[Show abstract][Hide abstract] ABSTRACT: Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10(-6) by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.
[Show abstract][Hide abstract] ABSTRACT: We sought association of genetic variants in the renin-angiotensin system (RAS) and vitamin D system with acute pancreatitis (AP) development and severity.
The endocrine RAS is involved in circulatory homeostasis through the pressor action of angiotensin II at its AT1 receptor. However, local RAS regulate growth and inflammation in diverse cells and tissues, and their activity may be suppressed by vitamin D. Intrapancreatic angiotensin II generation has been implicated in the development of AP.
Five hundred forty-four white patients with AP from 3 countries (United Kingdom, 22; Germany, 136; and The Netherlands 386) and 8487 control subjects (United Kingdom 7833, The Netherlands 717) were genotyped for 8 polymorphisms of the RAS/vitamin D systems, chosen on the basis of likely functionality.
The angiotensin-converting enzyme I (rather than D) allele was significantly associated with alcohol-related AP when all cohorts were combined (P = 0.03). The renin rs5707 G (rather than A) allele was associated with AP (P = 0.002), infected necrosis (P = 0.025) and mortality (P = 0.046).
The association of 2 RAS polymorphisms with AP suggests the need for further detailed analysis of the role of RAS/vitamin D in the genesis or severity of AP, particularly given the ready potential for pharmacological manipulation of this system using existing marketed agents. However, further replication studies will be required before any such association is considered robust, particularly given the significant heterogeneity of AP causation and clinical course.
Annals of surgery 04/2014; 261(1). DOI:10.1097/SLA.0000000000000655 · 8.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1, encoding carboxypeptidase A1, in subjects with nonalcoholic chronic pancreatitis (cases) and controls in a German discovery set and three replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10(-16)). The association was strongest in subjects aged ≤10 years (9.7%; OR = 84.0, P = 4.1 × 10(-24)). In the replication sets, defective CPA1 variants were present in 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE:: To determine the value of pancreatic stone protein in predicting sepsis-related postoperative complications and death in the ICU. DESIGN:: A prospective cohort study of postoperative patients admitted to the intensive care unit. Blood samples were taken within three hours for analysis from admission to the intensive care unit including pancreatic stone protein, white blood cell counts, C-reactive protein, interleukin-6, and procalcitonin. The Mannheim Peritonitis Index and Acute Physiology and Chronic Health Evaluation II clinical scores were also determined. Univariate and multivariate analyses were performed to determine the diagnostic accuracy and independent predictors of death in the ICU [Clinicaltrials.gov, NCT01465711]. SETTING:: An adult medical-surgical intensive care unit in a teaching hospital in Germany. PATIENTS:: Ninety-one consecutive postoperative patients with proven diagnosis of secondary peritonitis admitted to the ICU were included in the study from August 17, 2007, to February 8, 2010. INTERVENTIONS:: Peripheral vein blood sampling. MEASUREMENTS AND MAIN RESULTS:: Univariate analysis demonstrated that pancreatic stone protein has the highest diagnostic accuracy for complications and is the best predictor for death in the ICU. Pancreatic stone protein had the highest overall efficacy in predicting death with an odds ratio of 4.0 vs. procalcitonin (odds ratio 3.2), interleukin-6 (odds ratio 2.8), C-reactive protein (odds ratio 1.3), and white blood cell counts (odds ratio 1.4). By multivariate analysis, pancreatic stone protein was the only independent predictor of death. CONCLUSIONS:: In a population of patients with sepsis-related complications, serum-pancreatic stone protein levels demonstrate a high diagnostic accuracy to discriminate the severity of peritonitis and to predict death in the ICU. This test could be of value in the clinical diagnosis and therapeutic decision-making in the ICU.
