Endoscopic vacuum therapy significantly improves clinical outcomes of anastomotic leakages after 2-stage, 3-stage, and transhiatal esophagectomies.

BACKGROUND: Anastomotic leakages after esophagectomies continue to constitute significant morbidity and mortality. Intrathoracic anastomoses pose a high risk for mediastinitis, sepsis, and death, if a leak is not addressed timely and appropriately. However, there are no standardized treatment recommendations or algorithms as for how to treat these leakages. METHODS: The study included all patients at the University Hospital Regensburg, who developed an anastomotic leakage after esophagectomy with gastric pull-up reconstruction from 2007 to 2022. Patients receiving conventional treatment options for an anastomotic leakage (stents, drainage tubes, clips, etc.) were compared to patients receiving endoscopic vacuum-assisted closure (eVAC) therapy as their mainstay of treatment. Treatment failure was defined as cervical esophagostomy formation or death. RESULTS: In total, 37 patients developed an anastomotic leakage after esophagectomy with a gastric pull-up reconstruction. Twenty patients were included into the non-eVAC cohort, whereas 17 patients were treated with eVAC. Treatment failure was observed in 50% of patients (n = 10) in the non-eVAC cohort and in 6% of patients (n = 1) in the eVAC cohort (p < 0.05). The 90-day mortality in the non-eVAC cohort was 15% (n = 3) compared to 6% (n = 1) in the eVAC cohort. Cervical esophagostomy formation was required in 40% of cases (n = 8) in the non-eVAC cohort, whereas no patient in the eVAC cohort underwent cervical esophagostomy formation. CONCLUSION: eVAC therapy for leaking esophagogastric anastomoses appears to be superior to other treatment strategies as it significantly reduces morbidity and mortality. Therefore, we suggest eVAC as an essential component in the treatment algorithm for anastomotic leakages following esophagectomies, especially in patients with intrathoracic anastomoses.

Reversal of end-ileostomy in patients with Crohn's disease.

PURPOSE: End-ileostomy after two-staged ileocolic resection is frequently performed in Crohn's disease patients at high risk for postoperative complications. However, there is paucity on data regarding the morbidity after the stoma reversal. METHODS: One hundred thirty patients undergoing closure of end-ileostomy between 1994 and 2016 were included. Data collection was retrospective in 11 first, and it was prospective in 119 last patients. Anastomotic complications were defined as anastomotic leak, perianastomotic abscess, and perianastomotic peritonitis. RESULTS: The median interval between ileostomy construction and reversal was 4.0 months. Ninety-seven of 121 patients with available data (80%) gained weight between both surgeries. Hemoglobin level increased between surgeries in 107 patients (85%). Fifteen patients (11.5%) received parenteral fluid substitution or parenteral nutrition between both surgeries. There were 37 hospital readmissions during the time between stoma construction and reversal (29%). After ileostomy reversal, 14 patients developed anastomotic complications (11%). By multivariate regression analysis, preoperative steroid intake (hazard ratio 4.5, 95% CI: 1.11-18.0, p = 0.035) and hospital readmission for infectious complications (HR 4.5, 95% CI: 1.11-18.0, p = 0.035) were statistically significantly associated with an increased risk to develop postoperative anastomotic complications. There were no postoperative deaths. CONCLUSION: Closure of end-ileostomy could be complicated by some serious morbidity. These risks should be taken into consideration weighing carefully between the one- and two-stage ileocolic resection in Crohn's disease patients.

Mortality after liver surgery in Germany.

BACKGROUND: Mortality rates after liver surgery are not well documented in Germany. More than 1000 hospitals offer liver resection, but there is no central regulation of infrastructure requirements or outcome quality. METHODS: Hospital mortality rates after liver resection were analysed using the standardized hospital discharge data (Diagnosis-Related Groups, ICD-10 and German operations and procedure key codes) provided by the Research Data Centre of the Federal Statistical Office and Statistical Offices of the Länder in Wiesbaden, Germany. RESULTS: A total of 110 332 liver procedures carried out between 2010 and 2015 were identified. The overall hospital mortality rate for all resections was 5·8 per cent. The mortality rate among 17 574 major hepatic procedures was 10·4 per cent. Patients who had surgery for colorectal liver metastases (CRLMs) had the lowest mortality rate among those with malignancy (5·5 per cent), followed by patients with gallbladder cancer (7·1 per cent), hepatocellular carcinoma (9·3 per cent) and intrahepatic cholangiocarcinoma (11·0 per cent). Patients with extrahepatic cholangiocarcinoma had the highest mortality rate (14·6 per cent). The mortality rate for extended hepatectomy was 16·2 per cent and the need for a biliodigestive anastomosis increased this to 25·5 per cent. Failure to rescue after complications led to mortality rates of more than 30 per cent in some subgroups. There was a significant volume-outcome relationship for CRLM surgery in very high-volume centres (mean 26-60 major resections for CRLMs per year). The mortality rate was 4·6 per cent in very high-volume centres compared with 7·5 per cent in very low-volume hospitals (odds ratio 0·60, 95 per cent c.i. 0·42 to 0·77; P < 0·001). CONCLUSION: This analysis of outcome data after liver resection in Germany suggests that hospital mortality remains high. There should be more focused research to understand, improve or justify factors leading to this result, and consideration of centralization of liver surgery.

