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1.  Prediction of Postoperative Mortality in Liver Transplantation in the Era of MELD-Based Liver Allocation: A Multivariate Analysis 
PLoS ONE  2014;9(6):e98782.
Background and Aims
Liver transplantation is the only curative treatment for end-stage liver disease. While waiting list mortality can be predicted by the MELD-score, reliable scoring systems for the postoperative period do not exist. This study's objective was to identify risk factors that contribute to postoperative mortality.
Between December 2006 and March 2011, 429 patients underwent liver transplantation in our department. Risk factors for postoperative mortality in 266 consecutive liver transplantations were identified using univariate and multivariate analyses. Patients who were <18 years, HU-listings, and split-, living related, combined or re-transplantations were excluded from the analysis. The correlation between number of risk factors and mortality was analyzed.
A labMELD ≥20, female sex, coronary heart disease, donor risk index >1.5 and donor Na+>145 mmol/L were identified to be independent predictive factors for postoperative mortality. With increasing number of these risk-factors, postoperative 90-day and 1-year mortality increased (0–1: 0 and 0%; 2: 2.9 and 17.4%; 3: 5.6 and 16.8%; 4: 22.2 and 33.3%; 5–6: 60.9 and 66.2%).
In this analysis, a simple score was derived that adequately identified patients at risk after liver transplantation. Opening a discussion on the inclusion of these parameters in the process of organ allocation may be a worthwhile venture.
PMCID: PMC4048202  PMID: 24905210
2.  CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells 
A blockade of CD44 is considered a therapeutic option for the elimination of leukemia initiating cells. However, anti-panCD44 can interfere with hematopoiesis. Therefore we explored, whether a CD44 variant isoform (CD44v)-specific antibody can inhibit leukemia growth without attacking hematopoiesis. As a model we used CD44v10 transfected EL4 thymoma cells (EL4-v10).
The therapeutic efficacy of anti-panCD44 and anti-CD44v10 was evaluated after intravenous application of EL4/EL4-v10. Ex vivo and in vitro studies evaluated the impact of anti-panCD44 and anti-CD44v10 as well as of EL4 and EL4-v10 on hematopoietic stem cells (HSC) in cocultures with bone marrow stroma cells with a focus on adhesion, migration, cell cycle progression and apoptosis resistance.
Intravenously injected EL4-v10 grow in bone marrow and spleen. Anti-panCD44 and, more pronounced anti-CD44v10 prolong the survival time. The higher efficacy of anti-CD44v10 compared to anti-panCD44 does not rely on stronger antibody-dependent cellular cytotoxicity or on promoting EL4-v10 apoptosis. Instead, EL4 compete with HSC niche embedding. This has consequences on quiescence and apoptosis-protecting signals provided by the stroma. Anti-panCD44, too, more efficiently affected embedding of HSC than of EL4 in the bone marrow stroma. EL4-v10, by catching osteopontin, migrated on bone marrow stroma and did not or weakly interfere with HSC adhesion. Anti-CD44v10, too, did not affect the HSC – bone marrow stroma crosstalk.
The therapeutic effect of anti-panCD44 and anti-CD44v10 is based on stimulation of antibody-dependent cellular cytotoxicity. The superiority of anti-CD44v10 is partly due to blocking CD44v10-stimulated osteopontin expression that could drive HSC out of the niche. However, the main reason for the superiority of anti-CD44v10 relies on neither EL4-v10 nor anti-CD44v10 severely interfering with HSC – stroma cell interactions that, on the other hand, are affected by EL4 and anti-panCD44. Anti-panCD44 disturbing HSC embedding in the osteogenic niche weakens its therapeutic effect towards EL4. Thus, as far as leukemic cells express CD44v isoforms, the therapeutic use of anti-panCD44 should be avoided in favor of CD44v-specific antibodies.
PMCID: PMC4022365  PMID: 24684724
Leukemia; Antibody therapy; CD44v10; Hematopoiesis; Bone marrow stroma
3.  Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy 
BMC Cancer  2014;14:174.
Despite introduction of effective chemotherapy protocols, it has remained uncertain, if patients with colorectal cancer (CRC) liver metastases should receive adjuvant therapy. Clinical or molecular predictors may help to select patients at high risk for disease recurrence and death who obtain a survival advantage by adjuvant chemotherapy.
A total of 297 patients with potentially curative resection of CRC liver metastases were analyzed. These patients had no neoadjuvant therapy, no extrahepatic disease and negative resection margins. The primary endpoint was overall survival. Patients’ risk status was evaluated using the Memorial Sloan-Kettering Cancer Center clinical risk score (MSKCC-CRS). Multivariable analyses were performed using Cox proportional hazard models.
