Does neoadjuvant treatment before oncologic esophagectomy affect the postoperative quality of life? A prospective, longitudinal outcome study.

To evaluate the cancer patients' quality of life (QoL) following esophagectomy the focus was placed on the impact of neoadjuvant treatment before surgery. For patients undergoing oncologic surgery, the QoL is generally accepted as an important outcome parameter in addition to clinical parameters. This prospective nonrandomized study evaluated QoL in patients treated by preoperative chemo(radio)therapy followed by either surgery or surgery alone with special focus on the postoperative course. QoL was assessed in 131 consecutive patients who underwent surgery for esophageal cancer. The EORTC-QLQ-C30 and a tumor-specific module were administered before surgery, at discharge, 3, 6, 12, and 24 months after surgery. Clinical data were collected prospectively and a follow up was performed every 6 months. The histological type of cancer was squamous cell carcinoma in 49.6% and adenocarcinoma in 50.4%. There was no significant difference between patients that were treated neoadjuvantly and those that were first operated on with regard to morbidity, mortality, and survival rates (5-year survival rate of 34%). Most QoL scores dropped significantly below the baseline in the early postoperative period and recovered slowly during the follow-up period to almost preoperative levels in many scores. There was no statistically significant difference in any of the QoL scales between neoadjuvantly treated or primary operated patients. Esophageal resections are associated with significant deterioration of QoL, which slowly recovers during the follow-up period to an almost preoperative level. Neoadjuvant treatment seems to not further negatively affect the QoL deterioration.

Abashian-Booth-Crowe effect in basic double-pionic fusion: a new resonance?

We report on an exclusive and kinematically complete high-statistics measurement of the basic double-pionic fusion reaction pn→dπ(0)π(0) over the full energy region of the ABC effect, a pronounced low-mass enhancement in the ππ-invariant mass spectrum. The measurements, which cover also the transition region to the conventional t-channel ΔΔ process, were performed with the upgraded WASA detector setup at COSY. The data reveal the Abashian-Booth-Crowe effect to be uniquely correlated with a Lorentzian energy dependence in the integral cross section. The observables are consistent with a narrow resonance with m=2.37 GeV, Γ≈70 MeV and I(J(P))=0(3(+)) in both pn and ΔΔ systems. Necessary further tests of the resonance interpretation are discussed.

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer.

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

Use of a NOTES closure device for full-thickness suturing of a postoperative anastomotic esophageal leakage.

Leakages at surgical anastomoses in the gastrointestinal tract represent a challenging clinical problem. Standard therapy entails conservative or surgical revision of the anastomotic area with high morbidity and mortality up to 30 %. None of the previous endoscopic approaches, which include stenting, endoscopic clip closure, and fibrin glue injection, are sufficiently established for routine clinical use. We report a case of a 68-year-old woman with a postoperative leakage and abscess at the esophagojejunostomy. The defect was closed with two anchor-lock sutures. The patient was able to resume oral food intake 5 days later and made a full recovery with endoscopically documented mucosal healing at the site of the anastomosis. In summary, endoscopic suturing may be a promising approach for the treatment of postoperative leaks that warrants further, controlled investigation.

Drainage of esophageal leakage using endoscopic vacuum therapy: a prospective pilot study.

BACKGROUND AND STUDY AIMS: Major leakage from an esophageal anastomosis is a life-threatening surgical complication. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is a new method for treating such leakage. PATIENTS AND METHODS: Between June 2007 and June 2009, five patients (mean age 68 years) who developed anastomotic leakage after esophageal surgery were prospectively evaluated. After endoscopic diagnosis of a major leakage, polyurethane sponges were endoscopically positioned in the wound cavity of the anastomosis. Continuous suction was applied via drainage tubes fixed to the sponges. Initially sponges were endoscopically changed three times per week. RESULTS: In all five patients treatment was successful. Median time to reduce levels of inflammation markers by 50 % was 10 days for white blood cell (WBC) count and 7 days for C-reactive protein (CRP). The smallest initial wound cavity size was 42 cm (3) and the largest was 157 cm (3). The median duration of drainage was 28 days, with a median of 9 sponge changes and a median time to total cavity closure of 42 days. Two patients needed anastomotic dilation by Savary-Miller bougienage due to stenosis found on further follow-up. One of these patients died of acute severe hemorrhage from an aortoanastomotic fistula after the dilation procedure. CONCLUSIONS: Endoscopically assisted vacuum therapy is a well-tolerated and effective therapeutic option for treatment of major esophageal leaks after surgery. Additional surgery was avoided in all cases. However, the occurrence of a delayed aortoesophageal fistula calls for careful further investigation of this new technique.

