Preservation of the round ligament to accommodate transient portal hypertension after major hepatectomy.

PURPOSE: Posthepatectomy liver failure (PHLF) remains a leading cause of death after extensive liver resection. Apart from the size and function of the remaining liver remnant, the development of postresection portal hypertension (pHT) plays a crucial role in the development of PHLF. We hypothesize that the umbilical vein in the preserved round ligament (RL) may recanalize in response to new-onset pHT after extended hepatectomy, thus providing a natural portosystemic shunt. METHODS: In this exploratory study, RL was preserved in 10 consecutive patients undergoing major liver resection. Postoperative imaging was pursued to obtain evidence of reopened umbilical vein in the RL. The postoperative course, including the occurrence of PHLF, as well as the rate of procedure-specific complications were recorded. RESULTS: None of the 10 cases presented with an adverse event due to preservation of the RL. In 6 cases, postoperative imaging demonstrated reopening of the umbilical vein with hepatofugal flow in the RL. The rates of procedure-related surgical complications were lower than would be expected in this population; in particular, the rate of occurrence of PHLF as defined by the International Study Group of Liver Surgery (ISGLS) was low. CONCLUSION: Our results support the theoretical concept of portosystemic pressure relief via a preserved umbilical vein after major liver surgery. As preservation of the RL is easily done, we suggest keeping it intact in extended hepatectomy cases and in patients with preexistent pHT.

[Portal vein thrombosis-treatment options]. / Pfortaderthrombosen ­ therapeutische Möglichkeiten.

Portal vein thrombosis is a rare disease that describes a thrombosis in the extrahepatic or intrahepatic portion of the portal vein. Chronic liver disease or malignancy of the liver itself is often already present. However, inflammation or malignancy of nearby organs can also cause portal vein thrombosis. In addition, portal vein thrombosis can also occur in patients who have no corresponding previous illness. With every newly diagnosed portal vein thrombosis, an interdisciplinary decision is necessary: radiological intervention for recanalization, solitary anticoagulant therapy or surgical procedures (e.g., shunt installation or liver transplantation) have to be discussed. It is necessary to contact an appropriate center for this. The therapeutic decision must include the portal vein thrombosis etiology and accompanying diseases of the patient.

Effect of platelet inhibition with perioperative aspirin on survival in patients undergoing curative resection for pancreatic cancer: a propensity score matched analysis.

BACKGROUND: The importance of platelets in the pathogenesis of metastasis formation is increasingly recognized. Although evidence from epidemiologic studies suggests positive effects of aspirin on metastasis formation, there is little clinical data on the perioperative use of this drug in pancreatic cancer patients. METHODS: From all patients who received curative intent surgery for pancreatic cancer between 2014 and 2016 at our institution, we identified 18 patients that took aspirin at time of admission and continued to throughout the inpatient period. Using propensity score matching, we selected a control group of 64 patients without aspirin intake from our database and assessed the effect of aspirin medication on overall, disease-free, and hematogenous metastasis-free survival intervals as endpoints. RESULTS: Aspirin intake proved to be independently associated with improved mean overall survival (OS) (46.5 vs. 24.6 months, *p = 0.006), median disease-free survival (DFS) (26 vs. 10.5 months, *p = 0.001) and mean hematogenous metastasis-free survival (HMFS) (41.9 vs. 16.3 months, *p = 0.005). Three-year survival rates were 61.1% in patients with aspirin intake vs. 26.3% in patients without aspirin intake. Multivariate cox regression showed significant independent association of aspirin with all three survival endpoints with hazard ratios of 0.36 (95% CI 0.15-0.86) for OS (*p = 0.021), 0.32 (95% CI 0.16-0.63) for DFS (**p = 0.001), and 0.36 (95% CI 0.16-0.77) for HMFS (*p = 0.009). CONCLUSIONS: Patients in our retrospective, propensity-score matched study showed significantly better overall survival when taking aspirin while undergoing curative surgery for pancreatic cancer. This was mainly due to a prolonged metastasis-free interval following surgery.

Mechanisms of Metastasis in Colorectal Cancer and Metastatic Organotropism: Hematogenous versus Peritoneal Spread.