ANTECEDENTES: En Alemania, los datos de mortalidad después de la cirugía no están bien documentados. En más de 1.000 hospitales se realizan resecciones hepáticas, pero no existe una regulación central de los prerrequisitos estructurales necesarios y de la calidad de los resultados. MÉTODOS: Las tasas de mortalidad hospitalaria relacionadas con las resecciones hepáticas se analizaron utilizando los datos estandarizados del alta hospitalaria (Diagnóstico de grupos relacionados, DRG), la clasificación internacional de enfermedades 10 (ICD10) y la clave de procedimientos y operaciones (códigos OPS) proporcionados por el RDC de la Oficina Federal de Estadística y Oficinas de Estadística de Länder en Wiesbaden, Alemania. RESULTADOS: Se identificaron un total de 110.332 procedimientos hepáticos (de 2010 a 2015). La tasa global de mortalidad hospitalaria para todas las resecciones fue del 5,8%. Las resecciones hepáticas mayores (n = 15.333) presentaron una mortalidad del 10,4%. Los pacientes con metástasis hepáticas colorrectales (colorectal liver metastases, CRLM) tuvieron la mortalidad más baja de entre los pacientes con neoplasias malignas (5,5%), seguidos de los pacientes con cáncer de vesícula biliar (7,1%), colangiocarcinoma intrahepático (intrahepatic colangiocarcinoma, iCC) (11,0%) y carcinoma hepatocelular (hepatocellular carcinoma, HCC) (9,3%). Los pacientes con colangiocarcinoma extrahepático (extrahepatic cholangiocarcinoma, eCC) presentaron la mortalidad más alta (14,6%). Las hepatectomías extendidas (16,2%) y la necesidad de una anastomosis biliodigestiva (biliodigestive anastomosis, BDA) aumentaron la mortalidad a un 25,5%. La falta de solución de algunas complicaciones llevó a tasas de mortalidad de más del 30% en algunos subgrupos. Hubo una relación significativa volumen-resultado para las CRLM en centros de alto volumen (25,3 a 59,7 resecciones mayores/año; razón de oportunidades, odds ratio, OR 0,60, i.c. del 95%: 0,42-0,77; P < 0,001), lo que resultó en una disminución en las tasas de mortalidad de 7,5/6,4/7,5/6,5% a 4,6%. CONCLUSIÓN: El análisis de los resultados después de la resección hepática en Alemania muestra una alta mortalidad hospitalaria inesperada. Este análisis indica la necesidad de efectuar una investigación más específica para comprender, mejorar o justificar los factores que determinan estos hallazgos.

Risk of postoperative morbidity in patients having bowel resection for colonic Crohn's disease.

BACKGROUND: The aim of the present multicenter study was to analyze the incidence and risk factors associated with postoperative morbidity in patients who had colorectal resection for colonic Crohn's disease. METHODS: Consecutive patients undergoing colorectal resection for colonic Crohn's disease at seven surgical units in 1992-2017 were included. Exclusion criteria were: proctectomy for perianal disease, surgery for cancer, previous colectomies, surgery before 1998. Abdominal colectomy and proctocolectomy were defined as extended resections; all other operations were classified as segmental resections. Postoperative intraabdominal septic complications (IASC) were: anastomotic leaks, peritonitis and abscess. RESULTS: One hundred ninety-nine patients met the inclusion criteria: 116 patients had segmental resections and extended resections were performed in 83 patients. An anastomosis was constructed in 122 patients and an additional stoma was formed in 15 of those cases. Segmental resections were performed significantly more frequently in stricturing or penetrating disease (93% vs. 61%, p < 0.001) and were completed by an anastomosis more often than extended resections (78% vs. 37%, p < 0.001). The overall IASC rate was 17%. On multivariate analysis, formation of an anastomosis (Hazard ratio 2.9; 95% CI 1.1-7.7; p = 0.036) and preoperative hemoglobin level of < 10 g/dl (Hazard ratio 3.1; 95% CI 1.1-9.1; p = 0.034) were associated with an increase of postoperative IASC rate. Preoperative medication did not influence postoperative outcome. CONCLUSIONS: Severe preoperative anemia is associated with an increased postoperative morbidity. Resections completed by an anastomosis pose an increased postoperative complication risk in patients with colonic Crohn's disease as compared to resections without an anastomosis.

