tbuckley/cabot-search huggingface dataset:
A phase I clinical study of safingol followed by cisplatin: promising activity in refractory adrenocortical cancer with novel pharmacology
Authors: R. D. Carvajal, A. H. Merrill, H. Dials, A. Barbi, G. K. Schwartz
Journal: Journal of Clinical Oncology (2006)

13044 Background: Safingol (L-threo-dihydrosphingosine), originally identified as a competitive inhibitor of protein kinase C, has been re-identified as an inhibitor of sphingosine kinase (SK). Inhibition of SK induces apotosis and autophagy by increasing intracellular conversion of sphingosine to ceramide. In vivo, safingol enhances the antitumor activity of cisplatin in a sequence dependent manner (safingol→cisplatin). Methods: We designed a phase I trial of escalating doses of safingol (60→120→240→ 360→480→600 mg/m 2 ) followed 1 hr later by fixed-dose cisplatin 75 mg/m 2 given q21 days in pts with advanced solid tumors. Standard phase I eligibility critieria apply. Prior cisplatin is allowed. Results: 13 evaluable pts have been enrolled: 5 male/8 female, median age 54 (range 36–68), median KPS 90% (range 80–100%), mean number of priors 2.8 (range 1–6). 2 dose limiting toxicities (DLT) were observed with escalation of safingol to 240 mg/m 2 (gr 3 fatigue, gr 3 hyponatremia), both felt to be due primarily to cisplatin. The protocol was amended to reduce cisplatin to 60 mg/m 2 , given with 240 mg/m 2 of safingol. We observed 1 DLT (persistent gr 3 thrombocytopenia) at this dose level. Pharmacokinetic (PK) analysis by mass spectroscopy shows nearly complete clearance of safingol from circulation within 24 hours of treatment with a 10-fold greater amount of safingol in whole blood than in plasma. An increase in sphingosine and dihydroceramide levels were observed with therapy, and N-acyl- and N-methyl- metabolites of safingol were detected. We observed 1 PR (4+ months) in a pt with cisplatin-refractory adrenocortical cancer metastatic to the liver and lung after only 1 cycle of therapy. 1 additional pt with adrenocortical cancer has SD (2+ months) on therapy. Conclusions: Escalating doses of safingol can be safely administered with a fixed dose of cisplatin. PK data reveal acyl- and methyl-safingol for the first time in human plasma, with a significant fraction of safingol bound to human blood cells. We observed unusual activity in pts with adrenocortical cancer. Further dose escalation of safingol with cisplatin 60 mg/m 2 is ongoing, and additional PK data and complete sphingolipid profiles will be presented. (Supported by NCI R21-CA112910). No significant financial relationships to disclose.
Validation of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Symptom Index (FOSI) in a phase II clinical trial of pertuzumab in patients with advanced ovarian cancer
Authors: J. Beaumont, S. Yount, D. Lalla, D. Lubeck, M. Derynck, B. Karlan, D. Cella
Journal: Journal of Clinical Oncology (2007)

16021 Background: The FOSI is a very brief(8-item) index derived from the FACT-O to measure symptom response to treatment for ovarian cancer(OC). We evaluated its performance in a single arm Phase II clinical trial. Methods: The FOSI was administered to patients with advanced OC participating in a single arm Ph II clinical trial of pertuzumab(Gordon et al, JCO (2006) v24:4324;2006)). Pertuzumab, a humanized HER2 antibody is the first in a new class of investigational agents known as HER dimerization inhibitors(HDIs). Patients completed the FOSI at D1 of each 3 week cycle, up to 17 cycles. Validation analyses focused on data from the first 4 cycles and included Cronbach's alpha coefficients plus cross-sectional and longitudinal comparisons of groups defined by ECOG performance status (PS). Results: 62 patients completed the FOSI at baseline (B), 54 at cycle 2, 44 at cycle 3 and 27 at cycle 4. The FOSI showed acceptable internal consistency reliability with alphas of 0.73 to 0.80. The FOSI differentiated patients with PS 0 from those with PS =1 at each cycle (Table). There was a difference in FOSI scores in patients with worsened PS from those whose PS improved or was unchanged at cycle 2 only (p&lt;0.001). The ES (mean change/ SD of change scores) for the group with worsened PS was -0.77. The minimally important difference was estimated to be 2–3 points. Conclusions: The FOSI is a valid symptom measure in this population of OC patients, demonstrating acceptable reliability, validity and responsiveness to clinical change. [Table: see text] No significant financial relationships to disclose.
Detection of Mutations in the Tyrosinase Gene in a Patient with Type IA Oculocutaneous Albinism
Authors: Richard A. Spritz, Kathleen M. Strunk, Lutz B. Giebel, Richard A. King
Journal: New England Journal of Medicine (1990)

