tbuckley/cabot-search huggingface dataset:
A phase 2 study to evaluate the efficacy of darbepoetin-alfa administered using an extended dose schedule versus weekly dosing in cancer patients with chemotherapy-induced anemia
Authors: T. Rearden, L. Schwartzberg, L. Yee, B. Mirtsching, V. Charu, H. Lam, T. Lillie, R. Burkes, P. Silberstein
Journal: Journal of Clinical Oncology (2007)

19501 Background: Chemotherapy-induced anemia (CIA) can be effectively treated with darbepoetin alfa (DA) using different dosing schedules. Since chemotherapy (CTX) regimens involve various dosing schedules, the ability to synchronize DA dose with CTX could be beneficial. Methods: This phase 2, 25-week (wk), randomized, open-label study compares the efficacy and safety of DA administered using an extended dose schedule (EDS) (every 2 wks [Q2W] or every 3 wks [Q3W]) vs weekly (QW) dosing in patients (pts) with CIA. Pts were randomly assigned to receive DA EDS (either 300 mcg Q2W [with CTX QW, Q2W, or Q4W] or 500 mcg Q3W [with CTX Q3W]) vs 150 mcg DA QW (with CTX QW, Q2W, Q3W, or Q4W). Randomization was stratified by length of CTX cycle, screening hemoglobin (Hb) (&lt; 10 vs = 10 g/dL), and type of cancer (lung/gynecological vs other cancers). The primary endpoint was the change in Hb from baseline (BL) to wk 13; other endpoints included the change in Hb from BL to end of study (EOS), percentage of pts with = 1 transfusion (TFN) from BL to wk 13 and EOS, and safety. Results: Final data for the total 25-wk study period will be presented. Results from a planned interim analysis for all pts who were enrolled in the study and received = 1 dose of DA (n = 752) are shown for wk 13 endpoints (Table). The groups had similar mean change in Hb from BL to wk 13, with a difference (QW minus EDS) (95% CL) of 0.2 (-0.1, 0.4) g/dL. The % pts who achieved target Hb were also similar (difference [95% CL] = 0 [-7, 6]). At the time of the interim analysis, the incidence and types of adverse events were similar between the groups. Ten (3%) EDS and 15 (4%) QW pts had thromboembolic events, 5 (1%) EDS and 2 (1%) QW pts had cerebrovascular accidents, and 19 (5%) EDS and 22 (6%) QW pts had died. Conclusions: This is the first trial synchronizing DA dosing (Q2W and Q3W) with CTX schedules. The interim results suggest that DA administered once per CTX cycle is well-tolerated and efficacious in these patients. [Table: see text] No significant financial relationships to disclose.
Testosterone recovery after two years of androgen suppression in prostate cancer patients
Authors: F. Yoon, R. Choo, S. L. Gardner, G. Morton, E. F. Szumacher, P. Cheung, D. A. Loblaw, C. Danjoux
Journal: Journal of Clinical Oncology (2007)

5144 Background: The time course of testosterone (TST) recovery after prolonged androgen suppression (AS) is not well established. We examined TST recovery prospectively in prostate cancer (PCa) patients treated with 2 years of AS. Methods: 153 PCa men with pT3N0 or positive margins after radical prostatectomy (RP), or with PSA relapse (persistently detectable postoperative PSA [= 0.2 ng/mL], delayed detectable PSA = 6 months after surgery, or palpable/biopsy proven local recurrence after RP), were treated with radiation (RT) to the prostate bed (60 - 70 Gy in 30 - 35 fractions) plus 2 years of AS as part of a phase II study. AS consisted of nilutamide 100 mg PO tid for 4 weeks, starting within 1 week after completing RT, and busereline acetate 6.6 mg SC every 2 months for 2 years, starting within 2 weeks of nilutamide. The primary endpoint was PSA relapse-free survival. Serum TST levels were measured at baseline, every 4 months during AS, and every 6 months after completing AS. The planned sample size was 150 patients. Time to TST recovery was analyzed using the Kaplan-Meier method. Cox Proportional Hazards regression was used for a multivariate analysis of predictive factors for TST recovery. Results: 122 men completed the planned AS. Median follow up after finishing AS was 36.4 months (range 9.4 - 76.2). A castrate TST level was defined as =1.7 nmol/L (50 ng/dL), with normal levels being 10 - 40 nmol/L. All men achieved castrate TST levels on AS. Table 1 shows TST recovery at 36 months after completing AS and median times to recovery. Median recovery time to normal TST was 27 months, although 8% of men did not recover to above castrate levels by 3 years. On multivariate analysis, younger age (&lt;60 vs. =60) predicted for a significantly shorter recovery time to normal TST (P = &lt;0.0001), while baseline TST (&lt;10 nmol/L vs. =10.0 nmol/L) was of borderline significance (P = 0.06). Conclusions: TST recovery after 2 years of AS is protracted. Older men have significantly longer recovery times. [Table: see text] [Table: see text]
Prenatal Diagnosis of Classic Hemophilia
Authors: Stephen I. Firshein, Leon W. Hoyer, John Lazarchick, Bernard G. Forget, John C. Hobbins, Lionel P. Clyne, Frances A. Pitlick, W. Angus Muir, Irwin R. Merkatz, Maurice J. Mahoney
Journal: New England Journal of Medicine (1979)

