tbuckley/cabot-search huggingface dataset:
The effect of chemotherapy-induced anemia on the risk of dose delay and dose reduction.
Authors: Leila Family, Chun Chao, Lanfang Xu, Kimberly Cannavale, Olivia Sattiyapiwat, John Page, Roberto Rodriguez, Hairong Xu
Journal: Journal of Clinical Oncology (2015)

e20689 Background: Chemotherapy-induced neutropenia has been shown to be associated with dose delay and dose reduction. The effect of anemia is less known. The current study aims to evaluate moderate and severe anemia as potential risk factors for dose delay/dose reduction in subsequent cycles of chemotherapy. Methods: We identified a cohort of Kaiser Permanente patients diagnosed with incident non-Hodgkin’s lymphoma (NHL), breast, lung, gastric, ovarian or colorectal cancers between 2010-2012. Generalized linear mixed effects models were used to study the effect of anemia (grade 2 and 3-4 vs. grade 1/none) on subsequent chemotherapy dose delay/dose reduction, adjusting for potential confounders. Dose delay was defined as a ≥3 day delay from the expected administration of a given cycle. Dose reduction was defined as >15% decrease in dose for one or more myelosuppressive agents in a cycle. Results: Our study included 2043 breast, 558 colorectal, 113 gastric, 463 lung, 204 ovarian, and 574 NHL cancer patients. Anemia was significantly associated with subsequent dose delay/reduction overall, by stage, and for all cancer types except NHL (Table). Conclusions: We found that the occurrence of grade 2+ increased the risk of having a dose delay and/or dose reduction in the subsequent chemotherapy cycle. Residual confounding due to regimen should be considered in the future. Odds ratios* for the effect of anemia on dose delay/reduction. Cancer Type All Stage I-III Stage IV Overalla OR (95% CI) OR (95% CI) OR (95% CI) Grade 2b 1.46 (1.32, 1.62) 1.33 (1.18-1.49) 1.94 (1.58-2.38) Grade 3-4 2.02 (1.41, 2.89) 1.81 (1.18-2.76) 2.83 (1.42-5.62) Breast Grade 2 1.36 (1.17, 1.58) Grade 3-4 1.91 (1.15, 3.17) Colorectal Grade 2 1.41 (0.99, 2.02) Grade 3-4 7.48 (1.49, 37.67) Gastric Grade 2 2.07 (1.13, 3.77) Grade 3-4 1.78 (0.21, 15.26) Lung Grade 2 1.37 (1.02, 1.85) Grade 3-4 3.94 (1.83, 8.53) Ovarian Grade 2 1.24 (0.88, 1.75) Grade 3-4 6.13 (2.17, 17.31) NHL Grade 2 1.27 (0.94, 1.71) Grade 3-4 1.24 (0.57, 2.69) *Adjusted for age, sex, race/ethnicity, stage, cycle, comorbidities, platelet, liver function, kidney function, absolute neutrophil count, febrile neutropenia. a Adjusted for transfusion. bGrade 2: Hgb 8.0-9.9 g/dl; grade 3-4: Hgb <6.5-7.9 g/dl.
Genetic mechanisms and heterogeneity in familial myeloid leukemia
Authors: Catherine Carmichael, Ella Wilkins, Henrik Bengsston, Terry Speed, Robert Escher, Joelle Michaud, Ping Cannon, Feng-Qian Li, Graeme Suthers, Meryl Altree, Carolyn Butcher, Richard D'Andrea, Mark Currie, Graham Young, Nigel Patton, Kenneth Bradstock, Peter Bardy, Uday Popat, Olufunmilayo Olopade, Marshall Horwitz, Hamish Scott
Journal: Clinical Cancer Research (2007)