Critical care medicine 02/2013; 41(4). DOI:10.1097/CCM.0b013e3182771193 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Progredient tumor-growth does not mean necessarily nihilism since (because of the latest multimodal therapeutic options) it might be possible to convert the malignant disease into a chronic stage depending on tumor entity, specific tumor-associated findings and expertise of the interdisciplinary oncological/oncosurgical team to utilize available and potential therapeutic measures. The aim of this report on an unusual case (with its patient-associated, therapeutic and prognostic aspects) of a leiomyosarcoma of the inferior vena cava with advanced tumor growth (characterized initially by pulmonary and hepatic, later on by additional vertebral metastases) is to illustrate its changeful clinical course after and during multimodal treatment episodes comprising surgical (abdomino-/vascular-/cardio- and neurosurgical-locally, R0 resection status), radiological and chemotherapeutic measures. A relatively stable disease over a specific time period of 5 years and 6 months was achieved. The 54-year old female patient with metastasized leiomyosarcoma of the inferior vena cava underwent local tumor resection en bloc with inferior vena cava segmental resection (following vascular surgical interposition of a prosthesis) and hemihepatectomy as well as resection of hepatic segment I. After recovery, a multistep and -modal treatment was initiated comprising of various protocols of systemic chemotherapy, thermoablation of recurrent hepatic metastases, various brachytherapy procedures (for hepatic and pulmonary metastases) and resection of a cerebral metastasis by a neurosurgeon including subsequent radiation.
The patient demonstrates impressively that even in case of advanced tumor stage with initial, novel and recurrent metastases, a relatively stable disease over an intermediate time period (of more than 5 years) with an acceptable quality of life was achieved despite several complications.
Wiener Medizinische Wochenschrift 01/2013; 163(11). DOI:10.1007/s10354-012-0172-2
[Show abstract][Hide abstract] ABSTRACT: Surgical techniques for chronic pancreatitis may be divided into resections and drainage procedures. From a functional point of view, drainage operations in patients with chronic pancreatitis are superior, because less parenchyma is removed. Due to the frequency of local complications in chronic pancreatitis, however, the majority of operations in our hospital are resections. The most frequent indication for resection is pancreatic head enlargement with stenosis of the bile duct, pancreatic duct, and/or duodenum. Resection of the pancreatic body and/or tail is indicated only rarely in chronic pancreatitis. Drainage procedures include enteric drainage of pseudocysts or a dilated pancreatic duct into the jejunum or stomach. We prefer an anastomosis to Roux-en-Y jejunal limb which will protect the pancreatic duct or pseudocyst from entry of intestinal content. Both approaches, resection and drainage, can be combined. Total pancreatectomy for chronic pancreatitis is performed only in very selected patients because of its overriding metabolic sequelae in these often difficult patients, especially if they are alcoholics.
International Practices in Pancreatic Surgery, 01/2013: pages 65-77; , ISBN: 978-3-540-74505-1
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice.
IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin.
Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis.
Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
[Show abstract][Hide abstract] ABSTRACT: Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis.
The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls.
S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups.
Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development.
PLoS ONE 05/2012; 7(5):e37981. DOI:10.1371/journal.pone.0037981 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Its considerable size at the time of diagnosis and low grade of malignancy are typical features of the solid-pseudopapillary
tumor, which has a tendency to predominantly affect young females. A relationship to the long-term intake of oral contraceptives
is discussed. Invasive tumor growth or metastases have been observed only rarely until now.
Methods. The 53-yr-old female patient we report on here was treated by radical partial pancreatoduo-denectomy for a nonmetastasizing
solid-pseudopapillary tumor of the pancreatic head (T1bN0M0) 19 mo ago.
Results. Histopathological studies made a definitive diagnosis of solid-pseudopapillary tumor. The patient is recurrence-free, and
there are no signs of metastases at present. Since a microscopically invasive tumor growth is assumed, oncologically curative
resection should be preferred vs the less radical enucleation.
Conclusion. In this report, a case of the rare solid-pseudopapillary tumor of the pancreas is described. In contrast to other
pancreatic tumors, the semimalignant solid-pseudopapillary tumor has a favorable prognosis.
International Journal of Gastrointestinal Cancer 04/2012; 27(1):77-81. DOI:10.1385/IJGC:27:1:77
[Show abstract][Hide abstract] ABSTRACT: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP.
Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study.
