Stefan Englert

Resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (UICC stage IV): SYNCHRONOUS - a randomised controlled multicentre trial (ISRCTN30964555)

BackgroundCurrently, it remains unclear, if patients with colon cancer and synchronous unresectable metastases who present without severe symptoms should undergo resection of the primary tumour prior to systemic chemotherapy. Resection of the primary tumour may be associated with significant morbidity and delays the beginning of chemotherapy. However, it may prevent local symptoms and may, moreover, prolong survival as has been demonstrated in patients with metastatic renal cell carcinoma. It is the aim of the present randomised controlled trial to evaluate the efficacy of primary tumour resection prior to systemic chemotherapy to prolong survival in patients with newly diagnosed colon cancer who are not amenable to curative therapy.Methods/designThe SYNCHRONOUS trial is a multicentre, randomised, controlled, superiority trial with a two-group parallel design. Colon cancer patients with synchronous unresectable metastases are eligible for inclusion. Exclusion criteria are primary tumour-related symptoms, inability to tolerate surgery and/or systemic chemotherapy and history of another primary cancer. Resection of the primary tumour as well as systemic chemotherapy is provided according to the standards of the participating institution. The primary endpoint is overall survival that is assessed with a minimum follow-up of 36 months. Furthermore, it is the objective of the trial to assess the safety of both treatment strategies as well as quality of life.DiscussionThe SYNCHRONOUS trial is a multicentre, randomised, controlled trial to assess the efficacy and safety of primary tumour resection before beginning of systemic chemotherapy in patients with metastatic colon cancer not amenable to curative therapy.Trial registrationISRCTN30964555

Test–retest reliability and minimal detectable change of repeated sit-to-stand analysis using one body fixed sensor in geriatric patients

A majority of geriatric patients experience difficulty in performing sit-to-stand (SiSt) transitions. A detailed assessment of SiSt ability is a prerequisite for successful rehabilitation. Body fixed sensors (BFSs) are increasingly used to assess functional performances. As to date there is no system which analyzes clinically relevant phases of SiSt, the aim of this study was to determine the reliability of an automated approach for quantifying durations and angular velocities of trunk flexion and extension during repeated SiSt transitions using one BFS (DynaPort® Hybrid). Forty multimorbid geriatric patients aged 84.1 ± 6.6 years were included. Each patient participated in two test sessions with a 5 min rest period in between. Intra- and interrater reliability was assessed. Intraclass correlation coefficients (ICCs), absolute and relative standard measurement errors (SEMs, SEMs%) and minimal detectable changes (MDCs(95), MDCs(95)%) were calculated. ICCs were good to excellent for all variables in the total sample (0.80-0.94). The intraobserver group (50%) showed a higher number of excellent ICCs (≥.9) compared to the interobserver subgroup (10%). SEM% was low for all variables (6.9-12.7%). MDC(95)% ranged 19.2-34.4% and more variables ≤30% were found in the intra- (80%) compared to the inter-observer group (60%). Study results demonstrate that the BFS system provides a reliable analysis of SiSt phases in geriatric patients, and is a substantial improvement over the stopwatch approach used in clinical practice today.

Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease

It is well known that inflammation increases liver stiffness (LS) in patients with chronic hepatitis C (HCV) and alcoholic liver disease (ALD) independent of fibrosis stage, but no inflammation‐adapted cut‐off values have been settled so far. An early identification of rapid fibrosers, however, is essential to decide whom to treat first with the novel but expensive antiviral drugs.

Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases.

Background Post-stroke immune depression contributes to the development of infections which are major complications after stroke. Previous experimental and clinical studies suggested that humoral stress mediators induce immune dysfunction. However, prospective clinical studies testing this concept are missing and no data exists for other cerebrovascular diseases including intracerebral hemorrhage (ICH) and TIA. Methods We performed a prospective clinical study investigating 166 patients with TIA, ischemic and hemorrhagic stroke. We measured a broad panel of stress mediators, leukocyte subpopulations, cytokines and infection markers from hospital admission to day 7 and on follow-up after 2–3 months. Multivariate regression analyses detected independent predictors of immune dysfunction and bacterial infections. ROC curves were used to test the diagnostic value of these parameters. Results Only severe ischemic strokes and ICH increased some catecholamine metabolites, ACTH and cortisol levels. Immunodysfunction was eminent already on hospital admission after large brain lesions with lymphocytopenia as a key feature. None of the stress mediators was an independent predictor of lymphocytopenia or infections. However, lymphocytopenia on hospital admission was detected as an independent explanatory variable of later infections. NIHSSS and lymphocytopenia on admission were excellent predictors of infection. Conclusions Our results question the present pathophysiological concept of stress-hormone mediated immunodysfunction after stroke. Early lymphocytopenia was identified as an early independent predictor of post-stroke infections. Absence of lymphocytopenia may serve as a negative predictive marker for stratification for early antibiotic treatment.

