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Sabrina Ehnert,1 Teresa Lukoschek,2 Anastasia Bachmann,2 Juan J Martínez Sánchez,1 Georg Damm,3 Natascha C Nussler,4 Stefan Pscherer,5 Ulrich Stöckle,1 Steven Dooley,2 Sebastian Mueller,6 Andreas K Nussler11Eberhard Karls Universität Tübingen, BG Trauma Center, Tübingen, Germany; 2Mol Hepatology - Alcohol Associated Diseases, Department of Medicine II, Medical Faculty, Mannheim, Germany; 3Department of General, Visceral, and Transplantation Surgery, Charité University Medicine, Berlin, Germany; 4Clinic for General, Visceral, Endocrine Surgery and Coloproctology, Clinic Neuperlach, Städtisches Klinikum München GmbH, Munich, Germany; 5Department of Diabetology, Klinikum Traunstein, Kliniken Südostbayern AG, Traunstein, Germany; 6Department of Medicine, Salem Medical Center, Ruprecht-Karls-Universität, Heidelberg, GermanyBackground: Patients with alcoholic liver disease (ALD) often suffer from high blood pressure and rely on antihypertensive treatment. Certain antihypertensives may influence progression of chronic liver disease. Therefore, the aim of this study is to investigate the impact of the commonly used antihypertensives amlodipine, captopril, furosemide, metoprolol, propranolol, and spironolactone on alcohol-induced damage toward human hepatocytes (hHeps).Methods: hHeps were isolated by collagenase perfusion. Reactive oxygen species (ROS) were measured by fluorescence-based assays. Cellular damage was determined by lactate-dehydrogenase (LDH)-leakage. Expression analysis was performed by reverse-transcription polymerase chain reaction and Western blot. Transforming growth factor (TGF)-β signaling was investigated by a Smad3/4-responsive luciferase-reporter assay.Results: Ethanol and TGF-β1 rapidly increased ROS in hHeps, causing a release of 40%–60% of total LDH after 72 hours. All antihypertensives dose dependently reduced ethanol-mediated oxidative stress and cellular damage. Similar results were observed for TGF-β1-dependent damage, except for furosemide, which had no effect. As a common mechanism, all antihypertensives increased heme-oxygenase-1 (HO-1) expression, and inhibition of HO-1 activity reversed the protective effect of the drugs. Interestingly, Smad3/4 signaling was reduced by all compounds except furosemide, which even enhanced this profibrotic signaling. This effect was mediated by expressional changes of Smad3 and/or Smad4.Conclusions: Our results suggest that antihypertensives may both positively and negatively influence chronic liver disease progression. Therefore, we propose that in future patients with ALD and high blood pressure, they could benefit from an adjusted antihypertensive therapy with additional antifibrotic effects.Keywords: primary human hepatocytes, alcoholic liver disease, ethanol, TGF-β1, antihypertensives

Background: Cholecystectomies can sometimes be very complex operations, which place high demands on the surgeon., Objective: Are there preoperative and intraoperative procedures available for reducing the risk of intraoperative bile duct injuries during a complex cholecystectomy?, Results: The complexity of the operation should be estimated preoperatively. Extended diagnostic examinations, preoperative biliary stenting and the performance of the operation by an experienced surgeon may help to reduce the operative risk. In high-risk patients, postponing the cholecystectomy may be indicated. The timely intraoperative recognition of the impossibility to perform a regular cholecystectomy is of decisive importance. In this situation, so-called bail-out procedures, such as fundus-down cholecystectomy or subtotal cholecystectomy are warranted. Conversion from laparoscopic to open surgery is not always necessary., Conclusion: Bail-out procedures are useful to reduce the risk of bile duct injuries during complex cholecystectomy and can enable a safe completion of the operation., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The increase of minimum volumes for complex esophageal resections decided by the Federal Joint Committee (GBA) in Germany is currently the subject of intensive discussions., Objective: To shed light on the effects of minimum volume requirements from the perspective of a tertiary care hospital., Results: Strict adherence to the valid minimum volume requirements for esophageal surgery would significantly reduce the number of hospitals offering these procedures in Germany. The associated loss of revenue should not have any relevant negative economic consequences for most hospitals; however, the loss of complex esophageal surgery may result in a competitive disadvantage for these hospitals in times of shortage of qualified medical personnel. Another point of criticism is the assumption that the treatment quality can be recognized based solely on the numbers of patients., Conclusion: Despite the well-known volume-outcome relationship, minimum volume requirements do not define the lower limit of quality of surgical treatment. Therefore, additional evidence of treatment quality, such as structural or process quality as well as outcome parameters should be required, e.g. through certification. An obligatory synchronous certification could contribute to increasing the acceptance of minimum volume requirements in Germany., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The aim of the study was to investigate the predictive impact of extracranial metastatic patterns on course of disease and survival in patients with colorectal cancer (CRC) and brain metastasis (BM). A total of 228 patients (134 male [59%], 94 female [41%]) with histologically proven CRC and BM were classified into different groups according to extracranial metastatic patterns. Time intervals to metastatic events and survival times from initial CRC diagnosis, extracranial and intracranial metastasis were analyzed. Extracranial organs mostly affected were liver (102 of 228 [44.7%]) and lung (96 of 228 [42.1%]). Liver and lung metastases were detected in 31 patients (13.6%). Calculated over the entire course of disease, patients with lung metastasis showed longer overall survival (OS) than patients with liver metastasis or patients without lung metastasis (43.9 vs 34.6 [P = .002] vs 35.0 months [P = .002]). From the date of initial CRC diagnosis, lung metastasis occurred later in CRC history than liver metastasis (24.3 vs 7.5 months). Once lung metastasis was diagnosed, BM occurred faster than in patients with liver metastasis (15.8 vs 26.0 months; Δ 10.2 months). Accordingly, OS from the diagnosis of liver metastasis was longer than from lung metastasis (27.1 vs 19.6 months [P = .08]). Once BM was present, patients with lung metastasis lived longer than patients with liver metastasis (3.8 vs 1.1 months [P = .028]). Shortest survival times in all survival categories analyzed revealed patients with concurrent liver and lung metastasis. Patients with CRC and BM form a heterogeneous cohort where extracranial metastasis to liver or lungs predicts survival., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Background: Postoperative pancreatic fistula (POPF) is a major factor for morbidity and mortality after pancreatic resection. Risk stratification for POPF is important for adjustment of treatment, selection of target groups in trials and quality assessment in pancreatic surgery. In this study, we built a risk-prediction model for POPF based on a large number of predictor variables from the German pancreatic surgery registry StuDoQ|Pancreas., Methods: StuDoQ|Pancreas was searched for patients, who underwent pancreatoduodenectomy from 2014 to 2016. A multivariable logistic regression model with elastic net regularization was built including 66 preoperative und intraoperative parameters. Cross-validation was used to select the optimal model. The model was assessed via area under the ROC curve (AUC) and calibration slope and intercept., Results: A total of N = 2488 patients were included. In the optimal model the predictors selected were texture of the pancreatic parenchyma (soft versus hard), body mass index, histological diagnosis pancreatic ductal adenocarcinoma and operation time. The AUC was 0.70 (95% CI 0.69-0.70), the calibration slope 1.67 and intercept 1.12. In the validation set the AUC was 0.65 (95% CI 0.64-0.66), calibration slope and intercept were 1.22 and 0.42, respectively., Conclusion: The model we present is a valid measurement instrument for POPF risk based on four predictor variables. It can be applied in clinical practice as well as for risk-adjustment in research studies and quality assurance in surgery., (Copyright © 2018. Published by Elsevier B.V.)

