Publications by authors named "Jonas Rosendahl"

95 Publications

Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients.

Pancreatology 2021 Sep 10. Epub 2021 Sep 10.

Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. Electronic address:

Purpose: Loss of function variants of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been recently associated with chronic pancreatitis (CP) in Japanese, German and French patients. Here, we investigated the association of TRPV6 variants with CP in independent European cohorts of early-onset CP patients from Poland and Germany.

Patients And Methods: We enrolled 152 pediatric CP patients (median age 8.6 yrs) with no history of alcohol/smoking abuse and 472 controls from Poland as well as 157 nonalcoholic young CP patients (median age 20 yrs) and 750 controls from Germany. Coding regions of TRPV6 were screened by Sanger and next generation sequencing. Selected, potentially pathogenic TRPV6 variants were expressed in HEK293T cells and TRPV6 activity was analyzed using ratiometric Ca measurements.

Results: Overall, we identified 10 novel (3 nonsense and 7 missenses) TRPV6 variants in CP patients. TRPV6 p.V239SfsX53 nonsense variant and the variants showing significant decrease in intracellular Ca concentration in HEK293T cells (p.R174X, p.L576R, p.R342Q), were significantly overrepresented in Polish patients as compared to controls (6/152, 3.9% vs. 0/358, 0%; P = 0,0007). Nonsense TRPV6 variants predicted as loss of function (p.V239SfsX53 and p.R624X) were also significantly overrepresented in German patients (3/157; 2.0% vs 0/750; 0%, P = 0.005).

Conclusions: We showed that TRPV6 loss of function variants are associated with elevated CP risk in early-onset Polish and German patients confirming that TRPV6 is a novel CP susceptibility gene.
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http://dx.doi.org/10.1016/j.pan.2021.09.005DOI Listing
September 2021

[Pathogenesis of chronic pancreatitis].

Internist (Berl) 2021 Oct 15;62(10):1007-1014. Epub 2021 Sep 15.

Pädiatrische Ernährungsmedizin, Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Gregor-Mendel-Straße 2, 85354, Freising, Deutschland.

Long-term alcohol consumption and gene mutations are the most important causes of chronic pancreatitis. In addition to mutations in acinar genes, such as digestive enzymes and their inhibitors, defects in genes that primarily or exclusively affect the duct cells have also been described in recent years. Genetic changes are found not only in patients with a positive family history (hereditary pancreatitis) but also in so-called idiopathic and, to a lesser extent, in alcoholic chronic pancreatitis. The coming years will likely show that there are very complex interactions between environmental influences and numerous genetic factors.
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http://dx.doi.org/10.1007/s00108-021-01150-6DOI Listing
October 2021

Efficacy and Safety of Neoadjuvant Gemcitabine Plus Nab-Paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Cancer-A Systematic Review and Meta-Analysis.

Cancers (Basel) 2021 Aug 27;13(17). Epub 2021 Aug 27.

Department of Internal Medicine I, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, D-06120 Halle (Saale), Germany.

Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30-68%) and 36% (95% CI 17-58%) for BRPC and 16% (95% CI 7-26%) and 11% (95% CI 5-19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutropenia (range 5-77%) and neuropathy (range 0-22%) were the most commonly reported grade 3 to 4 adverse events. Neoadjuvant chemotherapy with GNP can be performed safely and with valuable effects in patients with BRPC and LAPC. The utility of GNP in comparison to FOLFIRINOX in the neoadjuvant setting requires further investigation in prospective randomized trials.
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http://dx.doi.org/10.3390/cancers13174326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430874PMC
August 2021

The three common polymorphisms p.A986S, p.R990G and p.Q1011E in the calcium sensing receptor (CASR) are not associated with chronic pancreatitis.

Pancreatology 2021 Aug 21. Epub 2021 Aug 21.

Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany. Electronic address:

Background: The calcium sensing receptor (CASR) is a G protein-coupled receptor that is responsible for assessing extracellular Ca levels and thus plays a crucial role in calcium homeostasis. Hypercalcemia is a metabolic risk factor for pancreatitis and rare CASR variants have been described in patients with chronic pancreatitis. At the carboxy-terminal tail of CASR, there is a cluster of three common polymorphisms, p.A986S (rs1801725), p.R990G (rs1042636) and p.Q1011E (rs1801726), which have been associated with chronic pancreatitis in various studies, but with conflicting results.

Methods: We examined 542 German and 339 French patients with chronic pancreatitis as well as 1025 German controls for the 3 common CASR polymorphism by melting curve analysis. For comparison, we used genotype data from 583 French controls from a previous study. In addition, we functionally analyzed the three variants by NFAT and SRE luciferase reporter systems as well as Western blotting and verified cell surface expression by ELISA.