An Intensive Exercise Program Improves Motor Performances in Patients with Dementia: Translational Model of Geriatric Rehabilitation

BACKGROUND Translation of intensive exercise programs developed specifically for patients with dementia into clinical settings is lacking. OBJECTIVE To determine if a progressive resistance and functional training program, previously evaluated in dementia outpatients, can be implemented in a geriatric inpatient setting in order to improve motor performances in patients with dementia. METHODS Eligible patients in one ward of a German geriatric hospital were assigned to the intervention group (IG, n = 74) and received intensive exercise training specifically designed for patients with dementia. Patients in the second ward were observed as a control group (CG, n = 74). All patients received usual care treatment. Primary endpoints were maximal lower extremity strength measured by a leg-press device and duration of the 5-chair-stand test for functional performance. Secondary outcomes included a number of parameters for strength and function. RESULTS The rehabilitation period averaged 18.1 ± 6.8 days. The IG significantly improved in both primary endpoints (change: maximal strength, IG: +51.9 ± 42.3% versus CG: +13.5 ± 51.8%, p < 0.001; functional performance, IG: -19.2 ± 22.3% versus CG: -3.8 ± 32.2% s, p = 0.037). Secondary outcomes confirmed effects for strength and some, but not all, functional parameters. Interestingly, low baseline motor status, but not cognitive status, predicted positive training response. CONCLUSION An intensive exercise program can be implemented in a geriatric rehabilitation setting to improve motor performances in patients with dementia. Results suggest that an intensification of training is feasible in the target group and substantially increases the benefits in comparison to receiving usual care exercise only.

Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study

BackgroundEndothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups.Methods55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months.ResultsHbA1c at baseline was, 7.3+/-0.7% in the oral group, 7.3+/-0.9% and 7.5+/-0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/-0.8%, 6.6+/-0.7% and 6.7+/-0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/-6.4 and 29.4+/- 6.7 units respectively) compared to the group on oral medication (23.2+/-6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/-0.14) at baseline to 0.76mm (+/-0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74).ConclusionThe study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus.Trial registration(Clinical Trials Identifier: NCT00523393).

Adaptive designs for single-arm phase II trials in oncology.

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two-stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two-stage design proposed by Chang et al. (Biometrics 1987; 43:865-874). However, the new design allows the use of mid-course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology.

Improving the flexibility and efficiency of phase II designs for oncology trials.

Phase II trials in oncology are usually conducted as single-arm two-stage designs with binary endpoints. Currently available adaptive design methods are tailored to comparative studies with continuous test statistics. Direct transfer of these methods to discrete test statistics results in conservative procedures and, therefore, in a loss in power. We propose a method based on the conditional error function principle that directly accounts for the discreteness of the outcome. It is shown how application of the method can be used to construct new phase II designs that are more efficient as compared to currently applied designs and that allow flexible mid-course design modifications. The proposed method is illustrated with a variety of frequently used phase II designs.

Optimal adaptive two-stage designs for phase II cancer clinical trials.

In oncology, single-arm two-stage designs with binary endpoint are widely applied in phase II for the development of cytotoxic cancer therapies. Simons optimal design with prefixed sample sizes in both stages minimizes the expected sample size under the null hypothesis and is one of the most popular designs. The search algorithms that are currently used to identify phase II designs showing prespecified characteristics are computationally intensive. For this reason, most authors impose restrictions on their search procedure. However, it remains unclear to what extent this approach influences the optimality of the resulting designs. This article describes an extension to fixed sample size phase II designs by allowing the sample size of stage two to depend on the number of responses observed in the first stage. Furthermore, we present a more efficient numerical algorithm that allows for an exhaustive search of designs. Comparisons between designs presented in the literature and the proposed optimal adaptive designs show that while the improvements are generally moderate, notable reductions in the average sample size can be achieved for specific parameter constellations when applying the new method and search strategy.

Methods for proper handling of overrunning and underrunning in phase II designs for oncology trials

Phase II studies in oncology are frequently conducted as two-stage single-arm trials with a binary endpoint indicating tumor response. As a common feature of these designs, the sample sizes of the two stages and the decision rules for the interim and the final analysis have to be pre-specified and adhered to strictly during the course of the trial in order to assure control of the type I error rate. In practice, however, the attained sample sizes often deviate from the planned ones leading to the situation of overrunning or underrunning. The currently available approaches to deal with this problem are either based on assumptions that are rarely met in practice or do not guarantee that the significance level is kept. However, strict control of the type I error rate plays an important role also for single-arm cancer trials, as they are frequently a fundamental part of the registration information. We propose a general methodology that allows handling both unintentional and intentional overrunning and underrunning while strictly controlling the type I error rate. Application of the proposed procedure and some of its characteristics are illustrated with a real phase II oncology trial.