Background: To date, it remains unclear whether locally advanced adenocarcinoma of the gastroesophageal junction (AEG) should be treated with neoadjuvant chemoradiation (nCRT), analogous to esophageal cancer, or with perioperative chemotherapy (pCT), analogous to gastric cancer. The purpose of this study was to analyze the data of the Munich Cancer Registry (MCR) and to compare pCT and nCRT in AEG patients., Patients and Methods: A total of 2,992 AEG patients, treated between 1998 and 2014, were included in the study. Baseline and tumor parameters as well as overall survival (OS) and tumor recurrence were compared between 56 patients undergoing nCRT and 64 patients undergoing pCT with UICC stage II/III cancer. In addition, uni- and multivariate analyses using Cox regression models were performed to evaluate the effect of tumor characteristics and treatment regimens on OS., Results: In patients with UICC stage II/III AEG treated with either nCRT or pCT, no significant differences were seen for baseline and tumor characteristics. While there was a significantly higher cumulative incidence of locoregional treatment failure after pCT (32.8%; 95% CI: 18.0-48.4%) compared with nCRT (7.4%; 95% CI: 2.3-16.5%; p = 0.007), there was no significant difference for distant treatment failure (52.9%; 95% CI: 35.4-67.7% and 38.4%; 95% CI: 23.7-52.9%; p = 0.347). When analyzing the whole cohort, patients who received pCT were younger (58.3 years vs. 63.0 years; p = 0.016), had a higher chance of complete tumor resection (81% vs. 67%; p = 0.033), more resected lymph nodes (p = 0.036), and fewer lymph node metastases (p = 0.038) compared with patients who received nCRT. Nevertheless, there was still a strong trend toward a higher incidence of local treatment failure after pCT (25.8%; 95% CI: 14.7-38.3% vs. 12.6%; 95% CI: 5.5-22.8%; p = 0.053). Comparable to the results for patients with UICC stage II/III, no difference was seen for the incidence of distant treatment failure. When excluding patients with UICC stage IV cancer, no significant difference was found for OS., Conclusion: For UICC stage II/III carcinoma, nCRT was associated with an improved locoregional tumor control compared with pCT, while no further significant differences were seen between nCRT and pCT for UICC stage II/III AEG. Moreover, there was a strong trend toward improved locoregional tumor control after nCRT when analyzing all patients treated with nCRT or pCT, despite these patients having higher risk factors.

Purpose: The aim of this study was to assess intraoperative, postoperative, and oncologic outcome in patients undergoing laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for benign and malignant lesions of the pancreas., Methods: Data from patients undergoing distal pancreatic resection were extracted from the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. After propensity score case matching, groups of LDP and ODP were compared regarding demography, comorbidities, operative details, histopathology, and perioperative outcome., Results: At the time of data extraction, the StuDoQ|Pancreas registry included over 3000 pancreatic resections from over 50 surgical departments in Germany. Data from 353 patients undergoing ODP (n = 254) or LDP (n = 99) from September 2013 to February 2016 at 29 institutions were included in the analysis. Baseline data showed a strong selection bias in LDP patients, which disappeared after 1:1 propensity score matching. A comparison of the matched groups disclosed a significantly longer operation time, higher rate of spleen preservation, more grade A pancreatic fistula, shorter hospital stay, and increased readmissions for LDP. In the small group of patients operated for pancreatic cancer, a lower lymph node yield with a lower lymph node ratio was apparent in LDP., Conclusions: LDP needed more time but potential advantages include increased spleen preservation and shorter hospital stay, as well as a trend for less transfusion, ventilation, and mortality. LDP for pancreatic cancer was performed rarely and will need critical evaluation in the future. Data from a prospective randomized registry trial is needed to confirm these results.

