The nuclear aryl hydocarbon receptor is involved in regulation of DNA repair and cell survival following treatment with ionizing radiation.

In the present study, we explored the role of the aryl hydrocarbon receptor (AhR) for γ-H2AX associated DNA repair in response to treatment with ionizing radiation. Ionizing radiation was able to stabilize AhR protein and to induce a nuclear translocation in a similar way as described for exposure to aromatic hydrocarbons. A comparable AhR protein stabilization was obtained by treatment with hydroxyl-nonenal-generated by radiation-induced lipid peroxidation. AhR knockdown resulted in significant radio-sensitization of both A549- and HaCaT cells. Under these conditions an increased amount of residual γ-H2AX foci and a delayed decline of γ-H2AX foci was observed. Knockdown of the co-activator ARNT, which is essential for transcriptional activation of AhR target genes, reduced AhR-dependent CYP1A expression in response to irradiation, but was without effect on the amount of residual γ-H2AX foci. Nuclear AhR was found in complex with γ-H2AX, DNA-PK, ATM and Lamin A. AhR and γ-H2AX form together nuclear foci, which disappear during DNA repair. Presence of nuclear AhR protein is associated with ATM activation and chromatin relaxation indicated by acetylation of histone H3. Taken together, we could show, that beyond the function as a transcription factor the nuclear AhR is involved in the regulation of DNA repair. Reduction of nuclear AhR inhibits DNA-double stand repair and radiosensitizes cells. First hints for its molecular mechanism suggest a role during ATM activation and chromatin relaxation, both essential for DNA repair.

UV-induced alterations of the skin evaluated over time by reflectance confocal microscopy.

BACKGROUND: Ultraviolet radiation (UVR) induces various alterations of the skin and plays a decisive part regarding the development of melanoma and non-melanoma skin cancer. For a closer examination of these phenomena in vivo reflectance confocal microscopy (RCM) is one of the most eligible options as it represents a diagnostic tool that allows a non-invasive examination of the skin, showing microanatomical structures and individual cells. OBJECTIVES: The aim of this study was using RCM to observe alterations of the skin induced by UVR and to describe the development of these changes. In addition, the findings were compared with histological examinations of the same area. METHODS: A small area in the gluteal region of 10 healthy subjects was exposed to a threefold individual minimal erythema dose of solar-simulated UVR. The following development of the sunburn reaction was evaluated with RCM 1, 24, 72 h and 1 week after UVR exposure. Furthermore, RCM images of unexposed skin were obtained, serving as a reference. To contrast histological examination with RCM, punch biopsies were performed at each point in time. The obtained data were interpreted regarding histological and RCM-based criteria on sunburn reaction. RESULTS: All important UVR-induced alterations of the skin could be shown in RCM beginning with an inflammatory reaction (inflammatory cells, vasodilatation, oedema), containing the formation of microvesicles, followed by the appearance of apoptotic keratinocytes (sunburn cells), activated melanocytes and at last, loss of the epidermal structure. There was an excellent correlation between RCM and histological features. CONCLUSIONS: Reflectance confocal microscopy is a highly valuable tool for non-invasive monitoring of UVR-induced changes of the skin over time. Furthermore, RCM provides a more detailed visualization of inflammatory cell formation and epidermal blood flow than histological examination can.

Surgery for multiple endocrine neoplasia type 1-associated primary hyperparathyroidism.