Study of Toll-like receptor gene loci in sarcoidosis.

Sarcoidosis is a multi-factorial systemic disease of granulomatous inflammation. Current concepts of the aetiology include interactions of unknown environmental triggers with an inherited susceptibility. Toll-like receptors (TLRs) are main components of innate immunity and therefore TLR genes are candidate susceptibility genes in sarcoidosis. Ten members of the human TLR gene family have been identified and mapped to seven chromosomal segments. The aim of this study was to investigate all known TLR gene loci for genetic linkage with sarcoidosis and to follow positive signals with different methods. We analysed linkage of TLR gene loci to sarcoidosis by use of closely flanking microsatellite markers in 83 families with 180 affected siblings. We found significant linkage between sarcoidosis and markers of the TLR4 gene locus on chromosome 9q (non-parametric linkage score 2.63, P = 0.0043). No linkage was found for the remaining TLR gene loci. We subsequently genotyped 1203 sarcoidosis patients from 997 families, 1084 relatives and 537 control subjects for four single nucleotide polymorphisms of TLR4, including Asp299Gly and Thr399Ile. This genotype data set was studied by case-control comparisons and transmission disequilibrium tests, but showed no significant results. In summary, TLR4 - w ith significant genetic linkage results - appears to be the most promising member of the TLR gene family for further investigation in sarcoidosis. However, our results do not confirm the TLR4 polymorphisms Asp299Gly and Thr399Ile as susceptibility markers. Our results rather point to another as yet unidentified variant within or close to TLR4 that might confer susceptibility to sarcoidosis.

[Description of the medical care of younger patients (<65 years) with colorectal cancer in Schleswig-Holstein--are diagnostics and therapy compliant with the actual S3-guidelines?]. / Deskription der medizinischen Versorgung von jüngeren Patienten (<65 Jahre) mit kolorektalem Karzinom in Schleswig-Holstein und Abgleich der Bereiche Diagnostik und Therapie mit der aktuellen S3-Leitlinie.

The Guideline Colorectal Cancer has been existed since 1999. In 2004, a revision was published in form of the S3-guideline (number of the AWMF registry: 021/007). In this study we aimed to evaluate whether diagnostics and therapy of colorectal cancer of younger patients (<65 years) in Schleswig-Holstein (SH) were in accordance with the guideline or not. Therefore patients from a molecular genetic research project ("popgen") were asked to complete a questionnaire regarding their medical care. Data from the self-administered questionnaire and from the routine data set of the epidemiological cancer registry SH were available for 245 patients (mean age: 56.9 years; 48.6% were females). Nearly 54% of the patients had a tumour located in the colon and 42.9% in the rectum. Most patients (65.7%) experienced locally progressing tumours (T3/T4). Positive lymph nodes were diagnosed in 41% of the patients, distant metastases in less than 1%. About 88% had a coloscopy, 62.4% an X-ray of the lung, and 78.7% a sonography of the abdomen in the course of the preoperative diagnostics. Of all patients, 97.1% have been operated. An adjuvant radiation was received by 31.7% and adjuvant chemotherapy was given to 36.3% of the patients. In order to assess medical care, reference values were defined for specific phrasings from the S3-guideline (e.g., "always indicated": > 95%). According to the data from the patients' questionnaires and according to the S3-guideline, quality indicators of the preoperative diagnostics in SH were beneath the assumed reference values. But the data on therapy procedures indicated a good or at least satisfactory medical care.

