tbuckley/cabot-search huggingface dataset:
National Trends in Use and Outcomes of Pulmonary Artery Catheters Among Medicare Beneficiaries, 1999-2013
Authors: Kevin Ikuta, Yun Wang, Austin Robinson, Tariq Ahmad, Harlan M. Krumholz, Nihar R. Desai
Journal: JAMA Cardiology (2017)

Recent studies have observed an increase in the rate of pulmonary artery catheter (PAC) use in heart failure admissions. Little is known about the national trends in other previously common indications for PAC placement, PAC use overall, or outcomes associated with PAC placement.To determine national trends in PAC use overall as well as across sociodemographic groups and key clinical conditions, including acute myocardial infarction, heart failure, and respiratory failure.Centers for Medicare and Medicaid Services inpatient claims data and International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to conduct a serial cross-sectional cohort study between January 1, 1999, and December 31, 2013, identifying hospitalizations during which a PAC was placed. Data analysis was conducted from September 25, 2015, to April 10, 2017.Rate of use of a PAC per 1000 admissions, 30-day mortality, and length of stay.Among the 68 374 904 unique Medicare beneficiaries in the study, there were 469 582 hospitalizations among 457 193 patients (204 232 women and 252 961 men; mean [SD] age, 76.3 [6.9] years) during which a PAC was placed. There was a 67.8% relative decrease in PAC use (6.28 per 1000 admissions in 1999 to 2.02 per 1000 admissions in 2013; P < .001), with 2 distinct trends: significant year-on-year decreases from 1999 to 2011, followed by stable use through 2013. There was variation in rates of PAC use across race/ethnicity, age, and sex, but use decreased across all subgroups. Although there were sustained decreases in PAC use for acute myocardial infarction (20.0 PACs placed per 1000 admissions in 1999 to 5.2 in 2013 [74.0% reduction]; P < .001 for trend) and respiratory failure (29.9 PACs placed per 1000 admission in 1999 to 2.3 in 2013 [92.3% reduction]; P < .001 for trend) during the study period, there was an initial decrease in PAC use in heart failure, with a nadir in 2009 followed by a subsequent increase (9.1 PACs placed per 1000 admissions in 1999 to 4.0 in 2009 to 5.8 in 2013). In-hospital mortality, 30-day mortality, and length of stay decreased during the study period.In the wake of mounting evidence suggesting a lack of benefit to the routine use of PACs, there has been a de-adoption of PAC use overall and across sociodemographic groups but heterogeneity in patterns of use across clinical conditions. The clinical outcomes of patients with PACs have significantly improved. These findings raise important questions about the optimal use of PACs and the drivers of the observed trends.
Association of a four-gene decision tree signature with response to platinum-based chemotherapy in patients with triple negative breast cancer.
Authors: Jelmar Quist, Hasan Mirza, Maggie Chon U Cheang, Melinda L. Telli, Christopher J. Lord, Andrew Nicholas James Tutt, Anita Grigoriadis
Journal: Journal of Clinical Oncology (2017)