A total of 137 (43%) patients had a MSKCC-CRS > 2. Adjuvant chemotherapy was administered to 116 (37%) patients. Patients who received adjuvant chemotherapy were of younger age (p = 0.03) with no significant difference in the presence of multiple metastases (p = 0.72) or bilobar metastases (p = 0.08). On multivariate analysis adjuvant chemotherapy was associated with improved survival in the entire cohort (Hazard ratio 0.69; 95% confidence interval 0.69–0.98). It improved survival markedly in high-risk patients with a MSKCC-CRS > 2 (HR 0.40; 95% CI 0.23–0.69), whereas it was of no benefit in patients with a MSKCC-CRS ≤ 2 (HR 0.90; 95% CI 0.57–1.43).
The MSKCC-CRS offers a tool to select patients for adjuvant therapy after resection of CRC liver metastases. Validation in independent patient cohorts is required.
PMCID: PMC4008001  PMID: 24612620
Colorectal cancer; FOLFOX; FOLFIRI; 5-FU; Leucovorin; Liver resection
4.  Quality of life after curative liver resection: A single center analysis 
AIM: To evaluate quality of life (QoL) after curative liver resection and identify variables associated with decreased QoL.
METHODS: From October 2001 to July 2004, 323 patients underwent liver resection. At 3-36 mo after discharge, 188 patients were disease free. QoL was assessed using the Short Form (SF)-12 Health Survey with mental and physical component scales (SF-12 MCS and PCS), supplemented with generic questions concerning pain and liver-specific items.
RESULTS: Sixty-eight percent (128/188) returned the questionnaire, which was completed in 75% (96/128) of cases. Median SF-12 PCS and MCS were 46.7 (interquartile range: 34.2-53.9) and 54.1 (42.8-58.2). Fifty percent were pain free with a median symptom score of 1.75 (1.38-2.13). PCS was higher after major hepatectomy [57% (55/96)] compared to minor resection (P = 0.0049), which represented an improved QoL. QoL was not affected by sex but by age compared to the general German population. MCS was higher after liver surgery for metastatic disease [55.9 (47.5-58.8)] compared to primary carcinoma [49.6 (36.5-55.1)] and benign disease [49.2 (37.7-56.3)] (P = 0.0317). There was no correlation between length of postoperative period and QoL. Pain, deficiencies in everyday life and a high symptom score significantly decreased MCS and PCS.
CONCLUSION: Most patients were only marginally affected even after major liver resection; however, minor complications were associated with decreased SF-12 MCS and PCS and need careful attention.
PMCID: PMC2874143  PMID: 20480524
Quality of life; Liver resection
5.  Suppression of transforming growth factor β signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations 
Gut  2006;56(5):685-692.
Transforming growth factors βs (TGF‐βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF‐βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild‐type (FVB−/−) and transgenic mice that are heterozygous (FVB+/−) for expression of a dominant negative type II TGF‐β receptor.
After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.
The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild‐type mice resulted in 6‐ and 36‐fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/− mice exhibited minimal alterations in response to caerulein with attenuated neutrophil–macrophage infiltrates. Moreover, acini from FVB+/− mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.
Our findings indicate that a functional TGF‐β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.
PMCID: PMC1942167  PMID: 17135311
6.  DISCOVER trial– Distal resection of the pancreas with or without coverage of the pancreatic remnant: study protocol of a randomised controlled trial 
Trials  2013;14:430.
Distal pancreatectomy for benign and malignant tumours is the second most common surgical procedure on the pancreas. Postoperative pancreatic fistulas (POPF) represent the most significant clinical complication, causing prolongation of hospital stay and the need for additional diagnostic and therapeutic procedures. Although various techniques for preventing POPF have been evaluated, to date, there is no available technique that ensures closure of the pancreatic remnant.
DISCOVER will aim to investigate differences in the postoperative course after a distal pancreatectomy comparing the standard surgical technique with an alternative technique that provides additional coverage of the pancreatic remnant by the falciform ligament. The primary endpoint of this trial will be the rate of POPF. As secondary endpoints, incidence of postoperative morbidity and mortality, length of hospital stay, and quality of life will be assessed.
DISCOVER is a single-centre, randomised, controlled surgical trial. For statistical analysis, a binary logistic regression model will be used. With a level of significance of 5% and a power of 80%, a sample size of 75 patients per group has been identified as necessary.
The findings of this trial will help to evaluate the usefulness of the coverage procedure at reducing the rate of POPF. The results could influence the standard procedure for remnant closure after distal pancreatectomy.
Clinical trials register (DRKS-ID: DRKS00000546)
PMCID: PMC3867413  PMID: 24330450
Coverage procedure; Distal pancreatectomy; Falciform ligament; Pancreatic fistula
7.  Ruptured angiosarcoma of the liver treated by emergency catheter-directed embolization 
Angiosarcoma is a rare primary malignant neoplasm of the liver with a poor prognosis. Here, we report a case of a patient with a ruptured hepatic angiosarcoma which was treated by emergency catheter-directed embolization, followed by left-sided hemihepatectomy.