OCULOCUTANEOUS albinism is a group of severe genetic disorders of pigmentation characterized by reduced or absent biosynthesis of melanin pigment in the melanocytes of the skin, hair follicle, and eye.1 Because of the striking phenotype, oculocutaneous albinism was one of the first genetic disorders recognized, and its typical clinical features,2 , 3 autosomal recessive mode of inheritance, and genetic heterogeneity2 3 4 are apparent even in classical descriptions. In the classic, most severe form of oculocutaneous albinism, Type IA, the lack of melanin biosynthesis results from the absence of activity of the enzyme tyrosinase (monophenol monooxygenase; EC 1.14.18.1) in pigment cells. Tyrosinase is a . . .
Geographic Patterns of Breast Cancer in the United States
Authors: William J. Blot, Joseph F. Fraumeni, B. J. Stone
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Geographic Patterns of Breast Cancer in the United States Get access William J. Blot, Ph.D., William J. Blot, Ph.D. Search for other works by this author on: Oxford Academic PubMed Google Scholar Joseph F. Fraumeni, Jr., Joseph F. Fraumeni, Jr. Search for other works by this author on: Oxford Academic PubMed Google Scholar B. J. Stone, Ph.D. B. J. Stone, Ph.D. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 59, Issue 5, November 1977, Pages 1407–1411, https://doi.org/10.1093/jnci/59.5.1407 Published: 01 November 1977 Article history Received: 25 April 1977 Accepted: 01 June 1977 Published: 01 November 1977
NCCN Bone Health Task Force: Key Recommendations
Authors: Azeez Farooki
Journal: Journal of the National Comprehensive Cancer Network (2014)

For patients with advanced cancers involving bone, the standard of care for maintaining bone health is the use of antiresorptive therapies such as bisphosphonates, selective estrogen-receptor modulators, and denosumab. However, although long-term adverse events are rare and the risk-benefit ratio of these agents is usually markedly in favor of treatment, clinicians should be aware that they can occur. At the NCCN 19th Annual Conference, Dr. Azeez Farooki presented the key findings of the NCCN Bone Health Task Force, focusing on such topics as screening for osteoporosis; the controversial use of drug holidays from chronic bisphosphonate therapy; the provocative yet unclear story surrounding the potential anticancer benefits of antiresorptive agents; imaging for metastatic bone disease; and safety considerations linked to calcium supplements, vitamin D, and bone-strengthening agents.
Racial Differences in Low Birth Weight
Authors: Joel C. Kleinman, Samuel S. Kessel
Journal: New England Journal of Medicine (1987)

To identify the risk factors responsible for differences in birth weight between blacks and whites, we investigated the effects of four maternal characteristics (age, parity, marital status, and education) on rates of very low birth weight (less than 1500 g) and moderately low birth weight (between 1500 and 2500 g). Using 1983 national data, we found that the black:white rate ratio was 3.0 for very low birth weight and 2.3 for moderately low birth weight. The four maternal factors had directionally similar but quantitatively different effects on very low and moderately low birth weight among blacks and whites. Furthermore, the racial differences in infants' birth weights were greater among low-risk than among high-risk mothers, especially for very low birth weight (black:white ratios of 3.4 and 1.7, respectively). We also examined secular trends in the rates of low birth weight among blacks and whites. Between 1973 and 1983, births of infants with moderately low birth weights decreased more among whites than among blacks, whereas births of infants with very low birth weights increased among blacks and decreased among whites. Fifteen percent of the decline in the rate of moderately low birth weight among whites could be attributed to favorable changes in maternal characteristics (primarily an increase in educational level). Among blacks, adverse changes in maternal characteristics (primarily an increase in births to unmarried women) accounted for 35 percent of the increase in the rate of very low birth weight. The adverse effects of childbearing by teenagers on the outcome of pregnancy among blacks appear to have been overemphasized. The persistence of large racial differences in birth weight, even among mothers at low risk, emphasizes the need for specific targeted interventions to achieve further improvements in infant health.
Definition of a COPD self-management intervention: International Expert Group consensus
Authors: Tanja W. Effing, Jan H. Vercoulen, Jean Bourbeau, Jaap Trappenburg, Anke Lenferink, Paul Cafarella, David Coultas, Paula Meek, Paul van der Valk, Erik W.M.A. Bischoff, Christine Bucknall, Naresh A. Dewan, Frances Early, Vincent Fan, Peter Frith, Daisy J.A. Janssen, Katy Mitchell, Mike Morgan, Linda Nici, Irem Patel, Haydn Walters, Kathryn L. Rice, Sally Singh, Richard Zuwallack, Roberto Benzo, Roger Goldstein, Martyn R. Partridge, Job van der Palen
Journal: European Respiratory Journal (2016)