Results: In both cohorts, neither the genotype nor the allele frequencies differed significantly between patients and controls. In both luciferase assays, p.R990G showed a significant leftward shift, indicating an increased responsiveness of the receptor. p.A986S showed a leftward shift in the SRE but not in the NFAT reporter assay, while the responsiveness of p.Q1011E did not differ from the wild-type. These functional studies therefore do not support the contributions of variant CASR to increasing the risk of pancreatitis.

Conclusions: The three frequent CASR polymorphisms are unlikely to increase the risk for chronic pancreatitis.
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http://dx.doi.org/10.1016/j.pan.2021.08.008DOI Listing
August 2021

The impact of atezolizumab and bevacizumab in hepatocellular carcinoma with activated ß-catenin signaling.

Cancer Rep (Hoboken) 2021 Jul 26:e1493. Epub 2021 Jul 26.

Department of Internal Medicine I, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.

Background: To date, no biomarkers exist to predict response or resistance to immunotherapy in hepatocellular carcinoma (HCC). Recent approaches to classify HCC into different immunological states revealed a negative correlation between Wnt/ß-catenin activation and immunogenicity and T-cell infiltration. If these "cold" tumors with primary resistance to checkpoint inhibition (CPI) may benefit from dual treatment of CPI and anti-angiogenic therapy has not been proved.

Case: Here, we describe the case of a male patient with metastatic HCC. After failure of standard of care treatment with lenvatinib, sorafenib and ramucirumab fourth-line systemic therapy with atezolizumab and bevacizumab were applied leading to a phenomenal response. Immunohistochemical evaluations were compatible with Wnt/ß-catenin pathway activation and accompanying low T-cell infiltration as well as low PD-L1 score.

Conclusion: Patients with Wnt/ß-catenin activation may benefit from combination therapy with atezolizumab and bevacizumab regardless of potential predictive markers for immune checkpoint inhibition.
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http://dx.doi.org/10.1002/cnr2.1493DOI Listing
July 2021

Targeting HDACs in Pancreatic Neuroendocrine Tumor Models.

Cells 2021 06 6;10(6). Epub 2021 Jun 6.

Department of Internal Medicine I, Martin Luther University, D-06120 Halle (Saale), Germany.

Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent a rare and heterogeneous tumor entity. In addition to surgical resection, several therapeutic approaches, including biotherapy, targeted therapy or chemotherapy are applicable. However, primary or secondary resistance to current therapies is still challenging. Recent genome-wide sequencing efforts in PanNET identified a large number of mutations in pathways involved in epigenetic modulation, including acetylation. Therefore, targeting epigenetic modulators in neuroendocrine cells could represent a new therapeutic avenue. Detailed information on functional effects and affected signaling pathways upon epigenetic targeting in PanNETs, however, is missing. The primary human PanNET cells NT-3 and NT-18 as well as the murine insulinoma cell lines beta-TC-6 (mouse) and RIN-T3 (rat) were treated with the non-selective histone-deacetylase (HDAC) inhibitor panobinostat (PB) and analyzed for functional effects and affected signaling pathways by performing Western blot, FACS and qPCR analyses. Additionally, NanoString analysis of more than 500 potentially affected targets was performed. In vivo immunohistochemistry (IHC) analyses on tumor samples from xenografts and the transgenic neuroendocrine Rip1Tag2-mouse model were investigated. PB dose dependently induced cell cycle arrest and apoptosis in neuroendocrine cells in human and murine species. HDAC inhibition stimulated redifferentiation of human primary PanNET cells by increasing mRNA-expression of somatostatin receptors (SSTRs) and insulin production. In addition to hyperacetylation of known targets, PB mediated pleitropic effects via targeting genes involved in the cell cycle and modulation of the JAK2/STAT3 axis. The HDAC subtypes are expressed ubiquitously in the existing cell models and in human samples of metastatic PanNET. Our results uncover epigenetic HDAC modulation using PB as a promising new therapeutic avenue in PanNET, linking cell-cycle modulation and pathways such as JAK2/STAT3 to epigenetic targeting. Based on our data demonstrating a significant impact of HDAC inhibition in clinical relevant in vitro models, further validation in vivo is warranted.
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http://dx.doi.org/10.3390/cells10061408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228033PMC
June 2021

Sequencing of the complex CTRB1-CTRB2 locus in chronic pancreatitis.

Pancreatology 2020 Dec 29;20(8):1598-1603. Epub 2020 Sep 29.

Department of Internal Medicine I, Martin Luther University, Halle, Germany. Electronic address:

Background: /Objectives: A recent Genome-wide Association Study (GWAS) in alcoholic chronic pancreatitis (ACP) identified a novel association with the CTRB1-CTRB2 (chymotrypsinogen B1, B2) locus, linked to a 16.6 kb inversion that was confirmed in non-alcoholic chronic pancreatitis (NACP). Moreover, recent findings on the function of CTRB1 and CTRB2 suggest a protective role in pancreatitis development. The aim of the present study was to investigate the CTRB1-CTRB2 locus for rare genetic variants associated with chronic pancreatitis (CP).