PMCID: PMC4066137  PMID: 16521200
Ruptured angiosarcoma; Liver; Embolization
8.  TIPSS for variceal hemorrhage after living related liver transplantation: A dangerous indication 
The introduction of transjugular intrahepatic portal-systemic stent-shunt (TIPSS) has been a major breakthrough in the treatment of portal hypertension, which has evolved to a large extent, into a routine procedure. A 21-year-old male patient with progressive graft fibrosis/cirrhosis requiring TIPSS for variceal hemorrhage in the esophagus due to portal hypertension was unresponsive to conventional measures two years after living related liver transplantation (LDLT). Subsequently, variceal hemorrhage was controlled, however, liver function decreased dramatically with consecutive multi organ failure. CT scan revealed substantial necrosis in the liver. The patient underwent successful “high urgent” cadaveric liver transplantation and was discharged on postoperative d 20 in a stable condition.
PMCID: PMC4066077  PMID: 16489658
Portal hypertension; Liver necrosis; Fibrosis; Cirrhosis
9.  Tumor-exosomes and leukocyte activation: an ambivalent crosstalk 
Tumor-exosomes being reported to suppress or promote a cancer-directed immune response, we used exosomes of the rat pancreatic adenocarcinoma BSp73ASML (ASML) to evaluate, whether and which steps in immune response induction can be affected by tumor-exosomes and how the impaired responsiveness can be circumvented.
ASML-exosomes bind to and are taken up by all leukocyte subpopulations in vivo and in vitro, uptake by CD11b+ leukocytes exceeding that by T and B cells. ASML-exosomes affect leukocyte proliferation via reduced CD44v6 up-regulation and lck, ZAP70 and ERK1,2 phosphorylation, which can be compensated by dendritic cells (DC). ASML-exosomes do not support Treg. Yet, impaired activation of anti-apoptotic signals is accompanied by slightly increased apoptosis susceptibility. IgM secretion is unaffected; NK and CTL activity are strengthened, ASML-exosomes co-operating with DC in CTL activation. ASML-exosomes transiently interfere with leukocyte migration by occupying migration-promoting receptors CD44, CD49d, CD62L and CD54 during binding/internalization.
ASML-exosomes might well serve as adjuvant in immunotherapy as they support leukocyte effector functions and have only a minor impact on leukocyte activation, which can be overridden by DC. However, exosome-induced modulation of immune cells relies, at least in part, on exosome uptake and message transfer. This implies that depending on the individual tumor's exosome composition, exosomes may distinctly affect the immune system. Nonetheless, whether immunotherapy can profit from using tumor-exosomes as adjuvant can easily be settled beforehand in vitro.
PMCID: PMC3519567  PMID: 23190502
Tumor-exosomes; T cell activation; CTL; NK; Apoptosis; Leukocyte migration
10.  New diagnostic criteria and severity assessment of acute cholecystitis in revised Tokyo guidelines 
The Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were published in 2007 as the world’s first guidelines for acute cholangitis and cholecystitis. The diagnostic criteria and severity assessment of acute cholecystitis have since been widely used all over the world. A validation study of TG07 has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. In addition, considerable new evidence referring to acute cholecystitis as well as evaluations of TG07 have been published. Consequently, we organized the Tokyo Guidelines Revision Committee to evaluate TG07, recognize new evidence, and conduct a multi-center analysis to revise the guidelines (TG13).
Methods and materials
We retrospectively analyzed 451 patients with acute cholecystitis from multiple tertiary care centers in Japan. All 451 patients were first evaluated using the criteria in TG07. The “gold standard” for acute cholecystitis in this study was a diagnosis by pathology. The validity of TG07 diagnostic criteria was investigated by comparing clinical with pathological diagnosis.
Of 451 patients evaluated, a total of 227 patients were given a diagnosis of acute cholecystitis by pathological examination (prevalence 50.3 %). TG07 criteria provided a definite diagnosis of acute cholecystitis in 224 patients. The sensitivity of TG07 diagnostic criteria for acute cholecystitis was 92.1 %, and the specificity was 93.3 %. Based on the preliminary results, new diagnostic criteria for acute cholecystitis were proposed. Using the new criteria, the sensitivity of definite diagnosis was 91.2 %, and the specificity was 96.9 %. The accuracy rate was improved from 92.7 to 94.0 %. In regard to severity grading among 227 patients, 111 patients were classified as Mild (Grade I), 104 as Moderate (Grade II), and 12 as Severe (Grade III).
The proposed new diagnostic criteria achieved better performance than the diagnostic criteria in TG07. Therefore, the proposed criteria have been adopted as new diagnostic criteria for acute cholecystitis and are referred to as the 2013 Tokyo Guidelines (TG13). Regarding severity assessment, no new evidence was found to suggest that the criteria in TG07 needed major adjustment. As a result, TG07 severity assessment criteria have been adopted in TG13 with minor changes.