There is an urgent need for consensus on what defines a chronic obstructive pulmonary disease (COPD) self-management intervention. We aimed to obtain consensus regarding the conceptual definition of a COPD self-management intervention by engaging an international panel of COPD self-management experts using Delphi technique features and an additional group meeting. In each consensus round the experts were asked to provide feedback on the proposed definition and to score their level of agreement (1=totally disagree; 5=totally agree). The information provided was used to modify the definition for the next consensus round. Thematic analysis was used for free text responses and descriptive statistics were used for agreement scores. In total, 28 experts participated. The consensus round response rate varied randomly over the five rounds (ranging from 48% (n=13) to 85% (n=23)), and mean definition agreement scores increased from 3.8 (round 1) to 4.8 (round 5) with an increasing percentage of experts allocating the highest score of 5 (round 1: 14% (n=3); round 5: 83% (n=19)). In this study we reached consensus regarding a conceptual definition of what should be a COPD self-management intervention, clarifying the requisites for such an intervention. Operationalisation of this conceptual definition in the near future will be an essential next step.
Acquisition of anti-apoptotic potential in the process of telomerase-mediated immortalizaion of human fetal lung fibroblasts
Authors: Jun Yuan, Benjamin Ming-Pang Yang, Karen L. Mackenzie
Journal: Cancer Research (2006)

5000   Immortalization process is an essential step in the multiple stages of carcinogenesis. Most cancer cells are immortal as a consequence of constitutive expression of telomerase, which prevents senescence and crisis (replicative barriers) by maintaining the length of specialized chromosomal-end structures, called telomeres. We have previously shown that ectopic expression of telomerase reverse transcriptase (hTERT) reconstitutes telomerase enzyme activity, elongates telomeres and increases the lifespan of primary human fetal lung fibroblasts (MRC5s)  1, 2 . Extensive clonal studies demonstrated that hTERT-transduced MRC5s (MRC5hTERT) had an extended lifespan, but underwent a telomere-independent crisis prior to immortalization. Immortalized MRC5hTERT cells had inactivated p16INK4a and retained a functional P53/p21 cip1  pathway. However, p16INK4a inactivation did not correspond with the transition through crisis, suggesting that additional events may have been involved in immortalization. The objective of the present study was to investigate the potential involvement of anti-apoptotic mechanisms in MRC5hTERT immortalization. Low passage of MRC5 cells, at 50 population doublings (PDs) and a series of MRC5hTERT cells at pre-crisis (60 and 100 PDs) and post-crisis (200 and 300 PDs) time points were tested for sensitivity to a variety of apoptosis-inducing agents, including okadaic acid (OA), actinomycin D (ActD), TNFa, H 2 O 2 , Taxol, and Vincristine. OA was the most potent inducer of apoptosis in MRC5 cells. However, Annexin V/propidium iodide staining and TUNEL assay demonstrated that all MRC5hTERT cells were significantly more resistant to OA than non-transduced MRC5 cells (p Exp Cell Res  259(2): 336-50.2. Taylor, L. M., et al (2004).  J Biol Chem  279(42): 43634-45.
Quality of Life (Qol) in Patients with Metastatic Colorectal Cancer (Mcrc) Receiving Maintenance Therapy After First-Line Inductive Treatment: a Qol Sub-Analysis of the Aio Krk 0207 Phase III Trial
Authors: J. Quidde, D. Arnold, S. Hegewisch-Becker, U. Graeven, C. Lerchenmüller, B. Killing, R. Depenbusch, C. Steffens, T. Lange, N. Marschner, G. Dietrich, S. Al-Batran
Journal: Annals of Oncology (2014)
Follow-up of Solitary Autonomous Thyroid Nodules Treated with 131I
Authors: Rose Goldstein, Ian R. Hart
Journal: New England Journal of Medicine (1983)

