥ 2 C1 CFZ doses except G4 thrombocytopenia without bleeding or G4 neutropenia ≤7D, ≥G3 febrile neutropenia, or any ≥G3 nonhematologic AE. Results: As of Jan 6, 2013, 24 pts have been enrolled in PhI: 6 for each dose level. There were 2 DLTs at 45mg/m 2 (fever, hypotension) resulting in a MTD of 36mg/m². In PhII, 45 additional pts received CMP at 36mg/m² CFZ for N=69 total PhI/II pts (median age 74y). ORR was 89% with 51% ≥VGPR. With median follow-up of 12 mo, the projected 2y OS was 89.9%. CMP was well tolerated without PN ≥G2. Conclusions: These results compare favorably to those of MPV, MPT, MP+lenalidomide (R), and R+dex in similar pts (ORR 71% San Miguel NEnglJMed2008, 76% Facon Lancet2007, 80% Palumbo JClinOncol2007 and 85% Rajkumar LancetOncol2010, respectively). CFZ 36mg/m 2 +MP is tolerable and effective in elderly NDMM pts. Treatment is ongoing. Final safety and efficacy data will be presented during the meeting. Clinical trial information: NCT01279694.
Trends in Private Equity Acquisition of Dermatology Practices in the United States
Authors: Sally Tan, Kira Seiger, Peter Renehan, Arash Mostaghimi
Journal: JAMA Dermatology (2019)

<h3>Importance</h3> Private equity (PE) firms invest in dermatology management groups (DMGs), which are physician practice management firms that operate multiple clinics and often acquire smaller, physician-owned practices. Consolidation of dermatology practices as a result of PE investment may be associated with changes in practice management in the United States. <h3>Objective</h3> To describe the scope of PE-backed dermatology practice acquisitions geographically over time. <h3>Design, Setting, and Participants</h3> This cross-sectional study examined acquisitions of dermatology practices by PE-backed DMGs in the United States. Acquisition and investment data through May 31, 2018, were compiled using information from 5 financial databases. Transaction data were supplemented with publicly available information from 2 additional financial databases, 2 financial news outlets, and press releases from DMGs. All dermatology practices acquired by PE-backed DMGs were included. Acquisitions were verified to be dermatology practices that provided medical, surgical, and/or cosmetic clinical care. Private equity financing data were included when available. The addresses of clinics associated with acquired practices were mapped using spatial analytics software. <h3>Main Outcomes and Measures</h3> The number and location of PE practice acquisitions over time were measured based on the date of deal closure, the geographic footprint of each DMG’s acquisition, and the financing of each DMG. <h3>Results</h3> Seventeen PE-backed DMGs acquired 184 practices between May 1, 2012, and May 22, 2018. These acquired practices accounted for an estimated 381 dermatology clinics as of mid-2018 (assessment period from May 1 to August 31). The total number of PE-owned dermatology clinics in the United States was substantially larger because these data did not reflect DMGs that opened new clinics (organic growth); acquisitions data represented only the ownership transfer of existing practices from physician to PE-backed DMG. Practice acquisitions increased each year, from 5 in 2012 to 59 in 2017. An additional 34 acquisitions took place from January 1 to May 31, 2018. The number of financing rounds to sustain transactions mirrored the aforementioned trends in practice acquisitions. Clinics associated with acquired practices spanned at least 30 states, with 138 of 381 clinics (36%) located in Texas and Florida. <h3>Conclusion and Relevance</h3> The study findings suggest that PE firms have a financial stake in an increasing number of dermatology practices throughout the United States. Further research is needed to assess whether and how PE-backed ownership influences clinical decision-making, health care expenditures, and patient outcomes.
Apolipoprotein B and PNPLA3 Double Heterozygosity in a Father–Son Pair With Advanced Nonalcoholic Fatty Liver Disease
Authors: Claire L. Jansson‐Knodell, Samer Gawrieh, Adam D. McIntyre, Tiebing Liang, Robert A. Hegele, Naga Chalasani
Journal: Hepatology (2019)