BACKGROUND: Surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) is difficult as the condition it is caused by asymmetrical multiple gland hyperplasia. It is uncertain which operative procedure provides the best outcome with regard to long-term normocalcaemia. METHODS: All patients who had surgery for genetically confirmed MEN1-associated pHPT between 1987 and 2009 were identified from a prospective database. Clinical data, operative procedures and outcome were analysed retrospectively. RESULTS: A total of 47 patients were identified. Twenty-three patients underwent total parathyroidectomy with thymectomy and autotransplantation (TPTX + AT), 11 patients subtotal parathyroidectomy (3-3.5 glands, SPTX) with thymectomy, and 13 patients selective gland excision (fewer than 3 glands, SGE). Rates of persistent disease, recurrent disease and permanent hypoparathyroidism after TPTX + AT were 4 per cent (1 patient), 4 per cent (1 patient) and 22 per cent (5 patients) respectively. Respective rates after SPTX were 0 per cent, 18 per cent (2 patients) and 45 per cent (5 patients), which were not statistically different from those following TPTX + AT. SGE resulted in persistent disease in 23 per cent (3 patients) and a significantly higher rate of recurrent disease (46 per cent, 6 patients; P = 0.004 versus TPTX, P = 0.210 versus SPTX), but permanent hypoparathyroidism did not occur. CONCLUSION: TPTX + AT and SPTX both seem adequate surgical procedures for the treatment of MEN1-associated pHPT and are associated with fewer recurrences than SGE.

[Surgical research in Germany--an international comparison]. / Chirurgische Forschung im internationalen Vergleich.

Surgical research in Germany occupies a lower position in international ranking than expected. According to the size of the population, the economic impact, the gross domestic product and the research funding capacity, the impact of German surgical research should be much higher. Reasons are a more intensive commitment to patient care, structural differences and a changing lifestyle in younger doctors in comparison to many leading countries. If the situation is to be improved all factors have to be evaluated and, if possible, changed. Overall, German surgeons are underrepresented as readers and authors in the scientific market, which is mostly in the English language.

[Mesh-wrapping of a traumatised liver with active bleeding: a subsequent complication--obstruction of the inferior vena cava]. / Hepatorrhaphie mittels Vicrylnetz bei Leberruptur Grad IV - Eine mögliche Komplikation: Verschluss der V. cava inferior.

In multiply traumatised patients injuries of the -liver are frequently seen. Depending on location and extent of the trauma, different techniques can be applied. In the presented case of a central liver trauma in a 21-year-old man with active bleeding, mesh-wrapping of both liver lobes was applied to achieve control of the bleeding. Postoperatively the patient developed constant hypertension, oliguria and severe anasarka of the lower half of the body caused by a near total obstruction of the inferior vena cava. After removal of the wrappings, all symptoms slowly disappeared. This case and the findings in similar cases in the literature suggest that there is an indication for wrapping a traumatised liver rather with diffuse and peripheral bleeding than with a central liver trauma.

Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.

OBJECTIVE: Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme. AIM: To evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years. METHODS: HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography. RESULTS: Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1). CONCLUSIONS: In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.

[Perineal hernia. A rare complication following abdominoperineal rectal amputation]. / Perineale Hernie : Seltene Komplikation nach abdominoperinealer Rektumamputation.

BACKGROUND: Abdominoperineal excision of the rectum is a standard procedure in deep-lying rectal cancer if the sphincter muscle cannot be preserved. Besides common complications such as impotence, disorders of urinary tract function, and prolonged wound healing, perineal hernia is a rare long-term phenomenon. Surgical repair can be done either through a transabdominal approach or transperineally. Long-term results show that both methods are feasible in this situation. We report the third case of perineal hernia in German literature. CASE REPORT: A 66-year-old man presented with a painful perineal tumor 2 years after abdominoperineal excision for rectal adenocarcinoma. Perineal hernia was confirmed by magnetic resonance imaging, and the patient underwent open mesh repair through a perineal approach. DISCUSSION: A number of surgical techniques have been described for the repair of perineal hernias. These include abdominal, perineal, and combined or laparoscopic approaches with or without mesh repair. The transabdominal route seems to have some advantages over the perineal approach. In cases of small hernias, the latter can however be the option of choice. In the presented case of an uncomplicated hernia, we decided on the perineal approach including mesh implantation to keep the trauma as small as possible.

Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival.