Breaking Out of the Lab: Measuring Real-Time Responses to Televised Political Content in Real-World Settings.

Real-time response (RTR) measurement is an important technique for analyzing human processing of electronic media stimuli. Although it has been demonstrated that RTR data are reliable and internally valid, some argue that they lack external validity. The reason for this is that RTR measurement is restricted to a laboratory environment due to its technical requirements. This paper introduces a smartphone app that 1) captures real-time responses using the dial technique and 2) provides a solution for one of the most important problems in RTR measurement, the (automatic) synchronization of RTR data. In addition, it explores the reliability and validity of mobile RTR measurement by comparing the real-time reactions of two samples of young and well-educated voters to the 2013 German televised debate. Whereas the first sample participated in a classical laboratory study, the second sample was equipped with our mobile RTR system and watched the debate at home. Results indicate that the mobile RTR system yields similar results to the lab-based RTR measurement, providing evidence that laboratory studies using RTR are externally valid. In particular, the argument that the artificial reception situation creates artificial results has to be questioned. In addition, we conclude that RTR measurement outside the lab is possible. Hence, mobile RTR opens the door for large-scale studies to better understand the processing and impact of electronic media content.

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study.

BACKGROUND: Vedolizumab, a monoclonal antibody targeting the α4ß7-integrin, is effective in inducing and maintaining clinical remission in Crohn's disease and ulcerative colitis according to randomised clinical trials. AIM: To determine the long-term effectiveness of vedolizumab in a real-world clinical setting. METHODS: This observational registry assessed the clinical outcome in patients treated with vedolizumab for clinically active Crohn's disease (n = 67) or ulcerative colitis (n = 60). Primary endpoint was clinical remission (HBI ≤ 4/pMayo ≤ 1) at week 54. Secondary endpoints included clinical response rates (HBI/pMayo score drop ≥3) and steroid-free clinical remission at weeks 30 and 54. RESULTS: Vedolizumab was stopped in 69/127 (56%) patients after a median time of 18 weeks (range 2-49) predominantly owing to lack or loss of response. Using nonresponder imputation analysis, clinical remission and steroid-free remission rates were 21% and 15% in Crohn's disease and 25% and 22% in ulcerative colitis, respectively. Lack of clinical remission was associated with prior treatment with anti-TNF or with steroids for more than 3 months in the last 6 months in ulcerative colitis. At week 14, the absence of remission in Crohn's disease or nonresponse in ulcerative colitis indicated a low likelihood of clinical remission at week 54 [2/31 (7%) in Crohn's disease, 4/41 (10%) in ulcerative colitis]. Accordingly, declining C-reactive protein in inflammatory bowel disease and/or lower faecal calprotectin in ulcerative colitis at week 14 predicted remission at week 54. CONCLUSION: Among patients who started vedolizumab for active inflammatory bowel disease, clinical remission rates are 21-25% after 54 weeks.

Role of the angiotensin AT(1) receptor in rat aortic and cardiac PAI-1 gene expression.

Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT(1)) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT(1) antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg(2)-Phe(8) (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT(1) antagonist candesartan. Angiotensin Val(3)-Phe(8) (Ang IV) and angiotensin Asp(1)-Pro(7) (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (P<0.01), and this response was completely blocked by AT(1) receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17- and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (P<0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (P<0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT(1) receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression.

'Complicated' autosomal dominant familial spastic paraplegia is genetically distinct from 'pure' forms.