Metastasis is the major cause of death in patients with colorectal carcinoma (CRC). The most common sites of metastasis are the liver and the peritoneum. Peritoneal carcinomatosis is often considered the end stage of the disease after the tumor has spread to the liver. However, almost half of CRC patients with peritoneal carcinomatosis do not present with liver metastasis. This brings up the question of whether peritoneal spread can still be considered as the end stage of a metastasized CRC or whether it should just be interpreted as a site of metastasis alternative to the liver. This review tries to discuss this question and summarize the current status of literature on potential characteristics in tumor biology in the primary tumor, i.e., factors (transcription factors and direct and indirect E-cadherin repressors) and pathways (WNT, TGF-ß, and RAS) modulating EMT, regulation of EMT on a posttranscriptional and posttranslational level (miRNAs), and angiogenesis. In addition to tumor-specific characteristics, factors in the tumor microenvironment, immunological markers, ways of transport of tumor cells, and adhesion molecules appear to differ between hematogenous and peritoneal spread. Factors such as integrins and exosomal integrins, cancer stem cell phenotype, and miRNA expression appear to contribute in determining the metastatic route. We went through each step of the metastasis process comparing hematogenous to peritoneal spread. We identified differences with respect to organotropism, epithelial-mesenchymal transition, angiogenesis and inflammation, and tumor microenvironment which will be further elucidated in this review. A better understanding of the underlying mechanisms and contributing factors of metastasis development in CRC has huge relevance as it is the foundation to help find specific targets for treatment of CRC.

[Oligometastases of neuroendocrine tumors-extent of surgery]. / Oligometastasierung bei neuroendokrinen Tumoren ­ Ausmaß der Chirurgie.

Neuroendocrine tumors (NETs) are rare neoplasms, which represent complex challenges in diagnosis and treatment. Even in the metastatic stage there are important differences in the type of tumor in comparison to gastrointestinal and pancreatic adenocarcinomas. Therefore, the disease courses are substantially different depending on the grade of differentiation. Even in the metastatic stage the 5­year survival rates of G1 tumors is up to 83%. Approximately 20% of small intestine NETs additionally show hormone activity, which can compromise survival and the quality of life. For individual treatment decisions the special tumor biology of these tumors must be taken into consideration more so than for other tumor entities. Surgery always becomes important for these tumors when a R0 resection appears possible. Oligometastasis of the liver and the lymph drainage system can be meaningfully approached by surgical treatment. In selected patients with an isolated liver involvement, a liver transplantation can be considered; however, even tumor debulking can lead to improvement in the quality of life and survival, especially for hormone active tumors with a carcinoid syndrome which cannot be conservatively controlled. The aim of this review is to present the value of surgical treatment options in the case of (oligo)metastasized NETs.

Moon phases and moon signs do not influence morbidity, mortality and long-term survival, after living donor kidney transplantation.

BACKGROUND: Approximately 11% of the German population are convinced that certain moon phases and moon signs may impact their health and the onset and clinical course of diseases. Before elective surgery, a considerable number of patients look to optimize the timing of the procedure based on the lunar cycle. Especially patients awaiting living donor kidney transplantation (LDKT) commonly look for an adjustment of the date of transplantation according to the moon calendar. This study therefore investigated the perioperative and long-term outcome of LDKT dependent on moon phases and zodiac signs. METHODS: Patient data were prospectively collected in a continuously updated kidney transplant database. Two hundred and seventy-eight consecutive patients who underwent LDKT between 1994 and December 2009 were selected for the study and retrospectively assigned to the four moon phases (new-moon, waxing-moon, full-moon, and waning-moon) and the corresponding zodiac sign (moon sign Libra), based on the date of transplantation. Preexisting comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. RESULTS: Of all LDKT procedures, 11.9, 39.9, 11.5, and 36.5% were performed during the new, waxing, full, and waning moon, respectively, and 6.2% during the moon sign Libra, which is believed to interfere with renal surgery. Survival rates at 1, 5, and 10 years after transplantation were 98.9, 92, and 88.7% (patient survival) and 97.4, 91.6, and 80.6% (graft survival) without any differences between all groups of lunar phases and moon signs. Overall perioperative complications and early graft loss occurred in 21.2 and 1.4%, without statistical difference (p > 0.05) between groups. CONCLUSION: Moon phases and the moon sign Libra had no impact on early and long-term outcome measures following LDKT in our study. Thus, concerns of patients awaiting LDKT regarding the ideal time of surgery can be allayed, and surgery may be scheduled independently of the lunar phases.