In this study, we evaluate whether Snail is expressed in adrenocortical cancer (ACC) and if its expression is related to patient outcome. One of the best known functions of the zinc-finger transcription factor Snail is to induce epithelial-to-mesenchymal transition (EMT). Increasing evidence suggests that EMT plays a pivotal role in tumour progression and metastatic spread. Snail and E-cadherin expression were assessed by immunohistochemistry in 26 resected ACCs and real-time quantitative RT-PCR expression analysis was performed. Data were correlated with clinical outcome and in particular with overall patient survival. Seventeen of 26 (65%) ACC tumour samples expressed Snail when assessed by immunohistochemistry. Snail expression was neither detected in normal adrenocortical tissue, nor in benign adrenocortical adenomas. Expression levels were confirmed on the mRNA level by Real-Time-PCR. Survival rates were significantly decreased in Snail-positive tumours compared to Snail-negative tumours: 10 out of 16 vs one out of eight patients succumbed to disease after a median follow up of 14.5 and 28.5 months, respectively (P=0.03). Patients with Snail-expressing ACCs presented in advanced disease (11 out of 12 vs 6 out of 14, P=0.01) and tend to develop distant metastases more frequently than patients with negative staining (7 out of 11 vs two out of eight, P=0.19). In conclusion, we describe for the first time that Snail is expressed in a large subset of ACCs. Furthermore, Snail expression is associated with decreased survival, advanced disease and higher risk of developing distant metastases.

The impact of parathyroid gland autotransplantation during bilateral thyroid surgery for Graves' disease on postoperative hypocalcaemia.

OBJECTIVE: The aim of this study was to compare the rate of hypocalcaemia after bilateral thyroid resection for Graves' Disease in patients with and without parathyroid gland autotransplantation (PTAT). PATIENTS AND METHODS: A total of 153 patients following thyroid surgery for Graves' disease were studied. Patients were divided into three groups. Subgroup I comprised of 129 patients without PTAT, Subgroup II comprised of 19 patients with PTAT of one parathyroid gland and Subgroup III comprised of 6 patients with PTAT of two parathyroid glands. Association between PTAT and postoperative hypocalcaemia (PH) after thyroidectomy was investigated. RESULTS: There were 27/128 (21.1%) patients with transient and 10/128 (7.8%) patients with permanent hypocalcemia within Subgroup I. Among Subgroup II 4/19 (21.1%) patients developed transient and no patient developed permanent hypocalcaemia, while in Subgroup III 2/6 (33.3 %) patients developed transient hypocalcaemia which became persistent. Thus, the frequency of permanent postthyroidectomy hypocalcaemia (PH) was significantly higher in the Subgroup III with PTAT of two parathyroid glands when compared to the Subgroup I without PTAT (p=0.032) and Subgroup II with PTAT of only one parathyroid glands (p=0.012). CONCLUSION: PTAT of one parathyroid gland is an effective procedure to reduce the incidence of permanent hypoparathyroidism after bilateral surgery for Graves disease. Transient hypoparathyroidism was not influenced by PTAT.

The impact of self-belief on laparoscopic performance of novices and experienced surgeons.

BACKGROUND: In many professions, nontechnical aspects such as motivation or coping with stress are known to influence performance, success, and outcome. These qualities are assessed and trained in novices for quality and safety reasons. This study explored the impact of self-belief of surgeons on laparoscopic performance using a virtual reality simulator (LapSim). METHODS: Eighteen inexperienced surgical residents (with less than ten laparoscopic procedures performed) and 22 advanced residents (with more than 50 laparoscopic procedures performed) filled out a ten-item questionnaire used for the assessment of the individual sense of general self-efficacy (GSE). Afterward the participants were asked to perform three defined tasks on the LapSim, each at two different levels of difficulty. The tasks consisted of coordination, dissection, and application of clips. To assess laparoscopic performance, the total time to complete the tasks, economy of motion, and damage parameters were analyzed and correlated with the GSE score by means of Bravis-Pearson correlation analysis. RESULTS: In novices, high GSE scores correlated with more errors and poor economy of motion, while in advanced residents, laparoscopic performance was independent of the level of assessed self-efficacy. CONCLUSION: In a small sample, high self-belief does not predict success. In novices it negatively correlates with laparoscopic skills, while in advanced residents it is independent of laparoscopic performance. Thus, training aspects seem to be of greater importance for laparoscopic skills. Nevertheless, nontechnical aspects like self-belief, motivation, stress-coping strategies, judgment, decision-making, and leadership should be included in the surgical curriculum.

