A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. Additive effects of psychostimulants, parent training, and self-control therapy with ADHD children. Recombinant human growth hormone treatment, using two dose regimens in children with chronic renal failure--a report on linear growth and adverse effects. Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Placebo-controlled, double-blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. Successful implementation of the randomized discontinuation trial design: an application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma--CALGB 69901. Postoperative nausea and vomiting after Faden operation. An outreach intervention to implement evidence based practice in residential care: a randomized controlled trial [ISRCTN67855475]. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. A randomized controlled trial to evaluate the effectiveness of a brief, behaviorally oriented intervention for cancer-related fatigue. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Recombinant human growth hormone post-renal transplantation in children: a randomized controlled study of the NAPRTCS. A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia. Berlin-Frankfurt-Münster Study Group. Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression. A prospective randomised evaluation of G-CSF or G-CSF plus oral antibiotics in chemotherapy-treated patients at high risk of developing febrile neutropenia. Issues that may determine the outcome of antipsychotic trials: industry sponsorship and extrapyramidal side effect. Evolution of the randomized controlled trial in oncology over three decades. Haemorheological pattern in initial mental deterioration: results of a long-term study using piracetam and pentoxifylline. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature. Impact of a drug-use review program intervention on prescribing after publication of a randomized clinical trial. Memory training and drug therapy act differently on memory and metamemory functioning: evidence from a pilot study. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Effectiveness of physical activity on cardiorespiratory fitness and health-related quality of life in young and middle-aged cancer patients shortly after chemotherapy. Comparing effects of methylphenidate, sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury. A trial of recombinant human granulocyte colony stimulating factor for the treatment of very low birthweight infants with presumed sepsis and neutropenia. Prefrontal repetitive transcranial magnetic stimulation as add on treatment in depression. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Randomized, double-blind, placebo-controlled, phase III study of recombinant human granulocyte-macrophage colony-stimulating factor as adjunct to induction treatment of high-grade malignant non-Hodgkin's lymphomas. A randomized controlled trial of a behavior advisory service for hospitalized older patients with confusion. Luteal phase dosing with paroxetine controlled release (CR) in the treatment of premenstrual dysphoric disorder. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom Medical Research Council Adult Leukaemia Working Party. Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group Trial. Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Radiochemotherapy with amifostine cytoprotection for head and neck cancer.
Fatigue is a commonly encountered symptom of human immunodeficiency virus (HIV) disease, associated with significant psychological and functional morbidity and poor quality of life. Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue.
                To compare the efficacy of 2 psychostimulant medications, methylphenidate hydrochloride (Ritalin) and pemoline (Cylert), with a placebo intervention for the treatment of fatigue in patients with HIV disease.
                In this double-blind trial, 144 ambulatory patients with HIV disease and persistent and severe fatigue were randomized to treatment with methylphenidate, pemoline, or placebo. Medications were titrated up to a maximum dose of 60 mg of methlyphenidate hydrochloride, 150 mg of pemoline, or 8 capsules of placebo daily. Fatigue was measured using 2 self-reported rating scales, the Piper Fatigue Scale (PFS) and the Visual Analogue Scale for Fatigue (VAS-F). We also used the timed isometric unilateral straight leg-raising task, a measure of muscular endurance. Quality-of-life and psychological well-being measures included the Beck Depression Inventory, the Brief Symptom Inventory, and the 36-Item Short-Form Medical Outcomes Study Health Status Survey. Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale. All measures were rated weekly.
                One hundred nine subjects completed the 6-week trial; 15 patients (41%) receiving methylphenidate and 12 patients (36%) receiving pemoline demonstrated clinically significant improvement compared with 6 patients (15%) receiving placebo. Patients receiving methylphenidate or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales (PFS total score, P=.04; affective subscale, P=.008; sensory subscale, P=.04; and VAS-F energy subscale, P=.02). Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group (P=.02). There were no significant differences in the efficacy between methlyphenidate and pemoline on any outcome measure studied. Improvement in fatigue was also significantly correlated with improvement in measures of depression, psychological distress, and overall quality of life. Severe side effects were relatively uncommon among this sample, and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication.
                Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylphenidate or pemoline. Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects. Moreover, improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress. We examined the efficacy and tolerability of augmentation with an extended release formulation of methylphenidate (OROS MPH, Concerta) in patients with major depression who were nonresponders or partial responders to antidepressants. Sixty subjects with treatment-resistant depression (TRD) participated in a 4-week, randomized, double-blind, placebo-controlled study of augmentation with methylphenidate (18-54 mg/d). The preexisting antidepressant dose was unchanged. The primary efficacy measure was change in the 21-item Hamilton Depression Rating Scale from randomization to end of treatment. Data were analyzed with intent-to-treat with last observation carried forward approach. There were no statistically significant differences between the methylphenidate (n = 30) and placebo (n = 30) groups in reduction in 21-item Hamilton Depression Rating Scale scores (drug, -6.9; placebo, -4.7) from baseline to end of treatment (F1,47 = 1.24, P = 0.22), although responders were numerically higher in the extended-release methylphenidate group (40.0%) than in the placebo group (23.3%). On the secondary efficacy measures of changes in Clinical Global Impression-Improvement and Severity scores and Beck Depression Inventory-Second Edition, the drug failed to separate from placebo, although the proportion of responders in the drug group were numerically higher than placebo. There were no significant differences in weight, heart rate, and blood pressure changes between the 2 groups. The common adverse events were loss of appetite, nausea, headache, and anxiety. The mean dose of drug was 34.2 mg/d. The study did not demonstrate a statistically significant benefit for augmentation with methylphenidate in TRD. Combination of methylphenidate with antidepressants was well tolerated. Adequately powered, randomized, controlled trials are necessary to fully evaluate the efficacy of extended-release methylphenidate in TRD. Utilizing a double-blind, placebo design, the effects of a high (0.8 mg/kg) and a low (0.4 mg/kg) dose of methylphenidate alone and in combination with behavioral parent training plus child self-control instruction were evaluated with 96 attention deficit hyperactivity disorder children. No evidence of the superiority of the combined conditions relative to medication alone was found. Some limited support was found for the hypothesis that the effects of a high dose of psychostimulant medication could be achieved by combining the low dose with a behavioral intervention. The importance of the latter finding is highlighted by the fact that both the benefits and untoward effects of the psychostimulants appear to increase with the dose. The aim of this study was to study the efficiency and the adverse effects of 2 or 4 IU/m2/day of growth hormone (GH) in the first year and 4 IU/m2/day in the second. Of 29 growth-retarded children with chronic renal failure (CRF) (aged 3.4-15.1 years), 23 completed the first year of therapy, and 16 completed the second year. Height velocity SDS (HVSDS) increased in the first year in the low-dose group with 3.0, and 3.8 in the high-dose group. In the second year, HVSDS increased by 1.3 in the low-dose group and by 2.1 in high-dose group (p < 0.05). The IGF-I/IGFBP-3 ratio rose identically during the first year (p < 0.01). The retarded bone age did not advance inappropriately. The integrated insulin levels (AUC) increased significantly after 1 year of therapy in both groups. HbA1c, levels did not change. The number of adverse events was highest in the low-dose group, in which one patient developed overt insulin dependent diabetes mellitus. In conclusion, glucose metabolism should be monitored in children with CRF during rhGH-treatment. GH therapy in our patients resulted in a significant increase in height velocity with no inappropriate bone age progression and few serious adverse effects, all without relation to the dose of rhGH. The low start dose (2 IU/m2/ day) was of no advantage compared to the high dose. To determine the efficacy and safety of methylphenidate in acute stroke rehabilitation.
