MRI-based contrast clearance analysis shows high differentiation accuracy between radiation-induced reactions and progressive disease after cranial radiotherapy.

BACKGROUND: Pseudoprogression (PsP) or radiation necrosis (RN) may frequently occur after cranial radiotherapy and show a similar imaging pattern compared with progressive disease (PD). We aimed to evaluate the diagnostic accuracy of magnetic resonance imaging-based contrast clearance analysis (CCA) in this clinical setting. PATIENTS AND METHODS: Patients with equivocal imaging findings after cranial radiotherapy were consecutively included into this monocentric prospective study. CCA was carried out by software-based automated subtraction of imaging features in late versus early T1-weighted sequences after contrast agent application. Two experienced neuroradiologists evaluated CCA with respect to PsP/RN and PD being blinded for histological findings. The radiological assessment was compared with the histopathological results, and its accuracy was calculated statistically. RESULTS: A total of 33 patients were included; 16 (48.5%) were treated because of a primary brain tumor (BT), and 17 (51.1%) because of a secondary BT. In one patient, CCA was technically infeasible. The accuracy of CCA in predicting the histological result was 0.84 [95% confidence interval (CI) 0.67-0.95; one-sided P = 0.051; n = 32]. Sensitivity and specificity of CCA were 0.93 (95% CI 0.66-1.00) and 0.78 (95% CI 0.52-0.94), respectively. The accuracy in patients with secondary BTs was 0.94 (95% CI 0.71-1.00) and nonsignificantly higher compared with patients with primary BT with an accuracy of 0.73 (95% CI 0.45-0.92), P = 0.16. CONCLUSIONS: In this study, CCA was a highly accurate, easy, and helpful method for distinguishing PsP or RN from PD after cranial radiotherapy, especially in patients with secondary tumors after radiosurgical treatment.

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC).

BACKGROUND: Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial. METHODS: This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale. DISCUSSION: An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life. TRIAL REGISTRATION: German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2.

BACKGROUND: Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of ≥70% European Carotid Surgery Trial (ECST) criteria. METHODS: SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported. FINDINGS: It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates. INTERPRETATION: The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials.

[Biomarkers and imaging for diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the BMBF consortium ArthroMark]. / Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

Rheumatic diseases are among the most common chronic inflammatory disorders. Besides severe pain and progressive destruction of the joints, rheumatoid arthritis (RA), spondyloarthritides (SpA) and psoriatic arthritis (PsA) impair working ability, reduce quality of life and if treated insufficiently may enhance mortality. With the introduction of biologics to treat these diseases, the demand for biomarkers of early diagnosis and therapeutic stratification has been growing continuously. The main goal of the consortium ArthroMark is to identify new biomarkers and to apply modern imaging technologies for diagnosis, follow-up assessment and stratification of patients with RA, SpA and PsA. With the development of new biomarkers for these diseases, the ArthroMark project contributes to research in chronic diseases of the musculoskeletal system. The cooperation between different national centers will utilize site-specific resources, such as biobanks and clinical studies for sharing and gainful networking of individual core areas in biomarker analysis. Joint data management and harmonization of data assessment as well as best practice characterization of patients with new imaging technologies will optimize quality of marker validation.

[Big data from clinical routine]. / Big Data aus dem klinischen Alltag.

BACKGROUND: Over the past 100 years, evidence-based medicine has undergone several fundamental changes. Through the field of physiology, medical doctors were introduced to the natural sciences. Since the late 1940s, randomized and epidemiological studies have come to provide the evidence for medical practice, which led to the emergence of clinical epidemiology as a new field in the medical sciences. Within the past few years, big data has become the driving force behind the vision for having a comprehensive set of health-related data which tracks individual healthcare histories and consequently that of large populations. OBJECTIVES: The aim of this article is to discuss the implications of data-driven medicine, and to examine how it can find a place within clinical care. MATERIALS AND METHODS: The EU-wide discussion on the development of data-driven medicine is presented. RESULTS: The following features and suggested actions were identified: harmonizing data formats, data processing and analysis, data exchange, related legal frameworks and ethical challenges. For the effective development of data-driven medicine, pilot projects need to be conducted to allow for open and transparent discussion on the advantages and challenges. The Federal Ministry of Education and Research ("Bundesministerium für Bildung und Forschung," BMBF) Arthromark project is an important example. Another example is the Medical Informatics Initiative of the BMBF. DISCUSSION AND CONCLUSION: The digital revolution affects clinic practice. Data can be generated and stored in quantities that are almost unimaginable. It is possible to take advantage of this for development of a learning healthcare system if the principles of medical evidence generation are integrated into innovative IT-infrastructures and processes.