Prenatal diagnosis of classic hemophilia (hemophilia A) in mid-trimester was achieved by means of immunoradiometric assays for factor VIII on fetal plasma and amniotic-fluid mixtures obtained by fetoscopy. Samples were analyzed from six male fetuses at risk for severe hemophilia and from nine control fetuses for which fetoscopy was carried out to attempt prenatal diagnosis of other genetic disorders. The factor VIII coagulant-antigen values for the control (non-hemophilic) samples were 17 to 94, and the factor VIII related-antigen concentrations were 50 to 155 U per deciliter. Three of the fetuses at risk for hemophilia had factor VIII values in the control range, and these infants were normal at birth. The other three fetuses had low concentrations of factor VIII coagulant antigen but normal concentrations of factor VIII related antigen. These values and the diagnoses of severe hemophilia were confirmed with blood from the abortuses.
CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC).
Authors: Robert J. Motzer, Padmanee Sharma, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey Alan Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel E. Castellano, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas Christoph Gauler, Takeshi Ueda, Huanyu Zhao, Ian M Waxman, Bernard Escudier
Journal: Journal of Clinical Oncology (2016)

498 Background: Based on assessment by an independent Data Monitoring Committee, a phase III trial of NIVO (n=410) vs EVE (n=411) in previously treated patients with advanced or metastatic RCC (NCT01668784) was halted early as it met its endpoint; superior overall survival (OS) was seen with NIVO vs EVE. We present outcomes by key baseline factors, prior therapy, and subsequent anticancer therapy. Methods: Patients with 1 or 2 prior anti-angiogenic therapies and measurable disease (RECIST v1.1) were randomized 1:1 to NIVO 3 mg/kg IV every 2 weeks or EVE 10 mg orally once daily. Primary endpoint was OS. A key secondary endpoint was objective response rate (ORR). Results: The Table shows OS and ORR by key baseline factors. Median follow-up was 17-18 mo. 77% and 23% of patients received 1 or 2 prior anti-angiogenic therapies, respectively, for advanced RCC, mainly sunitinib (63%) or pazopanib (32%). In patients who had prior sunitinib, median OS was 23.6 mo for NIVO vs 19.8 mo for EVE; in those who had prior pazopanib, median OS was not estimable (NE) for NIVO vs 17.6 mo for EVE. For those who had prior IL-2 (10%), median OS was NE for NIVO vs 17.2 mo for EVE. Outcomes by subsequent anticancer therapy are planned. Conclusions: A consistent OS benefit with NIVO vs EVE was found across baseline factors (Karnofsky performance status [KPS], Heng risk group, number of prior therapies), and specific prior therapies (sunitinib, pazopanib, IL-2) in previously treated patients with advanced RCC. ORR benefit with NIVO was also seen across baseline factors. Clinical trial information: NCT01668784. [Table: see text]
Cystic Fibrosis with Fecal Retention and Intussusception in Late Stages
Authors: Paul M. Brown, George A. Hallenbeck, Edward H. Soule, E. Omer Burgert
Journal: New England Journal of Medicine (1960)

