tbuckley/cabot-search huggingface dataset:
Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial
Authors: Steven M. Kawut, Christine L. Archer-Chicko, Angela DeMichele, Jason S. Fritz, James R. Klinger, Bonnie Ky, Harold I. Palevsky, Amy J. Palmisciano, Mamta Patel, Diane Pinder, Kathleen J. Propert, K. Akaya Smith, Frank Stanczyk, Russell Tracy, Anjali Vaidya, Mary E. Whittenhall, Corey E. Ventetuolo
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown.Objectives: We aimed to determine the safety and efficacy of anastrozole in PAH.Methods: We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers.Measurements and Main Results: A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co–primary outcomes were percent change from baseline in 17β-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: −40%; interquartile range [IQR], −61 to −26% vs. −4%; IQR, −14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = −12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo −2%; IQR, −7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events.Conclusions: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH.Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).
David Oliver: Groundhog days for doctors
Authors: David Oliver
Journal: BMJ (2016)

I recently saw a wonderful stage adaptation of Groundhog Day . Phil Connors, a misanthropic TV weatherman, gets stuck in small town America, living out the exact same day on a loop.

He soon realises that he can act wilfully without consequences—unlike doctors. For us, every interaction and decision has potential consequences, from life saving to catastrophic, and many are remembered by patients for years. Adopting Connors’s descent into complacency, recklessness, and nihilism isn’t an option.

The cast received a deserved standing ovation. I reflected that, for the first 50 shows or so, they must keep refining …
Phase I study of pasireotide in combination with FOLFIRI in gastrointestinal malignancies.
Authors: Jennifer Elizabeth Byer, Amit Mahipal, David Shibata, Erin M. Siegel, Khaldoun Almhanna, William J. Fulp, Irene Williams-Elson, Richard D. Kim
Journal: Journal of Clinical Oncology (2015)

e15201 Background: Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors. It is hypothesized to induce apoptosis by decreasing insulin like growth factor 1 (IGF-1) levels and inhibition of somatostatin receptor sst3. IGF-1 binds to IGF-1 receptor (IGF1R) promoting tumorigenesis. IGF1R is frequently overexpressed in gastrointestinal (GI) malignancies. Blocking of IGF1R in combination with cytotoxic chemotherapy, specifically irinotecan, has synergistic activity in pre-clinical models. The primary objective was to determine the maximum tolerated dose of SOM230 with FOLFIRI (5-fluorouracil, leucovorin, and irinotecan). Methods: This is an open label, dose escalation phase 1 clinical trial evaluating the combination of SOM230 and FOLFIRI. Traditional 3+3 design was utilized for dose escalation. All patients received FOLFIRI regimen on days 1 and 15 of a 28-day cycle and SOM230 intramuscularly once every 28 days. From November 2011 to January 2014, 16 patients were enrolled in SOM230 dose cohorts at 40mg, 60 mg, 80 mg, 100 mg and 120 mg. Plasma levels of IGF-1, IGFBP-1, and IGFBP-3 were measured by ELISA. Results: Tumor types included esophageal, biliary tract, colon, gastric, pancreatic, anal, and small bowel. The median age was 63 years old; 5 patients were female and 11 were male. ECOG-PS ranged 0 to 1. Of 16 patients, 2 patients achieved partial response (colon cancer and esophageal cancer), 7 patients had stable disease, and 6 patients progressed at first restaging scans using RECIST criteria. Median PFS was 3.6 months, and median survival was 7.2 months. No dose limiting toxicities were observed up to 120 mg administered. Grade 3 or 4 adverse events included neutropenia (40%), thrombocytopenia (6%), hyperglycemia (12%), hyponatremia (6%), and hypophosphatemia (6%). There was a statistically significant reduction in the levels of IGF-1 and IGFBP-3 after treatment with SOM230. Conclusions: The combination of FOLFIRI and SOM230 was reasonably well tolerated with expected toxicities. Preliminary signals for efficacy were noted. A larger randomized trial is needed to determine if the addition of SOM230 to FOLFIRI improves outcomes in patients with GI malignancies. Clinical trial information: NCT01434069.
One in 10 children becomes obese or overweight in primary school years
Authors: Gareth Iacobucci
Journal: BMJ (2016)

One in 10 children starting primary school in England at a healthy weight is obese or overweight on leaving, figures from Cancer Research UK have shown.1

The analysis showed that an average of 57 100 (10%) of children leaving primary school in England each year from 2012-13 to 2014-15 were overweight or obese by body mass index (BMI), having started school at a healthy BMI from 2006-07 to 2008-09.