[Introduction of a critical incident reporting system in a surgical university clinic. What can be achieved in a short term?]. / Einführung eines Critical Incident Reporting System in einer chirurgischen Universitätsklinik: Was kann kurzfristig erreicht werden?

BACKGROUND AND OBJECTIVE: "Critical incident reporting systems" (CIRS) are voluntary systems which, within the framework of risk management, provide pointers to the type and origin of critical incidents (including "errors"). The interest in introducing a CIRS is great, but whether it can fulfill its promises remains to be clarified. The aim of this study was to answer the question of whether an CIRS in a structured form would be acceptable to staff and whether it would be suitable for introducing targeted measures for achieving improvements. METHODS: The introduction of a CIRS in the Department of Visceral, Thoracic and Vascular Surgery proceeded according to the recommendations of the Action Alliance for Patients' Safety (Aktionsbündnis für Patientensicherheit e.V.). RESULTS: During a period of 13 months we received a total of 96 reports, 29.3% from various levels of carers/nurses, while 35.4% were from doctors. 40.6% of the incidents had been observed by the reporting person, in 38.5% of cases the reporting person had been involved in the incident and in 12.5% this person had helped in dealing with the incident. 38.5% of the reported critical incidents occurred between 06.00 and 12.00, while 34.4% occurred between 12:00 and 18:00 o/c. In 32.3% of cases the estimated duration of dealing with the incident was under four hours and between four and eight hours in 26%. During the first year of this study 12 actions were started and continued in consequence of an analysis of the reported critical incidents. CONCLUSION: After one year of the study it was found that a CIRS can be reliably introduced into a surgical department in accordance with the recommendations of the Action Alliane for Patients' Safety. When introduced correctly CIRS provides valuable information, which will lead to risk reduction in surgery.

Graft-dependent renal hyperparathyroidism despite successful kidney transplantation.

INTRODUCTION: Only a few reports can be found on the recurrence or persistence of hyperparathyroidism after total parathyroidectomy and autotransplantation (PTX + AT) following kidney transplantation (KTX). The objective of the present study was to assess the frequency and pathophysiological mechanisms responsible for the development of graft-dependent renal hyperparathyroidism (rHPT) after KTX. PATIENTS AND METHODS: Between 1986 and 2006, 69 patients underwent surgery for rHPT after KTX at our institution. Patients with reoperations at the parathyroid autograft (AT) were identified. Kidney graft function (KGF) was assessed by the glomerular filtration rate (GFR). Representative parts of the parathyroid gland chosen for autotransplantation during the initial parathyroidectomy and of the excised AT at reoperation were reanalyzed according to the morphologic pattern and the proliferative index. RESULTS: Eight of the 69 patients underwent reoperation of the AT. All patients had undergone initial PTX + AT before KTX. The GFR before parathyroid reoperation was 66.6 +/- 9.6 ml/min per1.73 m(2) (mean +/- SEM). Histopathological re-examination revealed nodular hyperplasia in the parathyroid tissue for autotransplantation and in the excised parathyroid autografts. The Ki67 index was increased in the glands chosen for autotransplantation prior to KTX, but was overall low in the excised autografts. DISCUSSION: Although not reported in the literature to date, tertiary hyperparathyroidism (tHPT) may arise from parathyroid autografts even in patients with a good KGF. In these cases, graft-dependent tHPT represents the inability of autonomous, nodular parathyroid tissue to regress despite the recovery of renal function. Non-nodular tissue should be selected for parathyroid autotransplantation to decrease the incidence of graft-dependent recurrent rHPT.

Open diverticulectomy in a patient with a giant symptomatic retro-pancreatic duodenal diverticulum. A case report.

