tbuckley/cabot-search huggingface dataset:
Nivolumab in Previously Untreated Melanoma without<i>BRAF</i>Mutation
Authors: Caroline Robert, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Kerry J. Savage, Micaela M. Hernberg, Celeste Lebbé, Julie Charles, Catalin Mihalcioiu, Vanna Chiarion-Sileni, Cornelia Mauch, Francesco Cognetti, Ana Arance, Henrik Schmidt, Dirk Schadendorf, Helen Gogas, Lotta Lundgren-Eriksson, Christine Horak, Brian Sharkey, Ian M. Waxman, Victoria Atkinson, Paolo A. Ascierto
Journal: New England Journal of Medicine (2014)

Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).
Effect of arthrographic shoulder joint distension with saline and corticosteroid for adhesive capsulitis
Authors: R Buchbinder, S Green
Journal: British Journal of Sports Medicine (2004)

Distension of the glenohumeral joint with saline and steroid has considerable short term benefit in adhesive capsulitis

Painful stiffening of the shoulder, first described by Duplay in 1834,1 and aptly labelled “frozen shoulder” by Codman,2 is a common cause of shoulder pain and disability. It is estimated to affect 2–5% of the general population and 10–20% of people with diabetes, with subsequent involvement of the contralateral shoulder estimated to occur in 5–40% of affected people.3,4 The cumulative incidence in general practice is estimated to be 2.4/1000/year (95% confidence interval 1.9 to 2.9).5 The condition is most common in the 5th and 6th decades and it is slightly more common among women. Based on his arthrographic findings of synovial inflammation and adhesions, the term “adhesive capsulitis” was first coined by Neviaser.6 These observations led to the commonly held hypothesis that inflammation of the capsule, leading to subsequent fibrosis, is responsible for the clinical features of this condition.

Patients typically present with a history of gradual onset of severe, disabling shoulder pain accompanied by progressive limitation of both active and passive glenohumeral movement.7 Three phases have been described: an early painful phase, usually lasting two to nine months; an intermediate stiff phase, lasting 4–12 months, during which the stiffness predominates and pain is less pronounced; and a final recovery phase lasting 5–24 months, characterised by gradual return of movement.7 The pain and stiffness result in severe disability, restricting activities of daily living, work, and leisure activities. Although early studies suggested a self limiting condition lasting two to three years,8 …
HDL Cholesterol Predicts Coronary Heart Disease Mortality in Older Persons
Authors: Maria-Chiara Corti
Journal: JAMA (1995)

<h3>Objectives.</h3> —To examine the relationship of total cholesterol and high-density lipoprotein cholesterol (HDL-C) with coronary heart disease (CHD) mortality and with occurrence of new CHD events in persons aged 71 years and older. <h3>Design.</h3> —Prospective cohort study with a median of 4.4 years of follow-up. <h3>Setting.</h3> —East Boston, Mass; New Haven, Conn; and Iowa and Washington counties, Iowa. <h3>Participants.</h3> —A total of 2527 women and 1377 men who completed an interview, had serum lipid determinations, and survived at least 1 year. New CHD events were evaluated in persons with no CHD history or hospitalization. <h3>Main Outcome Measures.</h3> —Death due to CHD (<i>ICD-9</i>codes 410 through 414 as underlying cause of death); new occurrence of CHD events (fatal CHD or hospitalization with CHD [<i>ICD-9</i>codes 410 through 414]). <h3>Results.</h3> —After adjustment for established CHD risk factors, the relative risk (RR) of death due to CHD for those with low HDL-C (&lt;0.90 mmol/L [&lt;35 mg/dL]) compared with the reference group (HDL-C ≥1.55 mmol/L [≥60 mg/dL]) was 2.5 (95% confidence interval [CI], 1.6 to 4.0). Elevated risk was present in subgroups aged 71 through 80 years (RR, 4.1; 95% CI, 1.9 to 8.8) and over 80 years (RR, 1.8; 95% CI, 0.99 to 3.4), and in men and women. Low HDL-C predicted an increased risk of occurrence of new CHD events (RR, 1.4; 95% CI, 1.1 to 2.0), with similar but nonsignificant results in subgroups of men and women. Total cholesterol was less consistently associated with CHD mortality than HDL-C. When we compared individuals with total cholesterol of at least 6.20 mmol/L (240 mg/dL) with the reference group with total cholesterol of 4.16 to 5.19 mmol/L (161 to 199 mg/dL), a significant risk of CHD mortality was seen for women (RR, 1.8; 95% CI, 1.03 to 3.0) but not for men (RR, 1.0; 95% CI, 0.5 to 2.0). In the total population, for each 1-unit increase in the total cholesterol/HDL-C ratio there was a 17% increase in the risk of CHD death that was statistically significant. <h3>Conclusions.</h3> —Low HDL-C predicts CHD mortality and occurrence of new CHD events in persons older than 70 years. Elevated total cholesterol was not found to be associated with CHD mortality in older men, but may be a risk factor for CHD in older women. (<i>JAMA</i>. 1995;274:539-544)
Heterozygous α‐antichymotrypsin and PiZ (α<sub>1</sub>‐antitrypsin deficiency
Authors: B. Lindmark, E. Svenonius, S. Eriksson
Journal: Allergy (1990)