We studied the long-term effects of 131I therapy for solitary autonomous thyroid nodules on the size of the nodule and on thyroid function. Twenty-three patients with autonomous thyroid adenomas that had been treated with 131I from 4 to 16.5 years earlier (mean, 8.5) were examined, and their thyroid function was tested. In 12 patients (54 per cent), the nodules were still palpable, and in 2 they had increased in size. Eight patients (36 per cent) had become hypothyroid. The incidence of hypothyroidism was not related to nodule size or the level of thyroid function before therapy with 131I or to the total dose of 131I that had been given. We conclude that 131I therapy for autonomous thyroid adenoma often causes hypothyroidism and in many cases does not eradicate the offending nodule.
Reproductive Risk Factors and Coronary Heart Disease in the Women’s Health Initiative Observational Study
Authors: Nisha I. Parikh, Rebecca P. Jeppson, Jeffrey S. Berger, Charles B. Eaton, Candyce H. Kroenke, Erin S. LeBlanc, Cora E. Lewis, Eric B. Loucks, Donna R. Parker, Eileen Rillamas-Sun, Kelli K. Ryckman, Molly E. Waring, Robert S. Schenken, Karen C. Johnson, Anna-Karin Edstedt-Bonamy, Matthew A. Allison, Barbara V. Howard
Journal: Circulation (2016)

Background— Reproductive factors provide an early window into a woman’s coronary heart disease (CHD) risk; however, their contribution to CHD risk stratification is uncertain. Methods and Results— In the Women’s Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C statistic, net reclassification index (or net reclassification index with risk categories of &lt;5%, 5 to &lt;10%, and ≥10% 10-year risk of CHD), and integrated discriminatory index were assessed. Among 72 982 women (CHD events, n=4607; median follow-up,12.0 [interquartile range, 8.3–13.7] years; mean [standard deviation] age, 63.2 [7.2] years), an age-adjusted reproductive risk factor model had a C statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages, and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C statistic increased from 0.726 to 0.730; integrated discriminatory index, 0.0013; P &lt;0.0001). Net reclassification for women with events was not improved (net reclassification index events, 0.007; P =0.18); and, for women without events, net reclassification was marginally improved (net reclassification index nonevents, 0.002; P =0.04) Conclusions— Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination, and do not materially improve net reclassification.
Paradox of Normal Selective Coronary Arteriograms in Patients Considered to Have Unmistakable Coronary Heart Disease
Authors: William Likoff, Bernard L. Segal, Hratch Kasparian
Journal: New England Journal of Medicine (1967)

CINE coronary arteriography affords a means of correlating clinical manifestations of coronary heart disease with responsible vascular abnormality in the living patient.1 2 3 4 5 Several of the comparative analyses have indicated that obstructing atherosclerosis can be demonstrated in at least 2 major coronary arteries in most patients with angina and abnormal electrocardiograms at rest and after exercise.1 2 3 4 In documenting the wide distribution and severity of the arterial disease in these patients the reports parallel earlier views based on comparisons between clinical and morbid findings.6 Obviously, the correlation does not hold when a significant anomaly of the coronary arteries, aortic regurgitation, aortic stenosis . . .
Retrospective study of rFVIIa, 4‐factor PCC, and a rFVIIa and 3‐factor PCC combination in improving bleeding outcomes in the warfarin and non‐warfarin patient
Authors: Emma DeLoughery, Brian Avery, Thomas G. DeLoughery
Journal: American Journal of Hematology (2016)