Jansson‐Knodell, Claire L.; Gawrieh, Samer; McIntyre, Adam D.; Liang, Tiebing; Hegele, Robert A.; Chalasani, Naga Author Information
Association of Coronary Artery Calcium With Long-term, Cause-Specific Mortality Among Young Adults
Authors: Michael D. Miedema, Zeina A. Dardari, Khurram Nasir, Ron Blankstein, Thomas Knickelbine, Sandra Oberembt, Leslee Shaw, John Rumberger, Erin D. Michos, Alan Rozanski, Daniel S. Berman, Matthew J. Budoff, Michael J. Blaha
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The level of coronary artery calcium (CAC) can effectively stratify cardiovascular risk in middle-aged and older adults, but its utility for young adults is unclear. <h3>Objectives</h3> To determine the prevalence of CAC in adults aged 30 to 49 years and the subsequent association of CAC with coronary heart disease (CHD), cardiovascular disease (CVD), and all-cause mortality. <h3>Design, Setting, and Participants</h3> A multicenter retrospective cohort study was conducted among 22 346 individuals from the CAC Consortium who underwent CAC testing (baseline examination, 1991-2010, with follow-up through June 30, 2014; CAC quantified using nonconrast, cardiac-gated computed tomography scans) for clinical indications and were followed up for cause-specific mortality. Participants were free of clinical CVD at baseline. Statistical analysis was performed from June 1, 2017, to May 31, 2018. <h3>Main Outcomes and Measures</h3> The prevalence of CAC and the subsequent rates of CHD, CVD, and all-cause mortality. Competing risks regression modeling was used to calculate multivariable-adjusted subdistribution hazard ratios for CHD and CVD mortality. <h3>Results</h3> The sample of 22 346 participants (25.0% women and 75.0% men; mean [SD] age, 43.5 [4.5] years) had a high prevalence of hyperlipidemia (49.6%) and family history of CHD (49.3%) but a low prevalence of current smoking (11.0%) and diabetes (3.9%). The prevalence of any CAC was 34.4%, with 7.2% having a CAC score of more than 100. During follow-up (mean [SD], 12.7 [4.0] years), there were 40 deaths related to CHD, 84 deaths related to CVD, and 298 total deaths. A total of 27 deaths related to CHD (67.5%) occurred among individuals with CAC at baseline. The CHD mortality rate per 1000 person-years was 10-fold higher among those with a CAC score of more than 100 (0.69; 95% CI, 0.41-1.16) compared with those with a CAC score of 0 (0.07; 95% CI, 0.04-0.12). After multivariable adjustment, those with a CAC score of more than 100 had a significantly increased risk of CHD (subdistribution hazard ratio, 5.6; 95% CI, 2.5-12.7), CVD (subdistribution hazard ratio, 3.3; 95% CI, 1.8-6.2), and all-cause mortality (hazard ratio, 2.6; 95% CI, 1.9-3.6) compared with those with a CAC score of 0. <h3>Conclusions and Relevance</h3> In a large sample of young adults undergoing CAC testing for clinical indications, 34.4% had CAC, and those with elevated CAC scores had significantly higher rates of CHD and CVD mortality. Coronary artery calcium may have potential utility for clinical decision-making among select young adults at elevated risk of cardiovascular disease.
Familial risk in pediatric cancer and implications for practice.
Authors: Karen Curtin, Ken R Smith, Alison M Fraser, Richard Pimentel, Wendy Kohlmann, Joshua David Schiffman
Journal: Journal of Clinical Oncology (2012)