[Influence of social characteristics on the duration of treatment, severity of the disease and social support of patients in a surgical intensive care unit]. / Einfluss sozialer Charakteristika auf die Behandlungsdauer, Erkrankungsschwere und soziale Unterstützung von Patienten einer operativen Intensivstation.

BACKGROUND: In critical illnesses low socioeconomic status (SES) is associated with higher morbidity and mortality. In addition to the SES, further factors at an individual level (e.g., sex, health insurance status and place of residence) may influence the severity of illness and medical treatment. We investigated these additional parameters in a secondary analysis of the ECSSTASI data. METHODS: Within the framework of the ECSSTASI study, 996 patients were recruited from a surgical intensive care unit. We examined the influence of sex, insurance status and place of residence on health-related behavior, disease severity, duration of intensive care and ventilation (28 ventilator-free days score, 28-VFDS) and social support by the next of kin. Multivariate-adjusted logistic regression analyses were carried out and odds ratios (OR) are presented with corresponding 95% confidence intervals. RESULTS: Among patients admitted to the intensive care unit, the disease severity (SOFA score >5) was significantly lower in women than in men (OR 0.62 [0.45-0.87]). Increasing size of the patient's town of residence was associated with a significantly shorter duration of treatment on the intensive care unit (OR 0.54 [0.32-0.91]). An increasing number of persons in the household was associated with a significantly increased risk of being ventilated longer compared to 1­person households (p = 0.028). Patients with private insurance (OR 1.87 [1.28-2.70]), patients from households with ≥4 persons (OR 1.92 [1.1-3.33]) and patients without German citizenship (OR 2.56 [1.39-4.55]) were visited significantly more often by next of kin. CONCLUSION: In addition to the SES, sociodemographic characteristics of the individual patient are associated with the course of treatment in intensive care medicine. The extent of social support by the next of kin depends on intercultural and individual patient characteristics. An increasing size of the town of residence and private health insurance status positively influence intensive care outcomes. In order to evaluate these data, further epidemiological studies in intensive care medicine are necessary.

Preservation of the superior rectal artery: influence of surgical technique on anastomotic healing and postoperative morbidity in laparoscopic sigmoidectomy for diverticular disease.

PURPOSE: To evaluate the impact of superior rectal artery (SRA) sparing technique on anastomotic leakage in laparoscopic sigmoidectomy for diverticular disease. MATERIAL AND METHODS: A retrospective multicenter analysis of all patients undergoing laparoscopic sigmoid resection for diverticular disease between 2002 and 2015 was conducted. Data were recorded in three hospitals: University Hospital Regensburg, Marienhospital Gelsenkirchen, and Städtisches Klinikum München Bogenhausen. The SRA was resected between 2002 and 2005. Since 2005, the artery was preserved in most cases. RESULTS: Two hundred sixty-seven patients were included. One hundred sixty patients presented with complicated diverticulitis (60%). The SRA was resected in 102 patients (group 1) and preserved in 157 patients (group 2, no data in eight cases). Anastomotic leakage occurred in 7% of patients in group 1 and 1.9% of patients in group 2 (p = 0.053). Duration of surgery was significantly shorter (157 vs. 183 min, p < 0.001) in group 2 patients. Length of hospital stay was without significant difference (group 1 8.2 days; group 2 8.3 days; p = 0.83). The conversion rate was higher in group 2 patients; however, the difference was not statistically significant (9 vs. 3%, p = 0.07). There was no significant difference between both groups regarding intraoperative complications and overall complication rate. The length of the resected specimen (19 vs. 21 cm, p = 0.001) was significantly shorter in group 2 patients. CONCLUSION: Preservation of the SRA seems to be associated with favorable outcome in patients undergoing laparoscopic sigmoid resection for diverticular disease.