PMCID: PMC3429769  PMID: 22872303
Acute cholecystitis; Murphy’s sign; Diagnostic criteria; Severity assessment; Guidelines
11.  Combining forces to hit cancer stem cells 
Oncoimmunology  2012;1(5):741-743.
TRAIL selectively kills cancer cells while bispecific antibody EpCAMxCD3 guides effector lymphocytes to cancer cells. Arming of ex vivo constructed TRAIL-lymphocytes with EpCAMxCD3 enhances contact time and affinity between lymphocytes and tumor cells and enforces tumor elimination. This boosts endogenous immune responses and augments the effect of cytotoxic tumor therapy.
PMCID: PMC3429579  PMID: 22934267
bispecific antibodies; apoptosis; granzyme/perforin; cancer stem cells; gene-immunotherapy
12.  New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo guidelines 
The Tokyo Guidelines for the management of acute cholangitis and cholecystitis were published in 2007 (TG07) and have been widely cited in the world literature. Because of new information that has been published since 2007, we organized the Tokyo Guidelines Revision Committee to conduct a multicenter analysis to develop the updated Tokyo Guidelines (TG13).
We retrospectively analyzed 1,432 biliary disease cases where acute cholangitis was suspected. The cases were collected from multiple tertiary care centers in Japan. The ‘gold standard’ for acute cholangitis in this study was that one of the three following conditions was present: (1) purulent bile was observed; (2) clinical remission following bile duct drainage; or (3) remission was achieved by antibacterial therapy alone, in patients in whom the only site of infection was the biliary tree. Comparisons were made for the validity of each diagnostic criterion among TG13, TG07 and Charcot’s triad.
The major changes in diagnostic criteria of TG07 were re-arrangement of the diagnostic items and exclusion of abdominal pain from the diagnostic list. The sensitivity improved from 82.8 % (TG07) to 91.8 % (TG13). While the specificity was similar to TG07, the false positive rate in cases of acute cholecystitis was reduced from 15.5 to 5.9 %. The sensitivity of Charcot’s triad was only 26.4 % but the specificity was 95.6 %. However, the false positive rate in cases of acute cholecystitis was 11.9 % and not negligible. As for severity grading, Grade II (moderate) acute cholangitis is defined as being associated with any two of the significant prognostic factors which were derived from evidence presented recently in the literature. The factors chosen allow severity assessment to be performed soon after diagnosis of acute cholangitis.
TG13 present a new standard for the diagnosis, severity grading, and management of acute cholangitis.
PMCID: PMC3429782  PMID: 22825491
Acute cholangitis; Biliary infection; Diagnostic criteria; Severity assessment; Charcot’s triad
13.  Effects of a Preconditioning Oral Nutritional Supplement on Pig Livers after Warm Ischemia 
HPB Surgery  2012;2012:783479.
Background. Several approaches have been proposed to pharmacologically ameliorate hepatic ischemia/reperfusion injury (IRI). This study was designed to evaluate the effects of a preconditioning oral nutritional supplement (pONS) containing glutamine, antioxidants, and green tea extract on hepatic warm IRI in pigs. Methods. pONS (70 g per serving, Fresenius Kabi, Germany) was dissolved in 250 mL tap water and given to pigs 24, 12, and 2 hrs before warm ischemia of the liver. A fourth dose was given 3 hrs after reperfusion. Controls were given the same amount of cellulose with the same volume of water. Two hours after the third dose of pONS, both the portal vein and the hepatic artery were clamped for 40 min. 0.5, 3, 6, and 8 hrs after reperfusion, heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), portal venous flow (PVF), hepatic arterial flow (HAF), bile flow, and transaminases were measured. Liver tissue was taken 8 hrs after reperfusion for histology and immunohistochemistry. Results. HR, MAP, CVP, HAF, and PVF were comparable between the two groups. pONS significantly increased bile flow 8 hrs after reperfusion. ALT and AST were significantly lower after pONS. Histology showed significantly more severe necrosis and neutrophil infiltration in controls. pONS significantly decreased the index of immunohistochemical expression for TNF-α, MPO, and cleaved caspase-3 (P < 0.001). Conclusion. Administration of pONS before and after tissue damage protects the liver from warm IRI via mechanisms including decreasing oxidative stress, lipid peroxidation, apoptosis, and necrosis.
PMCID: PMC3389686  PMID: 22791934
14.  Transient elastography with the XL probe rapidly identifies patients with nonhepatic ascites 
In contrast with other elastographic techniques, ascites is considered an exclusion criterion for assessment of fibrosis stage by transient elastography. However, a normal liver stiffness could rule out hepatic causes of ascites at an early stage. The aim of the present study was to determine whether liver stiffness can be generally determined by transient elastography through an ascites layer, to determine whether the ascites-mediated increase in intra-abdominal pressure affects liver stiffness, and to provide initial data from a pilot cohort of patients with various causes of ascites.
