tbuckley/cabot-search huggingface dataset:
High-Risk Premenopausal Luminal A Breast Cancer Patients Derive no Benefit from Adjuvant Cyclophosphamide-based Chemotherapy: Results from the DBCG77B Clinical Trial
Authors: Torsten O. Nielsen, Maj-Brit Jensen, Samantha Burugu, Dongxia Gao, Charlotte L. Tykjaer Jørgensen, Eva Balslev, Bent Ejlertsen
Journal: Clinical Cancer Research (2016)

Purpose: Luminal A breast cancers have better prognosis than other molecular subtypes. Luminal A cancers may also be insensitive to adjuvant chemotherapy, although there is little high-level evidence to confirm this concept. The primary hypothesis in this formal prospective-retrospective analysis was to assess interaction between subtype (Luminal A vs. other) and treatment (chemotherapy vs. not) for the primary endpoint (10-year invasive disease-free survival) of a breast cancer trial randomizing women to adjuvant chemotherapy, analyzed in multivariate Cox proportional hazards models using the Wald interaction test.Experimental Design: The Danish Breast Cancer Cooperative Group 77B clinical trial randomized 1,072 premenopausal women to no systematic treatment (control), levamisole, cyclophosphamide, or cyclophosphamide-methotrexate-fluorouracil arms. All arms included radiotherapy but no endocrine therapy. Researchers with no access to clinical data performed intrinsic subtype analysis on tissue microarrays using published immunohistochemical methods based on estrogen receptor, progesterone receptor, HER2, Ki67, and basal markers.Results: Patients (n = 709) had tissue available; chemotherapy benefit in these patients was similar to the original trial (HR, 0.56). Immunohistochemistry classified 165 as Luminal A, 319 Luminal B, 58 HER2-enriched, and 82 core basal (among 91 triple-negative). Patients with Luminal A breast tumors did not benefit from chemotherapy [HR, 1.06; 95% confidence interval (CI), 0.53-2.14; P = 0.86], whereas patients with non-luminal A subtypes did (HR, 0.50; 95% CI, 0.38-0.66; P < 0.001; Pinteraction = 0.048).Conclusions: In a prospective-retrospective analysis of a randomized trial, patients with Luminal A breast cancers did not benefit from adjuvant cyclophosphamide-based chemotherapy. Clin Cancer Res; 23(4); 946-53. ©2016 AACR.
Population Pharmacokinetic of Oral Busulfan in Japanese Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Noriaki Sasaki, Kentaro Ogata, Keita Yamauchi, Yasushi Takamatsu, Junji Suzumiya, Kazuo Tamura, Eiji Yukawa, Shuuji Hara, Nobufumi Ono
Journal: Blood (2005)
RCT utilizing acupuncture for management of insomnia associated with cancer.
Authors: Oxana Palesh, Nadia Haddad, Rosa Schnyer, Jamie M. Zeitzer, Eric Neri, Rachel Manber
Journal: Journal of Clinical Oncology (2015)

e20572 Background: Acupuncture is widely used by cancer patients and survivors for management of side effects. However, the empirical evidence supporting the efficacy of acupuncture for these symptoms is limited. Up to 80 % of cancer patients experience insomnia at some point during their treatment and survivorship. Although effective treatments exist, they often contribute burdensome side effects. Thus, non-pharmacological treatments are desirable for these patients. Methods: 68 Breast Cancer survivors aged 54 yrs. (SD = 10) who were experiencing insomnia were assessed with both self-report (Insomnia Severity Index, ISI) and clinical interview and randomized to receive either 12 sessions of real (N = 34) or sham (N = 34) acupuncture (Streitberger needle) for 6 weeks. Participants were excluded if they were taking medications for sleep or had unstable medical or psychiatric conditions. Real and sham acupuncture were delivered by licensed acupuncturists. Results: On average, women completed 11 out 12 sessions; there were no difference in attendance between real and sham acupuncture arms. There were main effects for insomnia (ISI), fatigue (BFI), and quality of life (FACT-F) (p < .0001) where all participants showed significant improvement in their symptoms at one-month follow-up (all p-values < .001) and 17.3% of patients experienced clinically significant improvement in their insomnia (Changed Score ≥ 8 on ISI). However, we found no significant differences on those measures between real versus sham acupuncture. We did find that patients’ chronotype type moderated the results in the real acupuncture group; those with more extreme morning types (22% of the sample) showed significantly more improvement in their insomnia compared to sham control arm. Acupuncture-specific variables (adherence, number of sessions and needles) did not affect the outcome. Conclusions: This study did not find significant differences between sham and acupuncture for insomnia. This may be due, in part, to a notable placebo effect with sham, previously reported in prior research. The presence of moderating variables such as chronotype is intriguing and provides additional insight for future research in determining for whom real acupuncture might be beneficial.
Progression-free survival (PFS) and overall survival (OS) in phase III trials of systemic chemotherapy in advanced non-small cell lung cancer (NSCLC).
Authors: K. Hotta, K. Kiura, N. Takigawa, M. Tabata, Y. Fujiwara, M. Tanimoto
Journal: Journal of Clinical Oncology (2010)