Cyclosporine A Inhibits the T-bet-Dependent Antitumor Response of CD8(+) T Cells.

Transplant recipients face an increased risk of cancer compared with the healthy population. Although several studies have examined the direct effects of immunosuppressive drugs on cancer cells, little is known about the interactions between pharmacological immunosuppression and cancer immunosurveillance. We investigated the different effects of rapamycin (Rapa) versus cyclosporine A (CsA) on tumor-reactive CD8(+) T cells. After adoptive transfer of CD8(+) T cell receptor-transgenic OTI T cells, recipient mice received either skin grafts expressing ovalbumin (OVA) or OVA-expressing B16F10 melanoma cells. Animals were treated daily with Rapa or CsA. Skin graft rejection and tumor growth as well as molecular and cellular analyses of skin- and tumor-infiltrating lymphocytes were performed. Both Rapa and CsA were equally efficient in prolonging skin graft survival when applied at clinically relevant doses. In contrast to Rapa-treated animals, CsA led to accelerated tumor growth in the presence of adoptively transferred tumor-reactive CD8(+) OTI T cells. Further analyses showed that T-bet was downregulated by CsA (but not Rapa) in CD8(+) T cells and that cancer cytotoxicity was profoundly inhibited in the absence of T-bet. CsA reduces T-bet-dependent cancer immunosurveillance by CD8(+) T cells. This may contribute to the increased cancer risk in transplant recipients receiving calcineurin inhibitors.

CRS-HIPEC Prolongs Survival but is Not Curative for Patients with Peritoneal Carcinomatosis of Gastric Cancer.

PURPOSE: Peritoneal carcinomatosis (PC) is a dismal feature of gastric cancer that most often is treated by systemic palliative chemotherapy. In this retrospective matched pairs-analysis, we sought to establish whether specific patient subgroups alternatively should be offered a multimodal therapy concept, including cytoreductive surgery (CRS) and intraoperative hyperthermic chemotherapy (HIPEC). METHODS: Clinical outcomes of 38 consecutive patients treated with gastrectomy, CRS and HIPEC for advanced gastric cancer with PC were compared to patients treated by palliative management (with and without gastrectomy) and to patients with advanced gastric cancer with no evidence of PC. Kaplan-Meier survival curves and multivariate Cox regression models were applied. RESULTS: Median survival time after gastrectomy was similar between patients receiving CRS-HIPEC and matched control patients operated for advanced gastric cancer without PC [18.1 months, confidence interval (CI) 10.1-26.0 vs. 21.8 months, CI 8.0-35.5 months], resulting in comparable 5-year survival (11.9 vs. 12.1 %). The median survival time after first diagnosis of PC for gastric cancer was 17.2 months (CI 10.1-24.2 months) in the CRS-HIPEC group compared with 11.0 months (CI 7.4-14.6 months) for those treated by gastrectomy and chemotherapy alone, resulting in a twofold increase of 2-year survival (35.8 vs. 16.9 %). CONCLUSIONS: We provide retrospective evidence that multimodal treatment with gastrectomy, CRS, and HIPEC is associated with improved survival for patients with PC of advanced gastric cancer compared with gastrectomy and palliative chemotherapy alone. We also show that patients treated with CRS-HIPEC have comparable survival to matched control patients without PC. However, regardless of treatment scheme, all patients subsequently recur and die of disease.

Improved Detection of preclinical Colorectal Liver Metastases by High Resolution Ultrasound including Molecular Ultrasound Imaging using the targeted Contrast Agent BR55.

PURPOSE: Aim of the present study was to investigate the sensitivity of high resolution ultrasound (HRU), standard contrast-enhanced ultrasound (CEUS) and CEUS using a novel vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agent for the detection of hepatic metastases in a mouse model of colorectal cancer using clinical standard technology. MATERIALS AND METHODS: The human colon cancer cell line HT29, transfected with luciferase cDNA for in vivo bioluminescence monitoring, was injected intrasplenically into CB17.SCID mice. Mice were monitored weekly by bioluminescence and after 2 and 4.5 weeks by HRU and CEUS. Contrast media (untargeted BR1, targeted BR55) was applied and digital cine loops from the arterial phase (15 - 45 sec), portal venous phase (50 - 120 s) and late phases (3 - 5 min, 1hour) of the whole liver were analyzed. Data were correlated with postmortem histopathology. RESULTS: Without contrast enhancement, lesions > 4 mm were reliably detected. After use of untargeted CEUS, lesions > 2 mm were reliably detected and enhanced rim vascularization and late-phase wash-out was shown. With BR55, lesions > 0.8 mm were reliably detected with excellent documentation of vascularization. A persistent contrast enhancement was seen > 30 min after injection. Contrast-enhancement patterns with BR55 significantly correlated with CD31 (R2 = 0.74) and VEGFR2-immunohistochemistry (R2 = 0.66). CONCLUSION: Detection of metastases by HRU and CEUS was earlier and more accurate than monitoring via bioluminescence. In vivo monitoring of hepatic micrometastases can thus be performed without prior modification of cancer cells using standard technology.

