Additive Hazards Models with Latent Treatment Effectiveness Lag Time

In many clinical trials to evaluate treatment efficacy, it is believed that there may exist latent treatment effectiveness lag times after which medical procedure or chemical compound would be in full effect. In this article, semiparametric regression models are proposed and studied to estimate the treatment effect accounting for such latent lag times. The new models take advantage of the invariance property of the additive hazards model in marginalizing over random effects, so parameters in the models are easy to be estimated and interpreted, while the flexibility without specifying baseline hazard function is kept. Monte Carlo simulation studies demonstrate the appropriateness of the proposed semiparametric estimation procedure. Data collected in the actual randomized clinical trial, which evaluates the effectiveness of biodegradable carmustine polymers for treatment of recurrent brain tumors, are analyzed.

MODELING DIFFERENTIATED TREATMENT EFFECTS FOR MULTIPLE OUTCOMES DATA

Multiple outcomes data are commonly used to characterize treatment effects in medical research, for instance, multiple symptoms to characterize potential remission of a psychiatric disorder. Often either a global, i.e. symptom-invariant, treatment effect is evaluated. Such a treatment effect may over generalize the effect across the outcomes. On the other hand individual treatment effects, varying across all outcomes, are complicated to interpret, and their estimation may lose precision relative to a global summary. An effective compromise to summarize the treatment effect may be through patterns of the treatment effects, i.e. "differentiated effects." In this paper we propose a two-category model to differentiate treatment effects into two groups. A model fitting algorithm and simulation study are presented, and several methods are developed to analyze heterogeneity presenting in the treatment effects. The method is illustrated using an analysis of schizophrenia symptom data.

Treatment of premenopausal women with early breast cancer: old challenges and new opportunities

Breast cancer occurring in women before the age of menopause continues to be a major medical and psychological challenge. Endocrine therapy has emerged as the mainstay of adjuvant treatment for women with estrogen receptor-positive tumours. Although the suppression of ovarian function (by oophorectomy, irradiation of the ovaries or gonadotropin releasing factor analogues) is effective as adjuvant therapy if used alone, its value has not been proven after chemotherapy. This is presumably because of the frequent occurrence of chemotherapy-induced amenorrhoea. Tamoxifen reduces the risk of recurrence by approximately 40%, irrespective of age and the ovarian production of estrogens. The worth of ovarian function suppression in combination with tamoxifen is unproven and is being investigated in an intergroup randomised clinical trial (SOFT [Suppression of Ovarian Function Trial]). Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are only being investigated in younger patients. The use of chemotherapies is identical in younger and older patients; however, at present the efficacy of chemotherapy in addition to ovarian function suppression plus tamoxifen is unknown in premenopausal patients with endocrine responsive disease. 'Targeted' therapies such as monoclonal antibodies to human epidermal growth factor receptor (HER)-2, HER1 and vascular endothelial growth factor, 'small molecule' inhibitors of tyrosine kinases and breast cancer vaccines are rapidly emerging. Their use depends on the function of the targeted pathways and is presently limited to clinical trials. Premenopausal patients are best treated in the framework of a clinical trial.

Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification

BACKGROUND: Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). METHODS: We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. RESULTS: Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2-1.5; P < 0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11,95% CI 1.04-1.18; P = 0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97-1.17; P = 0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. CONCLUSIONS: The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.

rFVIIa in the treatment of persistent hemorrhage in pediatric patients on ECMO following surgery for congenital heart disease

BACKGROUND: Patients who require extracorporeal membrane oxygenation (ECMO) postsurgery for congenital heart disease (CHD) frequently experience severe bleeding episodes. Whereas recombinant-activated factor VII (rFVIIa) has proven efficacy in counteracting intractable hemorrhage in various scenarios, its use in patients on ECMO is limited by the increased risk for thrombotic events. METHODS: Between December 2004 and January 2006, ECMO was used in 10 pediatric patients following cardiac surgery, of whom seven were treated with rFVIIa because of intractable hemorrhage. Their medical records were reviewed with respect to variations in chest tube output and transfusion requirements, occlusion of or thrombus formation in the ECMO circuit and the occurrence of thromboembolic events. Outcome and rate of ECMO circuit occlusion were compared with historic controls. RESULTS: Three patients died, and four survived (none of the deaths was attributable to thrombus formation or bleeding). All patients were treated with aprotinin prior to and during rFVIIa therapy. Two patients developed an occlusion of the oxygenator, one after receiving co-medication with a FXIII concentrate, another after RBC transfusion in the ECMO system. In two patients, thrombus formation was observed in the ECMO system on inspection after discontinuation. Thromboembolic events were not observed. CONCLUSIONS: Recombinant-activated factor VII in a median dosage of 90 microg.kg(-1) was used in seven pediatric patients on ECMO. Rates of ECMO system occlusions and mortality did not differ from historic controls. Neither the reduction of chest tube output nor the blood product transfusion requirements did reach statistical significance.