In a case‐control study we compared the prevalence of heterozygous deficiency of two closely related anti‐neutrophil protease inhibitors, α 1 ‐antitrypsin and α 1 ‐antichymotrypsin, in 172 consecutive children with asthma. In a cohort study the clinical spectrum and severity were compared. On the basis of family studies 5/172 (2.9%) were classified as heterozygotes for α 1 ‐antichymotrypsin deficiency, a high prevalence compared with that of an unselected adult population (prevalence ratio 4.5 (1.7–11.9), P &lt;0.005). This finding suggests that the carrier state of this rare allele (prevalence 0.64%) may predispose to asthma in children. Among these heterozygous patients the prevalence of positive RAST tests for foodstuffs was significantly increased (prevalence ratio 4.8 (1.7–13.2). P&lt;0.005) and 2/5 manifested food allergy with Quincke oedema. Either the PiMZ or SZ phenotype of α 1 ‐antitrypsin deficiency was found in 12 (7.0%) of the 172 patients, a prevalence similar to that of a normal population (prevalence ratio 1.3 (0.67–2.6), P = 0.44). However, the asthma was more severe among the Z allele carriers, judged by the number of hospital admissions, compared with the non‐Z asthmatic children (mean 2.92 vs. 1.72, P &lt;0.05). The results indicate that heterozygous deficiency of protease inhibitors directed against neutrophil proteases may affect the severity and clinical spectrum of childhood asthma, and to some degree be predisposing.
Maternal Calcium Intake and Offspring Blood Pressure
Authors: Matthew W. Gillman, Sheryl L. Rifas-Shiman, Ken P. Kleinman, Janet W. Rich-Edwards, Steven E. Lipshultz
Journal: Circulation (2004)

Background— Few data exist on the intergenerational influence of calcium intake during pregnancy on offspring blood pressure. Methods and Results— As part of the ongoing US prospective cohort study Project Viva, we analyzed 4091 Dinamap blood pressure measurements from 936 six-month-old infants whose mothers had completed food frequency questionnaires during the second trimester of pregnancy. We used mixed models to estimate effects of maternal calcium intake on offspring systolic blood pressure. Mean±SD daily total maternal calcium intake was 1494±523 mg, consisting of 1230±486 mg from foods and 264±191 mg from supplements. Mean±SD 6-month blood pressure was 89.9±12.9 mm Hg. From bottom to top quartile of dietary calcium from foods adjusted for energy intake and measurement conditions, mean infant systolic blood pressures were 91.0, 90.2, 90.9, and 90.2 mm Hg (trend P =0.62). From calcium supplements only, the values were 91.5, 90.2, 90.4, and 88.4 mm Hg (trend P =0.006). After further adjustment for demographic, anthropometric, dietary, social, and economic variables, the decrease in 6-month systolic blood pressure was −3.0 mm Hg (95% CI, −4.9 to −1.1) for each 500-mg increment of maternal supplemental calcium intake during pregnancy. We did not find evidence of effect modification by maternal vitamin D or potassium intake or by infant body mass index. First-trimester calcium intake was not associated with offspring blood pressure. Conclusions— These observational data suggest that supplementing maternal midgestational calcium intake may lower offspring blood pressure, thus helping to prevent hypertension in the next generation.
T Cell Receptor (TCR)-β Gene Recombination: Dissociation from Cell Cycle Regulation and Developmental Progression During T Cell Ontogeny
Authors: Michelle R. Tourigny, Svetlana Mazel, Douglas B. Burtrum, Howard T. Petrie
Journal: The Journal of Experimental Medicine (1997)

