Patient-reported outcomes at three months after pancreatic surgery for benign and malignant diseases - A prospective observational study.

BACKGROUND/OBJECTIVES: Pancreatic surgery may have a long-lasting effect on patients' health status and quality of life (QoL). We aim to evaluate patient-reported outcomes (PRO) 3 months after pancreatic surgery. METHODS: Patients scheduled for pancreatic surgery were enrolled in a prospective trial at five German centers. Patients completed PRO questionnaires (EQ-5D-5L, EORTC QLQ-PAN26, patient-reported happiness, and HADS-D), we report the first follow-up 3 months after surgery as an interim analysis. Statistical testing was performed using R software. RESULTS: From 2019 to 2022 203 patients were enrolled, a three-month follow-up questionnaire was available in 135 (65.5 %). 77 (57.9 %) underwent surgery for malignant disease. Patient-reported health status (EQ-5D-5L) was impaired in 4/5 dimensions (mobility, self-care, usual activities, pain, discomfort) for patients with malignant and 3/5 dimensions (mobility, self-care, usual activities) for patients with benign disease 3 months after surgery (p < 0.05). Patients with malignant disease reported an increase in depressive symptoms, patients with benign disease had a decrease in anxiety symptoms (HADS-D; depression: 5.00 vs 6.51, p = 0.002; anxiety: 8.04 vs. 6.34, p = 0.030). Regarding pancreatic-disease-specific symptoms (EORTC-QLQ-PAN26), patients with malignant disease reported increased problems with taste, weight loss, weakness in arms and legs, dry mouth, body image and troubling side effects at three months. Patients with benign disease indicated more weakness in arms and legs, troubling side effects but less future worries at three months. CONCLUSION: Patient-reported outcomes of patients undergoing pancreatic surgery for benign vs. malignant disease show important differences. Patients with malignant tumors report more severely decreased quality of life 3 months postoperatively than patients with benign tumors.

Proposal of a Multivariable Prediction Model for Graded Morbidity after Liver Resection for Colorectal Metastases.

BACKGROUND: Prognostic models to predict individual early postoperative morbidity after liver resection for colorectal liver metastases (CLM) are not available but could enable optimized preoperative patient selection and postoperative surveillance for patients at greater risk of complications. The aim of this study was to establish a prognostic model for the prediction of morbidity after liver resection graded according to Dindo. METHODS: N = 679 cases of primary liver resection for CLM were retrospectively analyzed using univariable and multivariable ordinal regression analyses. Receiver operating characteristics curve (ROC) analysis was utilised to assess the sensitivity and specificity of predictions and their potential usefulness as prognostic models. Internal validation of the score was performed using data derived from 129 patients. RESULTS: The final multivariable regression model revealed lower preoperative levels, a greater number of units of intraoperatively transfused packed red blood cells (pRBCs), longer duration of surgery, and larger metastases to independently influence postoperatively graded morbidity. ROC curve analysis demonstrated that the multivariable regression model is able to predict each individual grade of postoperative morbidity with high sensitivity and specificity. The areas under the receiver operating curves (AUROC) for all of these predictions of individual grades of morbidity were > 0.700, indicating potential usefulness as a predictive model. Moreover, a consistent concordance in Grades I, II, IV, and V according to the classification proposed by Dindo et al. was observed in the internal validation. CONCLUSION: This study proposes a prognostic model for the prediction of each grade of postoperative morbidity after liver resection for CLM with high sensitivity and specificity using pre- and intraoperatively available variables.

Transcriptome Profiling Identifies TIGIT as a Marker of T-Cell Exhaustion in Liver Cancer.

BACKGROUND AND AIMS: Programmed death 1 (PD-1) checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of treated patients. The roles of other coinhibitory molecules and their individual contributions to T-cell dysfunction in liver cancer, however, remain largely elusive. APPROACH AND RESULTS: We performed a comprehensive mRNA profiling of cluster of differentiation 8 (CD8) T cells in a murine model of autochthonous liver cancer by comparing the transcriptome of naive, functional effector, and exhausted, tumor-specific CD8 T cells. Subsequently, we functionally validated the role of identified genes in T-cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that up-regulation of the inhibitory immune receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) represents a hallmark in the process of T-cell exhaustion in liver cancer. Compared to PD-1, expression of TIGIT more reliably identified exhausted CD8 T cells at different stages of their differentiation. In combination with PD-1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor-infiltrating CD8 T cells in tissue samples of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma and identify two subsets of patients based on differential expression of TIGIT on tumor-specific T cells. CONCLUSIONS: Our transcriptome analysis provides a valuable resource for the identification of key pathways involved in T-cell exhaustion in patients with liver cancer and identifies TIGIT as a potential target in checkpoint combination therapies.