Methods: We analyzed 134 patients with ACP and 203 patients with NACP and compared them to up to 258 healthy controls. Genotyping was performed with polymerase chain reaction, followed by Sanger sequencing of all exons and the exon-intron-boundaries of CTRB1 and CTRB2. Finally, in silico analyses of the identified variants were conducted.

Results: None of the seven rare missense variants or the single 5'-UTR variant in CTRB1 and CTRB2 was associated with ACP or NACP. In silico analysis predicted that variant p. Trp5Leu in CTRB1 and variant c.-4C > T in CTRB2 might alter protein expression and variants p. Asp222His in CTRB1 and p. Ala247Thr in CTRB2 might affect protein function. However, all of these variants were also described in public databases.

Conclusions: The present study did not reveal an association of rare variants in CTRB1 and CTRB2 with ACP or NACP. Although rare missense variants were almost exclusively found in patients, only four variants were predicted to affect protein expression or function. Thus, a major influence of rare variants in the CTRB1-CTRB2 locus on CP development is unlikely.
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http://dx.doi.org/10.1016/j.pan.2020.09.017DOI Listing
December 2020

The quality of pain management in pancreatic cancer: A prospective multi-center study.

Pancreatology 2020 Oct 28;20(7):1511-1518. Epub 2020 Aug 28.

Department of Internal Medicine I, University Hospital Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with severe pain. Given the almost inevitably fatal nature of the disease, pain control is crucial. However, data on quality of pain management in PDAC is scarce.

Methods: This is a multi-center, prospective study to evaluate the quality of pain management in PDAC. Insufficient pain treatment (undertreatment) was prevalent if there was an incongruence between the patients level of pain and the potency of analgesic drug therapy. Determinants of pain and undertreatment were identified using multivariable logistic regression.

Results: 139 patients with histologically confirmed PDAC were analyzed. The prevalence of pain was 63%, with approximately one third of the patients grading their pain as moderate to severe. Palliative stage (OR: 3.37, 95%CI: 1.23-9.21, p = 0.018) and localization of the primary tumor in the body or tail (OR: 2.57, 95%CI: 1.05-6.31, p = 0.039) were independent determinants of pain. Of those reporting pain, 60% were undertreated and in 89% pain interfered with activities and emotions. Age ≥ 70 years (OR: 3.20, 95%CI: 1.09-9.41, p = 0.035) was an independent predictor of undertreatment. Patients with longer-known PDAC ( ≥ 30 days) showed improved pain management compared to new cases (OR: 0.19, 95%CI: 0.05-0.81, p = 0.025). Treatment by gastroenterologists (OR: 0.22, 95%CI: 0.05-0.89, p = 0.034) was associated with less undertreatment.

Conclusions: The results show a high proportion of PDAC patients with pain, pain interference and undertreatment, whose characteristics could help to identify patients at risk in the future. Several changes in the management of cancer-related pain are necessary to overcome barriers to optimal treatment.
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http://dx.doi.org/10.1016/j.pan.2020.08.017DOI Listing
October 2020

Neoadjuvant therapy in elderly patients receiving FOLFIRINOX or gemcitabine/nab-paclitaxel for borderline resectable or locally advanced pancreatic cancer is feasible and lead to a similar oncological outcome compared to non-aged patients - Results of the RESPECT-Study.

Surg Oncol 2020 Dec 7;35:285-297. Epub 2020 Sep 7.

Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

Introduction: The number of people aged 60 and above will rise from 46 million in 2015 to 157 in 2050 million, exceeding 30% of the population in many western countries. Consequently, the demand for oncological therapy for elderly patients will increase within the next decades. Currently, sufficient data on neoadjuvant therapy (NTx) of pancreatic cancer in elderly patients are lacking.

Methods: Data of a multinational, retrospective database were screened for patients having received preoperative FOLFIRINOX (FFx) or Gemcitabine/nab-paclitaxel (GNP) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC) before June 2017. Data were included in an intention-to-treat-analysis and outcomes were compared between non-aged and elderly patients using a cut-off age of 63 (comparison 1) and 70 years (comparison 2).

Results: Of 165 patients receiving NTx, 76 and 33 were older than 63 and 70 years. Baseline characteristics revealed that elderly patients preferably undergo GNP (comparison 1: p = 0.063; comparison2: p = 0.005), with less cycles of NTx (comparison 1: p = 0.057). Whereas reductions of NTx dosage was more common in elderly patients in comparison 1 (p = 0.003), resection rates (p = 0.575; p = 1.000) and median survival (p = 0.406; p = 0.499) were not different. Whereas resected patients showed no differences in survival (p = 0.328; p = 0.132), patients aged >70 years showed a decreased progression-free survival (p = 0.019).

