Hueseyin Bektas

Long-term results after surgery for acute mesenteric ischemia

BACKGROUND Acute mesenteric ischemia is associated with high mortality rates, and little is known about the long-term prognosis of patients after initially successful surgical intervention. METHODS Ninety patients were treated by vascular reconstruction or bowel resection, or both, between 1972 and 1993. The overall mortality was 66%. The outcomes and rehabilitational statuses of those 31 patients who were discharged from the hospital were analyzed retrospectively. Anticoagulation consisted of vitamin K antagonists in patients with venous thrombosis and arterial embolism or inhibition of thrombocyte aggregation in patients with arterial thrombosis and nonocclusive mesenteric ischemia. RESULTS In 31 patients discharged from the hospital venous thrombosis, arterial embolism, arterial thrombosis, and nonocclusive disease occurred in 19, 5, 5, and 2 patients, respectively. The 2- and 5-year survival rates were 70% and 50% and mainly related to cardiovascular comorbidity and malignant disease. Only one patient died after a recurrent attack of arterial mesenteric thrombosis. Twenty percent of the patients suffered from chronic short bowel syndrome after extensive bowel resection, but none required permanent parenteral nutrition. CONCLUSIONS Under appropriate anticoagulation there is a remarkably low risk of recurrent mesenteric ischemia. The impaired life expectancy of long-surviving patients is mainly due to cardiovascular comorbidity and malignancies.

Surgical treatment and outcome of iatrogenic bile duct lesions after cholecystectomy and the impact of different clinical classification systems.

Different injury patterns of iatrogenic bile duct lesions after cholecystectomy have prompted the proposal of several different clinical classification systems. The aim of this study was to validate these systems comparatively.

Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells

The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control.

Substance P and other neuropeptides do not induce mediator release in isolated human intestinal mast cells

Abstract  Neuropeptides such as substance P (SP) and related peptides are supposed to act as mast cell agonists, and thus as mediators of neuroimmune interactions. The data supporting this hypothesis were obtained mostly from rodent experiments. Here, we studied for the first time the effect of SP and other peptides on mediator release in human intestinal mast cells, either unpurified or enriched to 85–99% purity. We found that SP at 0.1–100 μmol L−1, or other peptides including neurokinin A and B, calcitonin gene‐related peptide, vasoactive intestinal peptide and serotonin at 1 μmol L−1 do not induce release of mediators such as histamine, sulphidoleukotrienes, and tumour necrosis factor α. The peptides also failed to cause mediator release in mast cells isolated from inflamed tissue derived from Crohns disease. Using reverse transcriptase‐polymerase chain reaction, flow cytometry and immunohistochemistry, we could show that human intestinal mast cells do not express the tachykinin receptors NK‐1, NK‐2, or NK‐3 under basal conditions. However, upon stimulation by immunoglobulin E (IgE) receptor‐crosslinking, which induces an extensive mediator release reaction, a subpopulation of mast cells clearly expressed NK‐1, the SP receptor. In conclusion, our data show that SP and other neuropeptides do not act as secretagogues in human intestinal mast cells that have not been pre‐activated by IgE receptor‐crosslinking.

Extended Resections of Ductal Pancreatic Cancer – Impact on Operative Risk and Prognosis

114 patients received a standard and 75 patients an extended resection of ductal pancreatic carcinoma at the Hanover Medical School, Germany, from 1971 until 1993. Standard pancreatic resections were combined with vascular resection and reconstruction in 46 and additional organ resections in 45 cases. Vascular resections affected the mesentericoportal vein in 37, the common hepatic in 10 and the superior mesenteric artery in 7 cases. Pancreas resections were combined with total gastrectomy in 23, partial colectomy in 17, hemihepatectomy in 14, adrenalectomy in 8 and nephrectomy in 5 patients. Curative resections could be accomplished in 86% of patients without and 81% with extended resections. Additional vascular resections neither increased the operative risk nor deteriorated the long-term prognosis after resection. Additional organ resections, however, significantly increased the risk of lethality and impaired the long-term prognosis. Especially resections of synchronous hepatic metastases and colectomies were associated with a poor survival probability.

Human Intestinal Fibroblasts Prevent Apoptosis in Human Intestinal Mast Cells by a Mechanism Independent of Stem Cell Factor, IL-3, IL-4, and Nerve Growth Factor

In rodents, fibroblasts (FBs) mediate stem cell factor (SCF)-dependent growth of mast cells (MCs). In humans, SCF is mandatory for MC differentiation and survival. Other factors such as IL-3, IL-4, and nerve growth factor (NGF) act in synergism with SCF, thus enhancing proliferation and/or preventing apoptosis in MCs. In this study, we studied in vitro interactions between human MCs and human FBs, both isolated from the intestine and purified to homogeneity. In coculture with FBs, MCs survived for up to 3 wk, whereas purified MCs cultured alone died within a few days. TNF-α and IL-1β, which both did not affect MC survival directly, enhanced FB-dependent MC growth. We provide evidence that FB-derived MC growth factors are soluble, heat-sensitive molecules which down-regulate MC apoptosis without enhancing MC proliferation. However, only low amounts of SCF were measured in FB-conditioned medium (<0.2 ng/ml). Moreover, blocking of SCF/c-kit interaction by anti-SCF or anti-c-kit Abs and neutralization of IL-3, IL-4, and NGF did not affect MC survival in the coculture system. In conclusion, our data indicate that human FBs promote survival of human MCs by mechanisms independent of SCF, IL-3, IL-4, and NGF. Such interactions between MCs and FBs may explain why MCs accumulate at sites of inflammatory bowel disease and intestinal fibrosis.