The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value <0.0001, OR 2.3, 95% CI 1.6-3.3). Distributions of genotype and allele frequencies of the p.I148M variant were comparable in patients with alcoholic CP, idiopathic and hereditary CP and in healthy controls.
The absence of an association of PNPLA3 p.I148M with alcoholic CP seems not to point to a common pathway in the development of alcoholic CP and alcoholic liver cirrhosis.
PLoS ONE 01/2012; 7(1):e29433. DOI:10.1371/journal.pone.0029433 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CFTR mutations enhance susceptibility for idiopathic chronic pancreatitis (ICP) and congenital bilateral absence of the vas deferens (CBAVD); however, it is unknown why CFTR heterozygotes are at increased disease risk. We recently showed that common CFTR variants are associated with aberrantly spliced transcripts. Here, we genotyped for common CFTR variants and tested for associations in two ICP (ICP-A: 126 patients, 319 controls; ICP-B: 666 patients, 1,181 controls) and a CBAVD population (305 patients, 319 controls). Haplotype H10 (TG11-T7-470V) conferred protection (ICP-A: OR 0.19, P<0.0001; ICP-B: OR 0.78, P = 0.06; CBAVD OR 0.08, P<0.001), whereas haplotype H3 (TG10-T7-470M) increased disease risk (ICP-A: OR 8.34, P = 0.003; ICP-B: OR 1.88, P = 0.007; CBAVD: OR 5.67, P = 0.01). The risk of heterozygous CFTR mutations carriers for ICP (OR 2.44, P<0.001) and CBAVD (OR 14.73, P<0.001) was fully abrogated by the H10/H10 genotype. Similarly, ICP risk of heterozygous p.Asn34Ser SPINK1 mutation carriers (OR 10.34, P<0.001) was compensated by H10/H10. Thus, common CFTR haplotypes modulate ICP and CBAVD susceptibility alone and in heterozygous CFTR and p.Asn34Ser mutation carriers. Determination of these haplotypes helps to stratify carriers into high- and low-risk subjects, providing helpful information for genetic counseling.
Human Mutation 08/2011; 32(8):912-20. DOI:10.1002/humu.21511 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rectal gastrointestinal stromal tumors are rare. To date, 12 gastrointestinal stromal tumors have been reported as pelvic vaginal masses. We describe a rectovaginal tumor in a 39-year-old woman. The tumor frequently recurred after multiple surgical excisions and interrupted imatinib treatment without metastasizing. Magnetic resonance tomography demonstrated a partial response under imatinib. The patient was alive with stable disease under imatinib 44 months from initial diagnosis. Molecular analysis showed a somatic 6-base pair deletion in exon 11 of c-KIT (W557_K558del) in both the primary tumor and the third recurrence; the recurrence had an additional exon 17 mutation (N822K). Comparative genomic hybridization analysis of the primary tumor showed loss of 14q and gain of 1q. Recurrence showed complete loss of nuclear p16 expression. Molecular studies and p16 status confirmed the typical characteristics of gastrointestinal stromal tumors with an aggressive phenotype underscoring the need for a special interdisciplinary treatment and for achieving complete local excision with free margins.
Human pathology 04/2011; 42(4):586-93. DOI:10.1016/j.humpath.2010.08.007 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammatory myofibroblastic tumors (IMTs) are a rare cause of echo-poor pancreatic head enlargement. Histologically, IMTs are characterized by spindle-shaped myofibroblasts or fibroblasts accompanied by a mixed immune cell infiltration. The most common localizations of IMTs have been reported in lung, mesentery and omentum, especially in children and young adults. IMTs show infiltrating growth, multilocular appearance and also metastasis have been reported. Curative resection is the only therapeutic option so far. In the palliative situation, evident data and clear guidelines for this rare tumor entity are missing. We report on a 44-year-old male with an unresectable IMT of the pancreatic head causing recurrent episodes of acute pancreatitis that resulted in a chronic obstructive course of the disease. The patient entered a palliative therapeutic regimen including radiation therapy and antiinflammatory medication. In a regular follow-up of 12 months, he presented with stable disease after initial progression. This case of local progressive IMT of the pancreatic head was managed with a palliative therapeutic regimen and is discussed based on the current literature.