Purpose: Besides classical colorectal adenocarcinomas (AC), mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC) occur. Controversy remains regarding their prognostic role. Aim of this study was to define prognostic and histopathological specifications of mucinous and signet-ring cell colorectal cancer., Methods: A total of 28,056 patients with AC, MAC, and SC between 1998 and 2012 in the catchment area of the Munich Cancer Registry were analyzed. Time to locoregional recurrence and distant recurrence was calculated by cumulative incidence. Survival was analyzed by the Kaplan-Meier method, calculation of relative survival, and Cox proportional hazards regression., Results: AC occurred in 25,172 patients (90 %), MAC in 2724 (9.7 %), and SC in 160 (0.6 %). AC were less frequently localized in the proximal colon (34 %) compared to MAC (57 %, p < 0.001) and SC (76 %, p < 0.001). Both, MAC and SC had higher T, N, and M categories, lymphatic invasion, and worse grading (p < 0.001 for each). There were significant differences regarding the 10-year cumulative incidence of locoregional recurrence (p < 0.001), and distant recurrence (p < 0.001). For AC, the 5-year overall survival was 59 % (95 % confidence interval 58.0; 59.3), for MAC 52 % (50.2; 54.2), and for SC 40 % (32.1; 48.5; p < 0.001). However, MAC or SC did not remain independent prognostic factors for overall survival compared to AC upon multivariable analysis (p = 0.981)., Conclusion: This large cohort reveals specific histopathological and recurrence patterns for patients with colorectal AC, MAC, and SC. MAC and SC are diagnosed at more advanced tumor stages and therefore entail reduced survival rates.

Background: Gastric cancer accounts for 5 % of cancer deaths. Proportions of older stomach cancer patients are increasing. Despite the still poor prognosis, standardised treatment has achieved improvements; nonetheless it is questionable whether all age groups have benefitted. Age and outcome need to be examined in a population-based setting., Methods: Analyses included Munich Cancer Registry (MCR) data from 8601 invasive gastric cancer patients, diagnosed between 1998 and 2012. Tumour and therapy characteristics and outcome were analysed by two age groups (<70 vs. ≥70 years). Survival was analysed using the Kaplan-Meier method and relative survival was computed as an estimation for cancer-specific survival. Additional landmark analyses were conducted by calculating conditional survival of patients who survived more than 6 months., Results: Fifty-nine per cent of the cohort were ≥70 years old. These patients had tumours with a slightly better prognosis and were treated with less radical surgery and adjuvant therapy than younger patients. The 5-year relative survival was 40 % for the youngest (<50 years) and 23 % for the oldest patients (≥80 years). Survival differences were diminished or eliminated after landmark analyses: The 5-year relative survival in age groups 50-59, 60-69 and 70-79 years was comparable (between 48 and 49.6 %) and slightly worse in the youngest and oldest (45 %), which may be explained by more aggressive tumours and effects of cellular senescence, respectively., Conclusion: The treatment and care of elderly gastric cancer patients in the MCR catchment area seems appropriate: if a patient's general condition allows oncologic resection and chemotherapy, it is conducted and the result is comparable between age groups.

