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Undifferentiated embryonal sarcoma of the liver treated with associating liver partition and portal vein ligation for staged hepatectomy in a young adult: A case report.

Schepelew D, Reese T, Horling K, Frenzel C, Oldhafer KJ.; Int J Surg Case Rep. 2019 Nov 30;66:221-227. doi: 10.1016/j.ijscr.2019.11.052

INTRODUCTION: Embryonal sarcomas of the liver (ESL) are extremely rare solid tumors appearing mainly in children. The therapeutic standard for an ESL is a margin free resection combined with chemotherapy. The Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure as a surgical therapy offers a curative approach for liver tumors of various origins where the future liver remnant (FLR) would be insufficient after a one-staged (extended) hemihepatectomy.
PRESENTATION OF CASE: A 19-year-old patient was diagnosed with an undifferentiated embryonal sarcoma of the liver (UESL) in the right liver lobe with oligometastatic spread to the lungs. After neoadjuvant chemotherapy remission was enough to plan a resection of the liver tumor. During the operation we changed our strategy from one-stage hepatectomy to ALPPS because of borderline FLR and macroscopic and histologic liver damage to avoid posthepatectomy liver failure. The interstage and postoperative course of the patient was uneventful beside postoperative bile leakage, which was treated by interventional drainage and stenting.
DISCUSSION:  The ALPPS-procedure as a comparatively new surgery was considered over a portal vein ligation or embolization. ALPPS shows a faster hypertrophy compared to standard one-staged hemihepatectomy with decreased or similar proliferation, apoptosis or angiogenesis (at least for CRLM)
CONCLUSION: In experienced centers the ALPPS-procedure is evolving as the safer approach in hemihepatectomys where the FLR is critical. Additionally, ALPPS can serve as an intraoperative option when liver volume and quality seem not to be sufficient and is to be considered when facing new tumor-entities.
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PerspectivesEstablishing a student-run free clinic in a major city in Northern Europe: a 1-year experience from Hamburg, Germany.

Drexler R, Fröschle F, Predel C, Sturm B, Ustorf K, Lehner L, Janzen J, Valentin L, Scheer T, Lehnert F, Tadzic R, Oldhafer KJ, Meyer TN.; J Public Health (Oxf). 2019 Dec 16. pii: fdz165. doi: 10.1093/pubmed/fdz165.

BACKGROUND: Student-Run Free Clinics (SRFCs) have been an integral part of US medical schools since the 1960s and provide health care to underserved populations. In 2018, we established an SRFC in Hamburg, Germany, a major city in Northern Europe. The aim of this study was to describe the central problems and to investigate the usefulness of an SRFC in a country with free access to medical care, such as Germany.

METHODS: All consecutive patients treated at the SRFC Hamburg between February 2018 and March 2019 that consented to this study were analyzed regarding clinical characteristics, diagnosis, readmission rate and country of origin.

RESULTS: Between February 2018 and March 2019, 229 patients were treated at the SRFC in Hamburg. The patients came from 33 different countries with a majority (n = 206, 90%) from countries inside the European Union. The most common reasons for visiting the SRFC were infections (23.2%), acute or chronic wounds (13.5%) and fractures (6.3%).

CONCLUSION: Our multicultural patients suffer mainly from infections and traumatological and dermatological diseases. We find similarities to published Canadian SRFC patient cohorts but differences in diseases and treatment modalities compared to US SRFCs. Importantly, we demonstrate the relevance and necessity of the SRFC in a major city in Northern Europe.

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Renal Impairment Is Associated with Reduced Outcome After Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy.

Reese T, Fard-Aghaie MH, Makridis G, Kantas A, Wagner KC, Malagó M, Robles-Campos R, Hernandez-Alejandro R, de Santibañes E, Clavien PA, Petrowsky H, Linecker M, Oldhafer KJ.; J Gastrointest Surg. 2019 Nov 19. doi: 10.1007/s11605-019-04419-2.

BACKGROUND: Impaired postoperative renal function is associated with increased morbidity and mortality after liver resection. The role of impaired renal function in the two-stage hepatectomy setting of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is unknown.

METHODS: An international multicenter cohort of ALPPS patients captured in the ALPPS Registry was analyzed. Particular attention was drawn to the renal function in the interstage interval to determine outcome after stage 2 surgery. Interstage renal impairment (RI) was defined as an increase of serum creatinine of ≥ 0.3 mg/dl referring to a preoperative value or an increase of serum creatinine of ≥ 1.5× of the preoperative value on the fifth postoperative day after stage 1.