Methods and results
Using the XL probe in an artificial ascites model, we demonstrated (copolymer phantoms surrounded by water) that a transient elastography-generated shear wave allows accurate determination of phantom stiffness up to a water lamella of 20 mm. We next showed in an animal ascites model that increased intra-abdominal pressure does not affect liver stiffness. Liver stiffness was then determined in 24 consecutive patients with ascites due to hepatic (n = 18) or nonhepatic (n = 6) causes. The cause of ascites was eventually clarified using routine clinical, imaging, laboratory, and other tools. Valid (75%) or acceptable (25%) liver stiffness data could be obtained in 23 patients (95.8%) with ascites up to an ascites lamella of 39 mm. The six patients (25%) with nonhepatic causes of ascites (eg, pancreatitis, peritoneal carcinomatosis) had a significantly lower liver stiffness (<8 kPa) as compared with the remaining patients with hepatic ascites (>30 kPa). Mean liver stiffness was 5.4 kPa ± 1.3 versus 66.2 ± 13.3 kPa.
In conclusion, the presence of ascites and increased intra-abdominal pressure does not alter underlying liver stiffness as determined by transient elastography. We suggest that, using the XL probe, transient elastography can be used first-line to identify patients with nonhepatic ascites at an early stage.
PMCID: PMC3846526  PMID: 24367229
ascites; liver stiffness; transient elastography; liver cirrhosis; noncirrhotic ascites; congestion; peritoneal carcinomatosis; intra-abdominal pressure; alcoholic liver disease
15.  Evaluation of the safety and efficacy of MonoMax® suture material for abdominal wall closure after primary midline laparotomy—a controlled prospective multicentre trial: ISSAAC [NCT005725079] 
Langenbeck's Archives of Surgery  2011;397(3):363-371.
Different suture techniques and various suture materials are in use to close midline incisions after primary laparotomy. The ISSAAC study aimed to assess the safety and efficacy of the new ultra-long-term absorbable, elastic monofilament suture material MonoMax® for abdominal wall closure.
This is a single-arm, multicentre prospective study that included 150 patients undergoing a primary elective midline incision. The control group consists of 141 patients from the INSECT study who received MonoPlus® or PDS® for abdominal wall closure. The incidences of burst abdomen and wound infection until the day of discharge were defined as the primary composite endpoints. The rate of incisional hernias 1 year after surgery, the length of postoperative hospital stay and safety parameters served as secondary endpoints. The study has been registered under [NCT005725079].
Eleven patients in the ISSAAC study [7.3%; 95% CI = (3.9; 13.1%)] experienced wound infection or burst abdomen until the day of discharge as compared to 16 [11.3%; 95% CI = (6.6; 17.8%)] patients in the INSECT control group (p = 0.31). The length of postoperative hospital stay was comparable in both study groups. One year after surgery, incisional hernias were observed in 21 ISSAAC patients (14.0%) in contrast to 30 hernias (21.3%) in the INSECT control group.
The ultra-long-term absorbable, elastic monofilament suture material MonoMax® is safe and efficient for abdominal wall closure.
PMCID: PMC3281202  PMID: 22183105
Laparotomy; Abdominal hernia; Fascia; Suture materials; Humans
16.  Involvement of the epidermal growth factor receptor in the modulation of multidrug resistance in human hepatocellular carcinoma cells in vitro 
Hepatocellular carcinoma (HCC) is a molecular complex tumor with high intrinsic drug resistance. Recent evidence suggests an involvement of the tyrosine kinase pathway in the regulation of ATP-binding cassette protein (ABC-transport protein) mediated multidrug resistance in cancer cells. The aim of this study was to examine whether EGFR inhibition sensitizes HCCs to chemotherapy and to elucidate its mechanism.
Chemotherapeutic treatment induces multidrug resistance and significantly increases ABC-transport protein expression and function in a time- and dose-dependent manner in HCC cells. Furthermore, cytostatic treatment increases the mRNA expression of tyrosine kinases and induces the phosphorylation of ERK. EGF activation of the tyrosine kinase pathway up-regulated the ABC-transport protein mRNA expression and enhanced the survival of resistant HCC cells. Consistent with these effects, inhibition of the EGFR using siRNA decreased the ABC-transport protein mRNA expression and inhibited the proliferation of resistant cells. Additional treatment with Gefitinib, a clinically approved EGFR inhibitor, caused a dose-dependent reversal of resistance to conventional chemotherapy.
The present study demonstrates that the multidrug resistance of HCC is modulated through the EGF-activated tyrosine kinase cascade. Consequentially, the restoration of chemosensitivity by EGFR inhibition may lead towards new tailored therapies in patients with highly resistant tumors.
PMCID: PMC3228664  PMID: 22088142
17.  Expression and prognostic value of circulating angiogenic cytokines in pancreatic cancer 
BMC Cancer  2011;11:286.