Background: The purpose of the study was to characterize the rare cohort of patients (pts) with metastatic colorectal cancer (mCRC) and brain metastasis (BM) and to identify prognostic subgroups., Patients and Methods: In collaboration with the Munich Cancer Registry, pts with mCRC and BM who were diagnosed between 1998 and 2011 were identified. Survival from the time of first diagnosis of colorectal cancer (CRC) (OS-1), from the time of diagnosis of metastatic disease (OS-2) and of BM (OS-3) was calculated regarding (1) the temporal occurrence of extra- and intracranial metastasis (meta- vs. synchronous) and (2) tumor and patient characteristics. For survival analysis the Kaplan-Meier estimator and Cox regression models were used., Results: A total of 228 pts (134 male [59%], 94 female [41%]) were identified. The median age was 63 years (142 pts [62%] were 65 years of age or younger). Most pts presented with primary tumors staged T3/4, N+, Grade 2. The primary tumor was located predominantly in the left colon (155 pts; 68%), especially in the rectum (95 pts; 42%). Median OS-1 was 35.6 months (95% confidence interval [CI], 30.1-41.1 months), OS-2 was 16.5 months (95% CI, 13.9-19.1 months), and OS-3 was 2.0 months (95% CI, 1.5-2.5 months). Median time from first CRC diagnosis to BM was 29.2 months. Subsequent BM after extracranial metastasis were observed in 184 pts (80.7%), whereas 31 pts (13.6%) presented with solitary BM. Univariate analysis did not reveal a prognostic variable for overall survival after diagnosis of BM., Conclusion: This study presents the largest number of pts with mCRC and BM analyzed to date. The results show that most mCRC pts develop BM as a late step in the course of disease. Median time from first CRC diagnosis to BM is 29.2 months. Only a few pts were diagnosed with BM early in the disease or with solitary BM. When BM is present survival is poor., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Acute primary peritonitis due to group A Streptococci (GAS) is a rare but life-threatening infection. Unlike other forms of primary peritonitis it affects predominantly young previously healthy individuals and thus is often confused with the more frequent secondary peritonitis. A case series of three patients is presented as well as a review of the literature focusing on pitfalls in the diagnose and therapy of GAS peritonitis., Methods: A retrospective analysis of three patients with primary GAS peritonitis was performed. Furthermore a systematic review of all cases of primary GAS peritonitis published from 1990 to 2013 was performed comparing demographics and clinical presentation, as well as radiological imaging, treatment and outcome., Results: All three female patients presented initially with high fever, nausea and severe abdominal pain. Radiological imaging revealed intraperitoneal fluid collections of various degrees, but no underlying cause of peritonitis. Broad antibiotic treatment was started and surgical exploration was performed for acute abdomen in all three cases. Intraoperatively fibrinous peritonitis was observed, but the correct diagnosis was not made until microbiological analysis confirmed GAS peritonitis. One patient died within 24h after admission. The other two patients recovered after multiple surgeries and several weeks on the intensive care unit due to multiple organ dysfunction syndrome. The fulminant clinical course of the three patients resembled those of many of the published cases: flu-like symptoms, high fever, severe acute abdominal pain and fibrinous peritonitis without obvious infectious focus were the most common symptoms reported in the literature., Conclusion: GAS primary peritonitis should be considered in particular in young, previously healthy women who present with peritonitis but lack radiological findings of an infectious focus. The treatment of choice is immediate antibiotic therapy. Surgical intervention is difficult to avoid, since the diagnosis of GAS peritonitis is usually not confirmed until other causes of secondary peritonitis have been excluded., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Gastric cancer accounts for 5 % of cancer deaths. Successful implementation of guideline-recommended treatment procedures should result in population-based outcome improvements despite the still poor prognosis. In this context, the objective of this study was to compare the outcome of gastric cancer by different levels of hospital care., Materials and Methods: Total of 8,601 patients with invasive gastric cancer documented between 1998 and 2012 by the Munich Cancer Registry were evaluated. Tumour and therapy characteristics and outcome were analysed in regard to five levels of hospital care: three levels were defined for general hospitals (level I-III), while university hospitals and speciality hospitals were grouped as separate classes. Survival was investigated using the Kaplan-Meier-method, computing relative survival, and by multivariate Cox proportional hazard regression., Results: The average age differed between 66 years in university hospitals and 75 years in hospitals providing a basic level of care (level I). No survival differences were found for patients treated in different levels of hospital care in 75 % of the patient cohort, namely the M0 patients. A better survival could only be shown for patients with M1 at diagnosis when treated in a university or level III hospital compared to those treated in other hospitals., Conclusion: The outcome difference of M1 patients is most likely caused by selection effects concerning health status differences and not by processes of health care attributable to level of hospital care. Thus, this study demonstrates and confirms appropriate treatment and care of gastric cancer over all levels of hospital care.

Background: The therapy for open abdomen remains challenging. Abdominal vacuum therapy seems to simplify the treatment and to enable a direct fascial closure in a high percentage of the patients., Patients and Methods: A retrospective analysis of 82 consecutive patients who underwent abdominal vacuum therapy between January 2005 and December 2007 was undertaken. Indications, -duration of treatment, complications as well as rate and type of abdominal wall closure were evaluated., Results: The 82 consecutive patients consisted of 46 % female and 54 % male patients with a median age of 65.5 years. The most frequent diagnoses were colorectal carcinoma (24 %, n = 28, colon n = 18 and rectum n = 10), inflammatory bowel dis-ease (13 %), perforated peptic ulcer (9 %), necrotising pancreatitis (7 %), peritoneal carcinosis (5 %), ileus (5 %) and mesenteric ischaemia (4 %). The predominant indication for vacuum therapy was peritonitis (88 %). Vacuum therapy treatment was applied for a median of 6 days (range: 1-73 days). 18 patients (22 %) received intraabdominal foam dressings without the fenestrated polyurethane layer. In 70 % of all cases the abdominal vacuum therapy was performed without complications. 16 patients (19.5 %) developed intestinal fistulas. However, fistulas were not observed among the patients who were treated with foam dressings without a polyurethane layer. Abdominal bleeding was observed in 8 patients (10 %) and a persistent abdominal compartment syndrome was seen in one patient. Nine patients (11 %) died during hospitalisation. After completion of the intraabdominal vacuum therapy, -direct fascial closure was feasible in 35 patients (43 %). In 47 patients (57 %) an absorbable synthetic mesh was required for fascial closure. Symptomatic incisional hernias -occurred in 22 % of the patients., Conclusion: Abdominal vacuum therapy simplifies the treatment of patients with abdominal catastrophes such as peritonitis or necrotising pancreatitis. The cost-effective intraperitoneal use of a foam dressing without a fenestrated polyurethane layer was possible without an increased rate of fistulas. This retrospective analysis demonstrates that abdominal vacuum therapy can be performed without complications in the majority of patients. Furthermore, direct fascial closure is possible in almost half of the patients., (© Georg Thieme Verlag Stuttgart ˙ New York.)

Impaired hepatic arterial perfusion after orthotopic liver transplantation (OLT) may lead to ischemic biliary tract lesions and graft-loss. Hampered hepatic arterial blood flow is observed in patients with hypersplenism, often described as arterial steal syndrome (ASS). However, arterial and portal perfusions are directly linked via the hepatic arterial buffer response (HABR). Recently, the term 'splenic artery syndrome' (SAS) was coined to describe the effect of portal hyperperfusion leading to diminished hepatic arterial blood flow. We retrospectively analyzed 650 transplantations in 585 patients. According to preoperative imaging, 78 patients underwent prophylactic intraoperative ligation of the splenic artery. In case of postoperative SAS, coil-embolization of the splenic artery was performed. After exclusion of 14 2nd and 3rd retransplantations and 83 procedures with arterial interposition grafts, SAS was diagnosed in 28 of 553 transplantations (5.1%). Twenty-six patients were treated with coil-embolization, leading to improved liver function, but requiring postinterventional splenectomy in two patients. Additionally, two patients with SAS underwent splenectomy or retransplantation without preceding embolization. Prophylactic ligation could not prevent SAS entirely (n = 2), but resulted in a significantly lower rate of complications than postoperative coil-embolization. We recommend prophylactic ligation of the splenic artery for patients at risk of developing SAS. Post-transplant coil-embolization of the splenic artery corrected hemodynamic changes of SAS, but was associated with a significant morbidity.

