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Objectives: The study sought to identify factors associated with increased risk of thrombosis after Fontan., Background: The Fontan procedure is the culmination of staged palliation for patients with univentricular physiology. Thrombosis is an important complication after this procedure., Methods: An international multicenter randomized controlled trial of acetylsalicylic acid versus warfarin for thromboprophylaxis after the Fontan procedure was conducted in 111 patients, and did not show a significant difference regarding thrombotic complications. We performed a secondary analysis of this previously published manuscript to identify factors associated with thrombosis in this population. Standardized prospective data collection included independent adjudication of all events., Results: At 2.5 years after randomization, time-related freedom from thrombosis was 69% (all venous, no arterial events), with 28% of thrombosis presenting with clinical signs or events. Hazard of thrombosis was highest immediately after Fontan with a gradual increase in risk during late follow-up. In multivariable models, factors associated with higher risk of thrombosis were pulmonary atresia with intact ventricular septum (hazard ratio [HR]: 3.64, 95% confidence interval [CI]: 1.04 to 12.70, p = 0.04), pulmonary artery distortion (HR: 2.35, 95% CI: 0.96 to 5.73, p = 0.06), lower pre-operative unconjugated bilirubin (HR: 0.84 μmol/l, 95% CI: 0.72 to 0.99, p = 0.04), use of central venous lines for >10 days or until hospital discharge (HR: 17.8, 95% CI: 3.97 to 79.30, p < 0.001), and lower FiO(2) 24 h after the procedure (HR: 0.67/10%, 95% CI: 0.45 to 1.00, p = 0.06). Patients on warfarin who consistently achieved minimum target international normalized ratio levels or those on acetylsalicylic acid had a decrease in risk of thrombosis compared with patients who often failed to meet target international normalized ratio level (HR: 3.53, 95% CI: 1.35 to 9.20, p = 0.01)., Conclusions: More favorable thromboprophylaxis strategies are needed in light of the difficulties in controlling warfarin therapy and the high prevalence of thrombosis in this population., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to compare the safety and efficacy of acetylsalicylic acid (ASA) and warfarin for thromboprophylaxis after the Fontan procedure., Background: Fontan surgery is the definitive palliation for children with single-ventricle physiology. Thrombosis is an important complication; the optimal thromboprophylaxis strategy has not been determined., Methods: We performed a multicenter international randomized trial of primary prophylactic anticoagulation after Fontan surgery. Patients were randomized to receive for 2 years either ASA (5 mg/kg/day, no heparin phase) or warfarin (started within 24 h of heparin lead-in; target international normalized ratio: 2.0 to 3.0). Primary endpoint (intention to treat) was thrombosis, intracardiac or embolic (all events adjudicated). At 3 months and 2 years after the Fontan procedure, transthoracic and transesophageal echocardiograms were obtained as routine surveillance. Major bleeding and death were primary adverse outcomes., Results: A total of 111 eligible patients were randomized (57 to ASA, 54 to heparin/warfarin). Baseline characteristics for each group were similar. There were 2 deaths unrelated to thrombosis or bleeding. There were 13 thromboses in the heparin/warfarin group (3 clinical, 10 routine echo) and 12 thromboses in the ASA group (4 clinical, 8 routine echo). Overall freedom from thrombosis 2 years after Fontan surgery was 19%, despite thrombosis prophylaxis. Cumulative risk of thrombosis was persistent but varying and similar for both groups (p = 0.45). Major bleeding occurred in 1 patient in each group., Conclusions: There was no significant difference between ASA and heparin/warfarin as primary thromboprophylaxis in the first 2 years after Fontan surgery. The thrombosis rate was suboptimal for both regimens, suggesting alternative approaches should be considered. (International Multi Centre Randomized Clinical Trial Of Anticoagulation In Children Following Fontan Procedures; NCT00182104)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Previous trials have suggested a quality-of-life (QOL) improvement for anemic cancer patients treated with erythropoietin, but few used QOL as the primary outcome. We designed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung (NSCLC)., Patients and Methods: A multicenter, randomized, double-blind, placebo-controlled trial was conducted. The proposed sample size was 300 patients. Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks., Results: Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm). This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 v 129 days; hazard ratio, 1.84; P = .04). The Steering Committee closed the trial. Patient numbers compromised the interpretation of the QOL analysis, but a positive Hgb response was noted with epoetin alfa treatment., Conclusion: An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.