The utility of circulating angiogenic cytokines (CAC) as biomarkers in pancreatic cancer has not been clarified yet. We investigated the expression and prognostic associations of seven CAC in patients with pancreatic cancer.
Serum samples were collected preoperatively in patients undergoing surgery for localized pancreatic cancer (n = 74), metastatic pancreatic cancer (n = 24) or chronic pancreatitis (n = 20) and in healthy controls (n = 48). Quantitative enzyme-linked immunosorbent assays and multiplex protein arrays were used to determine circulating levels of VEGF, VEGFR-1, PlGF, PDGF-AA, PDGF-BB, Ang-1 and EGF. Multivariate analyses on cancer-specific survival were performed with a Cox proportional hazards model.
VEGF (p < 0.0001), PDGF-AA (p < 0.0001), Ang-1 (p = 0.002) and EGF (p < 0.0001) were differentially expressed in patients with pancreatic cancer compared to healthy controls. The presence of lymph node metastases was associated with increased levels of all CAC except for PlGF, whereas there were only minor associations of CAC with other clinicopathologic variables. The multivariate model including the entire angiogenic panel revealed high levels of circulating PDGF-AA (hazard ratio 4.58; 95% confidence interval 1.43 - 14.69) as predictor of poor cancer-specific survival, whereas high levels of PDGF-BB (0.15; 0.15 - 0.88), Ang-1 (0.30; 0.10 - 0.93) and VEGF (0.24; 0.09 - 0.57) were associated with a favorable prognosis.
Circulating levels of certain angiogenic cytokines correlate with patients' prognosis after resection for pancreatic cancer, if a panel of several CAC is considered simultaneously. These data should be considered in future studies evaluating angiogenic factors as prognostic biomarkers and therapeutic targets in patients with pancreatic cancer.
PMCID: PMC3144458  PMID: 21729304
18.  Current State of Surgical Management of Pancreatic Cancer 
Cancers  2011;3(1):1253-1273.
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year survival rates to approximately 20–25%. Pancreatic surgery is a technically challenging procedure and has significantly changed during the past decades with regard to technical aspects as well as perioperative care. Standardized resections can be carried out with low morbidity and mortality below 5% in high volume institutions. Furthermore, there is growing evidence that also more extended resections including multivisceral approaches, vessel reconstructions or surgery for tumor recurrence can be carried out safely with favorable outcomes. The impact of adjuvant treatment, especially chemotherapy, has increased dramatically within recent years, leading to significantly improved postoperative survival, making pancreatic cancer therapy an interdisciplinary approach to achieve best results.
PMCID: PMC3756412  PMID: 24212660
pancreatic cancer; surgery; standard resection; extended approach
19.  Heterogeneous detection of circulating tumor cells in patients with colorectal cancer by immunomagnetic enrichment using different EpCAM-specific antibodies 
BMC Biotechnology  2010;10:35.
Circulating tumor cells (CTC) and disseminated tumor cells (DTC) are thought to be responsible for metastasis, so the detection of CTC may serve as individual prognostic factor in patients suffering from colorectal cancer. Therefore, a series of immunomagnetic enrichment methods for CTC have been developed using a variety of monoclonal antibodies against the Epithelial Cell Adhesion Molecule (EpCAM). However, it remains unclear whether all commercially available EpCAM antibodies show the same sensitivity and specificity. Furthermore, it remains unclear which method of sample preparation and cell extraction is most suitable for immunomagnetic enrichment and detection of CTC. In this study, we aimed to investigate whether the detection of CTC by a cytokeratin 20 reverse transcriptase-polymerase chain reaction (CK20 RT-PCR) may be influenced by the use of various Epithelial Cell Adhesion Molecule (EpCAM) antibodies for immunomagnetic isolation of CTC.
Using both EpCAM antibodies (mAb BerEP4 and mAb KS1/4) for immunomagnetic enrichment in blood samples of 39 patients with colorectal cancer we found heterogenous results in each patient with regard to tumor cell detection. In the tumor cell spiking experiments with whole blood samples the sensitivity of the CK 20 RT-PCR assay was higher using immunomagnetic beads coated with mAb KS1/4 compared to precoated mAb BerEP4 Dynabeads. Extraction of MNC fraction with Ficoll gradient centrifugation prior to immunomagnetic enrichment resulted in a higher sensitivity of the CK 20 RT-PCR assay.
We concluded that isolation and detection of CTC with immunomagnetic enrichment methods is critically dependent on the used EpCAM clone. Further studies with a larger number of patients should clarify if the enrichment protocol influences the prognostic value of the tumor cell detection protocol.
PMCID: PMC2868015  PMID: 20426872
20.  The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis 
Gut  2006;56(4):534-544.
Background and aim
Chronic pancreatitis is characterised by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neurochemical damage after nerve injury. The role of artemin and its receptor GFRα3 was investigated in patients with chronic pancreatitis.