THE relationship between cystic fibrosis (also referred to as "fibrocystic disease of the pancreas") and the abnormal meconium in neonatal meconium ileus is well established. Except for a few case reports, however, little has been written concerning the problems of intestinal evacuation that may occur later in the course of the disease. We wish to report on 3 children with this disease who had problems related to the colon.Case ReportsCase 1. A 6-year-old girl was first seen at the Mayo Clinic in June, 1954, with the chief complaint of a mass in the right lower quadrant of the . . .
Clonal Origin of Chronic Myelocytic Leukemia
Authors: Ronald D. Barr, Philip J. Fialkow
Journal: New England Journal of Medicine (1973)

BONE-marrow cells from the majority of patients with chronic myelocytic leukemia have a specific and characteristic aberration of chromosome 22, called the Philadelphia (Ph1) chromosome.1 This abnormality, which may be found even before the onset of overt leukemia,2 is present throughout the course of clinical disease. Although the Ph1 chromosome probably is important in the pathogenesis of the disease the primary causes (which presumably are also the factors inducing the chromosome abnormality) remain largely unknown. An indirect approach to elucidating causative factors involves determining the number of cells from which chronic myelocytic leukemia arises. Single-cell (clonal) origin would be . . .
Gonadotropin-Producing Anaplastic Large-Cell Carcinomas of the Lung
Authors: Frank D. Fusco, Saul W. Rosen
Journal: New England Journal of Medicine (1966)

PRODUCTION of gonadotropins is normally restricted to the pituitary and placenta. Tumors containing trophoblastic elements – choriocarcinomas, teratomas and embryonal-cell carcinomas – can also make gonadotropins, but with the exception of 2 hepatomas,1 , 2 gonadotropic activity has not been recovered from any other neoplasms. Yet an increasing number of reports have documented the elaboration of other hormones by nonendocrine tumors,3 , 4 especially by carcinomas of the bronchus.5 We report here the cases of 4 male smokers with gynecomastia whose histories, physical examinations, laboratory studies, clinical courses and autopsy findings were typical of bronchogenic carcinoma. Elevated levels of gonadotropic activity were present in . . .
Case 4-1980
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Ronald H. Blum, Walter G. J. Putschar
Journal: New England Journal of Medicine (1980)

Presentation of CaseAn 82-year-old woman was admitted to the hospital because of a mass in the left shoulder.She was well until nine months previously, when she began to have pain in the left shoulder accompanied by progressive swelling. Two months later needle aspiration of the joint yielded grossly bloody fluid, and methylprednisolone acetate was injected. X-ray films of the shoulder disclosed erosive dissolution of the acromioclavicular joint and the margin of the anatomical neck of the humerus. A needle biopsy revealed only blood and a fragment of normal skin.Five months before entry an arthrographic examination disclosed free . . .
An Association between Neonatal Severe Primary Hyperparathyroidism and Familial Hypocalciuric Hypercalcemia in Three Kindreds
Authors: Stephen J. Marx, Maurice F. Attie, Allen M. Spiegel, Michael A. Levine, Roz D. Lasker, Maurice Fox
Journal: New England Journal of Medicine (1982)

Four cases of neonatal severe primary hyperparathyroidism occurred in three families; familial hypocalciuric hypercalcemia was present in each kindred. The diagnosis of familial hypocalciuric hypercalcemia was based on the following features; hypercalcemia in many relatives (eight to 16 per kindred), without other features of the multiple endocrine neoplasia syndromes; recognition of hypercalcemia before the age of 10 in one to three relatives; hypocalciuric hypercalcemia in all relatives tested (five to 14 per kindred); and abnormal serum calcium levels despite parathyroidectomy in all additional relatives (one to five per kindred) undergoing this operation. The association of two uncommon syndromes (neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia) in these kindreds suggests that the two syndromes share a common genetic cause within each kindred.
P254 Utilising community empowerment and biometrics to improve tuberculosis treatment outcomes in Delhi’s slum population: the Op ASHA model
Authors: D Pan, E Lee, L Lock, R Batra, I Abubakar, S Batra, M Lipman
Journal: Thorax (2015)