Several immunotherapeutic approaches rely on antigen-specific T-cells. Restrictions in the T-cell receptor (TCR) repertoire were reported as indicator of anti-tumor cytotoxic T-lymphocyte (CTL) response in various tumor entities. It is unclear yet whether a TCR restriction in peripheral blood mirrors the tumor compartment. We compared the expression of TCR Vbeta-families for the quantification of TCR repertoire alterations in blood and tissue samples from patients with colorectal carcinoma. Blood samples from patients with colorectal carcinoma and healthy volunteers and tissue samples of normal colonic mucosa and colorectal carcinoma were analyzed. Relative Vbeta-family quantification was performed based on quantitative reverse transcribed PCR. Standard deviation and average mean of the single families were determined. Two variables describing the degree of Vbeta-repertoire restriction were defined. Forty-eight blood samples and 37 tissue samples were analyzed. TCR repertoire restriction was higher in blood of tumor patients than in blood of healthy controls (p < 0.05). No difference in the degree of TCR repertoire restriction was found between carcinoma and unaffected colon tissue. We found no corresponding elevated TCR families among the different compartments blood, normal colon, and carcinoma tissue of the same patient. In conclusion, we observed a repertoire restriction in peripheral blood as well as in tumor tissue of cancer patients. However, in tumor tissue, repertoire alterations were comparable to normal mucosa, suggesting compartment-specific TCR distribution rather than alterations due to tumor-T-cell interaction questioning the presence of highly restricted clonal T-cell expansions in colorectal cancer as they have been described in other, assumingly more immunogenic tumor entities.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are intraductally located, mucin-producing cystic neoplasms of the pancreas with a malignant potential. We report about a 54-year-old female who underwent segmental resection of the pancreas for non-invasive IPMN. The surgical margins were tumour-negative. Three years later a highly suspicious tumour of the pancreatic tail was detected during routine follow-up. Resection of the pancreatic tail was performed. The histological analysis revealed an adenocarcinoma. This case suggests the development of a pancreatic carcinoma from a non-invasive IPMN and raises the question about the extent of surgery of non-invasive IPMNs of the pancreas.

Background: Altered expression of estrogen receptors alpha and beta (ERalpha and ERbeta) has been hypothesized to play a role in carcinogenesis. However, little is known about the sex-specific differences of ER expression in colorectal cancer (CRC)., Objective: This study examined ERalpha and ERbeta protein levels in male and female patients with CRC., Methods: Using Western blot analysis, the intensity of ERalpha and ERbeta protein levels was determined in tumor tissue and in corresponding normal colon mucosa from patients with CRC., Results: All 64 white patients (33 men, mean [SEM] age 64.1 [13.1] years, age range 26-90 years; 31 women, mean age 68.5 [14.5] years, age range 39-91 years [4 were premenopausal at time of surgery]) expressed ERalpha and ERbeta protein in normal colon mucosa, and there were no significant differences between men and women. In tumor tissue, a significantly increased ERalpha protein level was observed in men (P = 0.02 vs normal tissue), whereas in women, the ERalpha level did not differ significantly between tumor and normal tissue. The level of ERbeta protein in CRC was significantly reduced in both men and women, but more so in men (P = 0.04 vs women). Furthermore, in men, the ERbeta level was significantly lower in poorly differentiated tumors than in moderately differentiated tumors (P < 0.03), whereas in women, poor differentiation of the tumor was not associated with a significant decrease of ERbeta level., Conclusions: Altered levels of ER subtypes resulting in an increased ERalpha:ERbeta ratio were found in patients with CRC. The observation of significantly greater alterations in men than in women supports the hypothesis of sex-specific differences in the pathogenesis of CRC.

Hypothesis: Total parathyroidectomy without autotransplantation in kidney transplant recipients leads to reduced recurrence rates and similar improvement of clinical symptoms compared with subtotal parathyroidectomy., Design: A retrospective cohort study., Setting: University clinic., Patients: Thirty-three patients with functioning renal grafts who underwent primary total (n = 17; group 1) or subtotal (n = 16; group 2) parathyroidectomy for renal hyperparathyroidism., Main Outcome Measures: Long-term levels of intact parathyroid hormone, serum calcium, phosphate, alkaline phosphatase, creatinine, and vitamin D; bone pain; use of medication; and incidence of persistent or recurrent hyperparathyroidism., Results: The mean length of follow-up was 31 months in group 1 and 41 months in group 2. In all patients, postoperative serum calcium and phosphate levels normalized and bone pain markedly decreased. Persistent hypocalcemia was not observed. Serum creatinine levels intermittently increased in both groups but returned to preoperative levels in most of the patients. In group 1, all patients had undetectable intact parathyroid hormone levels throughout the study period. In group 2, 2 patients had persistent and 3 patients developed recurrent hyperparathyroidism (31%) that required therapy with cinacalcet hydrochloride in 3 cases. In 4 of these 5 patients, intact parathyroid hormone levels were greater than 54 ng/L directly after operation. In all, 27 of 33 patients (82%) received cholecalciferol therapy. Additional calcium supplementation was used by 12 group 1 patients (71%) and 3 group 2 patients (19%)., Conclusions: Total parathyroidectomy in kidney transplant recipients appears to be safe and protective against persistent and recurrent disease. If subtotal parathyroidectomy is performed, the remnant should be small.