                A prospective, randomized, double-blind, placebo-controlled study.
                Twenty-one stroke patients consecutively admitted to a community-based rehabilitation unit.
                Three-week treatment of methylphenidate (or placebo) in conjunction with physical therapy. Methylphenidate was started at 5mg and increased gradually to 30mg (15mg at 8:00AM and 15mg at 12:00 noon), and discontinued before discharge.
                Mood measures included the Hamilton Depression Rating Scale (HAM-D) and Zung Self-Rating Depression Scale (ZDS). Cognitive status was evaluated using the Mini-Mental State Exam (MMSE). Motor functioning was assessed using the Fugl-Meyer Scale (FMS) and a modified version of the Functional Independence Measure (M-FIM). All measures were administered pretreatment and weekly thereafter. Side effects were measured after each increase in dosage and weekly.
                Patients receiving methylphenidate treatment scored lower on the HAM-D (F(1,18)=5.714, p=.028), lower on the ZDS (F(1,18)=4.206, p=.055), higher on the M-FIM (F(1,18)=5.374, p=.032), and higher on the FMS (F(1,9)=4.060, p=.075) than patients receiving placebo.
                Methylphenidate appears to be a safe and effective intervention in early poststroke rehabilitation that may expedite recovery. Stunted growth is a serious problem for children with chronic renal failure (CRF) despite normal endogenous growth hormone secretion and normal or elevated plasma concentrations of insulin-like growth factors (IGF) I and II. Biosynthetic growth hormone (GH) was given to 20 prepubertal children (eleven boys, nine girls; mean age 9.5 years, range 4-16) with CRF and severe growth retardation in a placebo-controlled, double-blind, cross-over trial. 6 months of subcutaneous injection of GH (4 IU/m2 per day) was either preceded or followed by 6 months of placebo injection. The patients had a full examination every 3 months. Sixteen children completed the study. Height velocity improved significantly with GH therapy (p less than 0.0001) and placebo (p less than 0.04), but the GH-induced height-velocity increase exceeded that of placebo by 2.9 cm per 6 months. There was a positive relationship between prestudy height velocity and height-velocity increase. Bone maturation was not affected. GH caused a significant increase in IGF-I and a moderate increase in IGF-II plasma concentrations. The pretreatment elevation of IGF-binding protein-1 decreased by almost 50% during GH therapy, while IGF-binding protein-3 increased significantly in concentration, although this increase was significantly smaller than the GH-induced increase in IGF-I. Fructosamine, lipid, and parathyroid concentrations remained constant. Renal function deterioration did not accelerate. Impressive height-velocity increase can be achieved with GH therapy in children with CRF and growth retardation without changes in renal function. Bone maturation appears unaffected suggesting improved final height. Treatment is best started before growth retardation becomes considerable. Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management.
                The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12+/-3 months, had CRF (GFR<or=60 ml/min per 1.73 m2), and had adequate nutritional intake and good metabolic control were recruited from eight pediatric nephrology departments from Spain and Portugal. Main outcome measures were body length, body weight, bone age, biochemical and hormonal analyses, renal function, bone mass, and adverse effects.
                Length gain in infants who were treated with GH was statistically greater (P<0.05) than that of nontreated children (14.5 versus 9.5 cm/yr; SD score 1.43 versus -0.11). The GH-induced stimulation of growth was associated with no undesirable effects on bone maturation, renal failure progression, or metabolic control. In addition, GH treatment improved forearm bone mass and increased serum concentrations of total and free IGF-I and IGF-binding protein 3 (IGFBP-3), whereas IGF-II, IGFBP-1, IGFBP-2, GH-binding protein, ghrelin, and leptin were not modified.
                Infants with CRF and growth retardation despite good metabolic and nutritional control benefit from GH treatment without adverse effects during 12 months of therapy. 5'-Methyltetrahydrofolic acid (5'-MTHF) in addition to standard psychotropic medication significantly improved clinical recovery in depressed patients with borderline or definite folate deficiency, and significantly reduced depressive symptoms in elderly normofolatemic patients after 3 weeks of treatment. In this equivalence study the effect of 5'-MTHF on depressive symptoms and cognitive status was compared to Trazodone (TRZ) in normofolatemic elderly patients with mild to moderate dementia and depression. Ninety-six patients with dementia, scoring 12-23 at the Mini Mental State Examination (MMSE) and > or = 18 at the Hamilton Depression Rating Scale (HDRS) after a 2-week placebo run-in, were randomized to receive either 5'-MTHF (50 mg/day p.o.) (47 patients) or TRZ (100 mg/day p.o.) (49 patients) in a double-blind design for 8 weeks. HDRS was assessed before, after 4 weeks and at the end of treatment; Rey's Verbal Memory (RVM) test for immediate and delayed recall was evaluated before and after treatment. After 4 weeks of treatment HDRS score was reduced from 23 +/- 5 to 20 +/- 6 in the 5'-MTHF (p < 0.05 vs baseline), and from 23 +/- 3 to 21 +/- 4 in the TRZ group (p < 0.05 vs baseline). A further significant decrease to 18 +/- 6 and 19 +/- 5 respectively was obtained at the end of the treatment period (p < 0.05 vs week 4) with 5'-MTHF and TRZ.(ABSTRACT TRUNCATED AT 250 WORDS) To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL).
                Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval).
                CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups.
                G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control. This open-label, randomized phase III study was designed to investigate the effects of erythropoietin alfa (EPO) in addition to adjuvant chemotherapy and pelvic radiotherapy (CRT) in patients with stage IB to II cervical cancer who had undergone radical hysterectomy.