In case of severe bleeding, the physician must rapidly and effectively halt bleeding without the risk of thromboembolic complications. Despite widespread use, no study has directly compared recombinant activated factor VII (rFVIIa), the rFVIIa and 3-factor prothrombin complex concentrate (PCC) combination ("combination"), and 4-factor PCC on their effectiveness in improving patient outcomes. This study examined the medical records of 299 patients, 65.2% on warfarin prior to admission, who received these hemostatic agents and were admitted to an ICU or through the emergency department at Oregon Health & Science University. Mortality, length of stay, change in international normalized ratio (INR), plasma use, and number of thromboembolic complications were used to assess effectiveness. In patients receiving warfarin, the combination group had the greatest decrease in INR as well as lowest overall INR, but experienced a higher number of clotting complications, while the rFVIIa group used the most plasma. Non-warfarin patients in the combination group had the shortest length of stay among survivors, but the rFVIIa group had the lowest mortality. Based on this data, it may be prudent to further study the use of rFVIIa in treating extreme bleeding in the non-warfarin patient, while this study supports other data that 4-factor PCC may be the most prudent for the warfarin patient. Am. J. Hematol. 91:705-708, 2016. © 2016 Wiley Periodicals, Inc.
Adjuvant LH-RH agonists for premenopausal early breast cancer: A meta-analysis of randomized clinical trials (RCTs) exploring the magnitude of the disease-free and overall survival (DFS/OS) benefit
Authors: P. Carlini, E. Bria, F. Cuppone, P. Papaldo, C. Nisticò, A. Fabi, E. M. Ruggeri, E. Terzoli, F. Cognetti, D. Giannarelli
Journal: Journal of Clinical Oncology (2007)

592 Background: LH-RH agonists are considered as a milestone for adjuvant treatment for premenopausal early breast cancer patients (pts). All RCTs in which ovarian ablation (OA) with/without tamoxifen (TAM) and/or chemotherapy (CT) was compared with tamoxifen (TAM) and/or chemotherapy (CT) were pooled to estimate the magnitude of the benefit in both DFS and OS. Methods: A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model according to the inverse variance and heterogeneity (Het) test were applied as well. Absolute benefits (AB) and the number of pts needed to treat (NNT) were calculated. A sensitivity analysis to test for effect robustness in 4 sub-populations (OA/OS vs CT; OA/OS + CT vs CT; OA + TAM vs CT; OA + TAM vs observation) was accomplished. Results: Fifteen RCTs were gathered (12,545 pts); one RCT did not report the OS result. Results are depicted in the table . Conclusions: Although differences across RCTs exist in median follow-up time (as demonstrated by heterogeneity), OA seems to significantly improve DFS when combined with CT over CT alone, when combined with TAM versus CT alone and when combined with TAM versus observation. Actually, these DFS benefits do not translate into an OS benefit, with the exception of the last subgroup. [Table: see text] No significant financial relationships to disclose.
Two thirds of patients in general practice don’t need to see a doctor, report says
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Only a third of people in England who go to a general practice should be seen by a doctor, says a report published by the public services think tank Reform.1

GPs currently take around two thirds of the 372 million appointments at GP surgeries every year, but GPs and other experts interviewed for the research said that around half of these appointments could be taken by nurses and other clinicians.

Reform has recommended that the UK government abandon its target to recruit an additional 5000 GPs by 2020, because it “is an inefficient allocation of NHS resource.”

It explained that the composition of the clinical workforce had shifted towards more GPs in recent years, with the number of GPs increasing between 2004 and 2014 at a faster rate (by 15%) than the number of practice nurses (by 11%). The report estimated that if nurses took …
Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50
Authors: Peter W.F. Wilson, Robert J. Garrison, William P. Castelli
Journal: New England Journal of Medicine (1985)

We studied the effect of estrogen use on morbidity from cardiovascular disease in 1234 postmenopausal women, aged 50 to 83 years, participating in the Framingham Heart Study's 12th biennial examination (index examination). The medication history recorded at biennial examinations 8 through 12 was used to classify the degree of estrogen exposure before eight years of observation for cardiovascular morbidity and mortality. Despite a favorable cardiovascular risk profile and control for the major known risk factors for heart disease, women reporting postmenopausal estrogen use at one or more examinations had over a 50 per cent elevated risk of cardiovascular morbidity (P less than 0.01) and more than a twofold risk for cerebrovascular disease (P less than 0.01) after the index examination. Increased rates for myocardial infarction (P less than 0.05) were observed particularly among the estrogen users who smoked cigarettes. Conversely, among nonsmokers estrogen use was associated only with an increased incidence of stroke (P less than 0.05). No benefits from estrogen use were observed in the study group; in particular, mortality from all causes and from cardiovascular disease did not differ for estrogen users and nonusers.