A53   Initial and downstream steps in leukemogenesis may be elucidated through studying families inheriting a predisposition to a purely haematological malignancy. These families allow the unique opportunity to study the “life” of a cancer stem cell throughout disease formation and shed light on the mechanisms involved in disease progression. To date, only two genes have been shown to be involved in familial AML, transcription factors RUNX1 and CEBPA. Only limited knowledge of the downstream events following these germline mutations has been attained. The study presented here is a comprehensive screen of not only germline RUNX1 and CEBPA mutations in familial AML, but also somatic events occurring downstream of these mutations throughout disease progression.  We have identified novel mutations in RUNX1 and a previously identified mutation in CEBPA in five pedigrees (four previously unpublished). We have also identified five pedigrees in which neither RUNX1 nor CEBPA are responsible. This finding confirms that genetic heterogeneity exists and additional leukaemia driver genes, that likely play important roles in sporadic leukaemia, await discovery.  In six pedigrees with germline RUNX1 or CEBPA mutation we further investigated the downstream events occurring during progression of disease, utilising affected tissue from different stages of leukemogenesis. We identified several novel secondary hits, including the first described cases of secondary hits to RUNX1 following germline mutation, and an individual with triallelic RUNX1 aberration. We also observed a marked reduction in expression from two separate RUNX1 alleles with distinct mutations; one nonsense and one missense.  Finally, using a combination of karyotype and SNP chip analyses, we observed both known and novel genomic copy number variations (CNVs) at several loci in 3 individuals. These loci involved genes such as RUNX1, ATM, FLT3 and the homeobox gene CDX2. However, in the remaining 4 individuals studied, we did not identify any potentially pathogenic CNVs. This implicates the involvement of other unidentified hits, such as epigenetic and/or point mutations, or loss of heterozygosity (LOH) without copy number variation. LOH will soon be addressed utilising SNP chip homozygosity call differences between affected and unaffected DNA samples.  Familial studies of leukemogenesis, such as presented here, will shed light on the initial steps in malignant transformation, and allow further characterisation of the pathways and mechanisms involved in leukemogenesis. This will aid in the development of novel therapeutic and treatment initiatives.
Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency
Authors: Dirk J. van Veldhuisen, Piotr Ponikowski, Peter van der Meer, Marco Metra, Michael Böhm, Artem Doletsky, Adriaan A. Voors, Iain C. Macdougall, Stefan D. Anker, Bernard Roubert, Lorraine Zakin, Alain Cohen-Solal
Journal: Circulation (2017)

Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined.We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data.A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care.Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562.
NGS-based multi-gene panel analysis in <i>BRCA1/2</i>-negative breast and ovarian cancer families.
Authors: Esther Pohl, Jan Hauke, Judit Horvath, Bernd Dworniczak, Andrea Gehrig, Dieter Niederacher, Norbert Arnold, Christian Sutter, Mateja Smogavec, Walter Just, Bernhard H.F. Weber, Julia Hentschel, Ulrike Faust, Karl Hackmann, Gunnar Schmidt, Eva Gross, Juliane Ramser, Kerstin Rhiem, Eric Hahnen, Rita K. Schmutzler
Journal: Journal of Clinical Oncology (2017)

1526 Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic mutations in the BRCA1 or BRCA2 genes. The population-specific mutation prevalence of non- BRCA1/2 genes associated with familial BC and/or OC is largely unknown and was determined in a large German cohort. Methods: Here, we present next-generation sequencing (NGS) data established from TruRisk (GC-HBOC-designed) or TruSight cancer gene panels. A cohort of 6,507 BRCA1/2-negative index cases fulfilling the inclusion criteria of the GC-HBOC for germline testing was analyzed. Illumina sequencing platforms were used and data analysis was carried out at each individual center using different analysis pipelines. Analysis of copy number variations (CNV) was not included in the present data evaluation. Results: By focusing on 8 confirmed BC/OC risk genes ( ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53), the 6,507 cancer patients revealed 165 different deleterious variants in 378 unrelated mutation carriers (5.8%). We found a high prevalence of CHEK2 (n = 150, 2.3%), ATM (n = 89, 1.4% ), and PALB2 (n = 72, 1.1%) mutations while RAD51C (n = 21, 0.3%), TP53 (n = 16, 0.2%), NBN (n = 15, 0.2%), CDH1 (n = 10, 0.2%), and RAD51D (n = 5, 0.1%) were less frequently mutated. Conclusions: The high frequency of pathologic mutations in the genes ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53, together accounting for almost 6% of familial BC/OC risk, highlights the importance of these genes to be included in BC/OC routine diagnostics. The relevance of these mutations in a clinical setting for early detection of breast and ovarian cancer needs to be established.
ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes
Authors: M. Loredana Marcovecchio, Scott T. Chiesa, Simon Bond, Denis Daneman, Sarah Dawson, Kim C. Donaghue, Timothy W. Jones, Farid H. Mahmud, Sally M. Marshall, H. Andrew W. Neil, R. Neil Dalton, John Deanfield, David B. Dunger
Journal: New England Journal of Medicine (2017)

Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting–enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents.
Stabilization of the c-Myc Protein by CAMKIIγ Promotes T Cell Lymphoma
Authors: Ying Gu, Jiawei Zhang, Xiaoxiao Ma, Byung-wook Kim, Hailong Wang, Jinfan Li, Yi Pan, Yang Xu, Lili Ding, Lu Yang, Chao Guo, Xiwei Wu, Jun Wu, Kirk Wu, Xiaoxian Gan, Gang Li, Ling Li, Stephen J. Forman, Wing-Chung Chan, Rongzhen Xu, Wendong Huang
Journal: Cancer Cell (2017)
Palliative Care in Heart Failure
Authors: Joseph G. Rogers, Chetan B. Patel, Robert J. Mentz, Bradi B. Granger, Karen E. Steinhauser, Mona Fiuzat, Patricia A. Adams, Adam Speck, Kimberly S. Johnson, Arun Krishnamoorthy, Hongqiu Yang, Kevin J. Anstrom, Gwen C. Dodson, Donald H. Taylor, Jerry L. Kirchner, Daniel B. Mark, Christopher M. O’Connor, James A. Tulsky
Journal: Journal of the American College of Cardiology (2017)
Cigarette Smoking and Endometrial Cancer
Journal: New England Journal of Medicine (1986)

A case control study of 510 cases of endometrial cancer and 727 controls  with other types of cancer aged 30-69 by the Drug Epidemiology Unit is  described.  Epidemiologic case-control studies suggest that smoking in  certain groups of women lowers the risk of endometrial cancer.  Possibly  this effect if real is due to the fact that smoking lowers estrogen  levels.  Endometrial cancer is known to be estrogen dependent.  4  studies found the risk of endometrial cancer lower in smokers but only  one was statistically significant.  2 studies found the effect limited  to postmenopausal women.  Current smokers in the DEU study has 0.7 times  the risk of endometrial cancer as never-smokers.  Those smoking >25  cigarettes daily had a risk of 0.5.  Taking a long list of factors into  account in multiple regression analysis including body mass parity  age age at menopause oral contraceptive and conjugated estrogen use  among others did not alter the results.
A High-Affinity Repebody for Molecular Imaging of EGFR-Expressing Malignant Tumors
Authors: Misun Yun, Dong-Yeon Kim, Joong-jae Lee, Hyeon-Sik Kim, Hyung-Seok Kim, Ayoung Pyo, Yiseul Ryu, Tae-Yoon Kim, Jin Hai Zheng, Su Woong Yoo, Hoon Hyun, Gyungseok Oh, Jaeho Jeong, Myeongju Moon, Jung-Hyun Min, Seong Young Kwon, Jung Young Kim, Euiheon Chung, Yeongjin Hong, Wansik Lee, Hak-Sung Kim, Jung-Joon Min
Journal: Theranostics (2017)