T cell lymphopoiesis involves extensive cell division and differentiation; these must be balanced by export and programmed cell death to maintain thymic homeostasis. Details regarding the nature of these processes, as well as their relationships to each other and to the definitive process of T cell receptor (TCR) gene recombination, are presently emerging. Two widely held concepts are that cell cycle status is inherently and inversely linked to gene recombination and that the outcomes of gene recombination regulate developmental progression. In this study, we analyze TCR-beta recombination and cell cycle status with respect to differentiation during early T cell ontogeny. We find that although differentiation, cell cycle fluctuations, and gene recombination are coincident during normal T cell development, differentiation and cell cycle status are not inherently linked to the recombination process or its products. Rather, recombination appears to occur in parallel with these events as part of a genetically patterned program of development. We propose that the outcome of gene recombination (i.e., TCR expression) may not influence developmental progression per se, but instead serves to perpetuate those developing cells that have been successful in recombination. The potential consequences of this model for the regulation of thymic lymphopoiesis and programmed cell death are discussed.
Atherosclerotic Arterial Remodeling in the Superficial Femoral Artery
Authors: Gerard Pasterkamp, Cornelius Borst, Mark J. Post, Willem P.T.M. Mali, Peter J.W. Wensing, Elma J. Gussenhoven, Berend Hillen
Journal: Circulation (1996)

In previous studies on atherosclerotic arterial remodeling, compensatory enlargement of the artery in response to plaque accumulation was inferred from pooled data based on one cross section per artery. We assessed local arterial remodeling individually by analyzing 45 artery segments at 0.5-cm intervals over a length of 10 to 15 cm.Twenty patients were studied by 30-MHz intravascular ultrasound (IVUS) before balloon angioplasty of the superficial femoral artery (370 cross sections), and 25 femoral artery segments were studied postmortem (551 cross sections). In each cross section, the area surrounded by the internal elastic lamina (IEL area) and the plaque area were measured. The IEL area was larger in the cross section with the largest plaque area than in the cross section with the smallest plaque area (32.5+/-13.0 and 32.0+/-11.5 mm2 versus 28.9+/-9.7 [P=NS] and 26.7+/-10.1 [P<.05] mm2 for IVUS and histology, respectively [mean+/-SD]). A significant positive correlation was found between plaque area and IEL area for the pooled data (r=.61 and r=.47 and slope=1.07 and 0.90 for IVUS and histology, respectively; both P<.001). In 12 of 20 and 16 of 25 individual arterial segments, however, no significant correlation was observed between plaque area and IEL area for IVUS and histology, respectively. A large variation was found in the correlation of the regression of plaque to IEL area (IVUS, r=-.40 to .89; histology, r=-.13 to .91) and slope (IVUS, -0.28 to 1.29; histology, -0.18 to 1.32).In the majority of atherosclerotic femoral arteries, significant compensatory enlargement could not be determined. It is inferred that arterial remodeling in response to plaque formation may vary among individuals.
Increasing Incidence of Type 1 Diabetes in Youth
Authors: Terri H. Lipman, Lorraine E. Levitt Katz, Sarah J. Ratcliffe, Kathryn M. Murphy, Alexandra Aguilar, Iraj Rezvani, Carol J. Howe, Shruti Fadia, Elizabeth Suarez
Journal: Diabetes Care (2013)

The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000-2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes.Diabetes cases were obtained through a retrospective population-based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period.The overall age-adjusted incidence rate in 2000-2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0-4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children.The incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985-1989 cohort. The most marked increases were among white children ages 10-14 years and black children ages 0-4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.
Medical Aspects of Oral Contraceptives
Authors: NEIL J. ELGEE
Journal: Annals of Internal Medicine (1970)

Many laboratory tests of persons taking oral contraceptives are distorted. Elevations of binding proteins increase total plasma cortisol and thyroxine, although adrenal and thyroid function remain normal. Serum iron and iron-binding capacity are increased. Slight sulfobromophthalein and serum glutamicoxalacetic transaminase elevations appear to be innocuous. Serum immunoreactive insulin and growth hormone levels are elevated. Postprandial blood glucose and fasting triglyceride generally increase slightly, but the triglyceride rise may be profound in a hypertriglyceridemic woman. Renin substrate is generally elevated and aldosterone, occasionally. Significant hypertension, subsiding on withdrawal of the medication, has been seen rarely. Migraine may worsen, and cerebrovascular ischemic episodes and thromboses may occur, especially in hypertensives. The prevalence of thromboembolic episodes is increased, comparable with that of pregnancy. Melasma, benign cervical polyps, and vulvovaginal moniliasis are also seen. Cholestatic jaundice, marked triglyceridemia, positive lupus erythematosus preparations, hypertension, worsening migraine, or thromboembolism are contraindications. Morbidity and mortality due to oral contraceptives are low, and the risks of pregnancy often outweigh those of the pill.
Adjuvant trastuzumab for breast cancer: Editorial does not mention health economics of drug
Authors: E Hamish McLaren
Journal: BMJ (2005)