                Two hundred fifty-seven patients were randomly assigned to four cycles of carboplatin/ifosfamide chemotherapy followed by external-beam pelvic radiotherapy (CRT group) or four cycles of carboplatin/ifosfamide chemotherapy and EPO followed by pelvic radiotherapy and EPO (CRT + EPO group). The primary end point was recurrence-free survival (RFS). Secondary end points included overall survival (OS), change in hemoglobin levels, and safety, including thromboembolic events.
                The estimated 5-year RFS rates were 78% for patients receiving CRT + EPO and 70% for patients receiving CRT. There was no statistically significant difference in RFS, although a trend favoring patients treated with CRT + EPO was observed (hazard ratio [HR], 0.66; 95% CI, 0.39 to 1.12; log-rank P = .06). Exploratory analyses suggest a benefit with CRT + EPO for patients with stage IB to IIA disease (HR, 0.39; 95% CI, 0.18 to 0.85; P = .014) or patients with complete resection (HR, 0.55; 95% CI, 0.31 to 0.98; P = .039). OS was similar in both groups (HR, 0.88; 95% CI, 0.51 to 1.50; log-rank P = .63). Patients treated with EPO maintained higher hemoglobin levels throughout CRT. No significant differences in safety profiles were observed between the two groups. Incidence of thrombovascular events was low (2%) and comparable between both groups.
                This study confirms that EPO can be added safely to CRT in patients with cervical cancer, but it failed to demonstrate a significant benefit in RFS and OS. To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design.
                Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups.
                A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted.
                CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents. The purpose of this study was to evaluate the antiemetic effect of prophylactic dimenhydrinate application prior to Faden operation and to compare the incidence of PONV between bimedial Faden operation (BMF) and horizontal recess-resect procedure (R&R).
                Ninety-nine children (4-10 years) scheduled for BMF were included in this prospective double-blind study. Midazolam (0.5 mg/kg body weight, BW) was administered orally for premedication 30 min before induction of anesthesia. Additionally, children weighing >/=23 kg received either dimenhydrinate suppositories or placebo. The placebo group was compared with 148 children who underwent R&R surgery without antiemetic prophylaxis during the same period. Anesthesia was induced with thiopentone (5-10 mg/kg BW) and vecuronium (0.1 mg/kg BW) bromide and maintained with halothane (1-2 vol%) in N(2)O/O(2) (65/35 vol%). Age, height, weight, and incidence of oculocardiac reflex were documented. PONV was classified into "no vomiting", "vomiting without therapy", and "vomiting requiring rescue medication". In the latter case dimenhydrinate was given again. The chi-square test was used for statistical analysis.
                Forty-eight patients received placebo, while 51 received dimenhydrinate. No differences between any groups were observed concerning age, height, weight, and incidence of oculocardiac reflex. Compared to R&R surgery, PONV requiring rescue medication occurred significantly more frequently after BMF (45% vs 23% after R&R). PONV after BMF was significantly less severe in the dimenhydrinate group than in the placebo group. The total incidence of PONV after BMF, however, was not significantly reduced.
                The high incidence of PONV after BMF can be explained by the greater invasiveness of BMF than R&R surgery. PONV requiring antiemetic rescue medication can be reduced by preoperative administration of dimenhydrinate suppositories. The aim of this project was to assess whether outreach visits would improve the implementation of evidence based clinical practice in the area of falls reduction and stroke prevention in a residential care setting.
                Twenty facilities took part in a randomized controlled trial with a seven month follow-up period. Two outreach visits were delivered by a pharmacist. At the first a summary of the relevant evidence was provided and at the second detailed audit information was provided about fall rates, psychotropic drug prescribing and stroke risk reduction practices (BP monitoring, aspirin and warfarin use) for the facility relevant to the physician. The effect of the interventions was determined via pre- and post-intervention case note audit. Outcomes included change in percentage patients at risk of falling who fell in a three month period prior to follow-up and changes in use of psychotropic medications. Chi-square tests, independent samples t-test, and logistic regression were used in the analysis.
                Data were available from case notes at baseline (n = 897) and seven months follow-up (n = 902), 452 residential care staff were surveyed and 121 physicians were involved with 61 receiving outreach visits. Pre-and post-intervention data were available for 715 participants. There were no differences between the intervention and control groups for the three month fall rate. We were unable to detect statistically significant differences between groups for the psychotropic drug use of the patients before or after the intervention. The exception was significantly greater use of "as required" antipsychotics in the intervention group compared with the control group after the pharmacy intervention (RR = 4.95; 95%CI 1.69-14.50). There was no statistically significant difference between groups for the numbers of patients "at risk of stroke" on aspirin at follow-up.
                While the strategy was well received by the physicians involved, there was no change in prescribing patterns. Patient care in residential settings is complex and involves contributions from the patient's physician, family and residential care staff. The project highlights challenges of delivering evidence based care in a setting in which there is a paucity of well controlled trial evidence but where significant health outcomes can be attained. To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC).
                Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors).
                This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072).
                With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication. To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F).
                Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point.
                Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed.
                Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention. It has been shown that nonpharmacologic interventions are effective management techniques for cancer-related fatigue (CRF) in cancer survivors. However, few studies have investigated their effectiveness in patients who are receiving chemotherapy. In this study, the authors tested the effectiveness of a brief behaviorally oriented intervention in reducing CRF and improving physical function and associated distress in individuals who were receiving chemotherapy.
                For this randomized controlled trial, 60 patients with cancer were recruited and received either usual care or the intervention. The intervention was delivered on an individual basis on 3 occasions over a period from 9 weeks to 12 weeks, and the objective of the intervention was to alter fatigue-related thoughts and behavior. Primary outcomes were assessed as follows: CRF using the Visual Analogue Scale-Global Fatigue; physical functioning using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 Questionnaire, and CRF-associated distress using the Fatigue Outcome Measure. Assessments were made on 4 occasions: at baseline (T0), at the end of chemotherapy (T1), 1 month after chemotherapy (T2), and 9 months after recruitment (T3). Normally distributed data were analyzed using t tests and random-slope/random-intercept mixed models.
                The intervention demonstrated a trend toward improved CRF, although this effect was reduced once confounders had been controlled statistically. There was a significant improvement in physical functioning (coefficient, 10.0; 95% confidence interval, 2.5-17.5; P = .009), and this effect remained once the confounding effects of mood disturbance and comorbid disorders were controlled statistically. No decrease in fatigue-related distress was detected.
                The behaviorally oriented intervention brought about significant improvements in physical functioning, indicated a trend toward improved CRF, but detected no effect for fatigue-related distress.
                (c) 2007 American Cancer Society. Women who receive adjuvant chemotherapy for breast cancer develop fatigue, and a subset reports cognitive impairment. Methylphenidate is reported to improve fatigue and to decrease cognitive impairment in other populations.