Immunological profiling of patients with ulcerative colitis leads to identification of two inflammatory conditions and CD1a as a disease marker.

BACKGROUND: Conventional approaches to understand mechanisms underlying the development of pathological manifestations in ulcerative colitis (UC) mostly rely on identification of certain cell types and cytokines followed by verification of their roles in vitro and in vivo. In light of the highly dynamic processes in UC, requiring the cross talk of immune cells, epithelial-, endothelial-, muscle cells and fibrocytes, this approach might neglect temporal and spatial connectivity of individually differing inflammatory responses. METHODS: We undertook a more holistic approach whereby we designed a flow cytometric analysis- and ELISA panel and determined the immunological profiles of UC patients in comparison to Non UC donors. This panel consisted of B-cells, T-cells, macrophages, monocytes, NK- and NK T-cells and subtypes thereof, the cytokines TGFß1 and HGF, the chemokine TARC and periostin. Blood was collected from 41 UC patients and 30 non-UC donors. Isolated PBMC were subjected to flow cytometric analysis and sera were analyzed by ELISA. Data were analysed by cluster- and correlation analysis. To corroborate that the identified cells reflected the inflammatory condition in the colon of UC patients, leucocytes were isolated from colons of UC patients and subjected to the same flow cytometric analysis. RESULTS: Immunological profiling followed by cluster- and correlation analysis led to the identification of two inflammatory conditions: An 'acute' condition characterized by adaptive immune cells as plasma cells,  TSLPR expressing CD11b+ macrophages, CD64 and CCR2 expressing CD14+ monocytes, HGF and TARC and a 'remodeling' condition signified by NK T-cells and TLSPR expressing CD14+ monocytes, TGFß1 and periostin. ROC analysis identified TARC and TGFß1 as biological markers with high potential to discriminate between these two conditions (Δ = -6687.72 ng/ml; p = 1E-04; AUC = 0.87). In addition, CD1a+ CD11b+ macrophages (Δ = 17.73% CD1a+ CD11b+; p = 5E-04; AUC = 0.86) and CD1a+ CD14+ monocytes (Δ = 20.35; p = 0.02, AUC = 0.75) were identified as markers with high potential to discriminate between UC and Non UC donors. CD1a+ CD11b+ macrophages and NK T-cells were found to be significantly increased in inflamed colons of UC patients as compared to non-UC control samples (p = 0.02). CONCLUSIONS: Immunological profiling of UC patients might improve our understanding of the pathology underlying individual manifestations and phases of the disease. This might lead to the development of novel diagnostics and therapeutic interventions adapted to individual needs and different phases of the disease. In addition, it might result in stratification of patients for clinical trials.

SPACE-2: A Missed Opportunity to Compare Carotid Endarterectomy, Carotid Stenting, and Best Medical Treatment in Patients with Asymptomatic Carotid Stenoses.

BACKGROUND: Because of recent advances in best medical treatment (BMT), it is currently unclear whether any additional surgical or endovascular interventions confer additional benefit, in terms of preventing late ipsilateral carotid territory ischemic stroke in asymptomatic patients with significant carotid stenoses. The aim was to compare the stroke-preventive effects of BMT alone, with that of BMT in combination with carotid endarterectomy (CEA) or carotid artery stenting (CAS) in patients with high grade asymptomatic extracranial carotid artery stenosis. METHODS: SPACE-2 was planned as a three-armed, randomized controlled trial (BMT alone vs. CEA plus BMT vs. CAS plus BMT, ISRCTN 78592017). However, because of slow patient recruitment, the three-arm study design was amended (July 2013) to become two parallel randomized studies (BMT alone vs. CEA plus BMT, and BMT alone vs. CAS plus BMT). RESULTS: The change in study design did not lead to any significant increase in patient recruitment, and trial recruitment ceased after recruiting 513 patients over a 5 year period (CEA vs. BMT (n = 203); CAS vs. BMT (n = 197), and BMT alone (n = 113)). The 30 day rate of death/stroke was 1.97% for patients undergoing CEA, and 2.54% for patients undergoing CAS. No strokes or deaths occurred in the first 30 days after randomization in patients randomized to BMT. There were several potential reasons for the low recruitment rates into SPACE-2, including the ability for referring doctors to refer their patients directly for CEA or CAS outwith the trial, an inability to convince patients (who had come "mentally prepared" that an intervention was necessary) to accept BMT, and other economic constraints. CONCLUSIONS: Because of slow recruitment rates, SPACE-2 had to be stopped after randomizing only 513 patients. The German Research Foundation will provide continued funding to enable follow up of all recruited patients, and it is also planned to include these data in any future meta-analysis prepared by the Carotid Stenosis Trialists Collaboration.