The accurate detection of disease-related biomarkers is crucial for the early diagnosis and management of disease in personalized medicine. Here, we present a molecular imaging of human epidermal growth factor receptor (EGFR)-expressing malignant tumors using an EGFR-specific repebody composed of leucine-rich repeat (LRR) modules. The repebody was labeled with either a fluorescent dye or radioisotope, and used for imaging of EGFR-expressing malignant tumors using an optical method and positron emission tomography. Our approach enabled visualization of the status of EGFR expression, allowing quantitative evaluation in whole tumors, which correlated well with the EGFR expression levels in mouse or patients-derived colon cancers. The present approach can be effectively used for the accurate detection of EGFR-expressing cancers, assisting in the development of a tool for detecting other disease biomarkers.
Sorafenib in Patients with Hepatocellular Carcinoma—Results of the Observational INSIGHT Study
Authors: Tom M. Ganten, Rudolf E. Stauber, Eckardt Schott, Peter Malfertheiner, Robert Buder, Peter R. Galle, Thomas Göhler, Matthias Walther, Ronald Koschny, Guido Gerken
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Sorafenib is the only currently approved systemic therapy for advanced hepatocellular carcinoma (HCC). We aimed to evaluate the safety and efficacy of sorafenib therapy in patients with HCC under real-life conditions regarding patient, tumor characteristics, and any adverse events at study entry and at follow-up visits every 2 to 4 months. Experimental Design: The current INSIGHT study is a noninterventional, prospective, multicenter, observational study performed in 124 sites across Austria and Germany between 2008 and 2014. Results: Median overall survival and time to progression (RECIST) were found to be dependent on baseline Barcelona Clinic Liver Cancer (BCLC) tumor stage (A: 29.2, B: 19.6, C: 13.6, D: 3.1 and A: 6.0, B: 5.5, C: 3.9, and D: 1.7 months, respectively), Child–Pugh liver function (A: 17.6, B: 8.1, C: 5.6 and A: 5.3, B: 3.3, C: 2.5 months, respectively), and performance status of the patient; however, age did not affect prognosis. Sorafenib-related adverse events at any grade occurred in 64.9% of patients, with diarrhea (35.4%), hand–foot–skin reaction (16.6%), nausea (10.3%), and fatigue (11.2%) occurring most frequently. Conclusions: Sorafenib treatment was shown to be effective in a real-life setting, in agreement with previously reported clinical trial data. The therapy was found to have an acceptable safety profile, with predominantly mild to moderate side effects. Clin Cancer Res; 23(19); 5720–8. ©2017 AACR.
Legionnaires’ disease in Europe, 2011 to 2015
Authors: Julien Beauté
Journal: Eurosurveillance (2017)

Under the coordination of the European Centre for Disease Prevention and Control (ECDC), the European Legionnaires’ disease Surveillance Network (ELDSNet) conducts surveillance of Legionnaires’ disease (LD) in Europe. Between 2011 and 2015, 29 countries reported 30,532 LD cases to ECDC (28,188 (92.3%) confirmed and 2,344 (7.7%) probable). Four countries (France, Germany, Italy and Spain) accounted for 70.3% of all reported cases, although their combined populations represented only 49.9% of the study population. The age-standardised rate of all cases increased from 0.97 cases/100,000 population in 2011 to 1.30 cases/100,000 population in 2015, corresponding to an annual average increase of 0.09 cases/100,000 population (95%CI 0.02–0.14; p = 0.02). Demographics and infection setting remained unchanged with ca 70% of cases being community-acquired and 80% occurring in people aged 50 years and older. Clinical outcome was known for 23,164 cases, of whom 2,161 (9.3%) died. The overall case fatality ratio decreased steadily from 10.5% in 2011 to 8.1% in 2015, probably reflecting improved reporting completeness. Five countries (Austria, Czech Republic, Germany, Italy, and Norway) had increasing age-standardised LD notification rates over the 2011−15 period, but there was no increase in notification rates in countries where the 2011 rate was below 0.5/100,000 population.
Risk factors of percutaneous cannulation failure by intensivists for veno-arterial extracorporeal life support for refractory cardiac arrest
Authors: V. Chhor, A. Follin, J. Joachim, B. Champigneulle, J. Chatelon, G. Favé, A. Neuschwander, J. Mantz, Romain Pirracchio
Journal: Intensive Care Medicine (2017)
Impact of age on treatment of primary melanoma patients.
Authors: Nathaniel H. Fleming, Jiaying Tian, Eleazar Vega-Saenz de Miera, Heidi L. Gold, Farbod Darvishian, Anna C. Pavlick, Russell S. Berman, Richard L. Shapiro, David Polsky, Iman Osman
Journal: Journal of Clinical Oncology (2013)