9561 Background: Using a unique genealogical resource, the Utah Population Database, we examined risk of cancer in 1st- through 3rd-degree relatives of 4,482 pediatric cancer cases ≤18 years old diagnosed between 1966 and 2009. We quantified cancer risk in relatives of children with cancer in order to determine evidence of a familial aggregation of cancer, identify high-risk pedigrees, and inform counseling protocols for genetic testing and screening. Methods: We estimated cancer risk in relatives of pediatric cases compared to random population controls matched 5:1 on sex, birth year, and birthplace. Odds ratios were calculated using conditional logistic regression, adjusting for number of biological relatives, their degree of relatedness, and their person-years at risk. We included all relatives of cases and controls with followup who linked to a pedigree of ≥2 generations; this approach has been shown to lead to unbiased risk estimates. As observations within families are non-independent, a robust variance estimator for cluster-correlated data was incorporated. Results: Mostly siblings, 1st-degree relatives (N=49 affected) of pediatric cases were at 2-fold increased risk of being diagnosed at age&lt;19 with cancer themselves (p&lt;10 -4 ); siblings of cases diagnosed at age&lt;5 had a 4-fold risk of pediatric cancer (p&lt;10 -7 ). Likewise, 2nd-degree relatives (N=61 affected) and cousins (N=105 affected) of cases had a ~2-fold risk of childhood cancer (p&lt;10 -4 ). Proband siblings were at increased risk for leukemia, brain tumor, epithelial neoplasia, and bone cancer. While 1st-degree relatives of pediatric cases had a slight increased risk of adult-onset cancer, when they do develop cancer they exhibit a 50% increased risk of a Li-Fraumeni Syndrome-related tumor diagnosis (N=142 affected relatives; p&lt;10 -4 ). Conclusions: Our findings provide evidence of familial aggregation of cancer and suggest a higher percent of pediatric cancers are related to hereditary syndromes than are adult cancers. We encourage a 3-generation family history be collected and routinely updated for all pediatric cancer patients, and those children with family histories of early-onset cancer be referred for genetic counseling and early surveillance when appropriate.
Symptoms and perception of airway obstruction in asthmatic patients: Clinical implications for use of reliever medications
Authors: Peter J. Barnes, Stanley J. Szefler, Helen K. Reddel, Bradley E. Chipps
Journal: Journal of Allergy and Clinical Immunology (2019)

Asthma causes the unpleasant sensation of breathlessness (dyspnea) caused by airway obstruction. Patients with poor perception of airway obstruction are at risk of delay in seeking medical attention and undertreatment, which can lead to avoidable deaths. Conversely, those with heightened perception are at risk of overtreatment and iatrogenic adverse effects with reliever medications, anxiety, and unnecessary use of health care resources.We sought to review evidence about symptom misperception in asthmatic patients and how to identify and manage affected patients, particularly with regard to reliever medications.We conducted a systematic literature search for studies of perception of airway function in asthmatic patients. We searched the OVID (Medline and Medline [R] in process [PubMed]), Embase, and Adisearch/Odyssey databases, restricting our search to human studies published in English from 1990-2018, with no restrictions on age, sex, or racial origin.We found that both underperception and overperception assessed during induced bronchoconstriction or bronchodilation or during changes in airway resistance were common across all age groups and that aging, disease severity, smoking, sex, ethnicity, psychologic factors, and medication are all associated with differences in perception. Importantly, airway inflammation was associated with impaired perception and a history of severe or near-fatal asthma. We also identified knowledge gaps, such as whether an individual patient's perception varies over time and the influence perception has on patients' use of reliever medication.We found that abnormal perception of airway obstruction has important clinical implications for the management of patients with asthma.
Resident memory CD8 T cells persist for years in human small intestine
Authors: Raquel Bartolomé-Casado, Ole J.B. Landsverk, Sudhir Kumar Chauhan, Lisa Richter, Danh Phung, Victor Greiff, Louise F. Risnes, Ying Yao, Ralf S. Neumann, Sheraz Yaqub, Ole Øyen, Rune Horneland, Einar Martin Aandahl, Vemund Paulsen, Ludvig M. Sollid, Shuo-Wang Qiao, Espen S. Baekkevold, Frode L. Jahnsen
Journal: The Journal of Experimental Medicine (2019)

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for &amp;gt;1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.
Clinical utility of the preoperative Glasgow prognostic score in patients undergoing potentially curative resection for colorectal cancer.
Authors: Donald C. Mcmillan, Campbell SD Roxburgh, Paul G Horgan
Journal: Journal of Clinical Oncology (2012)