The charity said that this was …
Reply to Zi-Jun Zou, Jia-Yu Liang, Yi-Ping Lu's Letter to the Editor re: Zhihua Lu, Guiting Lin, Amanda Reed-Maldonado, Chunxi Wang, Yung-Chin Lee, Tom F. Lue. Low-intensity Extracorporeal Shock Wave Treatment Improves Erectile Function: A Systematic Review and Meta-analysis. Eur Urol 2017;71:223–33
Authors: Zhihua Lu, Guiting Lin, Amanda Reed-Maldonado, Chunxi Wang, Yung-Chin Lee, Tom F. Lue
Journal: European Urology (2016)
CML Patients Show Sperm Alterations At Diagnosis That Are Not Improved On Tyrosine Kinase Inhibitor Treatment
Authors: Franck E. Nicolini, Françoise Huguet, Hélène Labussière-Wallet, Yann Guillermin, Madeleine Etienne, Marie-Pierre Fort, Isabelle Tigaud, Sandrine Hayette, Stephane Morisset, Mohamad Sobh, Fiorenza Barraco, Mauricette Michallet, Myriam Daudin, Volcy Soula, Sandrine Giscard d'Estaing, Gabriel Etienne
Journal: Blood (2012)
Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials
Authors: J.C.-H. Yang, L.V. Sequist, C. Zhou, M. Schuler, S.L. Geater, T. Mok, C.-P. Hu, N. Yamamoto, J. Feng, K. O'Byrne, S. Lu, V. Hirsh, Y. Huang, M. Sebastian, I. Okamoto, N. Dickgreber, R. Shah, A. Märten, D. Massey, S. Wind, Y.-L. Wu
Journal: Annals of Oncology (2016)

Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials.Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not.Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}.Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy.Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.
Interdisciplinary care rounds in the community: Changing the paradigm of supportive service involvement in cancer care.
Authors: Robert D. Siegel, Hal E. Crosswell, Terra Dillard, Jennifer Bayne, Tina Redenz, Kyle Duggan, Angela Belew
Journal: Journal of Clinical Oncology (2016)

83 Background: Although cancer centers have focused on optimizing seamless Multidisciplinary Care (MDC) at tumor boards and/or clinics, there has been little published on effective ways to involve supportive services into the management of cancer patients. Historically, supportive services have been initiated when there is an active need rather than in anticipation of that need. As an alternative to pursuing such "crisis management" in our patients, Bon Secours St. Francis Cancer Center (BSSF) initiated Interdisciplinary Care (IDC) Rounds in an effort to anticipate patient needs, enhance quality of life (QoL), and potentially limit avoidable emergency room and hospital admissions. Methods: We initiated IDC Rounds with participants from the following disciplines: medical oncology, navigation, clinic nursing, palliative medicine, financial counseling, psychology, nutrition, clinical research, adolescent and young adult, and oncology rehabilitation/survivorship (ORS). A database was created to track new patients with malignancies within three weeks of presentation and the subsequent recommendations made by the IDC team. Those recommendations are then forwarded to the primary medical oncologist who has the ability to agree to those recommendations in full or in part before they are actuated. Results: BSSF is a non-academic, community-based cancer program and receives over 1,300 referrals annually from a referral population of 1.32 million in 10 counties. Short term metrics demonstrate a 57% and 100% increase in referrals to ORS and palliative care, respectively. Successes and challenges including sustainability, cost and measurable impact will be discussed. Conclusions: We have shown that it is feasible in the community setting to create a process that will allow early integration of supportive services into the full service care of cancer patients. Results demonstrate an increase in short-term metrics such as referrals to supportive services. Our ultimate goal is that formalized IDC results not only in earlier involvement by needed services but enhanced QoL for our patients with fewer emergency room and hospital admissions. Those data will be compiled as the program matures.
Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies
Authors: Ludmila Perelygina, Stanley Plotkin, Pierre Russo, Timo Hautala, Francisco Bonilla, Hans D. Ochs, Avni Joshi, John Routes, Kiran Patel, Claudia Wehr, Joseph Icenogle, Kathleen E. Sullivan
Journal: Journal of Allergy and Clinical Immunology (2016)
Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma
Authors: Jonas Paludo, Joseph R. Mikhael, Betsy R. LaPlant, Alese E. Halvorson, Shaji Kumar, Morie A. Gertz, Suzanne R. Hayman, Francis K. Buadi, Angela Dispenzieri, John A. Lust, Prashant Kapoor, Nelson Leung, Stephen J. Russell, David Dingli, Ronald S. Go, Yi Lin, Wilson I. Gonsalves, Rafael Fonseca, P. Leif Bergsagel, Vivek Roy, Taimur Sher, Asher A. Chanan-Khan, Sikander Ailawadhi, A. Keith Stewart, Craig B. Reeder, Paul G. Richardson, S. Vincent Rajkumar, Martha Q. Lacy
Journal: Blood (2017)
Human Neuron Cultures: Micropatterning Facilitates the Long-Term Growth and Analysis of iPSC-Derived Individual Human Neurons and Neuronal Networks (Adv. Healthcare Mater. 15/2016)
Authors: Lena F. Burbulla, Kristin G. Beaumont, Milan Mrksich, Dimitri Krainc
Journal: Advanced Healthcare Materials (2016)