<h3>Introduction</h3> India accounts for more than one-fifth of the total global tuberculosis (TB) incidence. In response, the Revised National TB Control Program (RNTCP) of India has supported the decentralisation of service delivery with encouragement of active community participation. Operation ASHA is an international NGO that offers TB services to slum populations – a group that have proven difficult historically to engage. It employs a unique treatment approach involving community-based providers and biometric data registration to support adherence. We report treatment outcome for patients with presumed drug-susceptible tuberculosis managed by Op ASHA within Delhi’s slum districts. <h3>Methods</h3> Retrospective, observational cohort study focusing on patients within 14 southern Delhi slum districts started on treatment according to RNTCP guidelines between 1.4.2012 and 31.3.2013. Demographic and clinical information were systematically recorded. Patients still on treatment by the end of October 2013 were excluded from analysis. Successful outcomes were defined as bacteriologically confirmed cure or treatment completion. Adverse outcomes were: treatment default, conversion to MDR-TB treatment, treatment failure or death. <h3>Results</h3> 1217 patients were started on treatment. 29% were aged &lt;20; and 42% were female. 52% had pulmonary TB; of these 55% were sputum smear positive (58% grade II or III out of III). 218 (18%) subjects re-treated for TB were excluded from further outcome analysis. The remaining 999 patients had similar clinical characteristics to the whole study population. Successful outcome after 6 months of treatment was recorded in 85% of subjects (77% pulmonary, 91% extrapulmonary cases). Adverse outcomes were recorded in 16% of those with pulmonary TB. This was considerably less common in extrapulmonary TB, where it was recorded in only 6%. Death was reported in 3% of pulmonary and 1% of extrapulmonary patients. <h3>Conclusions</h3> The model of care achieves the WHO target for treatment completion of 85% in a population considered very high risk of failure under traditional TB programmes. Future work needs to focus on the factors that result in adverse outcomes, in particular for the key patient population with infectious pulmonary TB.
Myocardial Norepinephrine Concentration in Man
Authors: Charles A. Chidsey, Eugene Braunwald, Andrew G. Morrow, Dean T. Mason
Journal: New England Journal of Medicine (1963)

THE rauwolfia alkaloids have been widely used in clinical practice, but relatively little information concerning the mechanism of their circulatory action in man is available. Reserpine has been extensively studied in laboratory animals, and it has been demonstrated that after the parenteral administration of relatively large doses of this drug, postganglionic sympathetic nerves are no longer able to transmit impulses across the neuroeffector junctions.1 Also, in animals, a profound fall in the concentration of norepinephrine, epinephrine and serotonin throughout the body occurs after reserpine administration,2 3 4 and the sympathetic blockade produced by reserpine in laboratory animals has been attributed to the . . .
Reduction of Liver Blood Flow and Propranolol Metabolism by Cimetidine
Authors: John Feely, Grant R. Wilkinson, Alastair J. J. Wood
Journal: New England Journal of Medicine (1981)

We studied the influence of cimetidine on liver blood flow in eight normal subjects. Cimetidine acutely reduced liver blood flow during fasting by almost 25 per cent, as measured by indocyanine green clearance. Chronic cimetidine therapy (300 mg four times daily for seven days) reduced the flow by 33 per cent, as measured over eight hours by calculating the relative disposition of oral and intravenous propranolol. In addition to reducing the clearance of intravenous propranolol by decreasing liver blood flow, cimetidine also inhibited the metabolism of oral propranolol and thereby further reduced elimination. The reduction in clearance of oral propranolol correlated positively (r = 0.87, P<0.05) with the average steady-state concentration of plasma cimetidine, suggesting that the inhibition of drug metabolism by cimetidine is dose related. Pulse rates at rest were markedly lower after propranolol plus cimetidine than after propranolol alone. The reduction in liver blood flow produced by cimetidine has important therapeutic implications for patients with alterations in liver and gastrointestinal blood flow and when drugs are used whose hepatic elimination depends on liver blood flow. (N Engl J Med. 1981; 304:692–5.)
Abstract P405: Selenium Supplementation for the Primary Prevention of Cardiovascular Disease: A Cochrane Systematic Review
Authors: Karen Rees, Louise Hartley, Camilla Day, Aileen Clarke, Saverio Stranges
Journal: Circulation (2013)