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

Association of subcellular localization of TEAD transcription factors with outcome and progression in pancreatic ductal adenocarcinoma.

BACKGROUND: Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive. METHODS: A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival. CONCLUSION: Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.

Extended hepatic metastasectomy for renal cell carcinoma-new aspects in times of targeted therapy: a single-center experience over three decades.

PURPOSE: Despite the introduction of novel targeted therapies on patients with renal cell carcinoma, syn- and metachronous metastases (including hepatic lesions) are observed frequently and significantly influence patient survival. With introduction of targeted therapies as an effective alternative to surgery, therapeutical strategies in stage IV disease must be reevaluated. METHODS: This is a retrospective analysis of 40 patients undergoing hepatic resection of histologically confirmed RCC metastases at our institution between April 1993 and April 2017. RESULTS: The interval between nephrectomy for renal cell carcinoma and hepatic metastasectomy was 44.0 months (3.3-278.5). Liver resections of different extents were performed, including multivisceral resections. The median follow-up was 37.8 months (0.5-286.5). Tumor recurrence after resection of hepatic metastases occurred in 19 patients resulting in a median disease-free survival of 16.2 months (0.7-265.1) and a median overall survival of 37.8 months (0.5-286.5). Multivariable analysis identified multivisceral resection as an independent risk factor for disease-free and overall survival (p = 0.043 and p = 0.001, respectively). A longer interval between nephrectomy and hepatic metastasectomy was identified as an independent significant protective factor for overall survival (p < 0.001). Patients undergoing metastasectomy after introduction of sunitinib in Europe in 2006 (n = 15) showed a significantly longer overall survival (45.2 (9.1-111.0) versus 27.5 (0.5-286.52) months in the preceding era; p = 0.038). CONCLUSION: Hepatic metastasectomy, including major and extended resections, on patients with metastasized renal cell carcinoma can be performed safely and may facilitate long-term survival. Due to significant morbidity and increased mortality, multivisceral resections must be weighed against other options, such as targeted therapy.

Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.

PURPOSE: The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. Despite advances in surgical and non-surgical treatment, reported outcomes are still poor and surgical resection remains to be the only chance for long-term survival of affected patients. The identification and validation of prognostic factors and scores, such as the recently introduced resection severity index, for postoperative morbidity and mortality are essential to facilitate optimal therapeutic regimens. METHODS: This is a retrospective analysis of 269 patients undergoing resection of histologically confirmed intrahepatic cholangiocarcinoma between February 1996 and September 2018 at a tertiary referral center for hepatobiliary surgery. Regression analyses were performed to evaluate potential prognostic factors, including the resection severity index. RESULTS: Median postoperative follow-up time was 22.93 (0.10-234.39) months. Severe postoperative complications (≥ Clavien-Dindo grade III) were observed in 94 (34.9%) patients. The body mass index (p = 0.035), the resection severity index (ASAT in U/l divided by Quick in % multiplied by the extent of liver resection graded in points; p = 0.006), additional hilar bile duct resection (p = 0.005), and number of packed red blood cells transfused during operation (p = 0.036) were independent risk factors for the onset of severe postoperative complications. Median Kaplan-Meier survival after resection was 27.63 months. Preoperative leukocytosis (p = 0.003), the resection severity index (p = 0.005), multivisceral resection (p = 0.001), and T stage ≥ 3 (p = 0.013) were identified as independent risk factors for survival. CONCLUSION: Preoperative leukocytosis and the resection severity index are useful variables for preoperative risk stratification since they were identified as significant predictors for postoperative morbidity and mortality, respectively.

[Best supportive care in a young patient with locally advanced MSI-high colon cancer?] / Best supportive care bei einer jungen Patientin mit lokal fortgeschrittenem MSI-high-Kolonkarzinom?

