Patients with colorectal cancer and brain metastasis: The relevance of extracranial metastatic patterns predicting time intervals to first occurrence of intracranial metastasis and survival.

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.

Risk stratification for postoperative pancreatic fistula using the pancreatic surgery registry StuDoQ|Pancreas of the German Society for General and Visceral Surgery.

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.

Perioperative chemotherapy vs. neoadjuvant chemoradiation in gastroesophageal junction adenocarcinoma : A population-based evaluation of the Munich Cancer Registry.

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.

Laparoscopic versus open distal pancreatectomy-a propensity score-matched analysis from the German StuDoQ|Pancreas registry.

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.

Outcome of gastric cancer in the elderly: a population-based evaluation of the Munich Cancer Registry.

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.

[Measures for preventing bile duct injuries during difficult cholecystectomies-Bail-out procedures]. / Maßnahmen zur Vermeidung von Gallengangsläsionen bei schwieriger Cholezystektomie ­ Bail-out-Prozeduren.

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.

[Minimum volume requirements-perspective of a tertiary care hospital]. / Mindestmengen aus der Sicht einer Klinik der Schwerpunktversorgung.

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.

Comparison of T-cell receptor repertoire restriction in blood and tumor tissue of colorectal cancer patients.

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.

Evolving experience with prevention and treatment of splenic artery syndrome after orthotopic liver transplantation.

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.

The possible use of stem cells in regenerative medicine: dream or reality?

Stem cells are one of the most fascinating areas in regenerative medicine today. They play a crucial role in the development and regeneration of human life and are defined as cells that continuously reproduce themselves while maintaining the ability to differentiate into various cell types. Stem cells are found at all developmental stages, from embryonic stem cells that differentiate into all cell types found in the human body to adult stem cells that are responsible for tissue regeneration. The general opinion postulates that clinical therapies based on the properties of stem cells may have the potential to change the treatment of degenerative diseases or important traumatic injuries in the "near" future. We here briefly review the literature in particularly for the liver, heart, kidney, cartilage, and bone regeneration.

Sex-specific differences in the expression levels of estrogen receptor subtypes in colorectal cancer.

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.

Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort.

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.

Group A Streptococci: A rare and often misdiagnosed cause of spontaneous bacterial peritonitis in adults.

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.

Brain Metastasis in Colorectal Cancer Patients: Survival and Analysis of Prognostic Factors.

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.

Increased oxidative stress response in granulocytes from older patients with a hip fracture may account for slow regeneration.

Proximal femur fracture, a typical fracture of the elderly, is often associated with morbidity, reduced quality of life, impaired physical function and increased mortality. There exists evidence that responses of the hematopoietic microenvironment to fractures change with age. Therefore, we investigated oxidative stress markers and oxidative stress-related MAPK activation in granulocytes from the young and the elderly with and without fractured long bones. Lipid peroxidation levels were increased in the elderly controls and patients. Aged granulocytes were more sensitive towards oxidative stress induced damage than young granulocytes. This might be due to the basally increased expression of SOD-1 in the elderly, which was not further induced by fractures, as observed in young patients. This might be caused by an altered MAPK activation. In aged granulocytes basal p38 and JNK activities were increased and basal ERK1/2 activity was decreased. Following fracture, JNK activity decreased, while ERK1/2 and p38 activities increased in both age groups. Control experiments with HL60 cells revealed that the observed p38 activation depends strongly on age. Summarizing, we observed age-dependent changes in the oxidative stress response system of granulocytes after fractures, for example, altered MAPK activation and SOD-1 expression. This makes aged granulocytes vulnerable to the stress stimuli of the fracture and following surgery.

Level of hospital care and outcome of gastric cancer: a population-based evaluation of the Munich Cancer Registry.

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.

The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-ß1-induced cellular damage.

BACKGROUND: 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)-ß signaling was investigated by a Smad3/4-responsive luciferase-reporter assay. RESULTS: Ethanol and TGF-ß1 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-ß1-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.

Human hepatocytes: isolation, culture, and quality procedures.

The use of isolated human liver cells in research and development has gained increasing interest during the past years. The possible application may vary between elucidation of new biochemical pathways in liver diseases, drug development, safety issues, and new therapeutic strategies up to direct clinical translation for liver support. However, the isolation of human liver cells requires a well-developed logistic network among surgeons, biologists, and technicians to obtain a high quality of cells. Our laboratories have been involved in various applications of human liver cells and we have long-lasting experiences in human liver cell isolation and their application in R&D. We here summarize the present protocol of our laboratories for cell isolation from normal resected liver tissue, the most common tissue available. In addition, we discuss the necessary network in the clinic and quality controls to maintain human liver cells in culture and the effect of 3D extracellular matrix in cultured cells which results in preservation of hepatocyte epithelial polarity in the form of bile canaliculi and repression of epithelial to mesenchymal transitions occurring in 2D cultures.

Long-term results of subtotal vs total parathyroidectomy without autotransplantation in kidney transplant recipients.

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.

Long-term results after liver transplantation.

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.