Liver transplantation (OLT) has become a successful surgical therapy for terminal liver failure. We here report about long-term results of OLT in a single center over a period of 15 years. Between 1988 and 2002, 1365 adult OLTs were performed. Mean follow-up was 103 +/- 56 months. Main indications for OLT were viral-induced cirrhosis (27.1%), alcoholic liver disease (21%), tumors (15.7%) and cholestatic liver disease (14.6%). Retransplantation was necessary in 120 (9.6%) patients because of initial nonfunction (26.9%), recurrence of underlying disease (20.2%), acute and chronic rejection (16.8%) or thrombosis of the hepatic artery (16.8%). 275 patients (22.1%) died. Causes of death included recurrence of disease (32.1%), infections (21.8%), de novo malignancies (13.5%) and cardiovascular disease (11.6%). Patient survival after OLT was 91.4%, 82.5%, 74.7% and 68.2% after 1, 5, 10 and 15 years, and graft survival was 85.8%, 75.3%, 67.3% and 61.7% after 1, 5, 10 and 15 years, respectively. Patient survival after retransplantation was 81.6%, 68.8% and 57.1% and 48.0% after 1, 5, 10 and 15 years. This analysis reveals excellent long-term results after OLT achieved in a single center.

Objective: Patients undergoing pancreas resection carry several risk factors for nosocomial bacterial infections. Pre- and probiotics (synbiotics) are potentially useful for prevention of these infections., Summary Background Data: First trials in patients following major abdominal surgery including liver transplantation using one Lactobacillus (LAB) and one fiber showed significant reduction of infection rates and reduced length of antibiotic therapy compared with a control group. The present study was designed to analyze whether a combination of different LAB and fibers would further improve outcome., Methods: A prospective randomized monocentric double-blind trial was undertaken in 80 patients following pylorus-preserving pancreatoduodenectomy (PPPD). All patients received enteral nutrition immediately postoperatively. One group (A) received a composition of 4 LAB and 4 fibers, and another group (B) received placebo (fibers only) starting the day before surgery and continuing for 8 days. Thirty-day infection rate, length of hospital stay, duration of antibiotic therapy, noninfectious complications, and side effects were recorded., Results: The incidence of postoperative bacterial infections was significantly lower with LAB and fibers (12.5%) than with fibers only (40%). In addition, the duration of antibiotic therapy was significantly shorter in the latter group. Fibers and LAB were well tolerated., Conclusion: Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates and antibiotic therapy following PPPD.

The relevance of sobriety for outcome after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) is still discussed controversially. We conducted a retrospective analysis of 300 patients transplanted for ALD with regard to recurrent alcohol consumption, risk factors for drinking after OLT, and long-term survival. The 300 patients underwent OLT for ALD between 1989 and 2002. Median follow-up was 89 months. Incidence and severity of drinking, survival rates, and causes of death were assessed. Age, gender, duration of pretransplant sobriety, social support, presence of children, and the results of psychosomatic evaluation were analyzed for their impact on recurrent alcohol consumption after OLT. Drinking of various degrees was observed in 19% of ALD patients after OLT. Pretransplant sobriety of less than 6 months, absence of companion in life, presence of young children, and a predicted poor psychosomatic prognosis were associated with an increased risk of recurrent alcohol consumption, whereas age and gender were not independent risk factors. Survival rates of patients who resumed abusive drinking were significantly lower than survival rates of abstinent patients or patients with minor lapses. Recurrent alcoholic liver disease accounted for the vast majority of deaths among patients who resumed abusive drinking after OLT, whereas malignant tumors, infections, and cardiovascular disease were the most common causes of death among abstinent patients. In conclusion, abusive drinking after OLT is associated with poor long-term survival. Analysis of risk factors may help to identify patients with a high risk for recurrent alcohol abuse after OLT., ((c) 2006 AASLD.)

We describe a step-by-step protocol for measuring the stable products of the nitric oxide (NO) pathway: nitrite, nitrite plus nitrate and nitrate. This described protocol is easy to apply and is about 50 times more sensitive than the commonly used Griess reaction or commercially available assay kits based on the Griess reaction. It also allows the study of minimal changes in the NO pathway. With this method, it takes about 3 h to analyze the above-mentioned stable products in culture supernatants or in various body fluids, and the method has a sensitive linear range of 0.02-10.0 microM. This restricted linear range suggests that the technique is useful for studying small changes of nitrite and nitrate, rather than for routine diagnostic measurements.

The association between renal hyperparathyroidism (HPT) and differentiated thyroid carcinoma is discussed. To determine the prevalence and potential risk factors, we performed a retrospective analysis of our patients (1998-2004) and compared the data with the data from other surgical and autopsy studies. At our hospital, a total of 347 parathyroidectomies in 339 patients with renal HPT were performed. Most patients underwent preoperative ultrasound investigation of the thyroid gland and, if indicate, thyroid scintigraphy. Intraoperatively, both thyroid lobes were mobilized and palpated. Detected thyroid nodules were adequately resected and investigated histologically. A systematic analysis of the international literature was performed using the PubMed/MEDLINE system to identify publications on the prevalence of papillary thyroid carcinoma (PTC) in patients with renal HPT and in the overall population. Altogether, 133 patients (39.2%) underwent simultaneous thyroid surgery. The initial operation was hemithyroidectomy in 55 (16.2%), Dunhill operation in 36 (10.6%), unilateral subtotal resection in 17 (5.0%), bilateral subtotal resection in 5 (1.5%), and enucleation of a thyroid nodule in 18 (5.3%). A PTC was found in 8 of 339 patients (2.4%) and a follicular thyroid carcinoma in 1. Among 311 patients with primary cervical operation, 6 (1.9%) had a papillary thyroid carcinoma. All papillary tumors were classified as pT1 with a diameter of 1 to 12 mm; three were bifocal, and only one patient had positive lymph nodes. None of the analyzed factors showed a significant correlation with the occurrence of thyroid carcinoma. Depending on the screening method, the prevalence of occult PTC in European autopsy studies ranged from 5% to 9% and was markedly higher in almost all studies than in the present one. The prevalence of PTC in the present study makes an etiologic association between renal HPT and PTC unlikely. The clinical significance of these tumors remains unclear because all incidental tumors were small. However, if easily and safely feasible, relevant thyroid nodules should be removed during parathyroid surgery.

