Effect Of Different Treatment Regimes Research Articles

P0063CLINICAL CHARACTERISTICS OF PATIENTS WITH GENETICALLY CONFIRMED ALPORT SYNDROME

Abstract Background and Aims Alport syndrome (AS) is an inherited glomerular basement membrane disease caused by mutations in COL4A3, COL4A4 or COL4A5 genes. Recently, it has been reported that focal segmental glomerulosclerosis (FSGS) can be seen in AS and COL4A mutations can be detected in FSGS. In this study, we aimed to define the clinical characteristics of patients with genetically confirmed AS, in order to establish genotype-phenotype correlation and investigate the effects of different treatment regimes. Method A total of 87 pediatric AS patients included in this multicenter study. We retrospectively collected data from medical records and requested other centers to fill out a questionnaire, which included data regarding patient demographic features, family history, clinical and laboratory characteristics at first presentation, histopathological (if available) and genetic tests results, treatments and yearly follow-up results. Results A total of 87 (41 female, 46 male) genetically confirmed AS patients (COL4A5, n=43; COL4A3, n=25; COL4A4, n=19) were studied. Mean age at first presentation was 7.6±4.1 years and the median follow-up duration was 4.3 years (IQR 1.9–7.3). 14 (16.1%) of 87 patients presented with nephrotic syndrome (NS); renal biopsy findings showed FSGS in 11 (79%) of 14 patients with NS, and COL4A3 mutations were the most common (n=7, 50%) in this group. Of 14 NS patients, 12 received steroid, 11 received cyclosporine (CsA) and 4 received other immunosuppressives prior to genetic diagnosis. The inheritance pattern of the patients with NS was consistent with ARAS in 10 patients (71.4%), XLAS in 3 patients (21.4%), and ADAS in 1 patient (7.2%). During follow up, glomerular filtration rate (GFR) decreased below 90 ml/min/1.73 m2 in 24 of 87 patients (27.5%). COL4A3 mutations (n=14, 58.3%) were the leading genetic abnormality in patients who progressed to chronic kidney disease (CKD). At the last visit, GFR loss was significantly higher in patients with COL4A3 mutations when compared to patients with COL4A4 and COL4A5 mutations (p=0.04). Among patients with NS, 9 of 14 (64.2%) progressed to CKD. Genetic results of patients with NS who progressed to CKD were COL4A3 in 6 (66.7%), COL4A4 in 2 (22.2%) and COL4A5 in 1 (11.1%) patients. In survival analysis, renal survival rate without CKD was 12.1 years (95% CI: 6.7-17.5). After the first presentation, the 5-year cumulative risk of CKD was 51.8%, 12.6%, and 12.9% in patients with COL4A3, COL4A4 and COL4A5 mutations, respectively (p=0.001). We observed that patients with COL4A3 mutations, ARAS inheritance pattern, histopathology of FSGS or NS presentation progressed to CKD earlier (p<0.001 for COL4A3, p=0.01 for ARAS, p=<0.001 for FSGS, p=0.01 for NS presentation) when compared to those without. CsA treatment did not improve renal survival. Conclusion Detailed analyses of data from genetically confirmed Turkish patients with AS provided important clues regarding to the presentation, course and outcomes of the disease. COL4A3 mutations, ARAS inheritance pattern, NS presentation and FSGS finding in renal biopsy are major risk factors for progression to CKD. We recommend genetic testing for patients suspected of having AS. Furthermore, COL4A mutations should be considered in patients with FSGS and steroid resistant NS. This approach will shed light on the prognosis of patients and help with definitive diagnosis, preventing unnecessary and potentially harmful medications.

Fair treatment comparisons in observational research

AbstractThe proliferation of electronic health records, driven by advances in technology and legislative measures, is stimulating interest in the analysis of passively collected administrative and clinical data. Observational data present exciting challenges and opportunities to researchers interested in comparing the effectiveness of different treatment regimes and, as personalized medicine requires, estimating how effectiveness varies among subgroups. In this study, we provide new motivation for the local control approach to the analysis of large observational datasets in which patients are first clustered in pretreatment covariate space and treatment comparisons are made within subgroups of similar patients. The motivation for such an analysis is that the resulting local treatment effect estimates make inherently fair comparisons even when treatment cohorts suffer variation in balance (treatment choice fraction) across pretreatment covariate space. We use an example of Simpson's paradox to show that estimates of the overall average treatment effect, which marginalize over covariate space, can be misleading. Thus, we provide an alternative definition that uses a single, shared marginal distribution to define overall treatment comparisons that are inherently fair given the observed covariates. However, we also argue that overall treatment comparisons should no longer be the focus of comparative effectiveness research; the possibility that treatment effectiveness does vary across patient subpopulations must not be left unexplored. In the spirit of the now ubiquitous concept of personalized medicine, estimating heterogeneous treatment effects in clinically relevant subgroups will allow for, within the limits of the available data, fair treatment comparisons that are more relevant to individual patients.