Adjuvant trastuzumab for breast cancer Assessing HER2/neu status incurs more costs for treatmentEditor-The results of recent trials are likely to continue to fuel the demand for trastuzumab in the adjuvant setting of early breast cancer, 1 as well as a possible neoadjuvant treatment in the near future.However, Dent and Clemons did not discuss the difficulty in obtaining accurate and reproducible assessment of HER2/neu gene overexpression.Immunohistochemical testing measures HER2/neu protein expression whereas in situ hybridisation measures gene amplification.Patients with equivocal immunohistochemical results require in situ hybridisation to determine definitive status because interobserver variability using immunohistochemical testing is appreciable.At least 20% of patients with positive immunohistochemical results will be truly negative for HER2/neu gene amplification; these patients would not benefit from trastuzumab. 2 These difficulties in assessing HER2/ neu status have been encountered in studies testing trastuzumab, and in situ hybridisation testing has been used as the gold standard. 3 As the clinical utility of trastuzumab widens guidelines on HER2/neu testing must be clear to ensure appropriate use of trastuzumab.Clearly this testing will incur additional costs to trastuzumab treatment.
Treatment of Neuroblastoma Meningeal Carcinomatosis with Intrathecal Application of α-Emitting Atomic Nanogenerators Targeting Disialo-Ganglioside GD2
Authors: Matthias Miederer, Michael R. McDevitt, Paul Borchardt, Ira Bergman, Kim Kramer, Nai-Kong V. Cheung, David A. Scheinberg
Journal: Clinical Cancer Research (2004)

Abstract Labeling of specific antibodies with bifunctional chelated Actinium-225 (225Ac; an α generator) allows the formation of new, highly potent and selective α-emitting anticancer drugs. We synthesized and evaluated a radioimmunoconjugate based on 3F8, an IgG3 antibody that specifically binds to ganglioside GD2, which is overexpressed by many neuroectodermal tumors including neuroblastoma. The 225Ac-1,4,7,10-tetra-azacylododecane (DOTA)-3F8 construct was evaluated for radiochemical purity and sterility, immunoreactivity, cytotoxicity in vitro, induction of apoptosis on GD2-positive cells, as well as for pharmacological biodistribution and metabolism of the 225Ac generator and its daughters in a nude mouse xenograft model of neuroblastoma. The 225Ac-3F8 showed an IC50 of 3 Bq/ml (80 pCi/ml) on the neuroblastoma cell line, NMB7, in vitro. Apoptosis of these cells was not observed. Biodistribution in mice showed specific targeting of a subcutaneous tumor; there was redistribution of the 225Ac daughter nuclides mainly from blood to kidneys and to small intestine. Toxicity was examined in cynomolgus monkeys. Monkeys injected with 1 to 3 doses of intrathecal 225Ac-3F8 radioimmunoconjugate (80 to 150 kBq/kg total dose) did not show signs of toxicity based on blood chemistry, complete blood counts, or by clinical evaluations. Therapeutic efficacy of intrathecal 225Ac-3F8 was studied in a nude rat xenograft model of meningeal carcinomatosis. The 225Ac-3F8 treatment improved survival 2-fold from 16 to 34 days (P = 0.01). In conclusion, in vivo α generators targeted by 3F8 warrant additional study as a possible new approach to the treatment of carcinomatous meningitis.
Addition of the Oral NK<sub>1</sub> Antagonist Aprepitant to Standard Antiemetics Provides Protection Against Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy
Authors: R. de Wit, J. Herrstedt, B. Rapoport, A.D. Carides, G. Carides, M. Elmer, C. Schmidt, J.K. Evans, K.J. Horgan
Journal: Journal of Clinical Oncology (2003)

Purpose: This analysis evaluated whether the antiemetic efficacy of the NK 1 receptor antagonist aprepitant (EMEND ™ , Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy. Patients and Methods: Patients receiving cisplatin ≥ 70 mg/m 2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5. The primary end point was complete response (no emesis and no rescue therapy) over 5 days following cisplatin in up to six cycles. A cumulative probability analysis using a model for transitional probabilities was used to analyze the data. The aprepitant 375/250-mg regimen was discontinued early in light of new pharmacokinetic data. Results: In the first cycle, 64% of patients in the aprepitant group and 49% in the standard therapy group had a complete response. Thereafter, complete response rates for the aprepitant group were still 59% by cycle 6, but decreased to 34% by cycle 6 for the standard therapy group. Reasons for discontinuation were similar across treatment groups. Conclusion: Compared with patients who received standard therapy, those who received only the aprepitant regimen had better and more sustained protection against chemotherapy-induced nausea and vomiting over multiple cycles.