Expression of artemin and its receptor GFRα3 was studied in chronic pancreatitis (n = 66) and normal (n = 22) pancreatic tissues by quantitative reverse transcription‐polymerase chain reaction (QRT‐PCR) and western blot analysis. Artemin expression was correlated with pain and pathomorphological changes (inflammation, perineural inflammatory cell infiltration, neural alterations and fibrosis). Immunohistochemistry was used to localise artemin and GFRα3 in the tissues. To detect sources of artemin, primary human pancreatic stellate cells (hPSCs) were isolated and analysed by QRT‐PCR and immunocytology analysis.
In chronic pancreatitis, artemin and GFRα3 were significantly overexpressed and located in smooth muscle cells of arteries, Schwann cells and neural ganglia. Increased levels of artemin mRNA correlated with pain severity, inflammation, perineural inflammatory cell infiltration, neural density and hypertrophy. Furthermore, the severity of fibrosis was positively related with artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin mRNA which were upregulated by exposure to transforming growth factor (TGF)β1.
Overexpression of artemin in chronic pancreatitis might function as a compensatory upregulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGFβ1 seems not only to increase pancreatic fibrosis but also to contribute to neural alteration by stimulating artemin expression in hPSCs. However, overexpression of endogenous artemin does not seem to be sufficient to prevent pain in chronic pancreatitis.
PMCID: PMC1856869  PMID: 17047099
21.  A proposal for a new clinical classification of chronic pancreatitis 
BMC Gastroenterology  2009;9:93.
The clinical course of chronic pancreatitis is still unpredictable, which relates to the lack of the availability of a clinical classification. Therefore, patient populations cannot be compared, the course and the outcome of the disease remain undetermined in the individual patient, and treatment is not standardized.
To establish a clinical classification for chronic pancreatitis which is user friendly, transparent, relevant, prognosis- as well as treatment-related and offers a frame for future disease evaluation.
Diagnostic requirements will include one clinical criterion, in combination with well defined imaging or functional abnormalities.
A classification system consisting of three stages (A, B and C) is presented, which fulfils the above-mentioned criteria. Clinical criteria are: pain, recurrent attacks of pancreatitis, complications of chronic pancreatitis (e.g. bile duct stenosis), steatorrhea, and diabetes mellitus. Imaging criteria consist of ductal or parenchymal changes observed by ultrasonography, ERCP, CT, MRI, and/or endosonography.
A new classification of chronic pancreatitis, based on combination of clinical signs, morphology and function, is presented. It is easy to handle and an instrument to study and to compare the natural course, the prognosis and treatment of patients with chronic pancreatitis.
PMCID: PMC2804657  PMID: 20003450
22.  An open label randomized multicentre phase IIIb trial comparing parenteral substitution versus best supportive nutritional care in subjects with pancreatic adenocarcinoma receiving 5-FU plus oxaliplatin as 2nd or higher line chemotherapy regarding clinical benefit - PANUSCO 
BMC Cancer  2009;9:412.
Pancreatic cancer is an extremely aggressive malignancy. Subjects are afflicted with a variety of disconcerting symptoms, including profound cachexia. Recent data indicate that the outcome of oncological patients suffering from cancer cachexia could be improved by parenteral nutrition and that parenteral nutrition results in an improvement of quality of life and in prolonged survival.
Currently, there is no recommendation of routine use of parenteral nutrition. Furthermore, there is no clear recommendation for 2nd line therapy (or higher) for pancreatic adenocarcinoma but often asked for.
PANUSCO is an open label, controlled, prospective, randomized, multicentre phase IIIb trial with two parallel arms. All patients will be treated with 5-fluorouracil, folinic acid and oxaliplatin on an outpatient basis at the study sites. Additionally, all patients will receive best supportive nutritional care (BSNC). In the experimental group BSNC will be expanded with parenteral nutrition (PN). In contrast, patients in the control group obtain solely BSNC. Parenteral nutrition will be applied overnight and at home by experienced medical staff.
A total of 120 patients are planned to be enrolled. Primary endpoint is the comparison of the treatment groups with respect to event-free survival (EFS), defined as the time from randomization till time to development of an event defined as either an impairment (change from baseline of at least ten points in EORTC QLQ-C30, functional domain total score) or withdrawal due to fulfilling the special defined stopping criteria for chemotherapy as well as for nutritional intervention (NI) or death from any cause (whichever occurs first).
The aim of this clinical trial is to evaluate whether parenteral nutrition in combination with defined 2nd line or higher chemotherapy has an impact on quality of life for patients suffering from pancreatic adenocarcinoma.
Trial registration
Current Controlled Trials ISRCTN60516908.