9054 Background: Although patient age at diagnosis is not currently included in guidelines for treatment of primary melanoma, several lines of evidence suggest that patient age is an important, yet understudied, factor when considering treatment options. Here, we attempt to address the limited knowledge of the impact of age on primary melanoma treatment. Methods: In a prospectively enrolled and followed-up cohort of melanoma patients at NYU, we used logistic regression models to evaluate the association between patient age at diagnosis, tumor baseline characteristics, including BRAF and NRAS mutation status, and likelihood of receiving and responding to adjuvant therapy. We examined adjuvant therapy effectiveness using recurrence and melanoma-specific survival as endpoints. Results: 444 primary melanoma patients were included in the study (median follow-up: 6.3 years; age range: 19-95 years). Age was categorized into three groups spanning the range of age at presentation: younger (19-45 years; 24%), middle (46-70 years; 50%), and older (71-95 years; 26%). Older patients were significantly more likely to have advanced stage, nodular subtype (P &lt; 0.01, both variables), and BRAF wildtype tumors (P = 0.04). Controlling for these factors as well as gender, older patients experienced a higher risk of recurrence (HR older vs. younger 3.34, 95% CI 1.53-7.25; P &lt; 0.01). Of the 128/444 (29%) patients who were eligible for adjuvant treatment (clinical stage ≥ IIB), only 67/128 (52%) received treatment. Using a propensity score that accounts for stage at presentation, patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (OR 2.61, 95% CI 1.12-6.08; P = 0.03). In addition, a trend suggesting benefit from adjuvant therapy (defined as longer melanoma-specific survival) was observed only in the middle age group (P = 0.07). Conclusions: Our data suggest that older melanoma patients, despite having a significantly worse prognosis, are less likely to receive and benefit from adjuvant therapy. Further work is needed to understand the biological variables contributing to the limited response to treatment in elderly primary melanoma.
Percutaneous Edge-to-Edge Repair of Recurrent Severe Mitral Regurgitation After Surgical Mitral Valve Repair
Authors: Daniel Braun, Christian Frerker, Maria Isabel Körber, Oliver Gaemperli, Johannes Patzelt, Ulrich Schaefer, Christoph Hammerstingl, Peter Boekstegers, Ilka Ott, Hüseyin Ince, Holger Thiele, Jörg Hausleiter
Journal: Journal of the American College of Cardiology (2017)
Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood
Authors: Jesse W. Williams, Andrew Elvington, Stoyan Ivanov, Skyler Kessler, Hannah Luehmann, Osamu Baba, Brian T. Saunders, Ki-Wook Kim, Michael W. Johnson, Clarissa S. Craft, Jae-Hoon Choi, Mary G. Sorci-Thomas, Bernd H. Zinselmeyer, Jonathan R. Brestoff, Yongjian Liu, Gwendalyn J. Randolph
Journal: Circulation Research (2017)

Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective because of UCP1 (uncoupling protein 1)-dependent thermogenesis.We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression.Using mouse models of atherosclerosis housed at 3 different ambient temperatures, we observed that cold temperature enhanced, whereas thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1. However, whereas UCP1 deficiency promoted poor glucose tolerance, thermoneutral housing enhanced glucose tolerance, and this effect held even in the context of UCP1 deficiency. In conditions of thermoneutrality, but not UCP1 deficiency, circulating monocyte counts were reduced, likely accounting for fewer monocytes entering plaques. Reductions in circulating blood monocytes were also found in a large human cohort in correlation with environmental temperature. By contrast, reduced plaque growth in mice lacking UCP1 was linked to lower cholesterol. Through application of a positron emission tomographic tracer to track CCR2+ cell localization and intravital 2-photon imaging of bone marrow, we associated thermoneutrality with an increased monocyte retention in bone marrow. Pharmacological activation of β3-adrenergic receptors applied to mice housed at thermoneutrality induced UCP1 in beige fat pads but failed to promote monocyte egress from the marrow.Warm ambient temperature is, like UCP1 deficiency, atheroprotective, but the mechanisms of action differ. Thermoneutrality associates with reduced monocyte egress from the bone marrow in a UCP1-dependent manner in mice and likewise may also suppress blood monocyte counts in man.
Awarding of legal fees as penalty for unwanted treatment
Authors: G. R. Scofield
Journal: JAMA (1991)

<h3>To the Editor. —</h3> On behalf of Fleet Hospital FIVE in Saudi Arabia, my staff and I would like to express our sincere appreciation for providing us with weekly issues ofThe Journal. Your enthusiastic support is extremely reassuring to those deployed. Fleet Hospital FIVE is a 500-bed shore-based navy medical treatment facility in Saudi Arabia. The staff is composed of corpsmen, nurses, physicians, dentists, medical service officers, and the construction battalion. We have been kept busy with the treatment of personnel from all branches of the armed services as well as allied forces. The medical staff have been completing various training courses and have been doing quite a lot of reading to stay on top of our respective specialties. Issues ofThe Journalwill be a well-received addition to our medical library. Once again, thanks to you and the American Medical Association for your support and thoughtfulness.