7624 Background: With the increasing number of active compounds available in the salvage settings for advanced NSCLC, OS, the traditional end point for assessing efficacy of systemic chemotherapies, would be potentially confounded by the effects of post- study therapies. Here, we examined the association between the two parameters through a literature-based survey. Methods: We extracted hazard ratios (HRs) of both OS and PFS from each phase III trial of molecular-targeted agents in advanced NSCLC to analyze for a linear regression analysis weighed by trial size. To assess how degree OS-HR was confounded by the effects of post-study therapies, the absolute values for differences between OS-HR and PFS-HR in each trial were also calculated for the regression analysis. Results: A total of 24 trials were identified, evaluating 12 molecular-targeted agents in 17,826 advanced NSCLC pts. One trial had three treatment arms, which resulted in 25 pairs for the investigational and reference arms. There was little correlation between OS-HR and PFS-HR among the whole pairs (R2 = 0.252; p = 0.011). However, its correlation was stronger in trials where crossover treatment was prohibited (“prohibited”: 15 pairs, R2 = 0.709, p < 0.001; and “allowed”: 10 pairs, R2 = 0.033; p = 0.613). The absolute values for differences between OS-HR and PFS-HR varied from 0 to 1.15 in the 25 pairs with a median of 0.10. A multiple regression analysis revealed that the trial design for no prohibition of crossover treatment significantly increased the difference between OS- HR and PFS-HR (coefficient: 0.152, p = 0.032) whereas the sponsorship from pharmaceutical company tended to decrease the difference (coefficient: - 0.144, p = 0.066). Conclusions: Overall, the OS-HR was not correlated well with PFS-HR in phase III trials evaluating molecular-targeted agents for advanced NSCLC. Contrary, there was a stronger association between OS-HR and PFS-HR in the situation where the crossover after disease progression was not allowed. No significant financial relationships to disclose.
Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing
Authors: Takuro Miyazaki, Kazuo Tonami, Shoji Hata, Toshihiro Aiuchi, Koji Ohnishi, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Motohiro Takeya, Hiroyuki Itabe, Hiroyuki Sorimachi, Hiroki Kurihara, Akira Miyazaki
Journal: Journal of Clinical Investigation (2016)

Macrophages contribute to the development of atherosclerosis through pinocytotic deposition of native LDL-derived cholesterol in macrophages in the vascular wall. Inhibiting macrophage-mediated lipid deposition may have protective effects in atheroprone vasculature, and identifying mechanisms that potentiate this process may inform potential therapeutic interventions for atherosclerosis. Here, we report that dysregulation of exon junction complex-driven (EJC-driven) mRNA splicing confers hyperpinocytosis to macrophages during atherogenesis. Mechanistically, we determined that inflammatory cytokines induce an unconventional nonproteolytic calpain, calpain-6 (CAPN6), which associates with the essential EJC-loading factor CWC22 in the cytoplasm. This association disturbs the nuclear localization of CWC22, thereby suppressing the splicing of target genes, including those related to Rac1 signaling. CAPN6 deficiency in LDL receptor-deficient mice restored CWC22/EJC/Rac1 signaling, reduced pinocytotic deposition of native LDL in macrophages, and attenuated macrophage recruitment into the lesions, generating an atheroprotective phenotype in the aorta. In macrophages, the induction of CAPN6 in the atheroma interior limited macrophage movements, resulting in a decline in cell clearance from the lesions. Consistent with this finding, we observed that myeloid CAPN6 contributed to atherogenesis in a murine model of bone marrow transplantation. Furthermore, macrophages from advanced human atheromas exhibited increased CAPN6 induction and impaired CWC22 nuclear localization. Together, these results indicate that CAPN6 promotes atherogenicity in inflamed macrophages by disturbing CWC22/EJC systems.
Evaluation of electrolytic imbalance in patients with advanced colorectal and gastric cancer treated with anti-EGFR monoclonal antibody-based therapy
Authors: C. Funaioli, C. Pinto, F. Di Fabio, N. Malavasi, P. Di Tullio, S. Pini, B. Vincenzi, F. L. Rojas Llimpe, D. Santini, G. Tonini, A. A. Martoni
Journal: Journal of Clinical Oncology (2008)