Donor-derived tuberculosis after solid organ transplantation in two patients and a staff member.

Because of global mobility and migration resulting in a growing diversity of the donor pool, the risk for donor-derived tuberculosis in solid organ transplant recipients becomes more and more relevant, even in countries with a low overall tuberculosis incidence. Here, we describe a case series of donor-derived tuberculosis in 2 of 3 solid organ transplant recipients and one medical staff member in Germany resulting in the death of one recipient. This case series highlights the relevance of this topic to clinicians. It advocates for a better communication between organ procurement organizations and transplant centers regarding donor information and transplant recipient outcome. Furthermore, it underpins the necessity for a standardized critical incident reporting system in the german transplant system to improve short- and long-term recipient's safety, health and survival.

Should ALPPS be Used for Liver Resection in Intermediate-Stage HCC?

BACKGROUND: Extended liver resections in patients with hepatocellular carcinoma (HCC) are problematic due to hepatitis, fibrosis, and cirrhosis. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has been promoted as a novel method to induce hypertrophy for patients with extensive colorectal liver metastases, but outcomes in HCC have not been well investigated. METHODS: All patients registered in the international ALPPS Registry ( www.alpps.org ) from 2010 to 2015 were studied. Hypertrophy of the future liver remnant, perioperative morbidity and mortality, age, overall survival, and other parameters were compared between patients with HCC and patients with colorectal liver metastases (CRLM). RESULTS: The study compared 35 patients with HCC and 225 patients with CRLM. The majority of patients undergoing ALPPS for HCC fall into the intermediate-stage category of the Barcelona clinic algorithm. In this study, hypertrophy was rapid and extensive for the HCC patients, albeit lower than for the CRLM patients (47 vs. 76 %; p < 0.002). Hypertrophy showed a linear negative correlation with the degrees of fibrosis. The 90-day mortality for ALPPS used to treat HCC was almost fivefold higher than for CRLM (31 vs. 7 %; p < 0.001). Multivariate analysis showed that patients older than 61 years had a significantly reduced overall survival (p < 0.004). CONCLUSION: The ALPPS approach induces a considerable hypertrophic response in HCC patients and allows resection of intermediate-stage HCC, albeit at the cost of a 31 % perioperative mortality rate. The use of ALPPS for HCC remains prohibitive for most patients and should be performed only for a highly selected patient population younger than 60 years with low-grade fibrosis.

Automated low flow pump system for the treatment of refractory ascites: a single-center experience.

INTRODUCTION: Ascites is a common complication of liver cirrhosis and represents the main cause of hospitalization among patients with cirrhosis. First-line therapy for those patients is the use of diuretics and dietary sodium restriction. However, 10 % of patients per year become therapy refractory to diuretic treatment with the need of repeated high-volume paracentesis or transjugular intrahepatic portosystemic shunt (TIPS). For these patients, an automated pump system (Alfapump/Sequana Medical) was developed. Here, we describe our single-center experience of ten consecutively implanted pump systems. PATIENTS AND METHODS: Between 08/13 and 11/14, ten Alfapump systems were implanted in patients with refractory ascites all suffering from liver cirrhosis. Those patients were treated as a bridge to transplant (4/10) or as an end-stage therapy (6/10). Median follow-up was 165 days (23-379 days). RESULTS: Postimplant, the need of paracentesis could be markedly reduced to a mean of 0.45 (0-4/month) per month. In eight patients, paracentesis was not needed after implantation of the pump system. The median daily output volume was 1000 ml/day (450-2000 ml/day). Prerenal insufficiency was a recurrent complication in the postoperative period. DISCUSSION: The Alfapump system is a useful system in the treatment of patients suffering from therapy refractory ascites. However, due to the high level of comorbidities, careful patient selection and postoperative monitoring are required.

Spiegelmer Inhibition of MCP-1/CCR2--Potential as an Adjunct Immunosuppressive Therapy in Transplantation.

The rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are l-oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high-affinity Spiegelmer-based MCP-1 inhibitor (mNOX-E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti-MCP-1-Spiegelmer (mNOX-E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non-functional Spiegelmer (revmNOX-E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX-E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX-E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX-E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and 'alarmins' were significantly reduced, and the number of F4/80(+) cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP-1/CCR2 axis (mNOX-E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX-E36 may have potential as an adjunct immunomodulatory agent.