BACKGROUND: The familial spastic paraplegias (FSPs) are hereditary neurodegenerative disorders with an unknown pathogenesis. Pure and complicated forms are currently differentiated on clinical grounds. To date, no linkage studies in complicated FSP have been reported, and candidate genes have not been suggested. Three different gene loci responsible for pure autosomal dominant FSP and 1 for pure autosomal recessive FSP recently have been found. This raises the question of whether the complicated forms may also be linked to any of these loci. OBJECTIVE: To investigate whether complicated autosomal dominant FSP is allelic to any of the pure forms with defined loci. DESIGN: Clinical characterization of a large kindred that included 4 generations and multipoint linkage analyses. SETTING: Universitätsklinikum Charité, Humboldt-Universität Berlin, Neurologische Klinik und Poliklinik, Berlin, Germany. PATIENTS: Twenty-six family members, 13 of whom were affected. RESULTS: Thirteen members of a large family of 4 generations experienced a slowly progressive syndrome of spastic paraplegia. Hypomimia, bradykinesia, axial and limb rigidity, supranuclear gaze palsy, dysarthria, bladder and sphincter disturbances, cerebellar signs, and epilepsy were noted as additional features in some of the affected individuals. The mean age at onset was 20 years (range, 5-30 years), and the pattern of transmission was compatible with an autosomal dominant mode of inheritance. The CAG-repeat expansions in the spinocerebellar ataxia type 1 and Machado-Joseph disease genes were not found. Linkage analysis with the use of a panel of (AC)n dinucleotide repeat markers from the Généthon map demonstrated exclusion of all 4 FSP loci recently mapped by linkage to pure forms of FSP on chromosomes 14q, 2p, 15q, and 8. CONCLUSIONS: Complicated FSP in this family is not linked to any of the known pure FSP loci, including the recessive one. Therefore, the clinical differentiation of both forms still is of major relevance.ACKG

Oligonucleotide DNA fingerprinting: results of a multi-center study on reliability and validity.

We report the results of an empirical study of 256 paternity cases referred to 7 different German laboratories for DNA fingerprinting with oligonucleotide probe (CAC)5/(GTG)5. All parameters characteristic of such multilocus DNA fingerprints were found to differ significantly between the contributing centres. Despite these differences, clear-cut decisions between paternity and non-paternity could be made in all but one case. Furthermore, we found no systematic deviation of the gel-phenotype distribution among trios from random expectation as derived from commonly adopted analytical models. Thus, we conclude that oligonucleotide DNA fingerprinting is a robust and reliable means for the resolution of paternity cases.

Anticipation in inflammatory bowel disease: a phenomenon caused by an accumulation of confounders.

Inflammatory bowel disease (IBD) has a definite genetic component as documented by epidemiological and linkage evidence. It shows an earlier onset of disease in children of affected patients than in their parents. This has lead to speculations about genetic anticipation in this disorder. 2,007 IBD patients with sporadic disease and 472 multiplex familial cases (including 103 affected parents and 99 children of affected patients) were evaluated with a multi-item questionnaire as part of a study of inflammatory bowel disease genetics. The Mann-Whitney U-test and the general linear model were used for analysis. Clinical characteristics such as presence of fistulae, stenoses, extraintestinal manifestations, and other parameters, which are related to the severity of the disease, were found to be similar between familial and sporadic cases of IBD (corrected P > or = 0.31 for all tests). The mean-age-of onset in children of affected patients was 19.4 years earlier than in their parents. However, the age of the parental cohort was significantly higher (27 years) and the diagnostic interval also longer (1.7 years). If these confounders are corrected in a general linear model, no significant difference is evident for the age-of-onset between the groups (P > or = 0.52). There is no evidence for genetic anticipation in inflammatory bowel disease. The absence of genetic anticipation is consistent with the clinical similarity of familial and sporadic inflammatory bowel disease. This finding justifies the primary genetic analysis of familial disease under the assumption that their genetic background will be representative for all presentations of IBD.

Canine Malignant Mammary Tumours II. Adenocarcinomas, Solid Carcinomas and Spindle Cell Carcinomas.

A preliminary classification of 130 canine mammary adenocarcinomas, 76 solid carcinomas, and nine spindle cell carcinomas, together with several subtypes, was constructed from pooled, selected (metastasized) material. Each tumour in this series was classified by subjective assessment of its quantitatively predominant histological picture. Many adenocarcinomas and solid carcinomas of simple type were infiltrative, and lymphatic permeation was often found. The complex types of adenocarcinomas and of solid carcinomas were expansive, and lymphatic permeation was rare. Some metastasized adenocarcinomas were well differentiated. The clinical signs, distribution of metastases and some preliminary data on the times of survival of dogs with various types of carcinomas are discussed.