A Comprehensive Assessment Tool for Patient Registry Software Systems: The CIPROS Checklist.

BACKGROUND: Patient registries are an important instrument in medical research. Often their structure is complex and their implementation uses composite software systems to meet the wide spectrum of challenges. OBJECTIVES: For the implementation of a registry, there is a wide range of commercial, open source, and self-developed systems available and a minimal standard for the critical appraisal of their architecture is needed. METHODS: We performed a systematic review of the literature to define a catalogue of relevant criteria to construct a minimal appraisal standard. RESULTS: The CIPROS list is developed based on 64 papers which were found by our systematic review. The list covers twelve sections and contains 72 items. CONCLUSIONS: The CIPROS list supports developers to assess requirements on existing systems and strengthens the reporting of patient registry software system descriptions. It can be a first step to create standards for patient registry software system assessments.

Headache cessation by an educational intervention in grammar schools: a cluster randomized trial.

BACKGROUND AND PURPOSE: Headache is a common health problem in adolescents. There are a number of risk factors for headache in adolescents that are amenable to intervention. The aim of the study was to assess the effectiveness of a low-level headache prevention programme in the classroom setting to prevent these risk factors. METHODS: In all, 1674 students in 8th-10th grade at 12 grammar schools in greater Munich, Germany, were cluster randomized into intervention and control groups. A standardized 60-min prevention lesson focusing on preventable risk factors for headache (physical inactivity, coffee consumption, alcohol consumption and smoking) and providing instructions on stress management and neck and shoulder muscle relaxation exercises was given in a classroom setting. Seven months later, students were reassessed. The main outcome parameter was headache cessation. Logistic regression models with random effects for cluster and adjustment for baseline risk factors were calculated. RESULTS: Nine hundred students (intervention group N = 450, control group N = 450) with headache at baseline and complete data for headache and confounders were included in the analysis. Headache cessation was observed in 9.78% of the control group compared with 16.22% in the intervention group (number needed to treat = 16). Accounting for cluster effects and confounders, the probability of headache cessation in the intervention group was 1.77 (95% confidence interval = [1.08; 2.90]) higher than in the control group. The effect was most pronounced in adolescents with tension-type headache: odds ratio = 2.11 (95% confidence interval = [1.15; 3.80]). CONCLUSION: Our study demonstrates the effectiveness of a one-time, classroom-based headache prevention programme.

[Memorandum 'Development of health services research in Bavaria from the perspective of the Bavarian State Working Group 'Health Services Research (LAGeV)': status quo - potential - strategies']. / Memorandum "Weiterentwicklung der Gesundheitsversorgungsforschung in Bayern aus Sicht der Landesarbeitsgemeinschaft Gesundheitsversorgungsforschung: Status quo - Entwicklungspotenziale - Strategien".

The aim of the memorandum on the development of health services research (HSR) in Bavaria is to operationalise the global objectives of the State Working Group "Health Services Research" (LAGeV) and to collectively define future topics, specific implementation steps, methods as well as ways of working for the future course of the LAGeV. The LAGeV is an expert committee that integrates and links the competencies of different actors from science, politics and health care regarding HSR and facilitates their cooperation. The memorandum is based on an explorative survey among the LAGeV members, which identified the status quo of health services research in Bavaria, potential for development, important constraints, promoting factors, specific recommendations as well as future topics for the further development of HSR in Bavaria. From the perspective of the LAGeV members, the 12 most important future topics are: 1) Interface and networking research, 2) Innovative health care concepts, 3) Health care for multimorbid patients, 4)Health care for chronically ill patients, 5) Evaluation of innovations, processes and technologies, 6) Patient orientation and user focus, 7) Social and regional inequalities in health care, 8) Health care for mentally ill patients, 9) Indicators of health care quality, 10) Regional needs planning, 11) Practical effectiveness of HSR and 12) Scientific use of routine data. Potential for development of HSR in Bavaria lies a) in the promotion of networking and sustainable structures, b) the establishment of an HSR information platform that bundles information and results in regard to current topics and aims to facilitate cooperation as well as c) in the initiation of measures and projects. The latter ought to pinpoint health care challenges and make recommendations regarding the improvement of health care and its quality. The cooperation and networking structures that were established with the LAGeV should be continuously expanded and be used to work on priority topics in order to achieve the global objectives of the LAGeV.