Case Reports in Gastroenterology 10/2010; 4(3):443-451. DOI:10.1159/000320953
[Show abstract][Hide abstract] ABSTRACT: Chylothorax is an infrequent but serious complication after thoracic surgery. Optimal management is still controversial. Surgical re-interventions are associated with significant morbidity and mortality.
During a 2-year period, 3 patients developed chylothorax after oesophagectomy. This was treated conservatively, following our departmental protocol.
Conservative management (total parenteral nutrition, bowel rest, pleural drainage and octreotide, followed by a low-fat diet) was successful in all 3 cases within a reasonable period of time (14 - 18 days). CONCLUSION; We recommend conservative measures as the first-line treatment for postoperative chylothorax.
South African journal of surgery. Suid-Afrikaanse tydskrif vir chirurgie 08/2010; 48(3):86-8. · 0.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The product of CDKN2A, p16 is an essential regulator of the cell cycle controlling the entry into the S-phase. Herein, we evaluated CDKN2A promoter methylation and p16 protein expression for the differentiation of hepatocellular carcinoma (HCC) from other liver tumors.
Tumor and corresponding non-tumor liver tissue samples were obtained from 85 patients with liver tumors. CDKN2A promoter methylation was studied using MethyLight technique and methylation-specific PCR (MSP). In the MethyLight analysis, samples with > or = 4% of PMR (percentage of methylated reference) were regarded as hypermethylated. p16 expression was evaluated by immunohistochemistry in tissue sections (n = 148) obtained from 81 patients using an immunoreactivity score (IRS) ranging from 0 (no expression) to 6 (strong expression).
Hypermethylation of the CDKN2A promoter was found in 23 HCCs (69.7%; mean PMR = 42.34 +/- 27.8%), six (20.7%; mean PMR = 31.85 +/- 18%) liver metastases and in the extralesional tissue of only one patient. Using MSP, 32% of the non-tumor (n = 85), 70% of the HCCs, 40% of the CCCs and 24% of the liver metastases were hypermethylated. Correspondingly, nuclear p16 expression was found immunohistochemically in five (10.9%, mean IRS = 0.5) HCCs, 23 (92%; mean IRS = 4.9) metastases and only occasionally in hepatocytes of non-lesional liver tissues (mean IRS = 1.2). The difference of CDKN2A-methylation and p16 protein expression between HCCs and liver metastases was statistically significant (p < 0.01, respectively).
Promoter methylation of CDKN2A gene and lack of p16 expression characterize patients with HCC.
BMC Cancer 06/2010; 10(1):317. DOI:10.1186/1471-2407-10-317 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A sustained imbalance of pancreatic proteases and their inhibitors seems to be important for the development of chronic pancreatitis (CP). Mesotrypsin (PRSS3) can degrade intrapancreatic trypsin inhibitors that protect against CP. Genetic variants that cause higher mesotrypsin activity might increase the risk for CP.
We analyzed all 5 exons and the adjacent non-coding sequences of PRSS3 by direct sequencing of 313 CP patients and 327 controls. Additionally, exon 4 was investigated in 855 patients and 1,294 controls and a c.454+191G>A variant in 855 patients and 1,467 controls. The c.499A>G (p.T167A) variant was analyzed functionally using transiently transfected HEK 293T cells.
In the exonic regions, the previously described common c.94_96delGAG (p.E32del) variant and a novel p.T167A non-synonymous alteration were identified. Extended analysis of the p.T167A variant revealed no association to CP and in functional assays p.T167A showed normal secretion and activity. Variants of the intronic regions, including the extensively analyzed c.454+191G>A alteration, were not associated with the disease. Haplotype reconstruction using variants with a minor allele frequency of >1% revealed no CP-associated haplotype.
Although the trypsin inhibitor-degrading activity qualified PRSS3 as a candidate for a novel CP susceptibility gene, we found no association between a specific variant or haplotype and CP in our cohort with a high suspicion of genetically determined disease.