Background: Selenium is a key component of a number of selenoproteins with anti-oxidant properties, and may help to prevent chronic diseases including cardiovascular disease (CVD). However, observa...
Population pharmacokinetic (PK) and exposure-response analysis of nilotinib in newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: Results from ENESTnd.
Authors: T. P. Hughes, P. D. le Coutre, R. E. Clark, G. Saglio, R. A. Larson, Q. Yin, E. Demirhan, A. Hoenekopp, A. Hochhaus, H. Kantarjian
Journal: Journal of Clinical Oncology (2010)

6556 Background: Results from ENESTnd at 12 months (mo) demonstrated superior efficacy of nilotinib at both 300 mg BID and 400 mg BID doses over imatinib 400 mg QD. Methods: Full PK profiles of nilotinib were obtained at steady state from a subgroup of 34 pts, and sparse (pre-dose/Cmin and 3 hr post-dose/Cmax) concentration data were obtained over 12 mo from 542/563 treated pts. Results: Nilotinib concentrations were stable over 12 mo in both arms (Cmin: 1,158 ± 568 ng/mL [median 1,097 ng/mL] for 300 mg BID; 1,340 ± 621 ng/mL [median 1,217 ng/mL] for 400 mg BID). The average nilotinib Cmin and Cmax were 15.7% and 14.8% higher in the 400 mg BID arm than the 300 mg BID arm. Estimated relative bioavailability ratio was 0.84 for nilotinib 400 mg BID to 300 mg BID. Gender was a statistically significant covariate for nilotinib bioavailability: male pts had 10% lower bioavailability and systemic exposure than females, although this difference is not clinically meaningful. Age, body weight, ethnicity, and racial group did not significantly affect nilotinib PK. Total bilirubin elevation was higher in pts with higher nilotinib concentrations. For example, pts with nilotinib Cmin in quartiles Q1 (< 829 ng/mL, n = 113), Q2/3 (≥ 829 and ≤ 1,569 ng/mL, n = 229) and Q4 (> 1,569 ng/mL, n = 113), 0.9%, 4.8% and 7.1%, respectively, had grade 3/4 bilirubin elevation. Logistic regression confirmed a significant correlation between nilotinib daily AUC and total bilirubin. There was little evidence for a correlation between nilotinib exposure and elevation in AST or lipase. On average, an increase of 1000 ng/mL in nilotinib serum concentrations was associated with minimal increase in QTcF (4.2 to 6.9 msec). Although no relationship was observed for MMR at 12 mo with average nilotinib Cmin, there was a positive correlation with BCR-ABL transcript level reductions at 12 mo with nilotinib Cmin. Conclusions: There is a less than proportional dose-exposure relationship between nilotinib 300 mg BID and 400 mg BID. Exposure was stable over the 12 mo treatment course at both doses. Demographics were not a clinically important factor affecting nilotinib PK. The study is ongoing and additional PK data will be available. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Merck, Novartis Novartis Bristol-Myers Squibb, Merck, Novartis Bristol-Myers Squibb, Genzyme, Novartis The Royal Collage of Pathologists
A Critique of Methodology in Studies of Anticoagulant Therapy for Acute Myocardial Infarction
Authors: Robert H. Gifford, Alvan R. Feinstein
Journal: New England Journal of Medicine (1969)

Of 32 reports of anticoagulant therapy for acute myocardial infarction, appraised to ascertain the maintenance of eight methodologic standards that affect the scientific comparability of treated patients and controls, only 25 per cent described precise criteria for diagnosis of myocardial infarction; 59 per cent were performed as surveys of medical records rather than experimental trials, and 28 per cent did not have concurrent control groups. In most "Cooperative" studies, ancillary therapy at different hospitals was not co-ordinated. Treatment was allocated randomly in four studies,. assessed with appropriate prognostic stratifications in 17 and applied with double-blind technics in only one. No diagnostic criteria were described for thromboembolic phenomena. Anticoagulant therapy was ranked superior to none more often in reports that failed to fulfill the methodologic standards than in the reports that did. Although generally regarded as a problem in statistics, the current controversy about anticoagulants seems to have more basic scientific roots in the selection and classification of the patients who are the "experimental material.".