Molecular diagnostics are increasingly important to guide treatment decisions in oncologic patients. For instance, the presence of high-grade microsatellite-instability (MSI-high) is considered to be one of the major positive predictors of therapy response to immune-checkpoint inhibitors in patients with solid tumors. Based on impressive results from several immune-oncology trials, the American Food and Drug Administration (FDA) granted approval to immunotherapy in any previously treated, MSI-high solid cancer in 2017. Here, we report the clinical case of a young patient with MSI-high colorectal cancer. The case illustrates, that insurance companies in Germany are still reluctant to cover the cost of immunotherapy in this specific patient subgroup, which, in our opinion, results in an ethically problematic therapeutic dilemma.

Hepatocyte-induced CD4+ T cell alloresponse is associated with major histocompatibility complex class II up-regulation on hepatocytes and suppressible by regulatory T cells.

Hepatocyte transplantation is a promising therapeutic approach for various liver diseases. Despite the liver's tolerogenic potential, early immune-mediated loss of transplanted cells is observed, and longterm acceptance has not been achieved yet. Patients deemed tolerant after liver transplantation presented an increased frequency of regulatory T cells (Tregs), which therefore also might enable reduction of posttransplant cell loss and enhance longterm allograft acceptance. We hence characterized hepatocyte-induced immune reactions and evaluated the immunomodulatory potential of Tregs applying mixed lymphocyte cultures and mixed lymphocyte hepatocyte cultures. These were set up using peripheral blood mononuclear cells and primary human hepatocytes, respectively. Polyclonally expanded CD4+ CD25high CD127low Tregs were added to cocultures in single-/trans-well setups with/without supplementation of anti-interferon γ (IFNγ) antibodies. Hepatocyte-induced alloresponses were then analyzed by multicolor flow cytometry. Measurements indicated that T cell response upon stimulation was associated with IFNγ-induced major histocompatibility complex (MHC) class II up-regulation on hepatocytes and mediated by CD4+ T cells. An indirect route of antigen presentation could be ruled out by use of fragmented hepatocytes and culture supernatants of hepatocytes. Allospecific proliferation was accompanied by inflammatory cytokine secretion. CD8+ T cells showed early up-regulation of CD69 despite lack of cell proliferation in the course of coculture. Supplementation of Tregs effectively abrogated hepatocyte-induced alloresponses and was primarily cell contact dependent. In conclusion, human hepatocytes induce a CD4+ T cell alloresponse in vitro, which is associated with MHC class II up-regulation on hepatocytes and is susceptible to suppression by Tregs. Liver Transplantation 24 407-419 2018 AASLD.

Relevant prognostic factors influencing outcome of patients after surgical resection of distal cholangiocarcinoma.

BACKGROUND: Distal cholangiocarcinoma (DCC) is a rare but over the last decade increasing malignancy and is associated with poor prognosis. According to the present knowledge curative surgery is the only chance for long term survival. This study was performed to evaluate prognostic factors for the outcome of patients undergoing curative surgery for distal cholangiocarcinoma. METHODS: 75 patients who underwent surgery between January 2000 and December 2014 for DCC in curative intention were analysed retrospectively. Potential prognostic factors for survival were investigated including the extent of surgery using purposeful selection of covariates in multivariable Cox regression modeling. RESULTS: Preoperative biliary stenting (Hazard ratio (HR): 2.530; 95%-CI: 1.146-6.464, p = 0.020), the extent of surgery in case of positive histological venous invasion (HR: 1.209; 95%-CI: 1.017-1.410, p = 0.032), lymph node staging (HR: 2.183; 95%-CI: 1.250-3.841, p = 0.006), perineural invasion (HR: 2.118; 95%-CI: 1.147-4.054, p = 0.016) and postoperative complications graded in points according to Clavien-Dindo (HR: 1.395; 95%-CI: 1.148-1.699, p = 0.001) were indentified as independent significant risk factors for survival. Patients receiving preoperative biliary stenting showed prolonged duration between onset of symptoms and date of operation (p = 0.048). CONCLUSIONS: Preoperative biliary stenting reduces survival possibly due to delayed surgery. The extent of surgery is not an independent risk factor for survival except for patients with concomitant histological venous invasion. Oncological factors and postoperative surgical complications are independent prognostic factors for survival.

Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells.

BACKGROUND & AIMS: Even after potentially curative R0 resection, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis owing to high rates of local recurrence and metastasis to distant organs. However, we have no suitable transgenic animal models for surgical interventions. METHODS: To induce formation of pancreatic tumor foci, we electroporated oncogenic plasmids into pancreata of LSL-KrasG12D × p53fl/fl mice; mutant Kras was expressed in p53fl/fl mice using a sleeping beauty transposon. We co-delivered a transposon encoding a constitutively active form of Akt2 (myrAkt2). Carcinogenesis and histopathologic features of tumors were examined. Metastasis was monitored by bioluminescence imaging. Tumors were resected and mice were given gemcitabine, and tumor recurrence patterns and survival were determined. Immune cells were collected from resection sites and analyzed by flow cytometry and in depletion experiments. RESULTS: After electroporation of oncogenic plasmids, mice developed a single pancreatic tumor nodule with histopathologic features of human PDAC. Pancreatic tumors that expressed myrAkt2 infiltrated the surrounding pancreatic tissue and neurons and became widely metastatic, reflecting the aggressive clinical features of PDAC in patients. Despite early tumor resection, mice died from locally recurring and distant tumors, but adjuvant administration of gemcitabine after tumor resection prolonged survival. In mice given adjuvant gemcitabine or vehicle, gemcitabine significantly inhibited local recurrence of tumors, but not metastasis to distant organs, similar to observations in clinical trials. Gemcitabine inhibited accumulation of CD11b+Gr1intF4/80int myeloid-derived suppressor cells at the resection margin and increased the number of natural killer (NK) cells at this location. NK cells but not T cells were required for gemcitabine-mediated antitumor responses. CONCLUSIONS: Gemcitabine administration after resection of pancreatic tumors in mice activates NK cell-mediated antitumor responses and inhibits local recurrence of tumors, consistent with observations from patients with PDAC. Transgenic mice with resectable pancreatic tumors might be promising tools to study adjuvant therapy strategies for patients.

Prediction of survival and tumor recurrence in patients undergoing surgery for pancreatic neuroendocrine neoplasms.

BACKGROUND: This study strives to define prognostic models for outcome after surgery for malignant pancreatic neuroendocrine tumors. METHODS: Forty-one patients were included. Prognostic models for mortality and disease recurrence were developed with multivariate binary logistic regression. RESULTS: The proposed prognostic model for tumor recurrence risk after surgery in percentage (AUROC = 0.774, 95%CI = 0.611-0.937) is: Risk in % = Exp(Y)/(1 + Exp(Y)), with Y = -4.360 + (0.015 × tumor diameter in cm) + (0.010 × preoperative platelet count in thousand/µl) + (1.077 × distant metastases, if yes = 1; if no = 0) + (-0.026 × Ki-67-positive cells in %) + (-1.086 × upper abdominal pain, if yes = 1; if no = 0). The proposed prognostic model for observed 3-year survival probability after surgery in % (AUROC = 0.932, 95%CI = 0.857-0.999) is: Survival probability in % = Exp(Y)/(1 + Exp(Y)), with Y = -12.492 + (0.054 × preoperative platelet count in thousand/µl) + (0.112 × minimal distance of the resection margin from the tumor in mm) + (-1.574 × number of positive lymph nodes) + (2.292 × histological tumor infiltration, if yes = 1; if no = 0) CONCLUSIONS: The platelet count was identified as a relevant risk factor. Proposed prognostic models with good model-fit display properties that indicate potential clinical usefulness.

Cholangitis in the postoperative course after biliodigestive anastomosis.