Conclusion: Elderly patients treated with NTx show encouragingly high resection rates. If comorbidities allow for FFx or GNP, elderly patients with LAPC/BRPC can offered NTx with the prospect of survival comparable to younger patients.
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http://dx.doi.org/10.1016/j.suronc.2020.08.031DOI Listing
December 2020

[Challenges of the COVID-19 pandemic in gastrointestinal endoscopy: expectations and implementation of recommendations].

Z Gastroenterol 2020 Nov 16;58(11):1074-1080. Epub 2020 Sep 16.

Universitätsklinikum Halle, Klinik für Innere Medizin I, Halle, Germany.

Introduction:  The COVID-19 pandemic represents a major challenge for health care systems worldwide. Recent data suggests an increased risk for personnel of gastrointestinal (GI) endoscopy units for SARS-CoV-2 infections. Several societies have provided recommendations for the current situation, but their feasibility is unclear and real-world data on preparedness of endoscopy units are lacking.

Aims & Methods:  A web-based survey among German GI-endoscopy heads was conducted from April 1 to April 7, 2020. It comprised 33 questions based on the ESGE (European Society of Gastrointestinal Endoscopy) recommendations and was distributed electronically by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS).

Results:  Of 551 completed surveys, 202 (37 %) endoscopy units cancelled less than 40 % of their procedures. Small-volume units (< 4000 procedures/year) cancelled significantly less procedures than high-volume units (> 4000). Complete spatial separation of high-risk patients was possible in only 17 %. Most units systematically identified patients at risk (91 %) and used risk adapted personal protective equipment (PPE, 85 %). For the future, shortages in PPE (83 %), staff (69 %) and relevant financial losses (80 %) were expected.

Conclusions:  Recommendations on structural measures were only partially fulfilled and cancellations of procedures were heterogeneous. Clear definitions of indications to perform endoscopies during such a pandemic are needed. Further, structural recommendations should be adapted and strategies to compensate financial losses need to be developed.
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http://dx.doi.org/10.1055/a-1246-3455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724582PMC
November 2020

Capability of processed EEG parameters to monitor conscious sedation in endoscopy is similar to general anaesthesia.

United European Gastroenterol J 2021 Apr 11;9(3):354-361. Epub 2021 Feb 11.

Department of Internal Medicine I, University Hospital Halle, Halle (Saale), Germany.

Background: Reliable and safe sedation is a prerequisite for endoscopic interventions. The current standard is rather safe, yet, an objective device to measure sedation depth is missing. To date, anaesthesia monitors based on processed electroencephalogram (EEG) have not been utilised in conscious sedation.

Objective: To investigate EEG parameters to differentiate consciousness in endoscopic propofol sedation.

Methods: In total, 171 patients aged 21-83 years (ASA I-III) undergoing gastrointestinal and bronchial endoscopy were enrolled. Standard monitoring and a frontotemporal two-channel EEG were recorded. The state of consciousness was identified by repeated requests to squeeze the investigator's hand.

Results: In total, 1132 state-of-consciousness (SOC) transitions were recorded in procedures ranging from 5 to 69 min. Thirty-four EEG parameters from the frequency domain, time-frequency domain and complexity measures were calculated. Area under the curve ranged from 0.51 to 0.82 with complexity and optimised frequency domain parameters yielding the best results.

Conclusion: Prediction of the SOC with processed EEG parameters is feasible, and the results for sedation in endoscopic procedures are similar to those reported from general anaesthesia. These results are insufficient for a clinical application, but prediction capability may be increased with optimisation and modelling.
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http://dx.doi.org/10.1177/2050640620959153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259428PMC
April 2021

German bronchoscopy unit readiness for the COVID-19 pandemic: a nationwide survey.

ERJ Open Res 2020 Jul 31;6(3). Epub 2020 Aug 31.

Dept of Internal Medicine I, University Hospital Halle, Halle, Germany.

Background: The worldwide impact of the coronavirus disease 2019 (COVID-19) pandemic is unprecedented. Among the aerosol generating procedures, bronchoscopy in particular is an indispensable diagnostic and therapeutic tool that comes with a high risk of infection. Therefore, national societies have issued guidance statements. However, the individual ability of bronchoscopy units to follow these recommendations is largely unknown.

Methods: We conducted a nationwide survey from 1 April 2020 to 7 April 2020 to which 218 German endoscopy units, 105 solely bronchoscopy and 113 interdisciplinary, responded. The survey was distributed electronically the German Respiratory Society.