1006 Background: Approaches to capture the molecular complexity of triple negative breast cancers (TNBCs) are lacking. We sought to classify TNBCs into subgroups with common biological features based on transcriptomic and genomic data using a Bayesian algorithm. Methods: Matched gene expression and copy number microarray data was available for the Guy’s (n = 88) and METABRIC (n = 112) TNBC cohorts. CONEXIC was used to derive a decision tree signature for classification. Performance of the signature was tested in 7 TNBC cohorts (total n: 1,368), including 2 clinical trials assessing the efficacy of gemcitabine and carboplatin with and without iniparib. In the early-stage PrECOG 0105 Phase II neoadjuvant trial (n = 43), subtypes were evaluated in relation to response by residual cancer burden (RCB). In the metastatic Sanofi Phase III trial (n = 224), subtypes were assessed by RECIST. Results were compared to the BL1 TNBCtype-4 subtype and assessed using a multivariate analysis. Results: The integrative analysis using CONEXIC identified a four-gene signature. Across 7 TNBC cohorts this classification identified 6 entities, including 5 smaller groups and 1 major. Characterisation of the latter subgroup, referred to as MC6, revealed enrichment of CD4+ and CD8+ immune signatures, increased genomic instability and reduction in negative regulation of the MAPK signalling pathway. In PrECOG, 25 out of 41 MC6-TNBCs (61%, OR = 1.19, 95% CI = 0.37 to 3.81, P = 0.79) had RCB 0/I. Similarly, 65% of the BL1-TNBCs had an RCB 0/I, however in a smaller population (11 out of 17, OR = 1.30, 95% CI = 0.35 to 5.31), P = 0.77). In Sanofi Phase III, the objective response rate (ORR) in MC6-TNBCs was 46% versus 30% in non-MC6-TNBCs (OR = 1.97, 95% CI = 1.03 to 3.77, P = 0.04), in comparison to BL1-TNBCs with an ORR of 41% versus 32% in non-BL1-TNBCs (OR = 1.47, 95% CI = 0.75 to 2.86), P = 0.26). Conclusions: These results demonstrate that a four-gene signature can identify a subgroup of TNBCs responsive to platinum-based chemotherapy in the metastatic setting. The distinct features of these TNBCs suggest investigation of alternative actionable interventions with immunotherapy or MEK inhibitors in relation to this signature.
Sensory integration and neuromodulatory feedback facilitate Drosophila mechanonociceptive behavior
Authors: Chun Hu, Meike Petersen, Nina Hoyer, Bettina Spitzweck, Federico Tenedini, Denan Wang, Alisa Gruschka, Lara S Burchardt, Emanuela Szpotowicz, Michaela Schweizer, Ananya R Guntur, Chung-Hui Yang, Peter Soba
Journal: Nature Neuroscience (2017)
Effect of interferon-α in osteosarcoma xenografts
Authors: Christoph R. Müller, Heidi M. Namløs, Sigbjørn Smeland, Gunnar Sæter, Ola Myklebost
Journal: Cancer Research (2005)

1047  Introduction: Both clinical and preclinical data suggest efficacy of human interferon-α in the adjuvant treatment of primary osteosarcoma of the bone. Wether interferon has the ability to maintain remission following combination chemotherapy is being tested in a randomized trial (EURAMOS 1). In order to examine the molecular basis of this effect, we tested interferon in a panel of osteosarcoma xenografts. Methods: Fragments of tissue from osteosarcoma patients were transplanted subcutaneously in the flanks of nude mice (Balb c nu/nu) and passaged four times before considered stably established. Take rate was about one in five. Of the six donors, three were untreated prior to sampling and three had received preoperative treatment with methotrexate and doxorubicin. Mice were treated with daily s.c. injection of 3E5 IU interferon α2b or monopegylated interferon α2b 130 μg/kg every third day. 21 days treatment started when tumours entered the exponential growth phase (60-100mm3), and growth was followed to a volume of at least 2000mm3. The pharmacokinetics of pegylated interferon was studied with radioiodide labelled substance. In three xenografts, global gene expression changes following treatment were investigated by 16k cDNA arrays. Results: Elimination of pegylated interferon was considerably faster than expected from human data, with an estimated initial elimination half-life of 17-22 hours. Pegylated Interferon delayed growth in two out of six xenografts (specific growth delay of 7,5 and 1). Not pegylated interferon was tested in three xenografts, one responsive and two non responsive. In the doses tested, not pegylated interferon was more effective inducing regression and even cure in some tumours. Pegylated interferon activated specific genes in all xenografts peaking at 24 hours. Conclusion: Interferon α2b controlled tumour growth in two out of six osteosarcoma xenografts exerting direct antitumour activity in this model. We employ the model to examine interferon’s effects on the molecular level.
A randomized, open-label, multicentre, phase IV study evaluating palbociclib plus endocrine treatment versus a chemotherapy based treatment strategy in patients with hormone receptor positive/HER2-negative metastatic breast cancer in a real world setting.
Authors: Sibylle Loibl, Jana Barinoff, Sabine Seiler, Thomas Decker, Carsten Denkert, Kristina Luebbe, Jenny Furlanetto, Volkmar Mueller, Christoph Mundhenke, Marcus Schmidt, Gunter von Minckwitz, Mathias Uhlig, Nicole Burchardi, Marc Thill
Journal: Journal of Clinical Oncology (2017)