BACKGROUND: Hepatobiliary surgery with biliodigestive anastomosis (BDA) results in a loss of the sphincter of Oddi with consecutive ascension of bacteria into the bile system which may cause cholangitis in the postoperative course. METHODS: Patients who received reconstruction with a BDA after hepatobiliary surgery were analyzed retrospectively for their postoperative course of disease depending on intraoperatively obtained bile cultures and antibiotic prophylaxis. RESULTS: Two hundred forty-three patients were included in the analysis, 49.4 % of whom had received endoscopic stenting before the operation. Stenting was significantly associated with the presence of drug-resistant bacteria in the intraoperatively obtained bile sample (p < 0.001, OR = 4.09). Of all patients, 14.4 % developed postoperative cholangitis. This was significantly associated with the postoperative length of stay in the intensive care unit (p = 0.002, OR = 1.035). The highest incidence of postoperative cholangitis was found in patients with cholangiocellular carcinoma (n = 12, p = 0.046, OR = 2.178). Patients were more likely to harbor strains with resistance against the antibiotic that was given intraoperatively. CONCLUSION: The risk for the presence of drug-resistant bacteria is increased by preoperative stenting of the common bile duct. Bile culture by intraoperative swabs can be altered by the perioperative antibiotic prophylaxis as it induces microbiological selection in the common bile duct.

Species-specific regulation of fibrinogen synthesis with implications for porcine hepatocyte xenotransplantation.

BACKGROUND: Patients with liver failure could potentially be bridged with porcine xenogeneic liver cell transplantation. We examined species-specific differences between primary human and porcine hepatocytes in the regulation of coagulation protein expression and function. METHODS: Isolated primary human and porcine hepatocytes were stimulated with either porcine or human interleukin (IL)-6 (10 ng/ml), IL-1ß (10 ng/ml), and tumor necrosis factor-alpha (TNF-α, 30 ng/ml). mRNA expression of coagulation factors were measured by RT-PCR and real-time PCR. Cell culture supernatants were used for the measurement of fibrinogen by ELISA and determination of fibrin clot generation. RESULTS: Fibrinogen expression in human hepatocytes increased after IL-6 treatment (P = 0.010) and decreased after TNF-α treatment (P = 0.005). Porcine hepatocytes displayed a lower increase in fibrinogen expression after IL-6 treatment as compared to hepatocytes of human origin (P = 0.021). Porcine hepatocytes responded contrarily following TNF-α treatment with an increased expression of fibrinogen resulting in a significant species-specific difference between human and porcine hepatocytes (P = 0.029). Fibrin polymer generation by human hepatocytes was stable and widely branched after IL-6 treatment, while stimulation with TNF-α displayed no fibrin generation at all. In contrast, treatment of porcine hepatocytes with TNF-α resulted in generation of a stable and widely branched fibrin polymer, and stimulation with IL-6 only leads to generation of partial fibrin aggregates. CONCLUSION: We identified species-specific differences in the regulation of fibrinogen mRNA expression and fibrin generation under inflammatory stimuli. In hepatic xenotransplantation of porcine origin, these interspecies differences might lead to a loss of physiological coagulation function and a loss of transplanted cells.

Long-term results after adult ex situ split liver transplantation since its introduction in 1987.

BACKGROUND: Split liver transplantation is still discussed controversially. Utilization of split liver grafts has been declining since a change of allocation rules for the second graft abolished incentives for German centres to perform ex situ splits. We therefore analysed our long-term experiences with the first ex situ split liver transplant series worldwide. METHODS: A total of 131 consecutive adult ex situ split liver transplants (01.12.1987-31.12.2010) were analysed retrospectively. RESULTS: Thirty-day mortality rates and 1- and 3-year patient survival rates were 13, 76.3, and 66.4 %, respectively. One- and three-year graft survival rates were 63.4 and 54.2 %, respectively. The observed 10-year survival rate was 40.6 %. Continuous improvement of survival from era 1 to 3 was observed (each era: 8 years), indicating a learning curve over 24 years of experience. Patient and graft survival were not influenced by different combinations of transplanted segments or types of biliary reconstruction (p > 0.05; Cox regression). Patients transplanted for primary sclerosing cholangitis had better survival (p = 0.021; log-rank), whereas all other indications including acute liver failure (13.6 %), acute and chronic graft failure (9.1 %) had no significant influence on survival (p > 0.05; log-rank). Biliary complications (27.4 %) had no significant influence on patient or graft survival (p > 0.05; log-rank). Hepatic artery thrombosis (13.2 %) had a significant influence on graft survival but not on patient survival (p = 0.002, >0.05, respectively; log-rank). CONCLUSIONS: Split liver transplantation can be used safely and appears to be an underutilized resource that may benefit from liberal allocation of the second graft.

Respiratory risk score for the prediction of 3-month mortality and prolonged ventilation after liver transplantation.