                Women were randomised early during their chemotherapy to receive d-methylphenidate (d-MPH), a form of methylphenidate, or an identical appearing placebo. All participants took placebo for one cycle to ensure compliance and then study medication until completion of chemotherapy. Subjects were assessed at baseline, end of chemotherapy and at approximately 6 months follow-up with the High Sensitivity Cognitive Screen (HSCS) and the Hopkins Verbal Learning Test-Revised (HVLT-R). They also completed the self-report Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-F (F = fatigue) questionnaires, evaluating quality of life and fatigue.
                A total of 57 evaluable women were randomised: 29 to d-MPH and 28 to placebo; the study did not meet its accrual goal of 170 patients, mainly because women were reluctant to take additional medication in general and methylphenidate in particular. Groups were well matched for age (median, 50 years) and education. d-MPH and placebo were well tolerated. There were no significant differences between the randomised groups in classification of cognitive function by HSCS or in summed FACT-F fatigue scores (the primary endpoints of the study) at any of the assessments. There were also no differences in HLTV-R scores or quality of life.
                This study is underpowered, but there are no trends to suggest that d-MPH, taken concurrently with adjuvant chemotherapy, improves quality of life or fatigue. Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken.
                Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment.
                After one year, the delta SDS (standardized height) was +0.49 +/- 0.10 in the treatment group (N = 30) compared to -0.10 +/- 0.08 in the control group (N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups.
                In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events. Overall chemotherapeutic treatment results in pediatric acute lymphoblastic leukemia (ALL) are good, with event-free survival (EFS) rates over 70%. However, for a subset of patients characterized by high-risk (HR) features the outcome is less favorable, with EFS rates below 50%. Intensification of chemotherapy may improve the outcome for those patients, but increased toxicity, particularly myelosuppression, limits the escalation of dose intensity. Recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) is known to reduce myelosuppression after cancer chemotherapy in adults. The objective of this study was to examine the effect of r-metHuG-CSF on myelosuppression in HR pediatric ALL patients and on the overall response rate to chemotherapy. Patients with HR pediatric ALL were randomized to receive nine alternating cycles of chemotherapy according to the German ALL-Berlin-Frankfurt-Münster 90 protocol either alone or followed by r-metHuG-CSF administered prophylactically at a dose of 5 microg/kg/d subcutaneously. In both groups, the planned interval between chemotherapy courses was a minimum of 21 days. We report here interim results of 34 patients. The incidence of febrile neutropenia (absolute neutrophil count <0.5 x 10(9)/L and oral temperature > or = 38.5 degrees C) was 17% in children receiving r-metHuG-CSF, as compared with 40% in the control group (P = .007). In addition, the median total duration of febrile neutropenia was reduced from 20.3 to 6.2 days per patient (P = .02). Culture-confirmed infections occurred less frequently in the r-metHuG-CSF group (8% v 15%; P = .04), and the total duration of intravenous antibiotic use was significantly reduced from 32.2 days to 18.2 days per patient (P = .02). A tighter adherence to the planned treatment schedule was also facilitated by r-metHuG-CSF (P = .007). With a median follow-up of 3.3 years, the estimated EFS of 4 years is 41% +/- 12%. In conclusion, r-metHuG-CSF administered prophylactically in the interval between chemotherapy courses significantly reduced febrile neutropenia, culture-confirmed infections, and duration of intravenous antibiotic administration and allowed for tighter adherence to the treatment schedule. The clinical effects of chlorpromazine (CPZ) administered in accordance with a double-blind design in one of three doses (200, 400 or 600 mg) were examined in 44 psychotic patients. The relationships between the effects and the CPZ concentrations in plasma and cerebrospinal fluid (CSF) were analyzed. The antipsychotic and side effects were rated according to the CPRS and the Simpson and Angus scale. CPZ concentrations were measured by a mass fragmentographic method. Treatment with CPZ resulted in a significant reduction of morbidity scores, without any clear dose relation. The final outcome was more favourable in women than in men. Extrapyramidal side effects but not somnolence were positively dose related. The antipsychotic effects tended to be positively related to the dose of CPZ in mg/kg as well as the CPZ concentrations in plasma and CSF. The greatest number of significant correlations between the CPZ concentration in CSF and the morbidity scores were seen after 2 weeks of treatment. The results indicated marked clinical improvement with CPZ concentrations above 1 ng/ml in CSF and 40 ng/ml in plasma. After 4 weeks of treatment the correlations between the CPZ concentrations and the clinical improvement were still positive but the coefficients were lower than at 2 weeks and only occasionaly significant. Extrapyramidal symptoms were significantly related to the CPZ concentrations in plasma and CSF. Somnolence was significantly related to the CPZ concentrations in CSF. Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths. Controverted results have been obtained using high frequency transcranial magnetic stimulation (HF-rTMS) as an antidepressant treatment.
                Forty patients suffering from drug-resistant major depression received ten sessions of HF-rTMS at 90% of the motor threshold on the left prefrontal cortex or sham stimulation, added to their pharmacological treatment, in a randomized double-blind design. In a second open phase, patients still fulfilling criteria of inclusion received ten additional sessions of HF-rTMS at 90 or 110%.
                Real, but not sham HF-rTMS, was associated with a significant decrease in the Hamilton Depression Rating Scale, but only twelve patients decreased more than 50%. Conclusions: Left prefrontal HF-rTMS was effectively associated with antidepressant treatment, although the size effect was small.
                Shortage of the sample and control difficulties of the placebo effect.
                Questionable in more than half of the patients studied. Febrile neutropenia (FN) remains a major dose-limiting complication among patients treated with chemotherapy. Haematopoietic colony stimulating factors (G-CSF and GM-CSF) made possible a significant improvement in the management of FN, both in the therapeutic and in the prophylactic approach. The use of antibiotic prophylaxis also permits a definite reduction of severe infections during neutropenia. Nevertheless, the possible role of these two interventions for secondary prevention of FN is still unclear.
                We conducted a prospective randomised trial by comparing the efficacy of granulocyte-colony stimulating factor (G-CSF) and the association of G-CSF with oral antibiotics in the secondary prevention of FN. We included in our study those patients who, after an episode of FN, continued to be treated with the same chemotherapy without reduction of dose intensity. They were randomised into two groups: the first received G-CSF (group G; filgrastim, 5 microg/kg day), and the second was treated with an association of G-CSF and amoxicillin/clavulanate plus ciprofloxacin (group G/ACC).
                Forty-eight patients were randomised (group G: n=23 and group G/ACC: n=25). There was no recurrence of FN among the patients receiving G-CSF and only one episode in the combined therapy group (p=1). With regard to the side effects, there was no significant difference in the two groups.