Pattern-mixture-type Estimation and Testing of Neuroblastoma Treatment Regimes.

Sequentially randomized designs are commonly used in biomedical research, particularly in clinical trials, to assess and compare the effects of different treatment regimes. In such designs, eligible patients are first randomized to one of the initial therapies, then patients with some intermediate response (e.g. without progressive diseases) are randomized to one of the maintenance therapies. The goal is to evaluate dynamic treatment regimes consisting of an initial therapy, the intermediate response, and a maintenance therapy. In this article, we demonstrate the use of pattern-mixture model (commonly used for analyzing missing data) for estimating the effects of treatment regimes based on familiar survival analysis techniques such as Nelson-Aalen and parametric models. Moreover, we demonstrate how to use estimates from pattern-mixture models to test for the differences across treatment regimes in a weighted log-rank setting. We investigate the properties of the proposed estimators and test in a Monte Carlo simulation study. Finally we demonstrate the methods using the long-term survival data from the high risk neuroblastoma study.

Comparison of treatment regimes with adjustment for auxiliary variables

Treatment regimes are algorithms for assigning treatments to patients with complex diseases, where treatment consists of more than one episode of therapy, potentially with different dosages of the same agent or different agents. Sequentially randomized clinical trials are usually designed to evaluate and compare the effect of different treatment regimes. In such designs, eligible patients are first randomly assigned to receive one of the initial treatments. Patients meeting some criteria (e.g. no progressive disease) are then randomized to receive one of the maintenance treatments. Usually, the procedure continues until all treatment options are exhausted. Such multistage treatment assignment results in treatment regimes consisting of initial treatments, intermediate responses and second-stage treatments. However, methods for efficient analysis of sequentially randomized trials have only been developed very recently. As a result, earlier clinical trials reported results based only on the comparison of stage-specific treatments. In this article, we propose a model that applies to comparisons of any combination of any number of treatment regimes regardless of the number of stages of treatment adjusted for auxiliary variables. Contrasts of treatment regimes are tested using the Wald chi-square method. Both the model and Wald chi-square tests of contrasts are illustrated through a simulation study and an application to a high-risk neuroblastoma study to complement the earlier results reported on this study.

Safety and effectiveness of different treatment regimes with tranexamic acid in elective cardiopulmonary bypass patients

Although tranexamic acid (TA) has been effective in reducing bleeding after cardiac surgery, the TA dosing scheme varies extremely and the agent is highly overdosed in most relevant trials. In a dose-dependent fashion, TA is associated with an increase of adverse events, particularly the observation of seizures. In this study we aimed to assess the safety and effectiveness of different treatment regimes of TA in cardiopulmonary bypass (CPB) patients.

Gynaecological cancer and sexual functioning: Does treatment modality have an impact?

Sexual dysfunction(s) are common after treatment of gynaecological cancer. At present, hardly any randomized studies have evaluated the effect of different treatment regimes on the sexual functioning of gynaecological cancer patients. During the past decade there has been more focus on evaluating complications along with survival. Our primary knowledge on the impact of gynaecological cancer treatment on female sexual functioning mainly derive from observational studies. The focus of the present paper is to give an update on potential physiological effects of different treatments on the sexual functioning of gynaecological cancer patients. While radical pelvic surgery may be associated with a substantial risk of acute complications due to haemorrhage, tissue oedema, nerve injury, infection and haematoma formation, pelvic radiotherapy causes acute negative effects on mucous membranes in the vagina, the bladder and the rectum, and on the skin. Both treatments have been shown to have a negative impact on sexual functioning, especially in cervical cancer patients. However, most studies agree that in the longer run, patients who are treated with surgery experience less sexual dysfunction than those who are given radical chemo-irradiation or combined surgery and chemo-irradiation. In the future, randomized controlled studies will hopefully clarify the effect of different combination treatment modalities on the sexual functioning of gynaecological cancer patients. An empathic attitude and willingness to discuss sexual issues with the patient and her partner is recommended as well the use of local estrogens or the non-hormonal lubricant Replens, and a vaginal dilator after brachytherapy.

On the Analysis of Long-Term Experiments

SummaryLong-term experiments are commonly used tools in agronomy, soil science and other disciplines for comparing the effects of different treatment regimes over an extended length of time. Periodic measurements, typically annual, are taken on experimental units and are often analysed by using customary tools and models for repeated measures. These models contain nothing that accounts for the random environmental variations that typically affect all experimental units simultaneously and can alter treatment effects. This added variability can dominate that from all other sources and can adversely influence the results of a statistical analysis and interfere with its interpretation. The effect that this has on the standard repeated measures analysis is quantified by using an alternative model that allows for random variations over time. This model, however, is not useful for analysis because the random effects are confounded with fixed effects that are already in the repeated measures model. Possible solutions are reviewed and recommendations are made for improving statistical analysis and interpretation in the presence of these extra random variations.