[Transplantation and hepatic, pancreatic, and biliary (HPB) surgery fellowship--a pilot project for a structured training in Germany]. / Fellowship für Transplantation und hepato-pankreatiko-biliäre (HPB) Chirurgie - Pilotprojekt für eine strukturierte Weiterbildung in Deutschland.

Currently, there is no structured training plan to become a transplant surgeon in Germany. Similar to the Anglo-Saxonian educational system we have implemented a 3-year fellowship in transplant and hepatic-, pancreatic-, biliary (HPB) surgery. The educational curriculum is based on the guidelines of the European Board of Surgery (EBS) for transplant and HPB surgery. Here, we describe the underlying thoughts, the selection process, structure and curriculum for this fellowship. Furthermore, we critically compare our programme to the established international training standards. So far, our programme has proven valuable. We believe a fellowship for transplant and HPB surgery is a reasonable approach to ensure a high quality training of the following generations of surgeons in this field.

[Tumor and transplantation]. / Tumor und Transplantation.

Tumor treatment and transplantation-associated with unavoidable mandatory immunosuppression-appear to be unreconcilable opposites. The clinical reality shows, however, that transplantation in many early stage primary tumors is the most effective treatment. The essential immunosuppression after transplantation can however promote tumor recurrence. Immunosuppression also leads to a significant increased rate of de novo tumors-in all organ transplant recipients. However, not all immunosuppressant drugs have the same effect on tumors. In experimental and clinical settings, the class of mTOR inhibitors has a clear antitumoral effect and is recommended as the immunosuppression treatment of choice in patients with increased tumor risk. The purpose of this review is to provide the reader with the scientific background regarding the clinical problem of tumors and transplantation.

[Pancreatic cancer in the elderly: guidelines and individualized therapy]. / Pankreaskarzinom im hohen Alter: Leitlinien und individualisierte Therapie.

The considerable increase of the aged population in western civilisation within the next years will result in a rising incidence of pancreatic cancer. Until the year 2020 an increment of 20  % of patients beyond 65 years old can be anticipated. Therefore, the focus will be on management of old and geriatric surgical patients leading to strategical re-evaluation of surgical indications under critical consideration of feasibility and purpose. Even under modern interdisciplinary therapy concepts the prognosis of ductal adenocarcinoma of the pancreas remains poor with an overall 5-year survival rate of less than 5  %. The surgical resection is still considered as the only potential curative treatment option with extended life expectancy; however, it is technically demanding and furthermore associated with significant morbidity. In particular, the quality of surgery of the now interdisciplinary therapy of pancreatic cancer is markedly improved when performed at a high-volume centres. Until now only a few retrospective data analyses evaluating the perioperative and long-term outcome after pancreatic tumor resections in geriatric patients exist. The available results, however, support radical surgical procedures even beyond the age of 75 years.

[Surgical quality of organ retrieval in Bavaria]. / Chirurgische Qualität der Organentnahme in Bayern.

Surgical problems during organ procurement may propagate complications in the transplant recipient. Ultimately, these problems may result in the complete loss of already scarce donor organs.Donor reports (Eurotransplant donor report) of 1,492 donor organs from January 2010 to August 2012 in the German Foundation of Organ Transplantation (DSO) region of Bavaria and corresponding organ quality forms were analyzed. Surgical problems were classified into 3 categories: (I) surgical problems recognized and reported by the donor surgeon, (II) surgical problems observed by the recipient surgeon but not reported by the donor surgeon and (III) surgical problems leading to organ loss. Surgical problems during this 20-month time period were reported for 17.6 % of organs; category I in 5.5 %, category II in 11.1 % and category III in 1 %. Damage of graft vasculature in 9.1 % was the most frequently reported problem. The mean error index for individual surgeons was 16 % and one out of the five Bavarian organ procurement centers had significantly more problems in all categories (30 %). Interestingly, surgeons who performed rapid retrieval procedures had more problems with quality than surgeons who took more time. Organ retrieval is prone to surgical problems. Especially in a system of organ transport, consistent reporting of surgical problems and quality assurance is needed to maintain and to improve surgical quality.

[Abdominal organ retrieval: strategies to improve quality]. / Viszerale Organexplantation: Maßnahmen zur Verbesserung der Qualität.

