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  • Wiley Online Library  (9)
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  • 1
    In: Journal of Gastroenterology and Hepatology, April 2006, Vol.21(4), pp.727-733
    Description: The etiology of achalasia is still unknown. The aim of the present study was to illucidate its underlying pathologies and their chronology by investigation of esophageal specimens in patients undergoing surgery (esophageal resection or myotomy) for achalasia. In 17 patients with achalasia, histopathologic examinations of the esophageal wall focussing on the myenteric plexus were performed. Preoperative diagnosis was based on clinical evaluation, esophagogastroscopy, barium esophagogram in all, and esophageal manometry in eight patients. The median age at the time of surgery was 54 years (range: 14–78 years). In eight cases, the complete esophageal, body and in nine cases a smooth muscle biopsy including parts of the myenteric plexus from the distal part of the esophagus (high pressure zone) was available. The tissue specimens were fixed in formalin and embedded in paraffin. The staining procedures were hematoxylin and eosin (HE), Elastica van Gieson (EvG), and periodic acid–Schiff (PAS) reaction. Immunohistochemical examinations were performed with antibodies against B and T ymphocytes, neurofilament, protein gene‐related product (PGP 9.5), S‐100 protein, myosin, desmin, smooth muscle actin and substance P. In 13 of 17 patients, a significant reduction of the number of intramural ganglion cells was present. Common findings were a severe fibrosis of the smooth muscle layer (10/17) and obvious myopathic changes of the smooth muscle cells (5/17). Staining for B and T lymphocytes found signs of inflammation in mucosal and muscular areas. Three patients exhibited a marked invasion of eosinophilic granulocytes of the muscularis propria (eosinophilia). Esophageal carcinoma had developed in three patients (squamous cell carcinoma in two and carcinoma in another patient with Barrett's esophagus and high‐grade dysplasia). Severe inflammatory reactions (neural, eosinophilic and mucosal) dominated in patients with a longstanding history of achalasia (〉10 years) as well as a marked endomysial fibrosis. The histopathological investigations of the esophageal wall in 17 patients undergoing esophageal resection or myotomy for achalasia suggest that the reduction of intramural ganglion cells might be a secondary change, probably due to inflammation triggered by autoimmune mechanisms or a chronic degenerative process of the central and/or peripheral part of the vagal nerve. The primary lesion could also be a severe myopathy of the smooth muscle cells.
    Keywords: Achalasia ; Auerbach'S Plexus ; Autoimmunity ; Intramural Inflammation ; Smooth Muscle Myopathy
    ISSN: 0815-9319
    E-ISSN: 1440-1746
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  • 2
    In: International Journal of Cancer, 01 July 2015, Vol.137(1), pp.230-237
    Description: Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis of locally advanced adenocarcinomas of the gastroesophageal junction. This study aimed to asses if serum microRNA profiles are useable as response indicators in this therapeutic setting. Fifty patients with locally advanced adenocarcinomas of the gastroesophageal junction were included in the study. All patients received neoadjuvant therapy and subsequently underwent surgical resection. Histomorphologic regression was defined as major histopathological response when resected specimens contained less than 10% vital residual tumor cells. Circulating RNA was isolated from pretherapeutic/post‐neoadjuvant blood serum samples. RNA from nine patients was applied to PCR microarray analyses Based on these findings possible predictive miRNA markers were validated by quantitative RT‐PCR analyses. Depending on the histomorphologic regression, a differential serum microRNA profile was identified by microarray analyses. Based on the divergent miRNA pattern, miR‐21, miR‐192, miR‐222, miR‐302c, miR‐381 and miR‐549 were selected for further validation. During neoadjuvant therapy, there was a significant increase of miR 222 and miR‐549. Although on an expanded patient cohort, the six microRNAs could not be validated as markers for therapy response, there was a significant correlation between a high miR‐192 and miR‐222 expression with a high T‐category as well as miR‐302c and miR‐222 expression significantly correlated with overall survival. Comprehensive miRNA profiling showed a differential microRNA expression pattern depending on the histomorphologic regression in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Moreover, using single RT‐PCR analyses a prognostic impact of miR‐222 and miR‐302c was detected. What's New? Advanced esophageal cancer is increasingly treated through combinations of therapeutic approaches, including neoadjuvant therapies. But only certain subsets of patients benefit from multimodal strategies, which has created a need for tools capable of predicting patient response. Potential, non‐invasive predictive markers include miRNAs. From microarray analyses, the authors of the present study were able to identify differential serum miRNA profiles among patients with advanced esophageal adenocarcinoma who received neoadjuvant therapy. Of six miRNAs selected for validation, two were found to be of potential prognostic significance. The findings warrant further investigation of the markers in studies with larger patient populations.