PMCID: PMC2787534  PMID: 19943918
23.  Diagnostic criteria and severity assessment of acute cholecystitis: Tokyo Guidelines 
The aim of this article is to propose new criteria for the diagnosis and severity assessment of acute cholecystitis, based on a systematic review of the literature and a consensus of experts. A working group reviewed articles with regard to the diagnosis and treatment of acute cholecystitis and extracted the best current available evidence. In addition to the evidence and face-to-face discussions, domestic consensus meetings were held by the experts in order to assess the results. A provisional outcome statement regarding the diagnostic criteria and criteria for severity assessment was discussed and finalized during an International Consensus Meeting held in Tokyo 2006. Patients exhibiting one of the local signs of inflammation, such as Murphy’s sign, or a mass, pain or tenderness in the right upper quadrant, as well as one of the systemic signs of inflammation, such as fever, elevated white blood cell count, and elevated C-reactive protein level, are diagnosed as having acute cholecystitis. Patients in whom suspected clinical findings are confirmed by diagnostic imaging are also diagnosed with acute cholecystitis. The severity of acute cholecystitis is classified into three grades, mild (grade I), moderate (grade II), and severe (grade III). Grade I (mild acute cholecystitis) is defined as acute cholecystitis in a patient with no organ dysfunction and limited disease in the gallbladder, making cholecystectomy a low-risk procedure. Grade II (moderate acute cholecystitis) is associated with no organ dysfunction but there is extensive disease in the gallbladder, resulting in difficulty in safely performing a cholecystectomy. Grade II disease is usually characterized by an elevated white blood cell count; a palpable, tender mass in the right upper abdominal quadrant; disease duration of more than 72 h; and imaging studies indicating significant inflammatory changes in the gallbladder. Grade III (severe acute cholecystitis) is defined as acute cholecystitis with organ dysfunction.
PMCID: PMC2784516  PMID: 17252300
Acute cholecystitis; Diagnosis; Severity of illness index; Guidelines; Infection
24.  Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines 
Because acute cholangitis sometimes rapidly progresses to a severe form accompanied by organ dysfunction, caused by the systemic inflammatory response syndrome (SIRS) and/or sepsis, prompt diagnosis and severity assessment are necessary for appropriate management, including intensive care with organ support and urgent biliary drainage in addition to medical treatment. However, because there have been no standard criteria for the diagnosis and severity assessment of acute cholangitis, practical clinical guidelines have never been established. The aim of this part of the Tokyo Guidelines is to propose new criteria for the diagnosis and severity assessment of acute cholangitis based on a systematic review of the literature and the consensus of experts reached at the International Consensus Meeting held in Tokyo 2006. Acute cholangitis can be diagnosed if the clinical manifestations of Charcot’s triad, i.e., fever and/or chills, abdominal pain (right upper quadrant or epigastric), and jaundice are present. When not all of the components of the triad are present, then a definite diagnosis can be made if laboratory data and imaging findings supporting the evidence of inflammation and biliary obstruction are obtained. The severity of acute cholangitis can be classified into three grades, mild (grade I), moderate (grade II), and severe (grade III), on the basis of two clinical factors, the onset of organ dysfunction and the response to the initial medical treatment. “Severe (grade III)” acute cholangitis is defined as acute cholangitis accompanied by at least one new-onset organ dysfunction. “Moderate (grade II)” acute cholangitis is defined as acute cholangitis that is unaccompanied by organ dysfunction, but that does not respond to the initial medical treatment, with the clinical manifestations and/or laboratory data not improved. “Mild (grade I)” acute cholangitis is defined as acute cholangitis that responds to the initial medical treatment, with the clinical findings improved.
PMCID: PMC2784515  PMID: 17252297
Cholangitis; Diagnosis; Severity of illness index; Guidelines
25.  Techniques of biliary drainage for acute cholangitis: Tokyo Guidelines 
Biliary decompression and drainage done in a timely manner is the cornerstone of acute cholangitis treatment. The mortality rate of acute cholangitis was extremely high when no interventional procedures, other than open drainage, were available. At present, endoscopic drainage is the procedure of first choice, in view of its safety and effectiveness. In patients with severe (grade III) disease, defined according to the severity assessment criteria in the Guidelines, biliary drainage should be done promptly with respiration management, while patients with moderate (grade II) disease also need to undergo drainage promptly with close monitoring of their responses to the primary care. For endoscopic drainage, endoscopic nasobiliary drainage (ENBD) or stent placement procedures are performed. Randomized controlled trials (RCTs) have reported no difference in the drainage effect of these two procedures, but case-series studies have indicated the frequent occurrence of hemorrhage associated with endoscopic sphincterotomy (EST), and complications such as pancreatitis. Although the usefulness of percutaneous transhepatic drainage is supported by the case-series studies, its lower success rate and higher complication rates makes it a second-option procedure.
PMCID: PMC2784512  PMID: 17252295
Cholangitis; Endoscopic sphincterotomy; Biliary drainage; Percutaneous; Endoscopy; Endoscopic cholangiopancreatography; Guidelines

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