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Clinical management of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) remains challenging. We recently introduced FMS-like tyrosine kinase 3 ligand (FLT3LG) as a possible biomarker for a proinflammatory tumor microenvironment. Here, we put a spotlight on the quantitative assessment of classical dendritic cells (cDC) and T cells in the context of FLT3LG mRNA levels in a retrospective study on NET G2/ G3 and NEC of pancreatic and gastric origin. Abundance of cDC and T cells and their relevant subpopulations were determined by immunofluorescent staining and correlated with FLT3LG mRNA levels as well as clinical outcome. Immune cell counts attested highly variable infiltration densities. Samples with presence of cDC or high numbers of T cells exhibited increased FLT3LG expression. Abundance of cDC, defined as HLA-DR+CD11c+ cells with CLEC9a (cDC1) or CD1c (cDC2), as well as CD3+ T cell and CTL (CD8+ CD3+) numbers correlated with FLT3LG mRNA levels and predicted disease-specific survival. Combining FLT3LG and T cell counts further improved this prediction. Therefore, tumor-infiltrating cDC and T cells are prognostic markers in NET G2/ G3 or NEC and FLT3LG mRNA may serve as a simple to use biomarker for a quantitative estimate of their abundance, mandating prospective evaluation in the context of immune-targeted therapies.

OBJECTIVE: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD).BACKGROUND: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT).METHODS: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD).RESULTS: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59-78) years, recipient age: 62 (IQR: 55-65) years, labMELD: 15 (IQR: 9-25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221-828) vs 796 (IQR: 477-1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12-56) vs 52 (IQR: 35-98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4-8) vs 8 (IQR: 5-18) days, P = 0.045; 20 (IQR: 16-27) vs 36 (IQR: 23-62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314).CONCLUSION: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.

Background: Major liver resection has evolved as the mainstay of treatment for patients with perihilar cholangiocarcinoma (pCCA). Here we assessed the suitability of preoperative future liver remnant (FLR) measurement to predict perioperative complications, since surgical morbidity and mortality are high compared to other malignancies.Methods: Between 2011 and 2016, 91 patients with pCCA underwent surgery in curative intent at our institution. The associations of surgical complications with FLR and clinico-pathological characteristics were assessed using logistic regression analyses. Different methods of FLR assessment, the calculatedFLR (cFLR; ratio of FLR to total liver volume), standardized FLR (sFLR; ratio of FLR to liver volume estimated by body surface area) and FLR to bodyweight ratio (FLR/BW) were tested for validity.Results: Multivariable analysis identified preoperative cholangitis (Exp(B) = 0.236; p = 0.030) as the single significant predictor of postoperative mortality and cFLR (Exp(B) = 0.009, p = 0.004) as the single significant predictor of major postoperative morbidity (Clavien-Dindo 3b). Based on these findings we designed a futility criterion (cFLR

Purpose Non-invasive high-grade (HG) bladder cancer is a heterogeneous disease that is characterized insufficiently. First-line Bacillus Calmette-Guérin instillation fails in a substantial amount of cases and alternative bladder-preserving treatments are limited, underlining the need to promote a further molecular understanding of non-invasive HG lesions. Here, we characterized pure HG papillary urothelial bladder cancer (pure pTa HG), a potential subgroup of non-invasive HG bladder carcinomas, with regard to molecular subtype affiliation and potential for targeted therapy. Methods An immunohistochemistry panel comprising luminal (KRT20, ERBB2, ESR2, GATA3) and basal (KRT5/6, KRT14) markers as well as p53 and FGFR3 was used to analyze molecular subtype affiliations of 78 pure pTa HG/papillary pT1(a) HG samples. In 66 of these, ERBB2 fluorescence in situ hybridization was performed. Additionally, targeted sequencing (31 genes) of 19 pTa HG cases was conducted, focusing on known therapeutic targets or those described to predict response to targeted therapies noted in registered clinical trials or that are already approved. Results We found that pure pTa HG/papillary pT1(a) HG lesions were characterized by a luminal-like phenotype associated with frequent (58% of samples) moderate to high ERBB2 protein expression, rare FGFR3 alterations on genomic and protein levels, and a high frequency (89% of samples) of chromatin-modifying gene alterations. Of note, 95% of pTa HG/papillary pT1 HG cases harbored at least one potential druggable genomic alteration. Conclusions Our data should help guiding the selection of targeted therapies for investigation in future clinical trials and, additionally, may provide a basis for prospective mechanistic studies of pTa HG pathogenesis.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.