                The use of G-CSF for the secondary prevention of FN is extremely effective and allows the maintenance of chemotherapy dose intensity. Our study showed that the addition of antibiotics does not seem to be required. This study presents a meta-analysis of the influence of several potentially biasing factors (eg industry support, extrapyramidal side effects) on efficacy of studies comparing second-generation antipsychotic (SGA) with first-generation antipsychotic (FGA) medications. We used the dataset from our previously published meta-analysis of 124 randomized controlled trials (RCTs) comparing SGAs with FGAs, to evaluate whether certain possible biases could influence the actual outcome on the total score of the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scores. Industry sponsorship was determined by contact with authors or publication statement. We calculated whether (1) industry sponsorship, (2) study quality, (3) extrapyramidal symptoms (EPS) properties, or (4) prophylactic antiparkinsonian medications influenced SGA vs FGA efficacy for each drug and averaged overall by two Hedges and Olkin-based meta-analyses. The analysis found that none of the factors was significantly associated with a particular outcome. While industry-sponsored articles may conclude their medication to be more favorable than that of a competitor in an RCT, we found that the observed efficacy was not influenced by sponsorship. Many attribute the finding that SGAs appears to be more efficacious than FGAs to be a result of EPS-decreasing efficacy (or its measurement). We were unable to confirm that the drug's EPS properties or antiparkinsonian management altered actual efficacy. The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs.
                Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non-small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure.
                A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively).
                RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm. A group of 80 elderly subjects affected with recent onset (less than 6 mth) slight to moderate mental deterioration was observed before and after oral drug treatment for a period of 28 wk. The study consisted of four randomized groups of subjects homogeneous for age, sex and life habits. The first group received a placebo, the second group received piracetam (1600 mg 3 times a day), the third group received pentoxifylline (400 mg 3 times a day), and the fourth group received a combination of piracetam and pentoxifylline. At the beginning and end of each phase of the study, neuropsychological and haemorheological parameters were evaluated in all subjects. The results show that the most evident improvement in psycho-intellectual performance, associated with an increase of whole blood filtration values, was obtained in the group treated with the two-drug combination. To test the hypothesis that in couples undergoing IUI, actively managed cycles using clomiphene citrate (CC) stimulation, ultrasound monitoring, and hCG timing will result in increased pregnancy rate (PR) per cycle compared with unstimulated urinary LH-timed cycles.
                Fifty-six couples with unexplained infertility (n = 26) or male factor infertility (n = 30) participated in the study.
                Tertiary academic medical center.
                Prospective, randomized, crossover. Couples were randomized initially to one of the two study groups (treatment A: LH-timed IUI; treatment B: CC-stimulated, hCG-timed IUI). If no pregnancy occurred, each couple alternated between the two regimens during subsequent cycles, up to a total of four cycles.
                Twenty-nine couples completed the study and the analysis of 95 cycles revealed that among the male factor infertility group, one pregnancy occurred during the 26 cycles of each treatment group (PR per cycle of 3.9% for both treatment groups). In contrast, among the unexplained infertility group, there was a marked difference in the effect of treatments. During treatment A only one pregnancy occurred in 20 cycles (PR of 5% per cycle) whereas during treatment B, six pregnancies occurred in 23 cycles (PR of 26.1% per cycle).
                If IUI is chosen as the treatment modality in unexplained infertility, the addition of active ovulation management that includes CC stimulation, ultrasound monitoring of folliculogenesis, and hCG timing of ovulation increases the PR per cycle. In couples with male infertility, PR per cycle is low and is apparently not affected by the addition of active ovulation management. To assess the effect of three different alcohol withdrawal therapy regimens in traumatized chronic alcoholic patients with respect to the duration of mechanical ventilation and the frequency of pneumonia and cardiac disorders during their intensive care unit (ICU) stay.
                A prospective, randomized, blinded, controlled clinical trial.
                A university hospital ICU.
                Multiple-injured alcohol-dependent patients (n=180) transferred to the ICU after admission to the emergency room and operative management. A total of 180 patients were included in the study; however, 21 patients were excluded from the study after assignment.
                Patients who developed actual alcohol withdrawal syndrome were randomized to one of the following treatment regimens: flunitrazepam/clonidine (n=54); chlormethiazole/haloperidol (n=50); or flunitrazepam/haloperidol (n=55). The need for administration of medication was determined, using a validated measure of the severity of alcohol withdrawal (Revised Clinical Institute Withdrawal Assessment for Alcohol Scale).
                The duration of mechanical ventilation and major intercurrent complications, such as pneumonia, sepsis, cardiac disorders, bleeding disorders, and death, were documented. Patients did not differ significantly between groups regarding age, Revised Trauma and Injury Severity Score and Acute Physiology and Chronic Health Evaluation II score on admission. In all except four patients in the flunitrazepam/clonidine group, who continued to hallucinate, the Revised Clinical Institute Withdrawal Assessment for Alcohol Scale decreased to <20 after initiation of therapy. ICU stay did not significantly differ between groups (p=.1669). However, mechanical ventilation was significantly prolonged in the chlormethiazole/haloperidol group (p=.0315) due to an increased frequency of pneumonia (p=.0414). Cardiac complications were significantly (p=.0047) increased in the flunitrazepam/clonidine group.
                There was some advantage in the flunitrazepam/clonidine regimen with respect to pneumonia and the necessity for mechanical ventilation. However, four (7%) patients had to be excluded from the study due to ongoing hallucinations during therapy. Also, cardiac complications were increased in this group. Thus, flunitrazepam/haloperidol should be preferred in patients with cardiac or pulmonary risk. Further studies are required to determine which therapy should be considered. Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity.
                From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients).
                Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively).
                EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS. It is possible that high dose GH treatment may have beneficial effects on growth but important adverse effects on cardiac function. We have therefore investigated the efficacy and cardiovascular effects of high dose biosynthetic human GH (r-hGH) treatment in children with idiopathic short stature and a normal pretreatment height velocity.
                Randomized controlled study.
                Twenty-nine short (height SDS < 1.5), normally growing (height velocity SDS > -1.5), prepubertal children referred to two specialist growth clinics.
                Children were randomly assigned to an observation group or to receive 'standard' (20 IU/m2/week) or 'high' (40 IU/m2/week) dose r-hGH by daily subcutaneous injection. At the end of 1 year the observation group were randomly assigned to 'standard' or 'high' dose r-hGH therapy for the second year of the study. Regular growth, biochemical and echocardiographic monitoring were performed throughout the study period.
                Changes in height velocity, HtSDS for bone age (HtSDSBA), left ventricular mass index (LVMI) and left ventricular function (fractional shortening) during 2 years treatment.