    Keywords: DNA Microarrays – Analysis ; Antineoplastic Agents – Analysis ; Microrna – Analysis;
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: International Journal of Cancer, 01 September 2010, Vol.127(5), pp.1197-1208
    Description: The receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 1‐3 (VEGFR1‐3), are frequently expressed in gastric cancer and are putative therapeutic targets in this disease. We have investigated the anti‐proliferative and chemosensitizing properties of the multitargeted small‐molecule RTK inhibitors sunitinib and vandetanib in a panel of 4 human gastric and esophageal cancer cell lines. In the 1st instance, the expression of potential targets of these small‐molecule inhibitors was examined by reverse transcriptase‐polymerase chain reaction, western blotting, and flow cytometry. EGFR mRNA and protein was detected in all cases, with VEGFR2 expression noted in all but 1 line. Both EGF and VEGF were shown to stimulate tumor cell growth, and both sunitinib and vandetanib were found to be associated with significant dose‐dependent inhibition of proliferation and an enhancement of apoptosis, as determined by MTT and propidium iodide/Annexin V labeling assays, respectively. The addition of sunitinib to VEGF‐stimulated NCI‐N87 cells was associated with a reduction in MAPK phosphorylation (pMAPK) but not Akt phosphorylation (pAkt), whereas the addition of vandetanib was associated with reductions in both VEGF‐ and EGF‐mediated VEGFR2 phosphorylation, pMAPK and pAkt. Co‐administration of sunitinib significantly enhanced the sensitivity of MKN‐45 cells to cisplatin and irinotecan. In addition, vandetanib synergistically enhanced the sunitinib‐associated inhibition of gastric cancer cell growth. In conclusion, these preliminary data confirm the importance of EGFR and VEGFR signaling in gastric cancer and suggest that the simultaneous inhibition of RTK‐pathways through sunitinib and vandetanib may provide therapeutic benefit in this disease.
    Keywords: Sunitinib ; Rtk ; Gastric Cancer ; Vandetanib ; Chemotherapy
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: John Wiley & Sons, Inc.
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  • 4
    In: International Journal of Cancer, 15 October 2016, Vol.139(8), pp.1696-1702
    Description: We explored the relationship between socio‐economic characteristics and cancer stage at presentation. Patients admitted to a university hospital for diagnosis and treatment of cancer provided data on their education, vocational training, income, employment, job, health insurance and postcode. Tumor stage was classified according to the Union International Contre le Cancer (UICC). To analyze disparities in the likelihood of late‐stage (UICC III/IV . I/II) diagnoses, logistic regression models adjusting for age and gender were used. Out of 1,012 patients, 572 (59%) had late‐stage cancer. Separately tested, increased odds of advanced disease were associated with post‐compulsory education compared to college degrees, with apprenticeship and no vocational training, with unemployment, disability pension, jobs with a low hierarchy level, blue collar jobs and with low income. Health insurance and community size were not related with late‐stage cancer. Jointly modelled, there was evidence for an independent effect of unemployment (odds ratio (OR) 1.7, CI 1.0–2.8), disability pension (OR 1.8, CI 1.0–3.2) and very low income (OR 2.6, CI 1.1–6.1) on the likelihood of advanced disease stage. It is of great concern that these socio‐economic gradients occur even in systems with equal access to health care. What's new? Low‐income cancer patients tend to die earlier than more affluent patients. But why is this so? Large cancer registries haven't provided an answer. In this German study, the authors analyzed individual patient data rather than the aggregated datasets of registries. The study found that, even with equal access to health care, low‐income and unemployed patients were more likely to present with late‐stage cancer at diagnosis. It is important to determine the reasons for this effect, as prognosis is considerably improved with early treatment.