Purpose Surgical resection constitutes the mainstay of curative treatment for intrahepatic cholangiocarcinoma (iCCA). Complete tumor clearance can only be achieved with extended liver resections and as such, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may facilitate surgical resectability. The present study aims to evaluate the technical feasibility and oncologic outcome of ALPPS in iCCA. Methods A set of 14 patients who underwent ALPPS in a single center between 2011 and 2017 were statistically analyzed for perioperative and oncologic outcome. Results Of all patients undergoing stage 1 of ALPPS, 12 (86%) patients were subsequently completed in stage 2 surgery. Patients who completed the ALPPS procedure showed a median overall survival (OS) of 4.2 years and a 3-year survival of 64%. Individuals without lymphatic metastases (n = 7) were all alive 1 year after surgery and if deceased, they died more than 4 years after surgery, while no patient with lymphatic metastases (n = 5) was alive 1 year after surgery. Conclusion This is the largest single-center experience of ALPPS in iCCA currently available in the literature showing excellent technical feasibility and encouraging overall survival in these patients.

Introduction: Cholangiocellular carcinoma (CCA) is an aggressive malignancy with a dismal prognosis. Among curative treatment options for CCA, radical surgical resection with extrahepatic bile duct resection, hepatectomy and en-bloc lymphadenectomy are considered the mainstay of curative therapy. Here, we aimed to identify prognostic markers of clinical outcome in CCA-patients who underwent surgical resection in curative intent.Material and methods: Between 2011 and 2016, 162 patients with CCA (perihilar CCA (pCCA): n = 91, intrahepatic CCA (iCCA): n = 71) underwent surgery in curative intent at our institution. Preoperative characteristics, perioperative data and oncological follow-up were obtained from a prospectively managed institutional database. The associations of overall-(OS) and disease-free-survival (DFS) with clinico-pathological characteristics were assessed using univariate and multivariable cox regression analyses.Results: The median OS and DFS were 38 and 36 months for pCCA and 25 and 13 months for iCCA, respectively. Lymphovascular invasion (LVI) and lymph node metastasis as well as surgical complications as assessed by the comprehensive complication index (CCI) and tumor grading were independently associated with OS for the pCCA (LVI; RR = 2.36, p = 0.028; CCI; RR = 1.04, p Conclusion: Major liver resections for CCA are feasible and safe in experienced high-volume centers. Lymph node metastasis and LVI are associated with adverse clinical outcome, supporting the role of systematic lymphadenectomy. The assessment of LVI may be useful in identifying high-risk patients for adjuvant treatment strategies. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Tumor angiogenesis plays a pivotal role in hepatocellular carcinoma (HCC) biology. Identifying molecular prognostic markers is critical to further improve treatment selection in these patients. The present study analyzed a subset of 10 germline polymorphisms involved in tumor angiogenesis pathways and their impact on prognosis in HCC patients undergoing partial hepatectomy in a curative intent. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 127 HCC patients at a German primary care hospital. Genomic DNA was extracted, and genotyping was carried out using polymerase chain reaction (PCR)–restriction fragment length polymorphism-based protocols. Polymorphisms in interleukin-8 (IL-8) (rs4073; p = 0.047, log-rank test) and vascular endothelial growth factor (VEGF C + 936T) (rs3025039; p = 0.045, log-rank test) were significantly associated with disease-free survival (DFS). After adjusting for covariates in the multivariable model, IL-8 T-251A (rs4073) (adjusted p = 0.010) and a combination of “high-expression” variants of rs4073 and rs3025039 (adjusted p = 0.034) remained significantly associated with DFS. High-expression variants of IL-8 T-251A may serve as an independent molecular marker of prognosis in patients undergoing surgical resection for HCC. Assessment of the patients’ individual genetic risks may help to identify patient subgroups at high risk for recurrence following curative-intent surgery.