[Extracorporeal CO2 removal as an alternative to tracheotomy in a patient with extubation failure]. / Extrakorporale CO2-Elimination als Alternative zur Tracheotomie bei Weaningversagen.

We report a patient with chest trauma who was admitted to the ICU after surgery. As he fulfilled protocol-based criteria, he was extubated 7 days after admission. However, despite intermittent non-invasive ventilation, the patient had to be re-intubated on day 10 owing to progressive hypercapnia. We decided to support the patient with a mid-flow veno-venous extracorporeal carbon dioxide removal (ECCO2­R) system instead of a tracheotomy. Sufficient CO2 removal was established with a blood flow of 1.5 l/min and the patient was successfully extubated within a few hours. After 5 days of ECCO2­R the patient could be weaned and transferred to a general ward in a stable condition.

mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma.

BACKGROUND: Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models. METHODS: Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used. RESULTS: In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg(-1)) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis. CONCLUSIONS: Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC.

Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Prognosis according to histochemical analysis of liver metastases removed at liver resection.

BACKGROUND: Liver metastases occur in 40-50 per cent of patients with colorectal cancer and determine long-term survival. The aim of this study was to examine the immunological architecture of colorectal liver metastases and its impact on patient survival. METHODS: Specimens from patients with colorectal liver metastases were stained with haematoxylin and eosin and Masson trichrome, immunostained for α-smooth muscle actin, CD4, CD45RO and CD8, and analysed by flow cytometry. In addition to histomorphological evaluation, immunohistochemically stained sections were analysed for cell numbers in the tumour area, infiltrative margin and distant liver stroma separately. These findings were correlated with clinical data and patient outcome. RESULTS: Tumour containment by a fibrotic capsule around liver metastases was observed in 37·8 per cent of 201 patients and was prognostic for improved survival (median (s.e.) survival 64 (6) and 31 (4) months for patients with capsule and no capsule respectively; P < 0·001) and independently led to higher R0 resection rates (P = 0·040). In multivariable analysis, CD45RO(+) cell infiltration at the peritumoral margin with low CD45RO(+) cell infiltration in the distant liver stroma (P = 0·001) and fibrotic capsule formation (P = 0·008) both independently prolonged patient survival. Using these two factors, a cellular immune score was designed and shown to stratify patient survival in test and validation samples (both P < 0·001). CONCLUSION: Fibrotic capsule formation and localized cell infiltration of colorectal liver metastases by CD45RO(+) cells were related to prolonged patient survival. Based on these immunological criteria a cellular immune score was developed to stratify patients according to prognosis.

High levels of procalcitonin in the early phase after pediatric liver transplantation indicate poor postoperative outcome.

BACKGROUND/AIMS: To date, no data is available about procalcitonin (PCT) levels and its relevance to morbidity and graft function in the early phase after pediatric liver transplantation (pLTx). The aim of this study was to analyse the prognostic relevance of early postoperative PCT elevations in pediatric liver recipients. METHODOLOGY: Thirty pediatric patients who underwent 32 liver transplantations were included into this observational single-center study. RESULTS: Patients with high PCT levels on postoperative day (POD) 2 had higher International Normalized Ratio values on POD 5 (p<0.05) and suffered more often from primary graft non-function (p<0.05). They also had a longer stay in the pediatric intensive care unit (p<0.01) and on mechanical ventilation (p=0.001). There was no correlation between PCT elevation and systemic infection. However, PCT levels were correlated with peak serum lactate levels immediately after graft reperfusion and elevation of serum aminotransferases on POD 1 (r2=0.61, p<0.001). CONCLUSIONS: High levels of PCT after pLTx are an early indicator of poor postoperative outcome and may reflect ischemia induced liver cell injury within the context of an ischemia- reperfusion injury.