3611 Background: There is now good evidence that, in addition to TNM stage, the pre-operative combination of the standardised measurements of C-reactive protein and albumin, the Glasgow Prognostic Score (mGPS) provides valuable prognostic information. The aim of the present study was to examine the clinical application of the pre-operative mGPS in a large mature cohort of patients undergoing potentially curative resection for colorectal cancer. Methods: From a prospectively maintained database, consecutive patients (n= 797) with histologically proven colorectal cancer who were considered to have undergone potentially curative resection between January 1997 and December 2010 in a single surgical unit at the Royal Infirmary, Glasgow were included in the study. Results: Patients with an elevated mGPS were more likely to be older (p&lt;0.001), female (p&lt;0.05), have colonic tumours (&lt;0.001), present as an emergency (p&lt;0.001), had higher TNM stage (p&lt;0.05) and more likely to die of their disease (p&lt;0.01). The median follow-up was 66 months and using 3 year cancer-specific mortality as an endpoint, the area under the receiver operator curve was 0.652 (95% CI, 0.591–0.714; p&lt;0.001) for the mGPS and 0.668 (95% CI, 0.610–0.727; p&lt;0.001) for TNM stage. The cancer-specific survival, at 3 years, varied between 86% and 64% according to the mGPS and between 88% and 72% according to TNM stage. The cancer-specific survival, at 3 years, in patients with a mGPS 0 was 91% and 81% for TNM stage II and III respectively. The cancer-specific survival, at 3 years, in patients with a mGPS 1 was 89% and 66% for TNM stage II and III respectively. The cancer-specific survival, at 3 years, in patients with a mGPS 2 was 77% and 43% for TNM stage II and III respectively. Conclusions: The results of the present study show the clinical utility of the pre-operative mGPS in predicting cancer specific survival of potentially curative surgery for colorectal cancer.
MIX —The first results of the ongoing prospective multicentre phase II study
Authors: M. Lux
Journal: Journal of Clinical Oncology (2006)

10756 Background: The treatment of patiens with metastatic breast cancer (MBC) previously treated with anthracycline represents a significant challenge. Several studies have shown that oral capecitabine is an effective and well-tolerated agent. Mitomycin C has notable therapeutic activity and presents additive effects. Primary endpoints of this ongoing prospective, multi-centre, phase II study are to evaluate the safety and efficacy of the combination. TTP and QoL are secondary endpoints. Methods: Patients receive six cycles of mitomycin C 8 mg/m 2 , d1, and capecitabine 2,000 mg/m 2 , d1–14, q21d. 46 patients are planned for treatment, 17 patients are already enrolled. Evaluation (RECIST) has to be done after the fourth and sixth cycle. Safety is evaluated in all patients. Data for 16 patients were analysed, one patient has not be monitored up to date. Results: All patients have been pre-treated with anthracyclines and 62.5% with taxanes. 68.8% had multiple sites of metastases. 6.3% received just 1 cycle, 6.3% 2, 12.5% 3, 31.3% 4 and 43.8% 6 cycles. 11.3% of the cycles received dose reduction and 12.7% interval prolongation. Following grade 3- and 4-toxicities (NCI CTC) were observed in the 71 cycles: dyspnea [3 × grade 3 and 2 × grade 4; all occurred in patients with pulmonal metastases or pleural effusions], nausea (1 × grade 3), thrombopenia (2 × grade 3), fatigue (1 × grade 3), mucositis (1 × grade 3) and hand-foot-syndrome (4 × grade 3). Best response rates were: 18.8% progressive disease, 37.5% stable disease, 31.3% partial remission and 12.5% complete remission. Conclusions: The treatment with mitomycin C and capecitabine presents a favourable safety profile, which is well tolerated and active in this setting. The safety commission recommends the continuation after revision of the preliminary data. No significant financial relationships to disclose.
Measuring transcripts of components of the BRCA1 DNA repair pathway, components of the hippo-YAP pathway, β-TrCP, HER2, AEG-1, EZH2 and other genes in advanced gastric cancer.
Authors: Jia Wei, Carlota Costa, Baorui Liu, Jose Javier Sanchez, Ana Gimenez Capitan, Lixia Yu, Zhengyun Zou, Xiaoping Qian, Xia Sun, Jie Shen, Clara Mayo, Miguel Angel Molina-Vila, Susana Benlloch, Miquel Taron, Rafael Rosell
Journal: Journal of Clinical Oncology (2012)