Hydatid cysts: does every picture tell a story?

Ultrasound imaging is an effective aid to the detection of abdominal cystic echinococcosis. Recently, the images produced have provided more information than just a diagnosis. Different cyst morphologies have been classified into types, and such classifications can be considered to represent a natural history of cyst development. Understanding how cyst structures alter with time is crucial to evaluating the effectiveness of different treatment regimes and to understanding natural degeneration of cysts that can occur. However, the developmental events seen in ultrasound need to be matched more closely to immunological and cellular events if we are to have a fuller appreciation of disease progression and regression. At a community level, the relative proportions of cyst types could also provide epidemiological information on disease transmission.

The child who soils

Soiling can best be understood in childhood with reference to normal anorectal function, and the development of the awareness of the social value of continence. The pathophysiology as well as the disturbed behaviour associated with faecal incontinence is described. An illustrative case history is given to emphasize the evolution of the problems with age. The range of associated problems from neuropathic rectum, megarectum with overflow soiling, and through to the more psychological encopresis is described with some suggested treatments. Although there is little hard evidence about effectiveness of different treatment regimes, there is a strong consensus that early multidisciplinary help for these common problems is likely to prevent major social and psychological consequences of coping with faecal incontinence in late childhood and adolescence.

Tuberculous Hydrocephalus: Comparison of Different Treatments With Regard to Icp, Ventricular Size and Clinical Outcome

The effect of different treatment regimes on intracranial pressure (ICP), degree of hydrocephalus and clinical outcome was evaluated in 81 children with tuberculous meningitis. 24 children underwent CSF shunting, while 57 with communicating hydrocephalus were randomly assigned to three treatment groups: antituberculous drugs only; or additional intrathecal hyaluronidase or oral acetazolamide and furosemide in addition to antituberculous treatment. The addition of acetazolamide and furosemide was significantly more effective in achieving normal ICP than antituberculous drugs alone. No difference was found in mortality or number of disabled survivors between groups. Of those surviving, nearly two-thirds with stage II tuberculous meningitis were mildly disabled and nearly one-half with stage III were severely disabled at follow-up, emphasising the need for early diagnosis of tuberculous meningitis in the young child.

Angiosarcoma of the face and scalp, prognosis and treatment.

72 patients with angiosarcoma (AS) of the face and scalp have been analyzed with respect of various prognostic factors and the effects of different treatment regimes. This disease predominantly occurs in the elderly (age range, 56-92 years), and affects men rather more frequently than women (men: 44, women: 28). The clinical presentation varied, and included bruise-like lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, pyoderma, and infected conditions. Due to lack of clinical awareness and problems with histologic assessment, delays in diagnosis were frequent. The majority of the tumors arose in the upper part of the face or scalp. Less commonly, the central part of the face was affected while only three tumors developed in the mandibular region. Overall the prognosis was poor; one half of the patients died within 15 months of presentation. Only 12% of the patients survived 5 years or more. Patients with lesions that were less than 10 cm in diameter responded better to treatment and statistically survived longer than those with larger lesions, emphasizing the crucial importance of early diagnosis. There is some indication that men, younger patients, patients with lesions on the central part of the face survived longer, but this was not of statistical significance. The histologic differentiation of the tumors at presentation also was of doubtful prognostic significance. Despite the overall poor prognosis, radical radiotherapy (mostly wide-field electron-beam therapy) in seven patients resulted in the apparent eradication of the local skin disease and prolonged survival of the patients. Pulmonary metastases developed 10 years later in two of those patients, however, but the face and scalp remained tumor-free.

The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy.

The linear-quadratic (LQ) dose-effect formalism is currently providing new perspectives into the ways in which alterations in the dose per fraction in conventional radiotherapy may be used to bring about improved results with respect to early or late normal tissue reactions. In this paper, using a model initially developed by Roesch, the LQ equations are explored further in terms of dose-rate rather than dose. By the incorporation of one other parameter, mu, which relates to the rate of repair of sub-lethal radiation damage, a more general formalism is obtained. In particular, equations are derived which can be used to examine the relative effectiveness of different treatment regimes, including those involving decaying sources. Such equations are of wider applicability than other LQ derivations which relate only to dose-response relationships. The extended equations, which are fully consistent with the existing LQ method, are also shown to lead directly to other independently established, relationships for protracted irradiation. The nature of the link between high and low dose-rate treatments is discussed, and some worked examples provide indications of how the new equations may be used to assess further the potential clinical benefits of low dose-rate treatments and permanent implants.