Survival of critically ill patients is significantly affected by prolonged ventilation. The goal of this study was the development of a respiratory risk score (RRS) for the prediction of 3-month mortality and prolonged ventilation after liver transplantation (LT). Two hundred fifty-four consecutive LT patients from a single center were retrospectively randomized into a training group for model design and a validation group. A receiver operating characteristic (ROC) curve analysis was used to test sensitivity and specificity. The accuracy of the predictions was assessed with the Brier score, and the model calibration was assessed with the Hosmer-Lemeshow test. Cutoff values were determined with the best Youden index. The RRS was calculated in the first 24 hours as follows: (laboratory Model for End-Stage Liver Disease score > 30 = 2.36 points) + (fresh frozen plasma > 13.5 U = 2.70 points) + (partial pressure of arterial oxygen/fraction of inspired oxygen ratio < 200 mm Hg = 2.23 points) + (packed red blood cells > 10.5 U = 3.50 points) + (preoperative mechanical ventilation = 3.87 points) + (preoperative dialysis = 2.83 points) + (donor steatosis hepatis > 40% = 2.95 points). The RSS demonstrated high predictive accuracy, good model calibration, and c statistics > 0.7 in the training and validation groups. The RSS was able to predict 3-month mortality [cutoff = 6.64, area under the (ROC) curve (AUROC) = 0.794] and prolonged ventilation (cutoff = 3.69, AUROC = 0.798) with sensitivities of 69% and 81%, specificities of 83% and 73%, and overall model correctness of 76% and 77%, respectively. In conclusion, this study provides the first prognostic model for the prediction of 3-month mortality and prolonged ventilation after LT with high sensitivity and specificity and good model accuracy. The application of the RRS to an external cohort would be desirable for its further validation and introduction as a clinical tool for intensive care resource planning and prognostic decision making.

Incidence and long-term risk of de novo malignancies after liver transplantation with implications for prevention and detection.

The goal of this study was the characterization of long-term cancer risks after liver transplantation (LT) with implications for prevention and detection. Site-specific cancer incidence rates and characteristics were compared retrospectively for 2000 LT patients from a single institution (January 1, 1983 to December 31, 2010) and the general German population with standardized incidence ratios (SIRs); the total follow-up at December 31, 2011 was 14,490 person-years. The cancer incidence rates for the LT recipients were almost twice as high as those for the age- and sex-matched general population (SIR = 1.94, 95% CI = 1.63-2.31). Significantly increased SIRs were observed for vulvar carcinoma (SIR = 23.80), posttransplant lymphoproliferative disorder/non-Hodgkin lymphoma (SIR = 10.95), renal cell carcinoma (SIR = 2.65), lung cancer (SIR = 1.85), and colorectal cancer (SIR = 1.41). The mean time between transplantation and diagnosis was 6.8 years. The mean age at the time of diagnosis was significantly lower for the cohort versus the general population with similar malignancies [50 years (both sexes) versus 69 and 68 years (males and females), P ≤ 0.006]. Tumors were diagnosed at more advanced stages, and there was a trend of higher grading, which suggested more aggressive tumor growth. Tumor treatment was performed according to accepted guidelines. Surprisingly, 5-year survival was slightly better in the study cohort versus the general population for renal cell carcinoma, lung cancer, colorectal cancer, and thyroid cancer. Long-term immunosuppression with different protocols did not lead to significantly different SIRs, although patients treated with mycophenolate mofetil had the lowest SIR for de novo cancers (1.65, 95% CI = 1.2-2.4). Alcoholic liver disease (SIR = 2.30) and primary sclerosing cholangitis (SIR = 3.40) as indications for LT were associated with an increased risk of de novo malignancies. In conclusion, risk-adapted cancer surveillance is proposed. Tumor treatment performed according to accepted guidelines appears adequate. Mycophenolate may lead to lower long-term risks for de novo cancers.

A multicentre, randomized clinical trial comparing the Veriset™ haemostatic patch with fibrin sealant for the management of bleeding during hepatic surgery.