Purpose: Most women with breast cancer are diagnosed at an early stage and more than 80% will be long-term survivors. Routine follow-up marks the transition from intensive treatment to survivorship. It is usual practice for routine follow-up to take place in specialist clinics. This study tested the hypothesis that follow-up by the patient's family physician is a safe and acceptable alternative to specialist follow-up., Patients and Methods: A multicenter, randomized, controlled trial was conducted involving 968 patients with early-stage breast cancer who had completed adjuvant treatment, were disease free, and were between 9 and 15 months after diagnosis. Patients may have continued receiving adjuvant hormonal therapy. Patients were randomly allocated to follow-up in the cancer center according to usual practice (CC group) or follow-up from their own family physician (FP group). The primary outcome was the rate of recurrence-related serious clinical events (SCEs). The secondary outcome was health-related quality of life (HRQL)., Results: In the FP group, there were 54 recurrences (11.2%) and 29 deaths (6.0%). In the CC group, there were 64 recurrences (13.2%) and 30 deaths (6.2%). In the FP group, 17 patients (3.5%) compared with 18 patients (3.7%) in the CC group experienced an SCE (0.19% difference; 95% CI, -2.26% to 2.65%). No statistically significant differences (P < .05) were detected between groups on any of the HRQL questionnaires., Conclusion: Breast cancer patients can be offered follow-up by their family physician without concern that important recurrence-related SCEs will occur more frequently or that HRQL will be negatively affected.

Objective(s): Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children., Study Design: This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely., Results: At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group., Conclusions: Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.

Introduction: The low molecular weight heparin (LMWH), reviparin-sodium was studied in dose-finding and pharmacokinetic studies in children with central venous lines (CVLs)., Materials and Methods: The dose-finding study was performed in 24 patients aged 3 days to 16 years. Dose adjustments were made using a nomogram based on anti-factor Xa levels (units (U)/ml) (target of 0.1-0.3 U/ml). The pharmacokinetic study was performed in 19 patients, 9 less than or equal to 5 kg (7 of whom were less than 3 months) and 10 greater than 5 kg (all more than 3 months)., Results: The dose-finding study demonstrated that children over 5 kg required 30 International Units (IU)/kilogram (kg), subcutaneous (SC) twice daily (BID), and children less than or equal to 5 kg required 50 IU/kg, SC BID, to achieve target levels. The pharmacokinetic study demonstrated that 80% of anti-factor Xa levels were within the target range with both patient groups having similar peak (average=0.26 U/ml) and trough (average=0.13 U/ml) levels., Conclusions: Peak anti-factor Xa levels (0.1-0.3 U/ml) using reviparin-sodium are achieved by administering 50 IU/kg in children greater than 3 months of age and 30 U/kg in children less than 3 months of age.

Objective(s): Central venous lines (CVLs) are major risk factors for venous thromboembolism (VTE) in children. The objective of PROTEKT was to determine if a low molecular weight heparin (reviparin-sodium) safely prevents CVL-related VTE., Study Design: This multi-center, open-label study, with blinded central outcome adjudication, randomized patients with new CVLs to twice-daily reviparin-sodium or standard care. The efficacy outcome was based on an exit venogram at Day 30 (+14 days), or earlier in case of CVL removal, or confirmed symptomatic VTE. The safety outcomes were major bleeding and death. Due to slow and restricted patient accrual, PROTEKT was closed prematurely., Results: With reviparin-sodium, 14.1% (11:78) of patients had VTE compared to 12.5% (10:80) of control patients (odds ratio=1.15; 95% confidence interval 0.42, 3.23); 2P=0.82). One patient had a major bleed and there were two deaths, all three events occurring in the standard care group., Conclusions: The use of reviparin-sodium for short-term prophylaxis of CVL-related VTE in children was safe but its efficacy remains unclear. Although underpowered, PROTEKT provided valuable information on event rates and predictors of CVL-related VTE.