Results: While 17% of units did not cancel any interventions, 16% cancelled >80% of their interventions. 73% were unable to completely separate high-risk patients. Most procedural measures, such as risk stratification in patients (95%), training to handle COVID-19 patients and personal protective equipment (PPE) (91%), risk adapted use of PPE (85%) and self-monitoring for staff (84%) were adopted well. Unit managers expected shortages in PPE (74%), staff shortages (68%) and severe financial losses (63%).

Conclusion: In the short-term, PPE shortages are perceived to be the most imminent threat to bronchoscopic activity as a whole. In this era of uncertainty, sound evidence to guide bronchoscopy units and an international concerted effort are urgently needed to formulate recommendations on facts and adapted to local conditions as described in this study.
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http://dx.doi.org/10.1183/23120541.00396-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456647PMC
July 2020

MR imaging of venous malformations: sciatic nerve infiltration patterns and involved muscle groups.

Sci Rep 2020 09 3;10(1):14618. Epub 2020 Sep 3.

Department of Radiology and Policlinic of Radiology, University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany.

The aim of this retrospective cross-sectional study was to provide an MRI-based examination framework of venous malformations (VMs) infiltrating the sciatic nerve and determine the frequency of nerve infiltration patterns and muscle involvement in correlation to the patients' quality of life. Pelvic and lower limb MR images of 378 patients with vascular malformations were examined retrospectively. Pain levels and restriction of motion were evaluated with a questionnaire. Cross-sectional areas of affected nerves were compared at standardized anatomical landmarks. Intraneural infiltration patterns and involvement of muscles surrounding the sciatic nerve were documented. Sciatic nerve infiltration occurred in 23/299 patients (7.7%) with VM. In all cases (23/23; 100%), gluteal or hamstring muscles surrounding the nerve were affected by the VM. Infiltrated nerves were enlarged and showed signal alterations (T2-hyperintensity) compared to the unaffected side. Enlarged nerve cross-sectional areas were associated with elevated pain levels. Three nerve infiltration patterns were observed: subepineurial (12/23; 52.2%), subparaneurial (6/23; 26.1%) and combined (5/23; 21.7%) infiltration. This study provides a clinically relevant assessment for sciatic nerve infiltration patterns and muscle involvement of VMs, while suggesting that VMs in gluteal and hamstring muscles require closer investigation of the sciatic nerve by the radiologist.
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http://dx.doi.org/10.1038/s41598-020-71595-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471964PMC
September 2020

Analysis of GPRC6A variants in different pancreatitis etiologies.

Pancreatology 2020 Oct 8;20(7):1262-1267. Epub 2020 Aug 8.

Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.

Background: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies.

Methods: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis.

Results: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis.

Conclusions: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
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http://dx.doi.org/10.1016/j.pan.2020.08.001DOI Listing
October 2020

PrescrAIP: A Pan-European Study on Current Treatment Regimens of Auto-Immune Pancreatitis.

Front Med (Lausanne) 2020 5;7:408. Epub 2020 Aug 5.

Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany.

Treatment of autoimmune pancreatitis (AIP) is based solely on consensus and has yet to become standardized. Consequently, therapeutic regimens vary greatly between countries and centers, and largely depend on the experience of the physician. At this moment, the optimal regimen for inducing disease remission and preventing relapse is unknown. The primary objective of this study is to describe current treatment regimens used in Europe, and to compare their effectiveness in inducing remission and preventing and treating relapse. The secondary objectives are: to identify risk factors for relapse; to assess the diagnostic accuracy of the Unified-AIP criteria; to assess the performance of the M-ANNHEIM score for predicting relapse; and to assess long-term outcomes including pancreatic exocrine insufficiency and pancreatic cancer. This is an international, retrospective, observational cohort study, performed in over 40 centers from 16 European countries. Eligible are all patients diagnosed with AIP from 2005 onwards, regardless of the used diagnostic criteria. Data on study subjects will be retrieved from the hospital's electronic medical records and registered with a standardized, web-based, electronic case report form (eCRF). To compare the effectiveness of treatment regimens in inducing remission, preventing relapse, and treating relapse, subjects will be stratified in groups based on: type of therapy; initial therapy dose; cumulative therapy dose; therapy tapering speed and duration; and having received maintenance therapy or not. Ethical and/or institutional review board approvals are obtained by all participating centers according to local regulations. The study complies with the General Data Protection Regulation (GDPR). All manuscripts resulting from the study will be submitted to peer-reviewed journals. This is the first pan-European retrospective registry for AIP. It will produce the first large-scale data on treatment of European patients with AIP, providing answers on the use and effectiveness of treatment regimens. In the future, this collaboration may provide a network for continuation into a prospective European registry.
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http://dx.doi.org/10.3389/fmed.2020.00408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419461PMC
August 2020

Respect - A multicenter retrospective study on preoperative chemotherapy in locally advanced and borderline resectable pancreatic cancer.