As cytomegalovirus (CMV) disease was a leading cause of death following liver transplantation in earlier reports, general CMV prophylaxis is widely used. We re-evaluated the impact of CMV in a recent time period under balanced immunosuppression and effective CMV diagnostics and therapy. A retrospective analysis of 1200 liver transplantations between 1988 and 2000 was performed comparing the incidence of CMV infection and disease and patient survival rates in two different time periods (before and after availability of the pp65-antigenaemia assay). In addition, risk factors for CMV in the recent time period were analysed. No ganciclovir prophylaxis was administered during the whole study period. The incidence of CMV tissue invasive disease decreased from 9.4% in period I to 2.7% in period II, whereas the incidence of viral syndrome was about 6% in both periods. Especially CMV pneumonia and generalized disease were almost abandoned in period II. Patients with tissue invasive disease, but not with infection or viral syndrome had reduced survival rates in both periods. However, the disease-specific mortality was 10% and 0% respectively. The overall rate of CMV infection in period II was low (25.9%). Risk factors for CMV infection in the univariate analysis were: Initial nonfunction, D+R- seroconstellation, acute liver failure, triple or quadruple immunosuppression, OKT3 or ATG treatment, transfusion of >10 packed red cells, steroid boluses, postoperative mechanical ventilation and retransplantation. In the multivariate analysis only quadruple or triple immunosuppression, OKT3-treatment, transplantation for acute liver failure and initial nonfunction. The incidence of CMV tissue invasive disease as well as the disease-specific mortality has markedly decreased during the last years. Using routine surveillance with the pp65-antigenaemia assay, CMV infection and disease rates compare well to data with long-term ganciclovir prophylaxis. As D+R- patients still more often develop symptomatic disease, pre-emptive therapy could be useful in this patient group.

Background and Objective: Intestinal transplantation (ITx) is the only causal therapy of short bowel syndrome (SBS). Long-term survival after ITx has been improved significantly during the last years. The experience with ITx at the Charite, Campus Virchow Klinikum, are described and discussed., Patients and Methods: Twelve isolated ITx and one multivisceral transplantation (including stomach, pancreatodudenal complex, small intestine, liver, ascending colon, right kidney, and adrenal gland) were performed. Mean recipient age was 37.7+/-10.6 yrs (median: 35 yrs; range: 27 - 58 yrs; M:F = 8:5). All patients had irreversible SBS (0 - 30 cm residual bowel length; mean: 11.8+/-11.4 cm; median: 13 cm)., Results: 6-months and 1-year patient and graft survival were 85 % (11/13) and 77 % (10/13), respectively. Reasons for graft loss and patient death were necrotizing enterocolitis, severe, muromonab-resistent, acute rejection, and graft ischemia due to complex coagulopathy. All other patients had good long-term outcome. They received enteral nutrition at six hours after operation and were persistently off total parenteral nutrition (TPN) by week two after ITx., Conclusion: ITx as established in our centre, with 1-year-patient and graft survival rates of 77 %, reflects current international standard. ITx is complementary to conservative and other operative methods of treating SBS. Referral and indication criteria need wider dissemination to prevent life-threatening complications of TPN.

OBJECTIVE This study focused on the effect of immunoregulatory cytokines on tissue injury after intestinal ischemia/reperfusion (IR). Furthermore, the role of nitric oxide, heme oxygenase-1 (HO-1) and the transcription factor NF-kappaB/Rel in the disease process was evaluated.SUMMARY BACKGROUND DATA Oxidative stress and inflammatory gene products contribute to ischemia/reperfusion injury (IRI). However, expression of stress proteins such as the inducible nitric oxide synthase (NOS-2) and HO-1 might also provide protection against IRI. METHODS IR was achieved in Lewis rats by selective clamping of the superior mesenteric artery. IL-2 or IL-10 was administered intravenously before reperfusion. Animals were killed 1 hour, 4 hours, and 24 hours after reperfusion. Tissue destruction was assessed by hyaluronic acid (HA) and aminoaspartate-transaminase (AST) serum levels, whereas reduction of glutathione (GSH) tissue levels was used as a marker for oxidative stress. Furthermore, the activation of NF-kappaB/Rel and the expression of NOS-2 and HO-1 were analyzed.RESULTS IR resulted in tissue destruction and significantly reduced GSH tissue levels in the intestines and liver. In addition, NF-kappaB/Rel activation and increased NOS-2 and HO-1 mRNA expression were detected in both organs after IR. IL-2 administration resulted in clinical improvement of the animals and was associated with increased NF-kappaB/Rel activation and enhanced NOS-2 and HO-1 mRNA expression. In contrast, IL-10 resulted in increased tissue destruction in both organs and sustained reduction of GSH levels in the intestines. Furthermore, IL-10 administration failed to enhance NF-kappaB/Rel activity, NOS-2 mRNA, or HO-1 mRNA expression after IR. CONCLUSION IL-10 resulted in increased tissue damage after intestinal IR. This detrimental effect of IL-10 might have been the result of reduced NOS-2 and HO-1 mRNA expression. In contrast, the beneficial effect of IL-2 might have relied on increased HO-1 expression and NOS-2 activity. These controversial effects of IL-2 and IL-10 might have been mediated through transcriptional regulation of NOS-2 and HO-1 gene expression.