    Keywords: Health Disparities ; Unemployment ; Income ; Education ; Rural/Urban ; Screening
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 5
    In: Journal of Magnetic Resonance Imaging, June 2014, Vol.39(6), pp.1436-1442
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/jmri.24301/abstract Byline: Andre Lollert, Theodor Junginger, Carl Christoph Schimanski, Stefan Biesterfeld, Ines Gockel, Christoph Duber, Katja Oberholzer Purpose To evaluate correlations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinicopathologic data as well as immunostaining of the markers of angiogenesis epidermal growth factor receptor (EGFR) and CXC-motif chemokine receptor 4 (CXCR4) in patients with rectal cancer. Materials and Methods Presurgical DCE-MRI was performed in 41 patients according to a standardized protocol. Two quantitative parameters (k.sub.21, A) were derived from a pharmacokinetic two-compartment model, and one semiquantitative parameter (TTP) was assessed. Standardized surgery and histopathologic examinations were performed in all patients. Immunostaining for EGFR and CXCR4 was performed and evaluated with a standardized scoring system. Results DCE-MRI parameter A correlated significantly with the N category (P = 0.048) and k.sub.21 with the occurrence of synchronous and metachronous distant metastases (P = 0.029). A trend was shown toward a correlation between k.sub.21 and EGFR expression (P = 0.107). A significant correlation was found between DCE-MRI parameter TTP and the expression of EGFR (P = 0.044). DCE-MRI data did not correlate with CXCR4 expression. Conclusion DCE-MRI is a noninvasive method which can characterize microcirculation in rectal cancer and correlates with EGFR expression. Given the relationship between the dynamic parameters and the clinicopathologic data, DCE-MRI data may constitute a prognostic indicator for lymph node and distant metastases in patients with rectal cancer. J. Magn. Reson. Imaging 2014;39:1436-1442. [c] 2013 Wiley Periodicals, Inc.
    Keywords: Rectal Cancer ; Dce‐Mri ; Tumor Microcirculation ; Egfr ; Cxcr4 ; Prognosis ; Histopathology ; Immunohistochemistry
    ISSN: 1053-1807
    E-ISSN: 1522-2586
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  • 6
    In: Journal of Gastroenterology and Hepatology, May 2018, Vol.33(5), pp.1067-1074
    Description: Byline: Michaela Muller, Christina Keck, Alexander J Eckardt, Sarah Werling, Till Wehrmann, Jochem Konig, Ines Gockel Keywords: achalasia; long-term remission; pneumatic dilation; predictors of recurrence Abstract Background and Aim Pneumatic dilation (PD) is the most popular nonsurgical treatment for achalasia. This study investigated predicting factors, including manometric subtypes for symptom recurrence in the long term, in patients with achalasia treated with a single PD. Methods Between 1983 and 2013, a total of 107 patients were treated initially with a single PD and included in this longitudinal cohort study. Outcomes were correlated with demographics, symptoms (Eckardt score), and esophagographic and manometric features. Manometric tracings were retrospectively classified according to the three subtypes of the Chicago classification. Results Ninety-one (85%) patients were successfully treated after the first PD. The median follow-up was 13.8 years (interquartile range 7-20). During follow-up, 54% of the patients experienced a clinical relapse. The overall cumulative success rates at 2, 5, 10, 15, 20, and 25 years were 64%, 53%, 49%, 42%, 36%, and 36%, respectively. Age 15 mmHg, a cardia width 1 cm 4 to 12 weeks post-dilation significantly correlated with symptom recurrence, whereas achalasia subtypes did not significantly correlate with the treatment results. Conclusion Pneumatic dilation in achalasia is an effective therapy in the short term, but its effect wanes in the very long term. Young age at presentation, a high lower esophageal sphincter pressure, a narrow cardia, and an esophageal barium column of 〉 1 cm after PD are predictive factors for the need of repeated treatment. Article Note: Declaration of conflict of interest: None of the authors have any commercial associations that might be a conflict of interest in relation to this investigation. Author contribution: Muller, M., Keck, C., and Gockel, I. contributed equally to all aspects of the article; Muller, M., Gockel, I., and Eckardt, A. J. drafted the paper; Werling, S. and Keck, C. collected the data; Eckardt, A. J., Konig, J., and Wehrmann, T. analyzed and interpreted the data and revised the paper critically for important intellectual content; Muller, M., Keck, C., and Eckardt, A. J. wrote the paper; and Gockel, I. and Wehrmann, T. critically revised the paper with important conceptual and editorial input. All authors give their final approval for publication. The paper includes data from C. Keck's thesis.