14631 Background: The largest studies have associated anti-EGFR monoclonal antibody treatment with hypomagnesemia, while other electrolytic imbalances has not been evaluated. The aim of this study was to evaluate the recurrence of electrolytic imbalances and, in particular, of hypokalemia in pts treated with regimens including cetuximab or panitumumab. Methods: Data were collected from 141 consecutive patients affected by advanced colorectal or gastric adenocarcinoma who received an anti-EGFR monoclonal antibody treatment in association with different chemotherapy regimens. The evaluation of the serum electrolytic value (Na1+, K1+ and Mg2+) and clinical symptoms was performed every week during the treatment. Therapy-related toxicity was evaluated according to NCI-CTC version 3.0. Results: The pt characteristics were: 86 males (61%), 55 females (39%); the primary tumor site was colon 103 (73%), stomach 38 (27%). One hundred and nineteen pts (84.4%) received irinotecan-based chemotherapy in combination with cetuximab or panitumumab, 10 pts (7.1%) cisplatin plus docetaxel regimen in combination with cetuximab and 1 pt (1%) a panitumumab alone. Cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) was administered to 126 pts (89.4%) and panitumumab (6 mg/kg every 2 weeks) to 15 pts (10.6%). Treatment was administered as first-line therapy in 50 pts (35.5%), and as a second or further line in 91 pts (64.5%). Pts received a median of 17 weeks (range 2–73) of treatment. This electrolytic imbalance was observed: hypokalemia grade 1–4: 45 pts (31.9%), grade 3–4: 19 pts (13.5%); hyponatremia grade 1–4: 49 pts (34.7%), grade 3–4: 8 pts (5.7%); hypomagnesemia grade 1–2: 48 (34%) (no grade 3–4). Grade 1–4 diarrhea occurred in 82 pts (58.1%) and grade 3–4 in 11 pts (7.8%). In multivariate analysis (logistic regression), hypokalemia was not associated with the primary tumor site, the line of therapy, the chemotherapy regimens or other potentially related toxicity (diarrhea). Conclusions: These data suggest that hypokalemia toxicity should be evaluated in pts treated with anti-EGFR antibodies. The mechanism related to the hypokalemia and electrolytic imbalance requires further evaluation. No significant financial relationships to disclose.
Abstract 10335: Systolic Motion of the Basal Right Ventricular Freewall is the Strongest Predictor of Global Function: A High Resolution 3D Cardiac Magnetic Resonance Study
Authors: Timothy Dawes, Antonio de Marvao, Wenzhe Shi, Daniel Rueckert, Stuart Cook, Declan P O'Regan
Journal: Circulation (2015)