TPS1115 Background: Although endocrine based therapy is recommended as first-line treatment in metastatic breast cancer (MBC) in patients with an HER2-/HR+ tumour up to 50% of the patients receive chemotherapy. Palbociclib (P) a CDK4/6 inhibitor improves PFS by 42% in endocrine sensitive and resistant HER2-/HR+ MBC when added to an endocrine therapy (ET). Patients included in clinical trials are often criticised not to be representative for real world breast cancer patients. Methods: Patients with first-line HER2-/HR+ MBC who are candidate for mono-chemotherapy will be eligible to be randomised 1:1 to receive either P plus ET per label or mono-chemotherapy per investigator´s choice with or without maintenance ET. In both study arms, treatment will be given until disease progression, unacceptable toxicity, withdrawal of consent of the patient or change of initial treatment plan (either planned six chemotherapy cycles followed by maintenance ET or chemotherapy until disease progression). Primary objective is to compare the time-to-treatment failure (TTF), defined as time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity and death. Secondary objectives are progression free survival, overall survival at 36 months, amongst other time to event endpoints; investigator assessed overall clinical response; toxicity and compliance; patient well-being and health care utilization by daily monitoring treatment impact. Aim: 360 patients will be accrued to show an improved TTF for P in combination with ET. Recruitment will start in QII/2017 and is planned for approximately 18 months in 100 sites in Germany, Spain, Poland, Italy, France, UK and Canada. Conclusions: The aim of the trial is to demonstrate that an endocrine based strategy consisting of ET plus P is superior to a chemotherapy based strategy as first-line therapy in women with HER2-/HR+ breast cancer in a real world setting.
Role of axillary node dissection after mastectomy with positive sentinel nodes.
Authors: Tristen Sinae Park, Samantha Marie Thomas, Rachel Adams Greenup, Eun-Sil Shelley Hwang
Journal: Journal of Clinical Oncology (2017)

554 Background: The ACOSOG Z11 trial demonstrated that sentinel lymph node biopsy (SLNB) alone was safe for women with early stage node positive cancer undergoing breast conservation therapy with radiation. Little data exists regarding management of this population undergoing mastectomy. The purpose of our study is to determine the benefit of axillary lymph node dissection (ALND) or SLNB with adjuvant radiation in patients with 1-3 positive SLN after mastectomy. Methods: Using data from the National Cancer Database (2004-2014), we performed a retrospective review of patients who underwent mastectomy and were clinically node negative at presentation, but were found to have 1-3 positive nodes on pathology. Patients were categorized as undergoing SLNB alone (1-5 nodes examined) or ALND (≥8 nodes examined). Patients who received SLNB without ALND were further categorized by receipt of radiation treatment (RT). Patients with either neoadjuvant chemotherapy or stage IV disease were excluded. Results: Of 42,371 patients, 10.0% had SLNB+RT, 22.4% had SLNB alone, and 67.5% had ALND. Median age of the cohort was 58 years and median tumor size 2.3 cm. Median follow up was 4.1 years. After adjustment for covariates including age at diagnosis, tumor size, chemotherapy, endocrine therapy and receptor status, SLNB+RT had comparable overall survival to ALND (HR = 1.06, p = 0.52), but SLNB alone was found to be associated with a 25% increase in hazard of death compared to ALND (HR = 1.25, 95% CI 1.11-1.41, p &lt; 0.001). Conclusions: In clinically node negative patients with 1-3 positive sentinel nodes treated with mastectomy, SLNB alone was associated with a significantly increased risk of all-cause mortality compared to ALND or SLNB+RT. These results suggests that ALND may be avoided in these patients in the setting of adjuvant radiation, possibly avoiding the morbidity associated with axillary lymphadenectomy.
Effect of neoadjuvant chemotherapy on immune checkpoint expression in breast cancer.
Authors: Andrew Stiff, Christopher McQuinn, Robert Wesolowski, Maryam B. Lustberg, Raquel E. Reinbolt, Jeffrey Bryan VanDeusen, Sagar D. Sardesai, Nicole Olivia Williams, Anne M. Noonan, Shabana Jaynul Dewani, Bhuvaneswari Ramaswamy, William Edgar Carson
Journal: Journal of Clinical Oncology (2017)