    Keywords: Achalasia ; Long‐Term Remission ; Pneumatic Dilation ; Predictors Of Recurrence
    ISSN: 0815-9319
    E-ISSN: 1440-1746
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  • 7
    In: Journal of Gastroenterology and Hepatology, October 2014, Vol.29(10), pp.1800-1807
    Description: Nitric oxide (NO) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular interstitial cells of Cajal (ICC-IM) and vasoactive intestinal peptide (VIP) in lower esophageal sphincter (LES) function is still controversial. Therefore, we examined the function and morphology of the LES in vivo in NO-deficient (nNOS(-/-) ), ICC-IM-deficient (W/W(v) )-, and wild-type (WT) mice. Esophageal manometry was performed with a micro-sized transducer catheter to quantify LES pressure, swallow evoked LES relaxation, and esophageal body motility. The LES morphology was examined by semiquantitative analysis of the immunoreactivity (reduction grade I-IV) of neuronal NOS (nNOS), ICC-IM, and VIP and their correlation with esophageal function. nNOS(-/-) in comparison to WT mice showed a significantly higher LES mean resting pressure with an impaired swallow induced relaxation, whereas W/W(v) mice had a hypotensive LES with decreased relaxation. W/W(v) and nNOS(-/-) mice demonstrated differing degrees of tubular esophageal dysfunction. The reduced immunoreactivity of nNOS correlated with an increased LES pressure and decreased LES relaxation, respectively. Cajal-cell reduction correlated with impaired LES relaxation, whereas VIP reduction revealed no correlation with esophageal function. The reduction of ICC-IM and nNOS can cause dysfunction of the LES and esophageal peristalsis, whereas VIP reduction seems to have no effect. ICC-IM and nNOS deficiency might be independent relevant causes of esophageal dysfunction similar to that seen in human achalasia.
    Keywords: Achalasia ; Interstitial Cells Of Ajal ; Lower Esophageal Sphincter ; Nitric Oxide ; Vasoactive Intestinal Peptide
    ISSN: 0815-9319
    E-ISSN: 1440-1746
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  • 8
    In: Journal of Gastroenterology and Hepatology, June 2004, Vol.19(6), pp.720-722
    Keywords: Adolescent–Diagnosis ; Diagnosis, Differential–Diagnosis ; Diagnostic Techniques, Surgical–Diagnosis ; Female–Diagnosis ; Humans–Diagnosis ; Male–Diagnosis ; Middle Aged–Diagnosis ; Superior Mesenteric Artery Syndrome–Diagnosis ; Tomography, X-Ray Computed–Diagnosis;
    ISSN: 0815-9319
    E-ISSN: 1440-1746
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  • 9
    In: Transplant International, September 2009, Vol.22(9), pp.892-905
    Description: To examine the impact of steroid withdrawal from the immunosuppression protocols in liver transplantation. The electronic databases Medline, Embase, Pubmed and the Cochrane Library were searched. Meta‐analysis pooled the effects of outcomes of a total of 2590 patients enrolled into 21 randomized controlled trials (RCTs), using classic and modern meta‐analytic methods. Meta‐analysis of RCTs addressing patients transplanted for any indication showed no differences between corticosteroid‐free immunosuppression and steroid‐based protocols in most of the analyzed outcomes. More importantly, steroid‐free cohorts appeared to benefit in terms of diabetes mellitus development [R.R = 1.86 (1.43, 2.41)], Cytomegalovirus (CMV) infection [R.R = 1.47 (0.99, 2.17)], cholesterol levels [WMD = 19.71 (13.7, 25.7)], the number of patients that received the allocated treatment [O.R = 1.55 (1.17, 2.05)], severe acute rejection [R.R = 1.71 (1.14, 2.54)] and overall acute rejection [R.R = 1.31 (1.09, 1.58)] (when steroids were replaced in the steroid‐free arm). Taking RCTs into account independently when steroids were not replaced, overall acute rejection was favoring the steroid‐based arm [R.R = 0.75 (0.58, 0.98)]. Studies addressing exclusively transplanted HCV patients demonstrated a significant advantage of steroid‐free protocols considering HCV recurrence [R.R = 1.15 (1.01, 1.13)], acute graft hepatitis [O.R = 3.15 (1.18, 8.40)], and treatment failure [O.R = 1.87 (1.33, 2.63)]. No unfavorable effects were observed after steroid withdrawal during short‐term follow‐up. On the contrary, significant advantages were documented.
    Keywords: Evidence‐Based ; Liver Transplantation ; Meta‐Analysis ; Orthotopic Liver Transplantation ; Publication Bias ; Steroid Withdrawal
    ISSN: 0934-0874
    E-ISSN: 1432-2277
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