                Twenty-seven children completed the study. Ht velocity SDS increased with r-hGH therapy in a dose dependent fashion. First-year height velocity SDS was +5.7 in the high dose r-hGH group compared with +2.7 in the standard dose r-hGH group and -0.5 in the observation group (P < 0.001). In those children treated for 2 years HtSDSBA was -0.5 in the high dose group but had not changed significantly in the standard dose group (-1.7) (P = 0.01). After one year r-hGH treatment LVMI was 71 g/m2 (observation group), 73 g/m2 (20 IU/m2/week group) and 74 g/m2 (40 IU/m2/week group) (P = 0.77). LVMI increased significantly from baseline to 76 g/m2 after 2 years therapy with 40 IU/m2/week r-hGH (P = 0.04) but nevertheless remained within the normal range. Fractional shortening did not change significantly over 2 years of r-hGH therapy.
                High dose (40 IU/m2/week) r-hGH treatment of children with idiopathic short stature resulted in a greater short-term acceleration in growth rate than 'standard' dose therapy without an excessive advance in skeletal maturity and probably represents the optimal growth promoting dose for short, normally growing children. Whether continued high dose r-hGH therapy increases final height requires further study. Left ventricular morphology and function remained within the normal range during r-hGH therapy but regular monitoring of cardiovascular status should continue in non-GHD children receiving r-hGH in high doses over a longer time period. The effect of a drug-use review (DUR) program intervention on physician prescribing after the results of a randomized clinical trial were published was studied. A Veterans Administration (VA) cooperative study published in June 1986 showed that congestive heart failure (CHF) patients who had hydralazine and isosorbide added to their drug therapy had less mortality than patients given digoxin and diuretics with or without prazosin. Physicians with at least one CHF patient who was receiving the less effective therapy were randomly assigned to intervention and control groups. In September 1986, intervention-group physicians (n = 288) were mailed a letter and questionnaire from the DUR program coordinator, the journal article, and a drug history profile of a CHF patient who might benefit from the information. Control physicians received no mailing. The questionnaire asked whether the physicians already knew about the VA study, intended to alter their prescribing, and could identify factors that would affect their decision. Two thirds of intervention-group physicians were already aware of the VA study. One third indicated that they intended to alter drug therapy based on the study results; factors significantly associated with the intent to adopt a change were physician training and experience, comments by peers, new drug availability, and the size of the reduction in mortality. During four months after the intervention, only 5 physicians in the two groups switched their patients to both hydralazine and isosorbide (full change); 23 switched them to at least one of the drugs or discontinued prazosin (partial change). There was no significant difference in the number of full or partial changes between groups.(ABSTRACT TRUNCATED AT 250 WORDS) The aim of this study was to assess the influence of drug therapy (DT) with pramiracetam and memory training (MT), each alone, and in combination (DTMT), on both the objective memory and metamemory performance. Thirty-five non-depressed, non-demented healthy elderly (mean age: 64.8 years) with objective (story recall) and/or subjective (cognitive difficulties scale) memory loss were randomly included in four open-label conditions: an MT condition (n = 10), a DT condition (n = 8), a DTMT condition (n = 10), and a control (CTR) condition (n = 7). MT and DTMT subjects participated in 12 real-life tutor-guided MT sessions, once weekly, each lasting 1.5 hrs. The subjects were tested for objective (Randt memory test) and subjective (Sehulster metamemory scale; memory functioning questionnaire) memory proficiency prior to (t(0)) and shortly after treatment (t(1)). Results showed that objective memory gains of the two groups receiving pramiracetam were significantly larger than that of the MT and CTR groups. The ranking order in terms of decreasing score improvements was DTMT - DT - MT - CTR. Metamemory, on the other hand, displayed only a trend to between-group differences with opposite patterns for the DT and DTMT groups. In the DT group, the level of depression, negatively interfered with metamemory but not with actual memory performance. The present findings stress, once again, the complex relationships between memory, metamemory and affective status, which may be differently modified by DT and MT. High cortisol levels are found in severe mood disorders, particularly bipolar disorder. Hypercortisolaemia may cause or exacerbate both neurocognitive impairment and depressive symptoms. We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder. To test this hypothesis, 20 bipolar patients were treated with 600 mg/day of the corticosteroid receptor antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind crossover design. Over the total 6 weeks of the study, neurocognitive and neuroendocrine function were evaluated at baseline, days 21 and 42. Mood symptoms were evaluated weekly. Nineteen subjects completed the protocol; there were no drop-outs due to adverse events. Following treatment with mifepristone, selective improvement in neurocognitive functioning was observed. Spatial working memory performance was significantly improved compared to placebo (19.8% improvement over placebo). Measures of verbal fluency and spatial recognition memory were also improved after mifepristone. Beneficial effects on mood were found; Hamilton Depression Rating Scale scores were significantly reduced compared to baseline (mean reduction of 5.1 points) as were Montgomery-Asberg Depression Rating Scale scores (mean reduction of 6.05 points). No significant change occurred after placebo. These data require replication but provide preliminary evidence that glucocorticoid receptor antagonists may have useful cognitive-enhancing and possibly antidepressant properties in bipolar disorder. To evaluate the effectiveness of a supervised home-based flexible training program on cardiorespiratory fitness (CRF), mental distress, and health-related quality of life (HRQOL) parameters in young and middle-aged cancer patients shortly after curative chemotherapy.
                One hundred eleven patients age 18 to 50 years who had received chemotherapy for lymphomas or breast, gynecologic, or testicular cancer completed the trial. These patients were randomly allocated to either an intervention group (n = 59), which underwent a 14-week training program, or a control group (n = 52) that received standard care. Primary outcome was change in CRF, as determined by Astrand-Rhyming indirect bicycle ergometer test (maximum oxygen uptake [VO(2max)]), between baseline (T0) and follow-up (T1). Secondary outcomes were mental distress, as assessed by the Hospital Anxiety and Depression Scale, and HRQOL, as assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire. Two-way analysis of covariance was used to analyze changes from T0 to T1.
                VO(2max) increased by 6.4 mL/kg(-1)/min(-1) in patients in the intervention group and by 3.1 mL/kg(-1)/min(-1) in patients in the control group (P < .01). The fatigue score decreased by 17.0 points in the control group compared with only 5.8 points in the intervention group (P < .01). There were no intergroup differences in mental distress or HRQOL.
                A supervised, home-based, flexible training program has significant effect on CRF in young and middle-aged cancer patients shortly after curative chemotherapy, but it has no favorable effect on patients' experience of fatigue, mental distress, or HRQOL. This study aimed to investigate the effects of methylphenidate and sertraline compared with placebo on various neuropsychiatric sequelae associated with traumatic brain injury (TBI).