[Management of patients with the cardinal symptom dizziness or vertigo]. / Versorgungssituation von Patienten mit dem Leitsymptom Schwindel.

BACKGROUND: Vertigo and dizziness are common symptoms leading patients to consult a physician. The nationally representative "2003 Health Survey" depicts the epidemiology of the symptoms vertigo and dizziness across all of Germany. A breakdown of the data by region is not available. METHODS: Routine data of the Bavarian Association of Statutory Health Insurance Physicians accounting centre ("Kassenärztliche Vereinigung Bayerns", KVB) from 2008 were analysed using multilevel models to investigate individual and regional factors and the relevance of nonspecific regional heterogeneity. RESULTS: Altogether, 866,086 of 9,269,729 (9.34%) inhabitants received an ambulatory diagnosis of vertigo or dizziness, including 1.77 times as many women as men. Visits to the doctor because of vertigo or dizziness increased with age. After adjustments for age and sex, a North-South divide and a higher prevalence in the urban centres were apparent within Bavaria. The majority of patients were seen by their GP and nearby doctors. This held especially true for women. Also older patients were less likely to go to specialists further afield. CONCLUSION: This analysis of the KVB data of patients with vertigo or dizziness underlines the central role that is played by GPs in diagnosis and treatment. In order to correctly diagnose the underlying causes, treat patients or send them to specialists effectively, all doctors need to be trained about this relevant clinical symptom. The insufficient representation of clinically established vertigo disorders by the ICD-10 was problematic. The most frequently coded diagnosis was N95.1 "postmenopausal dizziness".

[Treatment of asymptomatic carotid artery stenosis: improvement of evidence with new SPACE-2 design necessary]. / Therapie asymptomatischer Karotisstenosen: Notwendige Klärung der Evidenz mit neuem SPACE-2-Design.

Asymptomatic carotid artery stenosis may be treated with carotid endarterectomy (CEA), carotid artery stenting (CAS) or with best medical treatment (BMT) only. Definitive and evidence-based treatment recommendations for one of these options are currently not possible. Studies showing an advantage of CEA over BMT alone do not meet current standards from a pharmacological point of view. On the other hand, more recent data point to a further stroke risk reduction using BMT according to current standards. Studies on carotid artery stenting as a third alternative treatment are partially insufficient, especially when comparing CAS with BMT. Initiated in 2009, the randomized, controlled, multicenter SPACE-2 trial is intended to answer the question about the best treatment option of asymptomatic carotid artery stenosis; however, to increase recruitment rates as a condition for the successful completion of this important study, the trial design had to be modified.

EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104.

BACKGROUND: We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study. METHODS: AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash. RESULTS: Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash. CONCLUSION: The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.

Randomised controlled trial with medical leeches for osteoarthritis of the knee.

OBJECTIVES: To evaluate the possible efficacy of medical leeches (Hirudo medicinalis) in the treatment of patients with active osteoarthritis of the knee. DESIGN: Unblinded, randomised controlled trial with outpatients in a crossover design with single interventions of either leeches or transcutaneous electrical nerve stimulation (TENS) as comparator. MAIN OUTCOME MEASURES: Change in Lequesne's combined index for pain and function and change (L.I.) and overall assessment of complaints by visual analog scale (VAS). Cross-over at day 42, with further observation period of 21 days. RESULTS: 52 out of 72 screened patients were randomised (intent to treat) to initial treatment with either eight leeches (group 1: 27 patients) or TENS (group 2: 25 patients). Due to phase effects, confirmatory evaluation had to be restricted to the first period. Between days 0 and 21, we observed highly significant (p<0.001) improvements for means of Lequesne's index from 12.07 to 9.37 and for VAS from 5.89 to 4.16 cm for leeches, but no significant differences for TENS. Effect size as group difference was -2.50 for L.I. (95% confidence interval -3.88 to -1.11), resp. -1.86 cm for VAS (95% confidence interval -2.85 to -0.87 cm). 12 patients (5 group 1, 7 group 2) did not finish the trial, mostly due to non-compliance (6). No serious adverse effects were observed. CONCLUSIONS: Single leech therapy showed significant, relevant and sustaining effects, comparable to other trials with leeches. The method deserves further research, esp. into mechanisms of possible specific effects and optimization of dosing by number of leeches and possible repeats.