Surgery for Exocrine Pancreatic Cancer – Who Are the 5- and 10-Year Survivors?

38 of 306 patients survived beyond 5 years after resection of an exocrine pancreatic carcinoma during a period from 1971 to 1993. Amongst the long-term survivors there were 12 patients with ductal, 22 with ampullary, 3 with distal bile duct and 1 with duodenal cancer. An active operative strategy was employed in order to resect the tumor whenever this was surgically possible. In a a retrospective analysis we have identified prognostic factors influencing long-term survival. The long-term prognosis was largely dependent on the tumor entity. Ampullary carcinomas had a significant advantage in terms of long-term survival over all other tumor entities. Other prognostic factors associated with long term survival were curative tumor resection, absence of lymphatic and distant metastases and a low tumor malignancy.

Repeat liver resection for colorectal metastases

Following resection of colorectal liver metastases (CLMs) up to 75 per cent of patients develop recurrent liver metastases. Although repeat resection remains the only curative therapy, data evaluating the outcome are deficient. This study analysed postoperative morbidity, mortality and independent predictors of survival following repeat resection of CLMs.

Expression of proliferation associated antigens and detection of numerical chromosome aberrations in primary human liver tumours : relevance to tumour characteristics and prognosis

AIMS: To assess cell proliferation and the presence of numerical chromosome aberrations involving chromosomes 1 and 8 in benign and malignant liver tumours. METHODS: Cell proliferation was studied immunohistochemically in paraffin wax embedded material from 62 primary liver tumours (20 hepatocellular carcinomas, 16 cholangiocellular carcinomas, 15 liver cell adenomas, 11 focal nodular hyperplasias), and the results were compared with histological characteristics and clinical data. Copy numbers of chromosomes 1 and 8 were assessed by interphase fluorescence in situ hybridisation (FISH) with satellite probes in fresh tumour material. RESULTS: The expression of proliferation associated antigen Ki67, using the monoclonal antibody MIB-1, and proliferating cell nuclear antigen (PCNA), using the antibody PC10, was found to be significantly higher in malignant versus benign liver tumours. Neither Ki67 nor PCNA expression were independent prognostic parameters. However, there was a tendency for a worse outcome (survival < 12 months) for patients with a high MIB-1 labelling index (> 20%) compared with patients having the same tumour stage and a low MIB-1 index. Aneusomy for chromosomes 1 and 8 was demonstrated by FISH in malignant tumours (six of seven hepatocellular carcinomas, four of five cholangiocellular carcinomas) but not in benign tumours (none of nine) or non-neoplastic liver (none of nine). CONCLUSION: Both the determination of the proliferating cell fraction and FISH analysis are useful for distinguishing hepatocellular carcinoma from liver cell adenoma or focal nodular hyperplasia; high fractions of proliferating cells are predictive of an early relapse.

Explanted Diseased Livers – A Possible Source of Metabolic Competent Primary Human Hepatocytes

Being an integral part of basic, translational and clinical research, the demand for primary human hepatocytes (PHH) is continuously growing while the availability of tissue resection material for the isolation of metabolically competent PHH remains limited. To overcome current shortcomings, this study evaluated the use of explanted diseased organs from liver transplantation patients as a potential source of PHH. Therefore, PHH were isolated from resected surgical specimens (Rx-group; n = 60) and explanted diseased livers obtained from graft recipients with low labMELD-score (Ex-group; n = 5). Using established protocols PHH were subsequently cultured for a period of 7 days. The viability and metabolic competence of cultured PHH was assessed by the following parameters: morphology and cell count (CyQuant assay), albumin synthesis, urea production, AST-leakage, and phase I and II metabolism. Both groups were compared in terms of cell yield and metabolic function, and results were correlated with clinical parameters of tissue donors. Notably, cellular yields and viabilities were comparable between the Rx- and Ex-group and were 5.3±0.5 and 2.9±0.7×106 cells/g liver tissue with 84.3±1.3 and 76.0±8.6% viability, respectively. Moreover, PHH isolated from the Rx- or Ex-group did not differ in regards to loss of cell number in culture, albumin synthesis, urea production, AST-leakage, and phase I and II metabolism (measured by the 7-ethoxycoumarin-O-deethylase and uracil-5′-diphosphate-glucuronyltransferase activity). Likewise, basal transcript expressions of the CYP monooxygenases 1A1, 2C8 and 3A4 were comparable as was their induction when treated with a cocktail that consisted of 3-methylcholantren, rifampicin and phenobarbital, with increased expression of CYP 1A1 and 3A4 mRNA while transcript expression of CYP 2C8 was only marginally changed. In conclusion, the use of explanted diseased livers obtained from recipients with low labMELD-score might represent a valuable source of metabolically competent PHH which are comparable in viability and function to cells obtained from specimens following partial liver resection.