e12126 Background: Even with neo-adjuvant chemotherapy (NAC) many breast cancer (BC) patients (pts) relapse, especially triple negative pts. The incorporation of checkpoint inhibitors into NAC for BC is being tested in clinical trials. How NAC affects checkpoint receptor expression is not known. Such information could aid in the rational selection of checkpoints to target during NAC. We sought to characterize changes in the frequency of circulating CD4 and CD8 T cells expressing PD1, CTLA4, LAG3, TIM3, and OX40 over the course of NAC. Methods: In this prospective trial, expression of PD-1, CTLA-4, Lag3, Tim3 and Ox40 on circulating CD4 and CD8 T cells were measured by FACS analysis in pts with operable breast cancer (BC) prior and at the end of NAC. The primary objective was to explore the association between NAC and expression levels of the immune checkpoints. Results: 1, 20 and 3 pts had clinical stage I, II, IIIA, respectively. Median age was 48. 11, 6 and 7 pts were triple negative (TN), HER2+ and hormone receptor (HR)+, respectively. Complete pathologic response rate was 45.8%. Globally CD4 T cells expressing CTLA4, Lag3, Ox40 and PD1 decreased following NAC (all p &lt; 0.01). Conversely, CD8 T cells expressing CTLA4, Lag3 and Ox40 significantly increased (all p &lt; 0.01). More CD8 T cells from HER2+ pts expressed Lag3 prior to therapy compared to HR+ pts (p &lt; 0.05) with a similar trend compared to TN pts. Prior to therapy more CD8 T cells from HER2+ and TN pts expressed Tim3 compared to HR+ pts (p &lt; 0.05 for each). Post therapy more CD4 T cells from HER2+ pts expressed PD1 compared to HR+ and TN pts (p = 0.027 and 0.018 respectively). Clinical response did not predict change in checkpoint expression. An interaction analysis revealed that HER2+ disease predicted a drop in CTLA4 CD4 T cells and a drop in Lag3 CD4 and CD8 T cells over NAC (p &lt; 0.05). Conclusions: This analysis identified changes in checkpoint receptor expression by CD4 and CD8 T cells in BC pts after NAC. Differences in checkpoint receptor expression were found between BC subgroups. This data provides a starting point for understanding checkpoint receptor expression changes with NAC, and could help guide the selection and timing of incorporating checkpoint inhibitors in BC.
Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC).
Authors: Gabriel N. Hortobagyi, Salomon M. Stemmer, Howard A. Burris, Yoon Sim Yap, Gabe S. Sonke, Shani Paluch-Shimon, Mario Campone, Katarina Petrakova, Kimberly L. Blackwell, Eric P. Winer, Wolfgang Janni, Sunil Verma, Pier Franco Conte, Carlos L. Arteaga, David A. Cameron, Fengjuan Xuan, Michelle Kristine Miller, Caroline Germa, Samit Hirawat, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2017)

1038 Background: Endocrine therapy (ET) is the basis of first-line (1L) treatment for HR+ ABC. However, ET resistance are almost universal. At the first interim analysis (IA) of MONALEESA-2 (NCT01958021), ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in patients (pts) with HR+, HER2– ABC. 1 Here we report updated efficacy and safety data from MONALEESA-2 with a further ~11 months of follow-up. Methods: Postmenopausal women with no prior therapy for ABC were randomized 1:1 toRIB (600 mg/day, 3-weeks-on/1-week-off) + LET(2.5 mg/day, continuous) vs PBO + LET. The primary endpoint was locally assessed PFS. Secondary endpoints include overall survival (OS; key) and safety. OS significance was defined by a p-value threshold of 3.15 x 10 -5 . Tumor assessments were performed every 8 weeks for the first 18 months, and every 12 weeks, thereafter. Results: 668 pts were enrolled (334 in each arm). At the second IA for OS (data cut-off Jan 2, 2017), the median duration of follow-up was 26.4 months; 116 deaths and 345 PFS events had occurred. OS data remain immature, with 15.0% vs 19.8% of pt deaths in the RIB + LET vs PBO + LET arm (HR = 0.746; 95% CI: 0.517–1.078; p= 0.059). Updated PFS analyses confirmed continued treatment benefit in the RIB + LET vs PBO + LET arm. The 24-month PFS rates (RIB + LET vs PBO + LET) were 54.7% vs 35.9%. Treatment benefit was consistent across pt subgroups. The most common Grade 3/4 laboratory abnormalities (≥10% of pts; RIB + LET vs PBO + LET) were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%). Conclusion: After 26+ months of follow-up, treatment benefit with 1LRIB + LET persists in postmenopausal women with HR+, HER2– ABC. The study remains immature for OS analysis. The safety profile of RIB + LET remains manageable. 1. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48. Clinical trial information: NCT01958021.
Adaptive Patterns of Mitogenome Evolution Are Associated with the Loss of Shell Scutes in Turtles
Authors: Tibisay Escalona, Cameron J. Weadick, Agostinho Antunes
Journal: Molecular Biology and Evolution (2017)