Dimitri Krainc, Milan Mrksich, and co-workers demonstrate the utility of microcontact printing technology for culturing of human neurons in defined patterns over extended periods of time on page 1894. This approach facilitates studies of neuronal development, cellular trafficking, and related mechanisms that require assessment of individual neurons and neuronal networks.
Brexit vote: absolute numbers are misleading
Authors: Christopher J Hanretty, Rob Ford
Journal: BMJ (2016)

Dorling writes that "the outcome of the EU referendum has been unfairly blamed on the working class in the north of England . . .[but] because of differential turnout and the size of the denominator population, most people who voted Leave lived in the south of England."1This statement is true but misleading.More people in the south of England voted Leave because there are more people in the south of England.If we take regions in the north of England to include the north east, north west, and Yorkshire and the Humber, figures from the Electoral Commission show that 4 325 965 people in the north voted Leave.If we take regions in the south to include the south west, south east, and London, then 5 750 908 people in the south voted Leave.However, the electorate in the north was only 11 053 689 people, compared with 16 028 306 in the south.Thus, the proportion of registered voters in the north who voted Leave was greater than the proportion in the south (39.1% v 35.9%).And the proportion voting Leave in the north is still greater than in the south if we express it instead in terms of the voting age population.As political scientists, we are not familiar with the habits of medical journals.In most analyses of voting behaviour it's common to focus on the relative risk of voting for a party or an outcome: an analysis that focuses on absolute numbers is therefore liable to mislead.If medical journals also tend to focus on relative risks then Dorling's analysis is also liable to mislead, notwithstanding qualifications in relation to "differential turnout and the size of the denominator population."
Abstract 20144: Aortic Arch Plaque Deteriorates With Advancing Chronic Kidney Disease Stage
Authors: Satoshi Nishiyama, Tetsu Watanabe, Shintaro Sasaki, Masahiro Wanezaki, Gensai Yamaura, Hiroki Takahashi, Takanori Arimoto, Tetsuro Shishido, Takuya Miyamoto, Isao Kubota
Journal: Circulation (2014)

Introduction: The patients with chronic kidney disease (CKD) are likely to suffer from cardiovascular diseases as well as end stage renal disease. CKD plays a role in development of atherothrombotic stroke. In the present study, we investigated the impact of advancing CKD stage on aortic arch plaque and carotid atherosclerosis which are important causes of atherothrombotic stroke. Methods: We enrolled 368 subjects (255 males, 66 ± 12 years) who underwent transesophageal echocardiography and carotid ultrasonography, and measured estimated glomerular filtration rate (eGFR). We defined arch plaque as wall thickness ≥4 mm and the presence of ulceration or mobile plaque in aortic arch. The common carotid artery maximum intima-media thickness (IMT-C max) and carotid artery plaque score was used as parameters of carotid atherosclerosis. Results: There were 31 patients with the history of atherothrombotic stroke. The eGFR correlated with IMT-C max, carotid plaque score and arch wall thickness. IMT-C max, carotid plaque score and arch wall thickness were increased with advancing CKD stage. An increase in IMT-C max was observed even in stage 2 and 3 while carotid plaque was frequently observed in stage 3b or higher. An increase in arch plaque was observed in stage 3a or higher. The patients with atherothrombotic stroke had significantly lower eGFR than those without. The prevalence of atherothrombotic stroke was increased in stage 3b or higher. Conclusions: Aortic arch plaque and carotid plaque deteriorated with advancing chronic kidney disease stage. Aortic arch plaque and carotid plaque were observed even in early stages of CKD.
Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations
Authors: Krista F. Huybrechts, Sonia Hernández-Díaz, Elisabetta Patorno, Rishi J. Desai, Helen Mogun, Sara Z. Dejene, Jacqueline M. Cohen, Alice Panchaud, Lee Cohen, Brian T. Bateman
Journal: JAMA Psychiatry (2016)