Although often incidentally found, diverticular disease of the small bowel and duodenum may generate complications and impose surgical treatment. Diagnosis of small bowel diverticulosis is difficult because the clinical picture is usually ambiguous. We report a case of diverticulosis of the whole intestine including a giant symptomatic retro-pancreatic duodenal diverticulum in a 74-year-old patient who presented with recurrent episodes of abdominal pain, weight loss and intestinal obstruction. The diagnosis was made by MRI enteroclysis and endoscopy. Open diverticulectomy with choledochostomy and insertion of a T-tube was performed and resulted in a rapid improvement of the symptoms.

Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas.

BACKGROUND: Gastrinomas are functional endocrine duodenopancreatic tumours and are responsible for Zollinger-Ellison syndrome (ZES). Clinical presentation, localization techniques and operative management were reviewed. METHODS: An electronic search of the Medline database was undertaken for articles published in English between January 1987 and May 2007. This timeframe was chosen because of the fundamental changes in operative strategy, antisecretory therapy and localization techniques during this period. RESULTS AND CONCLUSION: Most gastrinomas are located in the 'gastrinoma triangle', comprising the head of the pancreas, and the first and second parts of the duodenum. Some 20 per cent of gastrinomas occur in association with multiple endocrine neoplasia type 1 (MEN1) and 50-60 per cent of tumours are malignant at the time of diagnosis. Biochemical evidence justifies operation of which duodenotomy is an essential part. Only complete tumour resection allows 5- and 10-year survival rates of 90 per cent. Pylorus-preserving pancreaticoduodenectomy may be the procedure of choice for MEN1-ZES.

Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Differential effects of cetuximab and AEE 788 on epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) in thyroid cancer cell lines.

This study evaluated the role of EGF and the effects of EGF-targeting drugs (Cetuximab, AEE 788) on growth, apoptosis, and autocrine VEGF-secretion of thyroid cancer (TC) cells. Autocrine activation of the epidermal growth factor receptor (EGF-R) is commonly regarded to contribute to the malignant phenotype of TC cells and may therefore represent a rational therapeutic target. Out of a number of TC cell lines two anaplastic (Hth74, C643), one follicular (FTC133), and one papillary thyroid cancer cell line (TPC1) were analyzed in depth for VEGF-R-and EGF-R-expression, basal and EGF-stimulated (1-100 ng/ml) VEGF protein secretion and proliferation. Subsequently the antiprolifereative and antiangiogenic effect of cetuximab (Erbitux), a monoclonal antibody that blocks the EGF-R and AEE 788, a novel dual-kinase inhibitor of EGF-R and VEGF-R were assessed, and the downstream EGF-R signal transduction was analyzed by means of detecting phosphorylated pEGF-R, pVEGF-R, pAkt, and p-MAPK. EGF stimulated VEGF-mRNA expression and protein secretion in all TC cell lines. The EGF-R antagonist Cetuximab consistently decreased VEGF secretion in all TC cell lines (min. 15%, n.s. in C643 cells and max. 90% in Hth74 cells, P < 0.05), but did not affect tumor cell proliferation in vitro. In contrast, the EGF-R- and VEGF-R-kinase inhibitor AEE 788 not only reduced VEGF secretion (min. 55%, P < 0.05 in C643 and max. 75%, P < 0.05, in FTC133), but also exhibited a dose-dependent inhibition of tumor cell proliferation (min. 75%, P < 0.05 in C643 and max. 95%, P < 0.05 in Hth74) and was a potent inductor of apoptosis in two of four TC cell lines. These effects were always accompanied by reduced levels of pEGF-R, pVEGF-R, pAkt, and pMAPK. Although inhibition of the EGF-receptor by Cetuximab potently disrupts autocrine secretion of VEGF, only the concurrent inhibition of the VEGF- and EGF receptor, e.g., by AEE 788 induces reduced proliferation and apoptosis in vitro. This suggests a particular rationale for the use of tyrosine kinase inhibitors with dual modes of action such as AEE 788 in thyroid cancer.