Pancreatology 2020 Sep 9;20(6):1131-1138. Epub 2020 Jul 9.

Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

Background: Neoadjuvant chemotherapy has become a powerful tool to convert borderline resectable (BRPC) and locally advanced pancreatic cancers (LAPC) into a resectable scenario. However, data analyzing the optimal type of therapy are scarce. In the present multicenter retrospective study, we evaluated the influence of FOLFIRINOX (FFX) and gemcitabine (GEM)-based neoadjuvant therapy on patient prognosis.

Methods: Data on 239 patients from 7 centers across Europe was gathered using an online database. Patients having received their first cycle of chemotherapy for BRPC/LAPC before 06/2017, with a minimum follow-up of 12 months, were included in the intention-to-treat analysis.

Results: Patients treated with neoadjuvant FFX (n = 135) or gemcitabine + nab-paclitaxel (GNP) (n = 38) had significantly improved radiological response according to RECIST criteria as compared to single-agent GEM (n = 16), with a partial/complete response of 59.3%, 55.3% and 6.25% respectively (p = 0.001). Treatment with FFX (n = 135) and GNP (n = 38) resulted in higher resection rates compared to GEM (73.3%, 81.6% and 43.8%; p = 0.01 and p = 0.005). Regardless of regimen, patients who were resected had significantly prolonged overall survival compared to non-resected patients (p < 0.01). Complete pathological responses (ypT0 ypN0) were predominantly observed with FFX (p = 0.01). Adjuvant GNP in addition to successful neoadjuvant therapy and surgery resulted in a trend towards improved median survival as compared to postoperative observation (47.0 vs. 30.1 months, p = 0.06).

Conclusions: Representing one of the largest studies published so far, our results reveal that patients with BRPC/LAPC should be offered either FFX or GNP to improve chances of resection and with this also survival.
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http://dx.doi.org/10.1016/j.pan.2020.06.012DOI Listing
September 2020

CUX1-Transcriptional Master Regulator of Tumor Progression in Pancreatic Neuroendocrine Tumors.

Cancers (Basel) 2020 Jul 19;12(7). Epub 2020 Jul 19.

Department of Internal Medicine I, Martin Luther University, 06120 Halle (Saale), Germany.

Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts ( = 43 and = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.
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http://dx.doi.org/10.3390/cancers12071957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409270PMC
July 2020

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

Fluoroscopy-guided endoscopic sclerotherapy: a novel hybrid approach for symptomatic rectosigmoidal venous malformation (with video).

Gastrointest Endosc 2021 02 15;93(2):496-502. Epub 2020 Jun 15.

Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany.

Background And Aims: Recommendations for the treatment of lower GI bleeding do not include bleeding from venous malformations (VMs). The aim of this study was to delineate the usefulness of a novel hybrid intervention (fluoroscopy-guided endoscopic sclerotherapy) for the treatment of symptomatic VMs in the rectosigmoidal colon with bleeding.

Methods: The magnetic resonance images of 421 patients with VM, referred to multicenter vascular anomaly centers from 2009 to 2017, were analyzed retrospectively. Treatment was performed for all patients who experienced bleeding from rectosigmoidal VMs using fluoroscopy-guided endoscopic sclerotherapy with polidocanol foam as a novel approach.

Results: A total of 27 patients displayed VM in the rectosigmoidal area. Eleven of these presented with acute or previous bleeding and received treatment. Active bleeding was observed in 8 patients (72.7%), whereas 3 patients (27.3%) had signs of previous bleeding. Six of the 11 patients had anemia (54.5%). There were no adverse events within 24 hours of the intervention. In a 2-year follow-up period, only 1 patient (9.1%) presented with recurrent bleeding after 13 months and was successfully treated again with fluoroscopy-guided endoscopic sclerotherapy.

Conclusions: Fluoroscopy-guided endoscopic sclerotherapy was shown to be a safe and effective treatment of symptomatic VMs of the rectosigmoidal area. Thus, fluoroscopy-guided endoscopic sclerotherapy should be considered for patients with bleeding from VMs of the rectosigmoid after a comprehensive workup and interdisciplinary case discussion.
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http://dx.doi.org/10.1016/j.gie.2020.06.027DOI Listing
February 2021

European Guideline on IgG4-related digestive disease - UEG and SGF evidence-based recommendations.

United European Gastroenterol J 2020 07 18;8(6):637-666. Epub 2020 Jun 18.

Département de Médicine Interne Timone, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, Marseille, France.

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.
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http://dx.doi.org/10.1177/2050640620934911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437085PMC
July 2020

International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

Pancreatology 2020 Jun 8;20(4):579-585. Epub 2020 Apr 8.

Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.

Background: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP.

Methods: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient.

Results: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers.

Conclusions: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.
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http://dx.doi.org/10.1016/j.pan.2020.03.014DOI Listing
June 2020

German Endoscopy Unit Preparations for the Coronavirus Disease 2019 Pandemic: A Nationwide Survey.

Gastroenterology 2020 Aug 1;159(2):778-780.e3. Epub 2020 May 1.

Department of Internal Medicine I, University Hospital Halle, Saale, Germany. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.04.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194040PMC
August 2020

Safety and effectiveness of percutaneous sclerotherapy for venous disorders of the labia majora in patients with vascular malformations.

J Vasc Surg Venous Lymphat Disord 2020 11 19;8(6):1083-1089. Epub 2020 Mar 19.

Department of Radiology and Policlinic of Radiology, University Hospital Halle (Saale), Halle (Saale), Germany.

Objective: The aim of this study was to evaluate the safety and clinical outcomes of percutaneous sclerotherapy of venous disorders of the labia majora in patients with vascular malformations of the lower limbs.

Methods: Thirty percutaneous sclerotherapy treatments were performed over a 6-year period among 17 female patients with symptomatic venous malformation (VM) or secondary varicosis of the labia majora. Four patients were treated with sclerotherapy alone, 13 patients had additional procedures to control the VM before sclerotherapy. Polidocanol was used as sclerosant. Indications for sclerotherapy included pain, bleeding, thrombophlebitis, and swelling. Genitourinary symptoms were recorded. The number of treatments and procedure-related complications were registered. Complications were classified according to the Society of Interventional Radiology (SIR) classification system (grade A-E). The 3-month postintervention follow-up included magnetic resonance imaging, clinical examination, and a symptom-related questionnaire. If no reintervention was necessary, consultation was scheduled biannually.

Results: All patients had local swelling and pain; only a fraction of the patients had further symptoms with bleeding or thrombophlebitis (47% each). Eight patients required reintervention. No major complications were observed; minor complications such as postprocedural swelling occurred in 29% (SIR grade A), pain occurred in 17% (SIR grade B), and skin blistering developed in 5% (SIR grade B). Upon follow-up examination after a median of 40 months, 76% showed complete relief of symptoms, and 23% reported partial relief. All patients reported a substantial reduction in pain (75% >5 points in visual analogue scale) and swelling (88% complete cessation).

Conclusions: Percutaneous sclerotherapy is a safe and effective treatment option of VM and secondary varicosis of the labia majora.
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http://dx.doi.org/10.1016/j.jvsv.2020.01.008DOI Listing
November 2020

Author Correction: Rectosigmoidal manifestations of venous malformations: MR imaging findings and interdisciplinary therapeutic modalities.

Sci Rep 2020 Feb 7;10(1):2458. Epub 2020 Feb 7.

Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Department of Radiology and Policlinic of Radiology, Ernst-Grube-Straße 40, D-06120, Halle (Saale), Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59025-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005778PMC
February 2020

Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis.

Pancreatology 2020 Apr 20;20(3):377-384. Epub 2020 Jan 20.

The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.

Background/objectives: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer.

Methods: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry.

Results: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls.

Conclusions: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.
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http://dx.doi.org/10.1016/j.pan.2020.01.011DOI Listing
April 2020

Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.

Gastroenterology 2020 05 10;158(6):1626-1641.e8. Epub 2020 Jan 10.

Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.

Background & Aims: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca-selective ion channel, in an international cohort of patients and in mice.

Methods: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca imaging assays. CP was induced by repeated injections of cerulein in TRPV6 mice.

Results: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10). TRPV6 mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis.

Conclusions: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca balance in pancreatic cells. TRPV6 regulates Ca homeostasis and pancreatic inflammation.
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http://dx.doi.org/10.1053/j.gastro.2020.01.005DOI Listing
May 2020

Rectosigmoidal manifestations of venous malformations: MR imaging findings and interdisciplinary therapeutic modalities.

Sci Rep 2019 12 27;9(1):19916. Epub 2019 Dec 27.

Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Department of Radiology and Policlinic of Radiology, Ernst-Grube-Straße 40, D-06120, Halle (Saale), Germany.