The blatant problem of organ shortage leads to an increasing acceptance of organs from extended criteria donors. This increases the importance of the process of organ donation and retrieval. A working group of representatives of Bavarian retrieval surgeons and the procurement organization German Foundation of Organ Transplantation (DSO) was initiated to develop consensus-based recommendations for quality improvements in the field of organ retrieval on the basis of regional data. The main aim was to professionalize retrieval teams by specified training standards and to define objective qualifications for retrieval surgeons. Initial measures of the working group included agreement on standardized retrieval techniques and improvement of documentation in terms of quality forms and the return rate of the forms. Quality data are being analyzed prospectively with a new categorization of complications. Communication among centers and teams and complication reporting has already been improved and initial structural changes have been set up.

[Therapy of hepatocellular carcinoma before liver transplantation]. / Therapie des hepatozellulären Karzinoms vor Lebertransplantation.

Liver transplantation is the optimal therapy for patients with non-resectable early stage hepatocellular carcinoma (HCC) which is limited to the liver. During the sometimes long waiting period patients usually receive neoadjuvant bridging therapy to avoid tumor progression. The armamentarium of bridging therapies includes local ablative and systemic therapies as well as liver resection. The oncological benefit of neoadjuvant therapy for patients who receive a liver transplantation is unclear; however, bridging therapy keeps patients eligible for transplantation in the formal framework of current allocation rules. Moreover, response to therapy may serve as a surrogate marker for favorable tumor biology and may therefore help to guide the selection process for patients undergoing liver transplantation for HCC.

Influence of hepatitis C virus infection and high virus serum load on biliary complications in liver transplantation.

BACKGROUND: Biliary complications (BCs) and recurrent hepatitis C virus (HCV) infection are among the major causes of morbidity and graft loss following liver transplantation. The influence of HCV on BCs has not been definitely clarified. PATIENTS AND METHODS: We performed a retrospective cohort study to analyze risk factors and outcome of post orthotopic liver transplantation (OLT) BCs in 352 liver transplant recipients over 12 years in Munich, Germany (n = 84 with HCV; living donor and re-OLT were excluded). BCs diagnosed with imaging techniques and abnormal liver enzyme pattern, requiring an intervention, were considered. RESULTS: In a multivariate analysis, HCV serostatus and a high pre-and post-surgery HCV RNA serum load were independent risk factors for anastomotic strictures. HCV positivity and BCs alone did not alter graft loss. HCV-positive patients with BCs, however, had a significantly worse graft outcome (P = 0.02). Non-anastomotic strictures, bile leaks, and the number of interventions needed to treat bile leaks led to worse graft outcome in all patients. CONCLUSION: HCV positivity and a high HCV RNA serum load were risk factors for anastomotic strictures. BCs and HCV had an additive effect on graft loss.

Src tyrosine kinase inhibition suppresses lymphangiogenesis in vitro and in vivo.

PURPOSE: The close association of lymphatic and blood vessels and their coordinated development in vivo suggest that there are parallel mechanisms regulating hemangiogenesis and lymphangiogenesis. Here, we hypothesize that inhibition of the Src tyrosine kinase, apart from anti-hemangiogenic effects, results in a suppression of lymphangiogenesis. EXPERIMENTAL DESIGN: The ability of the Src kinase inhibitor PP2 to block Src in isolated lymphatic endothelial cells (LECs) was analyzed by Western Blot. The effects of PP2 on LEC proliferation, migration, and sprouting were assessed by MTT, Boyden chamber, and spheroid assays, respectively. The level of VEGF-C secreted by L3.6pl pancreatic carcinoma cells was measured by ELISA. For in vivo assessment of lymphangiogenesis, Src kinase inhibitor AZM475271 was used in mouse corneal micropocket and lymphangioma models. RESULTS: VEGF-C stimulation of isolated LECs led to an increased phosphorylation of Src kinase that was abrogated by PP2. Treatment with PP2 inhibited spheroid sprouting of LECs at even lower concentrations than suggested by the proliferation assay. Src inhibition significantly reduced the level of VEGF-C in L3.6pl supernatant. Treatment with PP2 also resulted in a significant reduction in the migratory activity of LECs. In vivo, Src inhibition reduced de novo formation of lymphangiomas and corneal neovascularization. CONCLUSIONS: Inhibition of Src kinase shows strong anti-lymphangiogenic activity in vitro and in vivo. Together with anti-angiogenic effects mediated by Src inhibition, this strategy may be attractive in the treatment of lymphatic and hematogeneous metastasis of cancer.