In the present era of organ transplantation with critical organ shortage, various strategies are employed to expand the pool of available allografts for kidney transplantation (KT). Even though, the use of allografts from extended criteria donors (ECD) could partially ease the shortage of organ donors, ECD organs carry a potentially higher risk for inferior outcomes and postoperative complications. Dynamic organ preservation techniques, modulation of ischemia-reperfusion and preservation injury, and allograft therapies are in the spotlight of scientific interest in an effort to improve allograft utilization and patient outcomes in KT.Preclinical animal experiments are playing an essential role in translational research, especially in the medical device and drug development. The major advantage of the porcine orthotopic auto-transplantation model over ex vivo or small animal studies lies within the surgical-anatomical and physiological similarities to the clinical setting. This allows the investigation of new therapeutic methods and techniques and ensures a facilitated clinical translation of the findings. This protocol provides a comprehensive and problem-oriented description of the porcine orthotopic kidney auto-transplantation model, using a preservation time of 24 hours and telemetry monitoring. The combination of sophisticated surgical techniques with highly standardized and state-of-the-art methods of anesthesia, animal housing, perioperative follow up, and monitoring ensure the reproducibility and success of this model.

In the face of a critical organ shortage in the Western world, various strategies are employed to expand the donor pool for orthotopic liver transplantation (OLT). Among them is the transplantation of organs from extended criteria donors, a valuable source of liver allografts, however, characterized by potential risks for post-OLT complications and inferior outcomes. In recent years, machine perfusion (MP) of the explanted donor liver as well as regional perfusion techniques has witnessed significant advancements. Here, we aim to discuss different modes of dynamic organ preservation in OLT. These include hypothermic and normothermic MP, hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols. Over recent years, multiple feasibility trials have demonstrated the clinical prospects of MP. In the context of OLT using organs from extended criteria donors, MP has numerous advantages compared to conventional cold storage, some of which include the preservation and reconditioning of borderline transplantable organs and the viability assessment of high-risk donor allografts. This review aims to address the topic of liver allograft MP, highlighting particularly the current trends in clinical applications and future perspectives. Furthermore, different approaches of liver storage and reconditioning are reviewed in the context of ongoing research.

The American journal of pathology 190(2), 323-332 (2020). doi:10.1016/j.ajpath.2019.10.004, Published by Elsevier, New York [u.a.]

BACKGROUND: Major liver resections with portal vein resection (PVR) have emerged as the preferred treatment for patients with perihilar cholangiocarcinoma (pCCA). Whether the resection of the liver should be preferably performed as left- (LH) or right-sided hepatectomy (RH) with or without hilar en-bloc technique is still subject of ongoing debate.METHODS: Between 2011 and 2016, 91 patients with pCCA underwent surgery in curative intent at our institution. Perioperative, pathological and survival data from all consecutive patients undergoing hilar en-bloc resection for pCCA were analyzed retrospectively. Patients undergoing hepatoduodenectomy (n = 8) or ALPPS (Associating liver partition and portal vein ligation for staged hepatectomy) (n = 2) were excluded from the analysis.RESULTS: Tumor grading, microvascular invasion, lymphovascular invasion, N-category, T-category, R-status and UICC-tumor staging were similar in the RH (n = 45) and LH (n = 36) groups. Perioperative morbidity and mortality were higher after RH compared to LH (mortality: 15.6% (7/45) vs. 8.3% (3/36) p = 0.003). Three-year (62% vs. 51%) and the 5-year OS (30% vs. 46%) were comparable between LH and RH groups respectively (p = 0.519, log rank).CONCLUSIONS: The present study supports the concept of surgically aggressive therapy in pCCA. LH and RH hilar en-bloc resection demonstrate a comparable long-term survival, suggesting that LH hilar en-bloc resections are feasible and safe in high-volume centers.

American journal of transplantation 19(11), 3207-3209 (2019). doi:10.1111/ajt.15568, Published by Wiley-Blackwell, Oxford [u.a.]

Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.