[Parent satisfaction with a child and family-centered treatment program for primary headache in childhood and adolescence]

Patient satisfaction represents a significant outcome criterion in the context of systemic psychotherapeutic therapy research. This study investigated parent satisfaction with a psychosocial treatment program (comprising three components: child group therapy, parents' evenings, systemic family sessions) for pediatric primary headache (diagnosed according to IHS criteria). 10 weeks after the end of the treatment program, the parents were sent a questionnaire containing open questions and ten-point numerical rating scales. The sample comprised n=48 families. The return rate was 89%. The qualitative content analysis showed a hierarchical category system consisting of 3 major categories, 7 main groups and 69 sub-categories. The parents stated that they were satisfied with (1.) the effects of the treatment program, (2.) the specific treatment techniques and the medical and psychosocial headache-related information provided, and (3.) the therapeutic relationship. The mean satisfaction for all three therapy components on the ten-point numerical rating scale was 8.1 with a standard deviation of 2.0 (child headache group: 8.5; parents' evenings: 8.2; family sessions: 7.5). The results are discussed with reference to methodological aspects: avoidance of ceiling effects and social desirability in measuring customer satisfaction, order effects of items, weighting of the significance of satisfaction levels as an outcome criterion.

Graves' ophthalmopathy: natural history and treatment outcomes

The pathogenesis of Graves' ophthalmopathy has not been yet clarified, and from a therapeutic standpoint Graves' ophthalmopathy remains an enigma. The natural course and effects of different treatment regimens are poorly documented.

Treatment and prognosis of AIDS-related lymphoma in the era of highly active antiretroviral therapy: findings from the Swiss HIV Cohort Study

OBJECTIVE: To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. METHODS: The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. RESULTS: During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/microl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53-5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01-5.67]), the international prognostic index score (HR 1.98-3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13-5.78]). CONCLUSIONS: Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged-as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.

Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types

BACKGROUND: Standard first-line combination antiretroviral treatment (cART) against human immunodeficiency virus 1 (HIV-1) contains either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Differences between these regimen types in the extent of the emergence of drug resistance on virological failure and the implications for further treatment options have rarely been assessed. METHODS: We investigated virological outcomes in patients from the Swiss HIV Cohort Study initiating cART between January 1, 1999, and December 31, 2005, with an unboosted PI, a PI/r, or an NNRTI and compared genotypic drug resistance patterns among these groups at treatment failure. RESULTS: A total of 489 patients started cART with a PI, 518 with a PI/r, and 805 with an NNRTI. A total of 177 virological failures were observed (108 [22%] PI failures, 24 [5%] PI/r failures, and 45 [6%] NNRTI failures). The failure rate was highest in the PI group (10.3 per 100 person-years; 95% confidence interval [CI], 8.5-12.4). No difference was seen between patients taking a PI/r (2.7; 95% CI, 1.8-4.0) and those taking an NNRTI (2.4; 95% CI, 1.8-3.3). Genotypic test results were available for 142 (80%) of the patients with a virological treatment failure. Resistance mutations were found in 84% (95% CI, 75%-92%) of patients taking a PI, 30% (95% CI, 12%-54%) of patients taking a PI/r, and 66% (95% CI, 49%-80%) of patients taking an NNRTI (P < .001). Multidrug resistance occurred almost exclusively as resistance against lamivudine-emtricitabine and the group-specific third drug and was observed in 17% (95% CI, 9%-26%) of patients taking a PI, 10% (95% CI, 0.1%-32%) of patients taking a PI/r, and 50% (95% CI, 33%-67%) of patients taking an NNRTI (P < .001). CONCLUSIONS: Regimens that contained a PI/r or an NNRTI exhibited similar potency as first-line regimens. However, the use of a PI/r led to less resistance in case of virological failure, preserving more drug options for the future.

Stent placement in the endovascular treatment of intracranial aneurysms

To analyze the immediate and midterm angiographic and clinical results of stent placement in the endovascular treatment of intracranial cerebral aneurysms.

[The treatment of orthostatic hypotension with metoclopramide]

The dopamine receptor antagonist metoclopramide (paspertin, primpéran, gastrosil, meclopran, gastro-timelets), used as monotherapy or in combination with an inhibitor of the cyclooxygenase enzyme, affords good results in orthostatic hypotension due to insufficiency of the sympathetic nervous system. The mechanism of action in these cases is unclear but is assumed to be elevation of vascular tone in the splanchnic vessels. A case is discussed which documents the effectiveness of metoclopramide therapy in orthostatic hypotension, even in absence of signs of autonomic dysfunction.

Treatment of patients with the hypereosinophilic syndrome with mepolizumab

BACKGROUND: The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity. METHODS: We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1-PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks. RESULTS: The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001). Serious adverse events occurred in seven patients receiving mepolizumab (14 events, including one death; mean [+/-SD] duration of exposure, 6.7+/-1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3+/-2.6 months). CONCLUSIONS: Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1-PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov].).