4068 Background: The primary goal of this study was to classify gastric cancer in two different sub-groups. We speculated that HER2-positive gastric cancers could be regulated by β-TrCP, while tumors unaffected by β-TrCP activation could be more dependent on the Hippo-YAP signaling pathway, in which TAZ increases the expression of AXL. Gastric cancer can overexpress AEG-1 and EZH2. The relationship between EZH2 and the Hippo-YAP pathway was explored in this study. We also explored BRCA1 complexes, including upstream components, such as 53BP1 and MMSET. Methods: Paraffin-embedded samples were collected from 132 advanced gastric cancer patients (p) treated with first-line FOLFOX, 58 of whom received second-line docetaxel-based treatment. Gene expression levels of HER2, β-TrCP, TAZ, AXL, EZH2, AEG-1, BRCA1, and genes involved in DNA repair pathways (RAP80, PIAS1, PIAS4, MDC1, 53BP1, MMSET, and UBC9) were quantified by real-time PCR. BIM, IDO, and SPINK1 were also examined. Results: A close correlation was found for the majority of the genes, for example, BRCA1-MMSET (rho=0.28; P=0.002) and AXL-TAZ (rho=0.58; P&gt;0.001). Median overall survival (OS) was 12.5 months (m). Among the 58 p receiving second-line docetaxel, in p with high levels of BRCA1, OS was 24.9 m, while it was 19.1 m in p with intermediate levels and 9.5 m in p with low levels (P=0.009). OS was 28.6 in p with high levels of MMSET, 13.8 in p with intermediate levels and 12.3 in p with low levels (P=0.001). In the multivariate analysis, only BRCA1 was a significant marker for OS (Table). Conclusions: The study showed the predictive value of BRCA1, which could be useful for customizing chemotherapy with or without docetaxel. In addition, MMSET requires further study since it is involved in DNA repair upstream of BRCA1. [Table: see text]
Abstract 16940: Serum Amine-based Metabolites and Their Association With Outcomes in Primary Prevention Implantable Cardioverter Defibrillator Patients
Authors: Yiyi Zhang, Elena Blasco-Colmenares, Amy Harms, Barry London, Indrani Halder, Madhurmeet Singh, Samuel Dudley, Rebecca Gutmann, Eliseo Guallar, Thomas Hankemeier, Gordon Tomaselli, Alan Cheng
Journal: Circulation (2015)

Background: Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. Objective: We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). Methods and Results: Baseline serum was quantitatively profiled for 42 known biologically-relevant amine-based metabolites among 402 patients from the PROSE-ICD Study (derivation group) and 240 patients from the GRADE Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. In multivariate Cox models adjusted for traditional cardiovascular risk factors, 3 amines (N-methyl-L-histidine, symmetric dimethylarginine [SDMA], and L-kynurenine) were associated with all-cause mortality in both derivation and validation cohorts (Figure 1). Additionally, L-histidine, SDMA, L-kynurenine, L-4-hydroxyproline, and L-glutamine were associated with ventricular arrhythmia-induced ICD shocks in one of the cohorts, suggesting their potential to be novel markers of ventricular arrhythmia (Figure 2). Conclusions: Utilizing metabolic profiling, we identified several novel amine markers that were associated with appropriate shock and mortality in primary prevention ICD patients. These findings shed insight into the potential biologic pathways leading to adverse events in these patients, which will in turn aid the development of newer therapeutics for reducing SCD and mortality.
Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)
Authors: C. Escuriola Ettingshausen, Erik Berntorp, Yesim Dargaud, Zeynep Gutowski, Claude Negrier, Anna Pavlova, Johannes Oldenburg
Journal: Blood (2018)