The aim of this study was to identify the frequency of rectosigmoidal involvement in patients with venous malformations (VM) of the lower extremities and to demonstrate multidisciplinary therapeutic options. The medical records and magnetic resonance images (MRI) of patients with VM of the lower extremities, over a six-year period, were reviewed retrospectively in order to determine the occurrence of rectosigmoidal involvement. Vascular interventions, surgical treatments, percutaneous and hybrid (endoscopy-guided angiography) sclerotherapy and procedural complications (according to Clavien-Dindo classification) were also noted. Of the 378 patients with vascular malformation of the lower limbs, 19 patients (5%) had documented venous rectosigmoidal malformation. All of these 19 patients reported episodes of rectal bleeding, while seven patients (36.8%) also had anemia. All patients underwent endoscopy. By endoscopy, seven patients (36.8%) showed discreet changes, and 12 patients (63.2%) showed pronounced signs of submucosal VM with active (47.3%) or previous (15.7%) bleeding. Treatment was performed in all patients with pronounced findings. Six patients underwent endoscopy-guided hybrid sclerotherapy, one patient underwent endoscopic tissue removal, one patient received percutaneous sclerotherapy and one patient received a combination of transvenous embolization and hybrid sclerotherapy. Three patients required open surgery. No complications occurred after conservative treatments; however, one complication was reported after open surgery. None of the treated patients reported further bleeding and anemia at the end of the follow-up period. In this cohort, rectosigmoidal VM occurred in 5% of patients presenting with a high incidence of rectal bleeding. Percutaneous or endoscopy-guided hybrid sclerotherapy appeared to be a safe and effective alternative to surgery.
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http://dx.doi.org/10.1038/s41598-019-56217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934467PMC
December 2019

Serum levels of advanced glycation end products and their receptors sRAGE and Galectin-3 in chronic pancreatitis.

Pancreatology 2020 Mar 17;20(2):187-192. Epub 2019 Dec 17.

Department of Internal Medicine I, Martin Luther University, Halle, Germany. Electronic address:

Background: /Objectives: AGE and their receptors like RAGE and Galectin-3 can activate inflammatory pathways and have been associated with chronic inflammatory diseases. Several studies investigated the role of AGE, Galectin-3 and sRAGE in pancreatic diseases, whereas no comprehensive data for chronic pancreatitis (CP) are available.

Methods: Serum samples from CP patients without an active inflammatory process (85 ACP; 26 NACP patients) and 40 healthy controls were collected. Levels of AGE, sRAGE and Galectin-3 were measured by ELISA. To exclude potential influences of previously described RAGE SNPs on detected serum levels, we analyzed variants rs207128, rs207060, rs1800625, and rs1800624 by melting curve technique in 378 CP patients and 338 controls.

Results: AGE and Galectin-3 serum levels were significantly elevated in both ACP and NACP patients compared to controls (AGE: 56.61 ± 3.043 vs. 31.71 ± 2.308 ng/mL; p < 0.001; Galectin-3: 16.63 ± 0.6297 vs. 10.81 ± 0.4835 ng/mL; p < 0.001). In contrast, mean serum sRAGE levels were significantly reduced in CP patients compared to controls (sRAGE: 829.7 ± 37.10 vs. 1135 ± 55.74 ng/mL; p < 0.001). All results were consistent after correction for gender, age and diabetes mellitus. No genetic association with CP was found.

Conclusions: Our extensive analysis demonstrated the importance of aging related pathways in the pathogenesis of CP. As the results were consistent in ACP and NACP, both entities most likely share common pathomechanisms. Most probably the involved pathways are a general hallmark of an inflammatory state in CP that is even present in symptom-free intervals.
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http://dx.doi.org/10.1016/j.pan.2019.12.013DOI Listing
March 2020

Mean muscle attenuation correlates with severe acute pancreatitis unlike visceral adipose tissue and subcutaneous adipose tissue.

United European Gastroenterol J 2019 12 9;7(10):1312-1320. Epub 2019 Oct 9.

Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany.

Background: Acute pancreatitis (AP) is a frequent disorder with considerable morbidity and mortality. Obesity has previously been reported to influence disease severity.

Objective: The aim of this study was to investigate the association of adipose and muscle parameters with the severity grade of AP.

Methods: In total 454 patients were recruited. The first contrast-enhanced computed tomography of each patient was reviewed for adipose and muscle tissue parameters at L3 level. Associations with disease severity were analysed through logistic regression analysis. The predictive capacity of the parameters was investigated using receiver operating characteristic (ROC) curves.

Results: No distinct variation was found between the AP severity groups in either adipose tissue parameters (visceral adipose tissue and subcutaneous adipose tissue) or visceral muscle ratio. However, muscle mass and mean muscle attenuation differed significantly with -values of 0.037 and 0.003 respectively. In multivariate analysis, low muscle attenuation was associated with severe AP with an odds ratio of 4.09 (95% confidence intervals: 1.61-10.36, -value 0.003). No body parameter presented sufficient predictive capability in ROC-curve analysis.

Conclusions: Our results demonstrate that a low muscle attenuation level is associated with an increased risk of severe AP. Future prospective studies will help identify the underlying mechanisms and characterise the influence of body composition parameters on AP.
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http://dx.doi.org/10.1177/2050640619882520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893994PMC
December 2019
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