BACKGROUND: Bleeding during hepatic surgery is associated with prolonged hospitalization and increased morbidity and mortality. The Veriset™ haemostatic patch is a topical haemostat comprised of an absorbable backing made of oxidized cellulose and self-adhesive hydrogel components. It is designed to achieve haemostasis quickly and adhere to tissues without fixation. METHODS: A prospective, randomized, multicentre, single-blinded study (n = 50) was performed to compare the use of a Veriset™ haemostatic patch with a fibrin sealant patch (TachoSil(®) ) (control) in the management of diffuse bleeding after hepatic surgery. Patients were randomized following the confirmation of diffuse bleeding requiring the use of a topical haemostat. Time to haemostasis was assessed at preset intervals until haemostasis was achieved. RESULTS: Both groups were similar in comorbidities and procedural techniques. The median time to haemostasis in the group using the Veriset™ haemostatic patch was 1.0 min compared with 3.0 min in the control group (P < 0.001; 3-min minimum application time for the control patch). This result was independent of bleeding severity and surface area. Both products had similar safety profiles and no statistical differences were observed in the occurrence of adverse or device-related events. CONCLUSIONS: Regardless of bleeding severity or surface area, the Veriset™ haemostatic patch achieved haemostasis in this setting significantly faster than the control device in patients undergoing hepatic resection. It was safe and easy to handle in open hepatic surgery.

Value of the SOFA score as a predictive model for short-term survival in high-risk liver transplant recipients with a pre-transplant labMELD score ≥ 30.

INTRODUCTION: The Sequential Organ Failure Assessment (SOFA) score has been applied for the prediction of survival in critically ill patients. We analysed the value of the SOFA score for the prediction of short-term survival after liver transplantation in high-risk liver transplant recipients with a labMELD score ≥30. PATIENTS AND METHODS: We conducted a retrospective single-centre analysis including 88 consecutive liver transplants in adults between January 1, 2007 and December 31, 2010 with a pre-transplant labMELD score ≥30. The SOFA score was assessed preoperatively, directly after transplantation and on post-operative days (PODs) 1-10. Combined and living-related liver transplants were excluded. Receiver operating characteristic (ROC) curve analysis with the Hosmer-Lemeshow test and application of the Brier score were used to calculate sensitivity, specificity, overall model correctness and calibration. Cutoff values were selected with the best Youden index. RESULTS: ROC curve analysis showed areas under the curve (AUROCs) >0.8 for the SOFA score on PODs 1-10 for the prediction of hospital mortality, 30-day mortality and 3-month mortality with Hosmer-Lemeshow test results that confirmed good model calibration (p > 0.05). The Brier score demonstrated an accuracy of prediction (<0.25) of hospital mortality, 30-day mortality and 3-month mortality for the SOFA scores on PODs 4-9 indicating superior accuracy on PODs 7 and 8 with cutoff values for the SOFA score between 16.5 and 18.5. The pre-transplant SOFA score failed to reach AUROCs >0.7 (0.603-0.663) for the prediction of short-term survival. CONCLUSIONS: Our results confirm the usefulness of the SOFA score in high-risk liver recipients during the early post-operative course, especially on PODs 7-8 for the prediction of hospital mortality, 30-day mortality and 3-month mortality and may be useful to predict futile early acute retransplantation.

SOCIUS Mentoring-A Novel Course to Encourage Students for a Career as Surgical Oncologists.

Surgical disciplines are affected by an increasing shortage of young doctors. Studies show that formerly interested students decide against a career in surgical disciplines at the end of their studies or during practical year. Measures to counteract this development are urgently needed. As a joint project between gynecology, urology, and general surgery, SOCIUS mentoring was designed to prepare and encourage students for a career in surgical oncology. The structured curriculum of SOCIUS mentoring contains six modules, including surgical skills, soft skills, mentoring, theory, clinical visitation, and congress participation and runs over one year. Effects on confidence towards physician skills and plans for a future career were evaluated with questionnaires. After participation, students reported increased confidence in surgical and soft skills. In addition, participants noted that they have specified their career goals and gained more confidence in surgery, as well as seeing more development potential for a career in surgery. We describe the implementation of a novel extracurricular program for motivated students that combines individual mentoring with surgical and soft skills training. Due to its modular structure, this concept can easily be transferred to other disciplines. SOCIUS mentoring, with its combination of mentoring and skills training, is a promising measure to prepare and motivate students for their surgical career and thus counteract the shortage of young talent.