Background: Right ventricular (RV) function has prognostic value in disease cohorts and the general population although its complex geometry and motion make rapid assessment difficult. Several two-dimensional regional measures are used to estimate global RV function, however the optimal measure is not known. Methods: High-resolution 3-dimensional cardiac magnetic resonance (3D-CMR) cine imaging of the whole heart was acquired in 300 healthy volunteers and a computational model of RV motion created. From this model, points where regional function was significantly associated with global function were identified, and a two-dimensional, Optimized Single-Point Marker (SPM-O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum-freewall displacement (SFD) and their fractional derivatives (TAPSE-F, SFD-F) in a test cohort (n=300). Performance in predicting RVEF was compared by correlation, bootstrapped linear regression and mean absolute error. Results: Three-dimensional imaging suggested that RVEF was significantly associated with systolic function in a contiguous 7.3cm 2 patch of the basal RV freewall which combined components of transverse (38%), longitudinal (35%) and circumferential (27%) contraction. SPM-O was identified where this patch coincided with the four-chamber view and combined longitudinal and transverse contraction. In the test cohort, all single-point surrogates correlated with RVEF (p&lt;0.01), but correlation was significantly higher for SPM-O (R = 0.44) than TAPSE (R = 0.24, p&lt;0.002) and SFD (R = 0.22, p&lt;0.001), and non-significantly higher than TAPSE-F (R = 0.40, p=0.50) and SFD-F (R = 0.43, p=0.86). SPM-O explained more of the observed variance in RVEF (19%) and predicted RVEF more accurately than any other 2D marker (median error 2.8 vs 3.6%, p&lt;0.001). Conclusions: Systolic motion of the basal RV freewall in the four-chamber plane is a more accurate surrogate of global function than other two-dimensional estimators. However, the performance of two-dimensional estimators is fundamentally limited by a failure to adequately summarize three-dimensional contractile patterns, such as those found in the right ventricle.
How much is too much? (Part 2) International Olympic Committee consensus statement on load in sport and risk of illness
Authors: Martin Schwellnus, Torbjørn Soligard, Juan-Manuel Alonso, Roald Bahr, Ben Clarsen, H Paul Dijkstra, Tim J Gabbett, Michael Gleeson, Martin Hägglund, Mark R Hutchinson, Christa Janse Van Rensburg, Romain Meeusen, John W Orchard, Babette M Pluim, Martin Raftery, Richard Budgett, Lars Engebretsen
Journal: British Journal of Sports Medicine (2016)

The modern-day athlete participating in elite sports is exposed to high training loads and increasingly saturated competition calendar. Emerging evidence indicates that inappropriate load management is a significant risk factor for acute illness and the overtraining syndrome. The IOC convened an expert group to review the scientific evidence for the relationship of load—including rapid changes in training and competition load, competition calendar congestion, psychological load and travel—and health outcomes in sport. This paper summarises the results linking load to risk of illness and overtraining in athletes, and provides athletes, coaches and support staff with practical guidelines for appropriate load management to reduce the risk of illness and overtraining in sport. These include guidelines for prescription of training and competition load, as well as for monitoring of training, competition and psychological load, athlete well-being and illness. In the process, urgent research priorities were identified.
Updated results: A phase I/IIa randomized trial of radium-223 + docetaxel versus docetaxel in patients with castration-resistant prostate cancer and bone metastases.
Authors: Michael J. Morris, Yohann Loriot, Christopher Sweeney, Karim Fizazi, Charles J. Ryan, Daniel H. Shevrin, Emmanuel S. Antonarakis, John Reeves, Kumari Chandrawansa, Martin Kornacker, Celestia S. Higano
Journal: Journal of Clinical Oncology (2016)

5075 Background: Radium-223 (Ra-223), an α emitter, and docetaxel (D), a chemotherapy, prolong overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC) patients (pts). This study examined safety and efficacy of Ra-223 + D v D alone. Preliminary phase IIa prostate-specific antigen (PSA) and alkaline phosphatase (ALP) data were previously reported (Morris et al. ASCO 2015). All pts have been randomized and have completed treatment. Methods: D-eligible pts with progressing CRPC and ≥ 2 bone metastases were randomized 2:1 to Ra-223 (50 kBq/kg q 6 wk × 5) + D (60 mg/m2 q 3 wk × 10) v D (75 mg/m2 q 3 wk × 10; step-down option to 60 mg/m2). Primary end point was safety; exploratory efficacy end points were PSA and ALP changes, progression-free survival (PFS), and OS. Results: 53 pts (36 Ra-223 + D; 17 D) were randomized; 33 Ra-223 + D and 13 D pts were treated. For pts in the Ra-223 + D arm, 25 (76%) had all 6 Ra-223 injections, and 20 (61%) had all 10 D cycles. For the D-alone pts, 5 (38%) received all 10 cycles (3 received 75 mg/m2, and 2 stepped down to 60 mg/m2). Pts in Ra-223 + D arm had a lower percentage of grade 3/4 treatment-emergent adverse events during treatment (Ra-223 + D, 49%; D, 62%); no Ra-223 + D and 2 (15%) D pts had febrile neutropenia; no pts had clinically significant thrombocytopenia in either arm. Ra-223 + D had longer time to all measures of progression and longer PFS (Table). Waterfall plots of PSA and ALP will be presented. Two Ra-223 + D pts and one D pt died of disease progression during 9-mo follow-up. Conclusions: Ra-223 + D was well tolerated. Ra-223 + D treated pts had longer times to progression and fewer adverse events v pts in D arm. Further studies of Ra-223 + D are planned. Clinical trial information: NCT01106352. Median, mo (95% CI); number of pts with events Ra-223 + D N = 32 D N = 13 Time to PSA progression* 6.6 (5.8, 9.1); 24 4.8 (2.8, 5.6); 12 Time to radiographic or clinical progression† 12.0 (8.2, 12.2); 18 9.3 (3.2, 12.2); 9 Time to PFS 6.2 (2.8, 8.8); 28 4.8 (2.8, 5.6); 12 *Per PCWG2 †Per RECIST and PCWG2
Response to Comment on Muraki et al. Potato Consumption and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies. Diabetes Care 2016;39:376–384
Authors: Isao Muraki, Qi Sun
Journal: Diabetes Care (2016)