Arterial steal syndromes (ASSs) after orthotopic liver transplantation (OLT) are characterized by arterial hypoperfusion of the graft caused by shifting of blood flow into the splenic or gastroduodenal artery. Despite their potentially devastating consequences, such as ischemic biliary tract destruction or graft failure, ASSs have received little attention to date. We report the incidence, diagnosis, and treatment of ASS among 1,250 consecutive OLTs. ASS was observed in 69 patients (5.9%). All these patients presented with elevated liver enzyme levels, impaired graft function, or cholestasis. Treatment consisted of splenectomy (n = 18), coil embolization of the splenic or gastroduodenal artery (n = 29), or reduction in splenic artery blood flow through administration of an artificial stenosis (banding; n = 9). Mild symptoms of ASS did not warrant treatment in 13 patients. However, 3 of these patients developed ischemic biliary destruction requiring re-OLT. Serious complications also were observed after splenectomy and coil embolization, requiring re-OLT in 18%. Conversely, no complications were observed after banding the splenic artery. Prophylactic banding of the splenic artery was performed in 97 patients and was associated with a complication rate of 4%. In summary, the incidence of ASS is similar to that of other vascular complications. Untreated ASSs may lead to serious complications in more than 30% of patients. Of a variety of treatment options, banding the splenic artery was associated with the lowest complication rate. Banding also may be performed prophylactically in selected patients to prevent the development of ASS after OLT.

Mesenteric artery occlusions are rare complications of Thrombangiitis obliterans (Buerger's disease). We report on a 30-year old male with Thrombangiitis obliterans and mesenteric occlusion as a complication of this disease. Because of unclear abdominal pain, laparoscopy was performed which showed small bowel infarction and reduced liver perfusion. After small bowel resection and a second examination, ischemia of the intestinum continued. Angiography was performed, which showed central occlusion of the celiac trunk and the superior mesenteric artery. Relaparotomy with the embolectomy of the superior mesenteric artery, venous bypass from the sup.mes.art. to the hepatic arteries and repeated small bowel resection was performed. The patient recovered completely and was discharged from hospital after 3 weeks. After a further admission to the hospital 3 weeks later with abdominal pain caused by acute occlusion of the right colonic artery and severe ischemia of the right hemicolon, a right hemicolectomy was performed. Now, one year after the last hospital admission, the patient shows no sign of having any abdominal problems.

Host defense mechanisms preventing bacterial invasion are particularly important in the gastrointestinal tract, since most gram-negative infections originate from there. Intraepithelial lymphocytes (IEL) seem to play an important role in this immune surveillance of the intestine, although their function in sepsis is not fully understood. To evaluate the characteristics of IEL in sepsis, C57BL/6 mice received a non-lethal dose of LPS and IEL were harvested at various time points thereafter. Although IEL displayed no phenotypic changes after endotoxemia, they displayed enhanced cytolytic activity and increased proliferation after LPS injection In addition, IEL from septic mice showed enhanced gamma interferon (IFN-gamma) production after LPS administration. The production of IFN-gamma may have induced the increased intestinal NOS-2 mRNA expression which was observed after endotoxemia. In conclusion, endotoxemia leads to functional activation of IEL without phenotypic changes. The activation of IEL and the subsequently increased NOS-2 expression may be important mechanisms in maintaining the mucosal barrier after sublethal LPS challenge.

Abstract. We performed 343 vascular reconstructions of the supraaortal arteries from April 1996 to April 2000. Of these patients, 30 underwent combined vascular reconstructions - 22 combined extrathoracal and 8 combined transthoracal reconstructions. In 15 patients, carotid endarterectomy was combined with other cervical surgical interventions. In 10 patients, the vascular operation was combined with surgical interventions in other regions. No permanent complications were observed 8-52 months postoperatively, with the exception of one hemiparesis in the complex vascular operations. Consequently, we recommend the simultaneous surgical approach after careful individual assessment.

Background and Aims: Dysfunction of the immune system with inappropriate responses of lymphocytes to various antigens has been implicated in the development of Crohn's disease. Therefore, the functional and phenotypic characteristics of intestinal intraepithelial lymphocytes (IEL) in comparison to peripheral blood lymphocytes (PBL) were analyzed in patients with and without Crohn's disease., Patients and Methods: Six patients with Crohn's disease and six control patients were studied. Isolated IEL and PBL were tested for cytolytic activity against the human adenocarcinoma cells DLD-1 and the human leukemia cells K562 in a 51Cr-release assay. Two-color flow cytometry was performed for phenotype analysis of isolated lymphocytes., Results: IEL from patients with Crohn's disease showed significantly increased cytolytic activity against epithelial-derived target cells when compared with IEL from control patients. In contrast, no functional changes were detectable among PBL from patients with Crohn's disease. IEL from patients with Crohn's disease contained a significantly higher percentage of CD8+ lymphocytes when compared with IEL from control patients, whereas no phenotypic changes were observed among PBL., Conclusions: In Crohn's disease, the functional and phenotypic changes of T cells are limited to lymphocytes of the intestinal mucosa. Furthermore, it is conceivable that the increased cytolytic activity of IEL contributes to the tissue damage in this disease.