                This was a 4 week, double-blind, parallel-group trial. Thirty patients with mild to moderate degrees of TBI were randomly allocated to one of three treatment groups (n = 10 in each group) with matching age, gender and education, i.e. methylphenidate (starting at 5 mg/day and increasing to 20 mg/day in a week), sertraline (starting at 25 mg/day and increasing to 100 mg/day in a week) or placebo. At the baseline and at the 4 week endpoint, the following assessments were administered: subjective (Beck Depression Inventory) and objective (Hamilton Depression Rating Scale) measures of depression; Rivermead Postconcussion Symptoms Questionnaire for postconcussional symptoms; SmithKline Beecham Quality of Life Scale for quality of life; seven performance tests (Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking, Mental Arithmetic, Short-Term memory, Digit Symbol Substitution and Mini-Mental State Examination); subjective measures of sleep (Leeds Sleep Evaluation Questionnaire) and daytime sleepiness (Epworth Sleepiness Scale). All adverse events during the study period were recorded and their relationships to the drugs were assessed.
                Neuropsychiatric sequelae seemed to take a natural recovery course in patients with traumatic brain injury. Methylphenidate had significant effects on depressive symptoms compared with the placebo, without hindering the natural recovery process of cognitive function. Although sertraline also had significant effects on depressive symptoms compared with the placebo, it did not improve many tests on cognitive performances. Daytime sleepiness was reduced by methylphenidate, while it was not by sertraline.
                Methylphenidate and sertraline had similar effects on depressive symptoms. However, methylphenidate seemed to be more beneficial in improving cognitive function and maintaining daytime alertness. Methylphenidate also offered a better tolerability than sertraline.
                2005 John Wiley & Sons, Ltd. The primary objective was to investigate the safety of recombinant human granulocyte colony stimulating factor (rhG-CSF) for the treatment of very low birthweight infants (VLBW) with sepsis and relative neutropenia, specifically with regard to worsening of respiratory distress and thrombocytopenia and all cause mortality. Secondary objectives were to evaluate duration of ventilation, intensive care, and antibiotic use as markers of efficacy.
                Neonates (< or = 28 days) in intensive care, with birth weights of 500-1500 g, absolute neutrophil count (ANC) of < or = 5 x 10(9)/l, and clinical evidence of sepsis, were randomly assigned to receive either rhG-CSF (10 microg/kg/day) administered intravenously (n = 13), or placebo (n = 15) for a maximum of 14 days, in addition to standard treatment and antibiotics. All adverse events, oxygenation index, incidence of thrombocytopenia, all cause mortality, duration of ventilation, intensive care and antibiotic treatment, and ANC recovery were compared between the two groups.
                Adverse events and oxygenation index were not increased by, and thrombocytopenia was not attributable to, treatment with rhG-CSF. At 6 and 12 months postmenstrual age, there were significantly fewer deaths in the group receiving rhG-CSF (1/13 v 7/15; p < or = 0.038). There was a non-significant trend towards a reduction in duration of ventilation, intensive care, and antibiotic use in the rhG-CSF group. There was a significantly more rapid increase in ANC in the rhG-CSF treated babies (p < 0.001).
                In a small randomised placebo controlled trial in a highly selected group of neonates, adjuvant treatment with rhG-CSF increased ANC rapidly, and no treatment related adverse events were identified. Mortality at 6 and 12 months postmenstrual age was significantly lower in the treatment group. A large trial investigating efficacy in a similar group of neonates is warranted. A growing number of studies report antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) in patients with major depression. The hypothesis that high frequency (20 Hz) rTMS (HF-rTMS) may speed up and strengthen the therapeutic response to sertraline in MD was tested. Twenty eight patients who had not yet received medication for the present depressive episode (n=12) or had failed a single trial of an antidepressant medication (n=16) were started on sertraline and randomised to receive either real of sham HF-rTMS. HF-rTMS was applied to the left dorsolateral prefrontal area in daily sessions (30 trains of 2 s, 20-40 s intertrain interval, at 90% motor threshold) on 10 consecutive working days. The results suggest that in this patient population, HF-rTMS does not add efficacy over the use of standard antidepressant medication. Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality.
                Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770.
                165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%).
                There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients.
                UK Alzheimer's Research Trust. We evaluated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; Sandoz Pharma [Basel, Switzerland]/Schering-Plough [Kenilworth, NJ]) as an adjunct to a modified (mainly cyclophosphamide and doxorubicin increased 1.5-fold) COP-BLAM regimen in the primary treatment of high-grade malignant non-Hodgkin's lymphomas (NHL). Patients (n = 182; stage II-IV; age, 15 to 73 years) were randomized to rhGM-CSF (400 micrograms) or placebo for 7 days subcutaneously after chemotherapy. Efficacy was analyzed for patients receiving at least 70% of study medication (n = 125). The frequency of clinically relevant infection was reduced by rhGM-CSF (28 v 69 infections, 16 v 30 patients, P = .02) with a cumulative probability of remaining infection free in 70% versus 48% (P = .05 log rank test at 190 days). Periods of neutropenia (P = .01 in 5 of 6 courses), days with fever (2.1 v 4.0, P = .04) and days of hospitalization for infection (3.5 v 8.0 days, P = .01) were significantly reduced. Complete response (CR) rates, assessed by prognostic risk, were 15 of 19 (79%) in treated versus 20 of 21 (95%) in controls in the low-risk group (P = .12). In the high-risk group, 31 of 45 (69%) treated patients achieved CR versus 25 of 52 (48%) of controls (P = .04). No difference in survival has been seen after 1 year. Only injection site reactions (45% treated v 7% controls) and rash (26% v 2%) occurred more frequently in treated patients (n = 176). These data show that rhGM-CSF is well tolerated in most patients with NHL, significantly reduces infection, and improves response. To determine whether individualized advice on non-pharmacological strategies for hospitalized older patients with confusion and behavioral problems can improve levels of agitation and reduce the use of psychotropic medication.
                Pragmatic randomized controlled trial in two metropolitan teaching hospitals in South Australia. Seventy-one older patients with confusion and a behavioral disturbance were randomly allocated to receive either an assessment and ongoing individualized advice from an extended practice nurse on non-pharmacological strategies or usual care. Usual care included an assessment by a geriatrician.
                Primary outcomes were levels of agitation (Pittsburgh Agitation Scale), appropriateness of psychotropic medication prescribing (Medication Appropriateness Index) and levels of psychotropics administered (chlorpromazine and diazepam dose equivalents). Secondary outcomes were length of stay, discharge destination, number of falls, restraint use and satisfaction from nursing staff and next of kin.