Paternity testing with oligonucleotide multilocus probe (CAC)5/(GTG)5: a multicenter study.

The statistical analysis is reported of 256 paternity cases referred to seven different German laboratories for multilocus DNA fingerprinting with oligonucleotide probe (CAC)5/(GTG)5 and restriction enzyme HinfI. All parameters characteristic of multilocus DNA fingerprints were found to differ significantly between the contributing centres: the number of analyzed gel positions, the number of bands scored per individual, the probability of occurrence of a band at a particular position, and the band-sharing probabilities between the mother and both child and alleged father. Despite these differences, paternity cases could be divided clearly into two distinct subgroups on the basis of (i) offspring bands that could not be assigned to either the mother or the alleged father and (ii) the extent of band-sharing between child and alleged father. This partitioning, which is likely to correspond to true and false paternity, confirms previous findings for other multilocus probes. A goodness-of-fit test on the normalized number of bands scored per individual revealed no systematic deviations from commonly adopted analytical models regarding electrophoretic bands as independent entities. Log10-likelihood ratios of paternity vs. non-paternity were calculated utilizing one of these models, and a clear-cut partitioning was again obtained which coincides with that mentioned before. Only one case could not be decided unambiguously, and was either due to two independent mutations or to a close relative of the alleged father being the true father.

A mechanistic, model-based approach to safety assessment in clinical development.

Assessing the safety of pharmacotherapies is a primary goal of clinical trials in drug development. The low frequency of relevant side effects, however, often poses a significant challenge for risk assessment. Methodologies allowing robust extrapolation of safety statistics based on preclinical data and information from clinical trials with limited numbers of patients are hence needed to further improve safety and efficacy in the drug development process. Here, we present a generic systems pharmacology approach integrating prior physiological and pharmacological knowledge, preclinical data, and clinical trial results, which allows predicting adverse event rates related to drug exposure. Possible fields of application involve high-risk populations, novel drug candidates, and different dosing scenarios. As an example, the approach is applied to simvastatin and pravastatin and the prediction of myopathy rates in a population with a genotype leading to a significantly increased myopathy risk.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e13; doi:10.1038/psp.2012.14; advance online publication 7 November 2012.

Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk.

The incidence rates and relative risks for colorectal cancer (CRC) are higher in men than in women. Sex steroids may play a role in this gender-associated difference in CRC risk. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in steroid hormone signaling (ESR1, ESR2, PGR, NR1I2, and SHBG), phase I- and II-metabolizing enzyme (COMT, HSD17B1, CYP1A1, CYP17A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, CYP2C19, and GSTP1), and hormone transporter (ABCB1) genes with the risk of CRC in German women and men, separately. From the population-based DACHS study (South Germany), 47 putatively functional SNPs were genotyped in 1798 CRC cases (746 women and 1052 men) and 1810 controls (732 women and 1078 men). Significant allele dose-response associations were observed with ESR2_rs1255998, ESR2_rs928554, HSD17B1_rs605059, and ABCB1_rs2229109 in women (P trend=0.004, 0.05, 0.03, and 0.05 respectively) and with ABCB1_rs1045642, ABCB1_rs9282564, and SHBG_rs6259 in men (P trend=0.01, 0.03, and 0.02 respectively). The ESR2_rs1255998_G allele showed the most significant association with risk for CRC in women, with a per-allele odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.88). This finding was replicated in an independent study from North Germany including 1076 female CRC cases and 1151 controls (OR=0.84, 95% CI 0.71-1.04), yielding a per-allele OR of 0.80 (95% CI 0.69-0.93, P trend=0.003) in the pooled sample. These findings implicate a role of ESR2 in the risk for developing CRC in women and suggest that HSD17B1, ABCB1, and SHBG genes may contribute to sex steroid-mediated effects on CRC development.