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.

Role of clinical and CT findings in the identification of adult small-bowel intussusception requiring surgical intervention.

BACKGROUND: In adults, intussusception has been considered traditionally to have an underlying aetiology. The aim of this study was to determine CT and clinical features of small-bowel intussusceptions that required surgical intervention. METHODS: Adult patients were identified in whom small-bowel intussusceptions were noted on CT images. The appearance, number, type (enteroenteric versus enterocolic), length and maximum short-axis diameter of intussusceptions, and presence of bowel obstruction (short-axis diameter of proximal small bowel greater than 3 cm) were analysed. The outcome was defined as surgical (complicated) or self-limiting (uncomplicated). Associations between complicated and uncomplicated intussusceptions and patient characteristics were investigated. RESULTS: Among 75 patients (56 male) with a mean age of 45 years, 103 intussusceptions were identified, of which 98 (95 per cent) were enteroenteric and 5 (5 per cent) enterocolic. Only 12 of 103 intussusceptions (12 per cent) in 12 of 75 (16 per cent) patients required surgical therapy and were considered to be complicated, with half of these having a neoplastic lead point. Length (P < 0.001), diameter (P < 0.001) and type (P = 0.002) of intussusception as well as presence of vessels (P = 0.023) within an intussusception on a CT scan, clinical symptoms (P = 0.007) and signs of bowel obstruction (P < 0.001) were associated with a surgical outcome. CONCLUSION: Clinical symptoms, signs of bowel obstruction, type and length of intussusception, and a visible tumour within an intussusception on CT scan were critical signs of complicated intussusception, requiring surgical intervention.

Stereotactic Percutaneous Electrochemotherapy as Primary Approach for Unresectable Large HCC at the Hepatic Hilum.

Electrochemotherapy (ECT) is a novel non-thermal ablative technique that combines chemotherapy and the application of electric pulses for reversible cell membrane electroporation. This method was recently performed in the treatment of deep-seated liver tumors during open surgery but experience about percutaneous ECT is rare and further developments like combination of percutaneous ECT with stereotactic navigated devices may be very promising. We report on a case of a 4.7 × 4.5 × 3.5 cm unresectable HCC at the hepatic hilum adjacent to the major vessels and the bile duct that was successfully treated using percutaneous ECT in combination with stereotactic navigation. Follow-up imaging 6 weeks and 6 months after ECT showed complete response.

Super selective percutaneous transhepatic coil embolization of intrahepatic pseudoaneurysm after pediatric liver transplantation: a case report.

BACKGROUND: Intrahepatic arterial pseudoaneurysms are a rare, life-threatening complication after pediatric liver transplantation. Treatment of choice represents interventional radiological management with endovascular embolization of the segmental artery proximal and distal to the aneurysm. However, this technique results in loss of arterial perfusion distal to the aneurysm with subsegment arterial ischemia. CASE PRESENTATION: We report a case of a 1-year-old girl with a pseudoaneurysm in the split-liver graft. Direct percutaneous, transhepatic access to the pseudoaneurysm was performed followed by super selective coil application into the aneurysm. CONCLUSION: Super selective percutaneous, transhepatic coil application is feasible even in pediatric patients after liver transplantation and results in preservation of the entire course of the liver artery.

[Surgical innovations in treatment of metastatic colorectal cancer : Complexity of metastatic surgery as example for personalized medicine]. / Chirurgische Innovationen in der Therapie des metastasierten kolorektalen Karzinoms : Die Komplexität der Metastasenchirurgie als Beispiel für personalisierte Medizin.

BACKGROUND: Extensive, bilobular and multifocal colorectal liver metastases (CLM) or metastases that are critically situated require an experienced surgeon and advanced surgical techniques to enable curative resection. OBJECTIVE: This article describes the toolbox of hepato-oncologic surgery including functional augmentation of liver segments by portal vein embolization/ligation, combinations of ablation and resection, two-stage resections and in situ split liver resection, also known as associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Furthermore, the curative resection of extrahepatic, oligometastatic disease are briefly discussed. MATERIAL AND METHODS: Review of current literature as well as discussion of the ALPPS procedure, which was developed at our institute. RESULTS: In recent years, oncologic resections for CLM have been significantly refined, leading to a constant increase of curative resection rates. CONCLUSION: In a multimodality treatment setting, surgical resection of CLM remains the gold standard curative approach and even in the event of presumed hopeless cases with extensive metastasis, experienced hepatobiliary surgeons must evaluate the resectability of colorectal metastases.

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.

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.

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.