The mitochondrial genome encodes several protein components of the oxidative phosphorylation (OXPHOS) pathway and is critical for aerobic respiration. These proteins have evolved adaptively in many taxa, but linking molecular-level patterns with higher-level attributes (e.g., morphology, physiology) remains a challenge. Turtles are a promising system for exploring mitochondrial genome evolution as different species face distinct respiratory challenges and employ multiple strategies for ensuring efficient respiration. One prominent adaptation to a highly aquatic lifestyle in turtles is the secondary loss of keratenized shell scutes (i.e., soft-shells), which is associated with enhanced swimming ability and, in some species, cutaneous respiration. We used codon models to examine patterns of selection on mitochondrial protein-coding genes along the three turtle lineages that independently evolved soft-shells. We found strong evidence for positive selection along the branches leading to the pig-nosed turtle (Carettochelys insculpta) and the softshells clade (Trionychidae), but only weak evidence for the leatherback (Dermochelys coriacea) branch. Positively selected sites were found to be particularly prevalent in OXPHOS Complex I proteins, especially subunit ND2, along both positively selected lineages, consistent with convergent adaptive evolution. Structural analysis showed that many of the identified sites are within key regions or near residues involved in proton transport, indicating that positive selection may have precipitated substantial changes in mitochondrial function. Overall, our study provides evidence that physiological challenges associated with adaptation to a highly aquatic lifestyle have shaped the evolution of the turtle mitochondrial genome in a lineage-specific manner.
The effect of aromatase inhibitors use on endothelial function among postmenopausal women with breast cancer.
Authors: Ronny Maor, Elad Maor, Amanda Wanous, Sandhya Pruthi, Amir Lerman, Nicole Sandhu
Journal: Journal of Clinical Oncology (2017)

e12064 Background: Data on long-term cardiovascular effects and safety of aromatase inhibitors (AI) are limited and conflicting. The purpose of the current study was to evaluate the effect of AI on vascular injury as assessed by peripheral endothelial function among women with breast cancer. Methods: This is an observational, prospective study of 96 postmenopausal women with breast cancer at initiation of treatment, with or without AI. All participants underwent baseline and 6-12 months follow up non-invasive peripheral endothelial function measurement. Reactive hyperemia index (RHI) was measured using the EndoPAT test. The primary endpoint was endothelial function deterioration of at least 20% between baseline and follow-up. Results: Mean age of the study population was 66±7 years. There was no statistical difference in demographic data between the groups. Compared with the control group, more women in the treatment group demonstrated worsening of RHI (53% vs. 42%, p = 0.207) between baseline and 6-12 month follow up measurement. There was no statistical difference between the groups at baseline. When RHI deterioration was evaluated as a dichotomous variable, with a 20% cutoff, women in the AI group demonstrated higher rates of RHI deterioration (28% vs. 8%, p=0.020). The risk of AIs for endothelial dysfunction was correlated with burden of cardiovascular (CV) risk, such that in women with &gt;3 CV risk factors, AIs were associated with increased risk of RHI deterioration (42% vs. 10%, p=0.016), whereas in women with &lt;2 CV risk factors, rates of RHI deterioration were similar in AI and control groups (20% vs. 7%, p = 0.232). Conclusions: This study suggests that AI therapy may be associated with vascular injury as detected by deterioration in endothelial function. The effect is more pronounced among women with higher baseline CV risk factor burden. The results of this study have potentially important implications for patients with breast cancer being treated with AI and for women at increased lifetime risk of breast cancer who may use AI for breast cancer risk reduction. Clinical trial information: NCT00719966.
Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors
Authors: Darren B. Taichman, Peush Sahni, Anja Pinborg, Larry Peiperl, Christine Laine, Astrid James, Sung-Tae Hong, Abraham Haileamlak, Laragh Gollogly, Fiona Godlee, Frank A. Frizelle, Fernando Florenzano, Jeffrey M. Drazen, Howard Bauchner, Christopher Baethge, Joyce Backus
Journal: PLoS Medicine (2017)

The International Committee of Medical Journal Editors announces requirements that a data sharing plan be prospectively registered, and a data sharing statement be included in submitted manuscripts, for clinical trials to be published in ICMJE journals.
Ahead Study: A 3 Year Follow-up of 522 Severe and Moderate Hemophilia a Patients
Authors: Johannes Oldenburg, Dimitrios Tsakiris, Cedric R. Hermans, RI Liesner, Kate Khair, Maria Gabriella Mazzucconi, Katharina N Steinitz-Trost, Gerald Spotts, Armin J Reininger, Alessandro Gringeri
Journal: Blood (2016)