<h3>Importance</h3> The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations. <h3>Objective</h3> To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs. <h3>Design, Setting, and Participants</h3> This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015. <h3>Exposures</h3> Use of APs during the first trimester, the etiologically relevant period for organogenesis. <h3>Main Outcomes and Measures</h3> Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery. <h3>Results</h3> Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders. <h3>Conclusions and Relevance</h3> Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.
Mortality reduction in adult community-acquired pneumonia in the UK (2009–2014): results from the British Thoracic Society audit programme
Authors: Priya Daniel, Mark Woodhead, Sally Welham, Tricia M Mckeever, Wei Shen Lim
Journal: Thorax (2016)

Community-acquired pneumonia (CAP) is a leading cause of death in the UK. In this analysis of 23 315 cases from the British Thoracic Society national CAP audit, an overall reduction in 30-day inpatient mortality over 6 years was observed—2014 compared with 2009 adjusted OR 0.86 (95% CI 0.68 to 1.08, p for trend 0.004). Significant increases in the proportions of patients who had (a) a chest X-ray and (b) the first antibiotic dose within 4 hours of admission were also observed (3.7% and 11.5% increases respectively). Further reductions in mortality may follow the 2016 National Institute for Health and Care Excellence Pneumonia Quality Standard.
Intensified Rituximab Induction Followed By Rituximab Maintenance For Low Grade B Cell Lymphoma: A Multicenter, Phase II Study
Authors: Kyouhei Yamada, Morio Sawamura, Takeshi Shimomura, Makoto Takeuchi, Shuichi Hanada, Takuya Komeno, Michihiro Hidaka, Takahiro Yano, Kiyoshi Kitano, Isao Yoshida, Nobumasa Inoue, Keizo Horibe, Watanabe Tomoyuki, Kazutaka Sunami, Hirokazu Nagai
Journal: Blood (2013)
Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM).
Authors: Myung-Ju Ahn, Dong-Wan Kim, Tae Min Kim, Chia-Chi Lin, Jayantha Ratnayake, David J Carlie, Xiaolu Yin, Zhenfan Yang, Haiyi Jiang, James Chih-Hsin Yang
Journal: Journal of Clinical Oncology (2016)

9003 Background: AZD3759 was the first EGFR inhibitor primarily designed to effectively across the blood brain barrier to tackle central nervous system (CNS) metastases in patients with EGFRm+ NSCLC. Here we report safety, pharmacokinetic (PK), efficacy and biomarker data from a Phase I, open-label, multicentre study of AZD3759 in patients with advanced stage EGFRm+ NSCLC (NCT02228369; sponsor AstraZeneca). Methods: Patients with EGFRm+ NSCLC who progressed from at least one line of EGFR TKI and one line chemotherapy were enrolled into the study. The primary objective was safety and tolerability, and secondary objectives include but not limited to PK and anti-tumor efficacy. There were 5 dose cohorts (dose ranging from 50mg bid to 500mg bid), with at least 2 BM and 1 LM in each cohort. Results: As of30 Dec, 2015,29 patients were recruited, 21 with measurable BM, 5 with LM and 3 with non-measurable/non BM & LM. All patients had received at least one line of EGFR TKI and chemotherapy. 17 out of 29 had prior brain radiation therapy. AZD3759 was well-tolerated up to 300mg bid, with the longest duration on treatment >40 weeks. Most common AEs included skin rash (total 45% with 17% ≥G3) and diarrhea (total 59% with 3% ≥G3). The Ctrough free plasma and CSF exposure were above pEGFR IC50 and IC90 at the doses ≥ 100 and 200 mg bid, respectively. Among 20 patients with measurable BM evaluable for RECIST assessment, 8 had tumor shrinkage in the brain, with 3 confirmed PR and 3 un-confirmed PR. Among 5 LM patients, 3 out of 4 had > 50% pEGFR inhibition in CSF tumor cells after one week treatment, and 4 out of 5 LM patients had > 50% tumor cell number decrease in CSF. 1 LM patient at 300mg bid had CSF clearance of tumor cells, and improvement of brain MRI imaging as well as CNS symptoms. 2 LM patients at the doses of 200mg and 300mg bid, respectively, are still on AZD3759 treatment after 19 and 29 weeks, respectively. Conclusions: AZD3759 was well tolerated, achieved sufficient CNS exposure and demonstrated promising anti-tumor activity in dose escalation phase. Phase II studies have been initiated in patients with LM and BM, respectively. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.