Background: Breast irradiation after lumpectomy is an integral component of breast-conserving therapy that reduces the local recurrence of breast cancer. Because an optimal fractionation schedule (radiation dose given in a specified number of fractions or treatment sessions over a defined time) for breast irradiation has not been uniformly accepted, we examined whether a 22-day fractionation schedule was as effective as the more traditional 35-day schedule in reducing recurrence., Methods: Women with invasive breast cancer who were treated by lumpectomy and had pathologically clear resection margins and negative axillary lymph nodes were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days (short arm) or whole breast irradiation of 50 Gy in 25 fractions over 35 days (long arm). The primary outcome was local recurrence of invasive breast cancer in the treated breast. Secondary outcomes included cosmetic outcome, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Cosmetic Rating System. All statistical tests were two-sided., Results: From April 1993 through September 1996, 1234 women were randomly assigned to treatment, 622 to the short arm and 612 to the long arm. Median follow-up was 69 months. Five-year local recurrence-free survival was 97.2% in the short arm and 96.8% in the long arm (absolute difference = 0.4%, 95% confidence interval [CI] = -1.5% to 2.4%). No difference in disease-free or overall survival rates was detected between study arms. The percentage of patients with an excellent or good global cosmetic outcome at 3 years was 76.8% in the short arm and 77.0% in the long arm; the corresponding data at 5 years were 76.8% and 77.4%, respectively (absolute difference = -0.6%, 95% CI = -6.5% to 5.5%)., Conclusion: The more convenient 22-day fractionation schedule appears to be an acceptable alternative to the 35-day schedule.

Objective: This study asks whether auditory hallucinations are reflected in a distinctive metabolic map of the brain., Method: Regional brain metabolism was measured by positron emission tomography with [18F]-fluorodeoxyglucose in 12 DSM-III schizophrenic patients who experienced auditory hallucinations during glucose uptake and 10 who did not. All patients were free of neuroleptics and 19 had never been treated with neuroleptics. Nine patients were reexamined after 1 year to assess effects of neuroleptic treatment., Results: Compared with the patients who did not experience hallucinations, the patients who did experience hallucinations had significantly lower relative metabolism in auditory and Wernicke's regions and a trend toward higher metabolism in the right hemisphere homologue of Broca's region. Hallucination scores correlated positively and significantly with relative metabolism in the striatum and anterior cingulate regions. Neuroleptic treatment resulted in a significant increase in striatal metabolism and a reduced frontal-parietal ratio, which was significantly correlated with a decrease in hallucination scores., Conclusions: Auditory hallucinations involve language regions of the cortex in a pattern similar to that seen in normal subjects listening to their own voices but different in that left prefrontal regions are not activated. The striatum plays a critical role in auditory hallucinations.

Since neuroleptic treatment produces a significant increase in striatal metabolism relative to cortical metabolism, we wished to determine whether the dopamine agonist apomorphine (APO) might have the opposite effect, and whether it would discriminate schizophrenic patients from healthy controls. Eleven neuroleptic-naive schizophrenic patients (diagnosed according to DSM-III) and eight normal subjects were compared with respect to cerebral accumulation of 18F-fluorodeoxyglucose measured by positron emission tomography following APO, 0.75 mg/70 kg (weight adjusted), or saline. Relative striatal glucose metabolism decreased significantly after APO in schizophrenic patients but not in control subjects. Post hoc analysis of data in 12 other regions revealed that relative superior temporal metabolism decreased very slightly, but significantly, in schizophrenic patients but not in control subjects after APO, and that the posterior frontal region increased in control subjects but not in the patient group.

The authors compare symptoms and neuropsychological test performance in DSM-III schizophrenic patients who reported prior substance abuse (N = 38) with those in patients who reported no such abuse (N = 25) to determine the impact of substance abuse on the psychopathology of schizophrenia. Positive and negative symptom scores were derived from the Schedule for Affective Disorders and Schizophrenia. Sixty neuropsychological measures drawn from commonly used tests of intelligence, memory, learning, fluency, and problem solving were calculated. Separate analyses were performed on patients in a psychotic episode who were free of neuroleptics (N = 27) and on those taking maintenance neuroleptics (N = 36). Among unmedicated patients, those who reported prior substance abuse had significantly higher thought disorder scores. Among neuroleptic-medicated patients, hallucination and delusion scores were significantly higher in the patients who reported prior substance abuse. The substance abuse followed withdrawal from social relations and preceded the onset of positive symptoms. None of the neuropsychological tests discriminated between abusers and nonabusers.