                Levels of agitation were modest at baseline with mean PAS intervention group 3.4 (SD = 0.5) and control group 4.0 (SD = 0.4) and both groups improved over time to 1.7 (SD = 0.4) for the intervention group and 1.8 (SD = 0.3) for the control group on the final day of data collection. Median length of follow-up was nine days. There was no effect of the intervention on levels of agitation, amount and appropriateness of psychotropic medication prescribed and administered, falls, length of stay, discharge destination, restraint use and nursing and next of kin satisfaction.
                A nursing consultation service providing individualized non-pharmacological advice does not improve patient agitation or use of psychotropic medication for older patients with confusion and behavioral problems in an acute hospital. This clinical trial evaluated luteal phase dosing with paroxetine controlled release (CR) (12.5 mg and 25 mg) in the treatment of premenstrual dysphoric disorder (PMDD).
                A multicenter, randomized, double-blind, placebo-controlled, 3-arm, fixed-dose study of luteal phase dosing with paroxetine CR in the treatment of PMDD. Three hundred seventy-three patients with PMDD were randomly assigned into the study. The primary measure of efficacy was the change from baseline in the mean luteal visual analogue scale (VAS)-Mood score. Secondary efficacy measures included disorder-specific evaluations, global assessments of disease severity, and assessments of functional impairment. Adverse events were recorded throughout the trial.
                Patients treated with either dose of paroxetine CR demonstrated significantly greater improvements on the primary efficacy measure (change from baseline in mean luteal phase VAS-Mood scores) and on the majority of secondary efficacy measures compared with patients randomly assigned to placebo.
                For the treatment of PMDD, luteal phase dosing with 12.5 mg and 25 mg of paroxetine CR is effective and generally well tolerated. Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants.
                Preterm infants who weighed < or = 1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes.
                Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 +/- 1464 mU/mL; placebo/control: 26 +/- 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70. Erythropoietin recipients had Mental Development Index scores of 96 +/- 11, and placebo/control infants had Mental Development Index scores of 78 +/- 7. Psychomotor Development Index scores were similar between groups (87 +/- 13 vs 80 +/- 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations > or = 500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL.
                Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome. Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs. The role of granulocyte colony stimulating factor (G-CSF) as supportive therapy following intensive induction chemotherapy for acute myeloid leukaemia (AML) in adults was investigated in a randomized trial. G-CSF (Lenograstim, 263 microg/d) or placebo was administered from day 8 after the end of chemotherapy until neutrophil recovery to 0.5 x 10(9)/l (or for up to 10 d). Eight hundred and three patients were entered. Neutrophil recovery was quicker with G-CSF (P < 0.0001), but this did not lead to differences in the number, severity or duration of infections. There were no substantial supportive care savings, although G-CSF patients spent 2 d less in hospital (P = 0.01). Complete remission (CR) rates were similar between arms (73% G-CSF, 75% placebo, P = 0.5), as were reasons for failure (induction death: P = 0.7; resistant disease: P = 0.5) and, for remitters, 5-year disease-free survival (34% vs. 38%, P = 0.3). Overall survival at 5 years was 29% with G-CSF vs. 36% with placebo (P = 0.10). Both CR rate (P = 0.006) and overall survival (P = 0.006) were worse with G-CSF in patients aged <40 years, but this may be a chance effect. There is some evidence from this trial of an adverse effect of G-CSF but these data need to be viewed in the context of the evidence from the other trials. Patients with advanced breast carcinoma and no prior chemotherapy were prospectively evaluated to assess the induction capabilities of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), Adriamycin and vincristine (AV), and CMF plus prednisone (CMFP). The crossover responsiveness from CMF or CMFP to AV and of AV to CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF and 86 on CMFP induction. One hundred and twelve patients were evaluated on crossover. Induction response rates were similar with 56% on AV, 57% on CMF and 63% on CMFP. Crossover response rates ranged from 32% to 41%. CMFP and AV were superior to CMF in terms of response duration (P = 0.05), and CMFP was superior to either in terms of time to treatment failure (P = 0.04), and survival (P = 0.03). Treatment failures occurred in only the on-study organ sites of disease in 73% of the patients and did not appear to be related to the response achieved. CMF was associated with more thrombocytopenia than either AV or CMFP (P = 0.03). AV was associated with fewer infections than CMFP (P = 0.02), less diarrhea than CMFP (P = 0.04), more emesis than CMF (P = 0.02), and more neurologic toxicity than either CMF or CMFP (P less than 0.0001). There was also more emesis with CMF than with CMFP (P = 0.006). CMFP was associated with greater delivery of CMF than was the CMF regimen despite a similar day 1 leukocyte distribution. These results strongly suggest that CMF(P) and AV are clinically noncross-resistant regimens, that AV and CMF are essentially equivalently active induction regimens, and that CMFP is superior to CMF and AV. 8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonis, Parkinsonism and tardive dyskinesia), together with their effect on homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias. Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front-line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two-stage, Phase II trial of FCM and FCM-R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty-two patients were entered, 26 in each arm. The overall response rates to FCM and FCM-R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4-35%) for FCM and 42% (95%CI:23-63%) for FCM-R, with eight patients achieving MRD negativity (3 FCM; 5 FCM-R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.
                © 2011 Blackwell Publishing Ltd. A randomized study was conducted to evaluate the protective activity of amifostine (A) against the dose-limiting toxicities of radiochemotherapy (RCT). Patients with head and neck cancer received radiotherapy (2 Gy/day 5 days a week up to 60 Gy) with carboplatin 70 mg/m2 on days 1-5 and 21-25 inclusive. Patients either received RCT alone (n = 14) or RCT + A at a dose of 500 mg prior to treatment with carboplatin (n = 25). There was a significant reduction in the incidence of grade 3/4 mucositis (P < 0.0001), acute grade 2 xerostomia (P < 0.0001) and grade 3/4 thrombocytopenia (P = 0.012) in these patients who received A. The incidence of grade 2 late xerostomia at 12 months is 16.7% and the incidence of loss of taste is 0% in patients treated with A, as opposed to 54.5% and 63.6% in patients who received RCT alone. There were 18 (72%) complete responses (CR) and 6 (24%) partial responses (PR) in patients who received A, compared with 6 (43%) CR and 6 PR (43%) in patients treated with RCT alone. The disease-free survival at 12 months is 85.7% in the RCT + A arm and 78.6% in the RCT alone arm. The use of amifostine reduces the incidence and severity of acute and late toxicities associated with RCT whilst preserving antitumour activity.
There is increasing evidence that psychostimulant trials provide evidence for improvement in CRF at a clinically meaningful level. There is still a requirement for a large scale RCT of methylphenidate to confirm the preliminary results from this review. There is new safety data which indicates that the haemopoietic growth factors are associated with increased adverse outcomes. These drugs can no longer be recommended in the treatment of CRF. Readers of the first review should re-read the document in full.