Dr. Bossi (1) raised an interesting point that the acrylamide content of french fries and potato chips may contribute to the positive associations between the intake of these foods and an elevated risk of developing type 2 diabetes (T2D) or gestational diabetes mellitus. Highly processed foods such as french fries and potato chips contain both nutrients intrinsic to the raw foods and ingredients added or generated during processing/cooking. In this regard, trans fat is …
Predicting Suicidal Behavior From Longitudinal Electronic Health Records
Authors: Yuval Barak-Corren, Victor M. Castro, Solomon Javitt, Alison G. Hoffnagle, Yael Dai, Roy H. Perlis, Matthew K. Nock, Jordan W. Smoller, Ben Y. Reis
Journal: American Journal of Psychiatry (2016)

Objective: The purpose of this article was to determine whether longitudinal historical data, commonly available in electronic health record (EHR) systems, can be used to predict patients’ future risk of suicidal behavior. Method: Bayesian models were developed using a retrospective cohort approach. EHR data from a large health care database spanning 15 years (1998–2012) of inpatient and outpatient visits were used to predict future documented suicidal behavior (i.e., suicide attempt or death). Patients with three or more visits (N=1,728,549) were included. ICD-9-based case definition for suicidal behavior was derived by expert clinician consensus review of 2,700 narrative EHR notes (from 520 patients), supplemented by state death certificates. Model performance was evaluated retrospectively using an independent testing set. Results: Among the study population, 1.2% (N=20,246) met the case definition for suicidal behavior. The model achieved sensitive (33%–45% sensitivity), specific (90%−95% specificity), and early (3–4 years in advance on average) prediction of patients’ future suicidal behavior. The strongest predictors identified by the model included both well-known (e.g., substance abuse and psychiatric disorders) and less conventional (e.g., certain injuries and chronic conditions) risk factors, indicating that a data-driven approach can yield more comprehensive risk profiles. Conclusions: Longitudinal EHR data, commonly available in clinical settings, can be useful for predicting future risk of suicidal behavior. This modeling approach could serve as an early warning system to help clinicians identify high-risk patients for further screening. By analyzing the full phenotypic breadth of the EHR, computerized risk screening approaches may enhance prediction beyond what is feasible for individual clinicians.
Adult onset asthma may increase risk of heart disease and stroke
Authors: Susan Mayor
Journal: BMJ (2016)

People who develop asthma in adulthood have a notably increased risk of cardiovascular disease (CVD) events including coronary death, myocardial infarction, and stroke than those without asthma, a large prospective study has shown.

The Wisconsin Sleep Cohort study, reported in the Journal of the American Heart Association ,1 included 1269 adults (mean age 47.3 ± 8.0 years) without CVD. They were followed up for a mean …
Quality Health Care
Authors: R H Palmer
Journal: JAMA (1996)

A new reality is emerging as cost limits are set for health care: quality of care is becoming a major concern to payers and patients. Increasingly, employers and state and federal governments pay fixed premiums per enrollee to managed care organizations (MCOs), who then pay physicians by mechanisms designed to limit use of service; the question inevitably arises, "Are necessary tests and treatments, safe implementation, or communication with patients cut to save money?" Employers and governments therefore demand information to compare plans on the quality of care they provide.<sup>1</sup> Most physicians encounter this new reality in the form of requirements for access to medical records and claims data for use in measuring performance. Managed-care organizations use these performance measurements to demonstrate accountability to employers and accreditors, but too few give the information back to physicians—a shocking waste of valuable information. [See also Medical Informatics.—Ed.] Physicians need periodic feedback