Neuropsychological test performance was compared in 37 neuroleptic treated DSM-III schizophrenic patients, 27 untreated schizophrenic patients, and 27 normal controls. Neuroleptic treated patients performed significantly less well than untreated patients at recalling a complex figure, at planning on a mazes test, and had poorer fine motor coordination. Controls and untreated patients performed equally well on these tests. The results were not altered in 16 neuroleptic treated patients who had been prescribed low doses of benztropine, nor 38 patients who reported prior substance abuse. Similar cognitive impairments are observed in Parkinson's disease and are associated with dopaminergic antagonist drugs in schizophrenics. Therefore, they do not comprise part of the Schizophrenic Deficit State. Two tests were better performed by controls than patients. Reaction time was slower and more variable in both treated and untreated patient groups than controls. The recall of paraphrased passages was significantly poorer in both patient groups than controls, a finding that is robust in subgroups matched for IQ. Neuroleptic treatment was associated with significantly better performance on this test.

The objective of the study was to determine dose-response relationships of growth hormone, vasopressin, blood pressure, heart rate, and behavioral responses to clonidine. Ten healthy male volunteers were tested with each of three doses of clonidine (0.7, 1.4, and 2.1 micrograms/kg) with at least 1 week between tests. All doses gave a significant growth hormone response with a peak at 50 min. The high dose gave a significantly higher response than either the medium dose or the low dose, which did not differ from each other. Within individual subjects, there was a consistency of response to the different doses; thus, three of the volunteers had responses of 5 ng/ml or higher to the low dose. Those three subjects had higher growth hormone peaks after the highest dose than did six other subjects. Vasopressin showed a drop following clonidine after the two higher doses. Systolic blood pressure dropped following clonidine, showing a significantly greater drop for the medium and high doses than for the low dose. Diastolic blood pressure also showed a drop, but responsiveness did not differ between doses. There was significant dryness of mouth produced by clonidine, but no difference between doses. There was a significant sedative effect following clonidine which was greater for the high dose than for the medium or low dose. The finding that some subjects had a growth hormone peak of 5 ng/ml or greater after the low dose supports the hypothesis that use of a low dose strategy may be useful in confirming supersensitivity in conditions where increased responsiveness is suspected. The lack of difference between blood pressure responses to the medium and high doses of clonidine--doses that have different effects on growth hormone--supports the hypothesis that differences in responsiveness of presynaptic and postsynaptic alpha 2-adrenergic receptors exist.

As part of an ongoing longitudinal study of drug-free schizophrenic patients, we serially sampled resting early morning prolactin levels in 10 subjects. In a preliminary analysis, these levels were compared to those found in matched normal control subjects over a 4-year period. Both control and schizophrenic subjects showed a marked annual variation in prolactin levels. Six schizophrenic patients sampled in each quarter of the year showed a significant annual rhythm, with prolactin highest in the spring (March-May). In seven schizophrenic patients and nine controls sampled at two seasons in the year, prolactin was significantly higher in spring-summer (March-August) than in fall-winter (September-February), with no difference between patients and control subjects.

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.

The growth hormone (GH) response to apomorphine hydrochloride (APO) was examined monthly in 12 schizophrenic patients on drug holiday for up to 22 months and compared with age- and sex-matched controls. There was more variability in the response of patients than controls on the first trial and on several subsequent challenges. Patients' and controls' GH responses to an APO challenge did not distinguish them from each other on the first trial. However, longitudinal data revealed that in a subgroup of five schizophrenic patients and five controls, studied for 12 consecutive trials, the GH response averaged over the 12 trials was significantly lower in the patients than in the controls. Moreover, when schizophrenics' responses on each successive trial were compared, responses decreased over time, but were significantly different from controls only in the later trials. Three of the patients were followed for more than 12 trials, and their GH responsivity increased in the later trials. GH response to APO was significantly correlated with positive symptom scores in three patients but not in four others. There was a trend toward an association between the occurrence of relapse and GH increment induced by APO. A significant association between change in body weight and change in GH response to APO was discovered, suggesting that a changing body weight may contribute to the variability in subjects' response to APO.