Growth velocity during infancy and onset of asthma in school-aged children.

BACKGROUND: Growth velocities during infancy might affect the risk of asthma in childhood. This study examines the association between peak height and weight velocities during the first 2 years of life and onset of asthma and wheeze up to 10 years of age. METHODS: Data from 9086 children who participated in the GINIplus and LISAplus birth cohorts were analyzed. Information on asthma was requested annually from 1 to 10 years and information on wheeze at 1, 2, 4, 6, and 10 years. Peak height and weight velocities were calculated using height and weight measurements obtained between birth and 2 years of age. Cox proportional hazards models and generalized linear mixed models were calculated after adjustment for potential confounding factors including birth weight and body mass index at 10 years of age. RESULTS: Per interquartile range increase in peak weight velocity (PWV), the risk of asthma increased significantly (adjHR: 1.22; CI: 1.02-1.47). The relationship between peak height velocity (PHV) and onset of asthma was nonsignificant (adjHR: 1.08; CI: 0.88-1.31). Wheeze was not significantly associated with PHV or with PWV (adjOR: 1.07; CI: 0.64-1.77 and adjOR: 1.11; CI: 0.68-1.79, respectively). CONCLUSIONS: Weight gain during infancy is positively associated with physician-diagnosed asthma in school-aged children.

A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias.

OBJECTIVE: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. METHODS: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. RESULTS: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated. CONCLUSIONS: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. LEVEL OF EVIDENCE: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

Time to locoregional recurrence after curative resection of rectal carcinoma is prolonged after neoadjuvant treatment: a systematic review and meta-analysis.

AIM: A systematic review of the literature with meta-analysis was performed to evaluate the time to locoregional recurrence after curative resection of rectal carcinoma, assuming that this time is prolonged after neoadjuvant radiochemotherapy and/or present day surgery. METHOD: English and German language peer-reviewed articles published between 1980 and 2007 were selected. Twenty-five of 118 studies fulfilled the defined inclusion and exclusion criteria. For some special questions, data of the Erlangen Registry of Colorectal Carcinoma (ERCRC) from 1985 to 1997 are reported. RESULTS: After conventional surgery of rectal carcinoma, 75% (range 66-84%) of locoregional recurrence presented during the first 2 years after resection. Following the introduction of total mesorectal excision surgery and the use of neoadjuvant treatment, a general reduction of the frequency of local recurrence combined with a prolongation of the time to local recurrence was observed. In the practice of today, in particular after neoadjuvant long-course radiochemo-or radiotherapy, 24% (range 8-40%) of all local recurrences present later than 5 years after primary therapy. In contrast, such late local recurrences are observed in only 8% (range 5-9%) following primary surgery alone. CONCLUSION: For a definite assessment of the therapeutic results regarding local control, a minimal follow up of 7-8 years either after neoadjuvant long-course radiochemo- or radiotherapy and a minimum of 5 years after surgery alone is necessary. For patients with primary surgery followed by adjuvant therapy, it is not possible to make a clear statement.

[Clinical characteristics, progression and risk factors of geographic atrophy]. / Klinische Merkmale, Progression und Risikofaktoren bei geographischer Atrophie.

Geographic atrophy (GA) as the late stage manifestation of age-related macular degeneration (AMD) is a progressive disease process afflicting the retinal pigment epithelium, choriocapillaris and the outer neurosensory retina. GA represents a complex, multifactorial disease governed by the interdependence of genetic, endogenous and exogenous factors. Diagnosis and monitoring of GA progression is largely based on various retinal imaging modalities. After the breakthrough in the treatment of wet AMD GA represents a large clinical challenge. Recent studies have contributed to a better understanding of the pathophysiological pathways, natural history and predictive markers for progression.