[Operative therapy of hepatocellular carcinoma]. / Operative Therapie des hepatozellulären Karzinoms.

BACKGROUND: Curative surgical strategies for hepatocellular carcinoma are liver resection and transplantation. METHODS: This overview is based on a selective literature search on therapeutic strategies for hepatocellular carcinoma. The new German S3 guidelines are outlined in detail but guidelines from other societies were also taken into consideration. RESULTS: The question of resectability is of utmost importance and should not only be evaluated in an interdisciplinary tumor board but also in an experienced liver center. Primary resectable hepatocellular carcinoma in patients without portal hypertension should be resected. Most patients without cirrhosis qualify for resection. In patients with Child grade A cirrhosis but without severe portal hypertension and a stable health status, a liver resection should be considered. At resection intraoperative ultrasound is standard. Intrahepatic tumor recurrences also can be re-resected or thermally ablated. New techniques for extended liver resections or minimally invasive liver resections are commonly used and have to be studied further. CONCLUSION: In addition to liver resection, liver transplantation now represents a standard therapy for hepatocellular carcinoma in cirrhosis. Observing the Milan selection criteria 5-year survival rates of 70-90 % can be achieved; however, increasing organ shortage leads to longer waiting times and thus higher risk of tumor progression. Therefore, patients on the waiting list should have follow-up imaging and bridging with surgical resection, radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) by interventional radiology. Living donor liver transplantation should be considered in all these patients with expected longer waiting times.

[Surgical technique for laparoscopic kidney donation]. / Die chirurgische Technik der laparoskopischen Nierenlebendspende.

OBJECTIVE: Dialysis cannot fully replace kidney function in patients diagnosed with end-stage renal disease. Patients undergoing dialysis therapy show a significantly reduced quality of life, morbidity and mortality compared to healthy individuals. Every patient diagnosed with end-stage renal disease should be evaluated for a potential kidney transplant, potentially by means of living-donor kidney donation. INDICATIONS: Via living-donor kidney donation, patients diagnosed with end-stage renal disease can receive a kidney transplant already before dialysis therapy needs to be initiated. Those patients show a significantly improved long-term graft and patient survival in comparison to patients transplanted after cadaveric organ donation. PROCEDURE: We here describe the evaluation process of living-donor kidney donation and the procedure of transperitoneal laparoscopic donor-nephrectomy. CONCLUSION: Although technically demanding, laparoscopic donor nephrectomy after careful donor evaluation is a safe procedure. An interdisciplinary medical-surgical management is important for both careful patient selection and life-long aftercare.

["In-situ split" (ISS) liver resection: new aspects of technique and indication]. / "In-situ-Split"- (ISS) Leberresektion: Neue Aspekte zu Technik und Indikation.

The combination of right portal vein ligation with complete parenchyma dissection ("in-situ split", ISS) for rapid hypertrophy induction of the left-lateral liver lobe is a novel strategy to convert primarily irresectable liver tumours into a resectable stage. Available data so far show a 60-80 % growth induction of the remnant liver within 7(- 9) days. Certainly, a novel concept that comprises two operations within a very short time period raises questions. Based on the very few literature reports that have been published so far, as well as our own experience, we here discuss technical issues such as the use of a plastic sheet on the resection margin, the possibility of laparoscopic dissection and the timing of the second operation. Moreover, aspects of the preoperative diagnostic work-up that is necessary are assessed. Finally, open questions, e.g., concerning the influence of preoperative chemotherapy and the use of ISS in patients with cirrhosis are evaluated. In summary, the assessment of chances and risks of this novel concept with regard to indication and technical issues helps to provide the potentially curative option of the "in-situ split" procedure to more patients with marginal or even irresectable liver tumours.

Inhibition of innate co-receptor TREM-1 signaling reduces CD4(+) T cell activation and prolongs cardiac allograft survival.

The innate receptor "triggering-receptor-expressed-on-myeloid-cells-1" (TREM-1) enhances downstream signaling of "pattern recognition receptor" (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1(+) antigen-presenting cells (APC) on alloreactive CD4(+) lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1(+) CD11b(+) MHC-II(+) F4/80(+) CCR2(+) APC and IFNγ-producing CD4(+) cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4(+) and CD8(+) cell infiltration. Remarkably, temporary inhibition of TREM-1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFNγ-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4(+) lymphocytes.

[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients.

BACKGROUND: Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients. METHODS: The EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period. DISCUSSION: C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022. TRIAL REGISTRATION: This trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020-000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20-1842-112.