RESULTS: A total of 705 patients were identified of which 7.5% had an interstage RI. Patients developing an interstage RI were significantly older. During stage 1, a longer operation time, higher rate of intraoperative transfusions, and additional procedures were observed in patients that developed interstage RI. After stage 1, interstage RI patients had more major complications and higher interstage mortality (1% vs. 8%, p < 0.001). Furthermore, these patients developed more and severe complications after completion of stage 2. Mortality of patients with interstage RI was 38% vs. 8% without interstage RI. In 41% of patients with interstage RI, the renal function recovered before stage 2; however, the mortality after stage 2 remained 28% in those patients. Risk factors for the development of an interstage RI were age over 67 years, prolonged operative time, and additional procedure during stage 1.

CONCLUSION: This study shows that interstage RI is a predictor for interstage and post-stage 2 morbidity and perioperative mortality. The causality of impaired renal function on outcome, however, remains unknown. Interstage RI may directly cause adverse outcome but may also be a surrogate marker for major complications.

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First intraoperative measurement of liver functional capacity during liver surgery using the 13 C-methacetin breath test: early results of a pilot study.

Makridis G, Oldhafer KJ.; J Hepatobiliary Pancreat Sci. 2019 Nov 9. doi: 10.1002/jhbp.699.

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The MEGNA Score and Preoperative Anemia are Major Prognostic Factors After Resection in the German Intrahepatic Cholangiocarcinoma Cohort.

Schnitzbauer AA, Eberhard J, Bartsch F, Brunner SM, Ceyhan GO, Walter D, Fries H, Hannes S, Hecker A, Li J, Oldhafer K, Rahbari N, Rauchfuss F, Schlitt HJ, Settmacher U, Stavrou G, Weitz J, Lang H, Bechstein WO, Rückert F.; Ann Surg Oncol. 2019 Oct 23. doi: 10.1245/s10434-019-07968-7.

BACKGROUND: Surgical resection is associated with the best long-term results for intrahepatic cholangiocarcinoma (ICC); however, long-term outcomes are still poor.

OBJECTIVE: The primary aim of this study was to validate the recently proposed MEGNA score and to identify additional prognostic factors influencing short- and long-term survival.

PATIENTS AND METHODS: This was a retrospective analysis of a German multicenter cohort operated at 10 tertiary centers from 2004 to 2013. Patients were clustered using the MEGNA score and overall survival was analyzed. Cox regression analysis was used to identify prognostic factors for both overall and 90-day survival.

RESULTS: A total of 488 patients undergoing liver resection for ICC fulfilled the inclusion criteria and underwent analysis. Median age was 67 years, 72.5% of patients underwent major hepatic resection, and the lymphadenectomy rate was 86.9%. Median overall survival was 32.2 months. The MEGNA score significantly discriminated the long-term overall survival: 0 (68%), I (48%), II (32%), and III (19%) [p <0.001]. In addition, anemia was an independent prognostic factor for overall survival (hazard ratio 1.78, 95% confidence interval 1.29-2.45; p <0.01).

CONCLUSION: Hepatic resection provides the best long-term survival in all risk groups (19-65% overall survival). The MEGNA score is a good discriminator using histopathologic items and age for stratification. Correction of anemia should be attempted in every patient who responds to treatment. Perioperative liver failure remains a clinical challenge and contributes to a relevant number of perioperative deaths.

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Defining Benchmark Outcomes for ALPPS.

Raptis DA, Linecker M, Kambakamba P, Tschuor C, Müller PC, Hadjittofi C, Stavrou GA, Fard-Aghaie MH, Tun-Abraham M, Ardiles V, Malagó M, Campos RR, Oldhafer KJ, Hernandez-Alejandro R, de Santibañes E, Machado MA, Petrowsky H, Clavien PA.; Ann Surg. 2019 Nov;270(5):835-841. doi: 10.1097/SLA.0000000000003539.

OBJECTIVE: The aim of this study was to use the concept of benchmarking to establish robust and standardized outcome references after the procedure ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy).

BACKGROUND AND AIMS: The recently developed ALPPS procedure, aiming at removing primarily unresectable liver tumors, has been criticized for safety issues with high variations in the reported morbidity/mortality rates depending on patient, disease, technical characteristics, and center experience. No reference values for relevant outcome parameters are available.

METHODS: Among 1036 patients registered in the international ALPPS registry, 120 (12%) were benchmark cases fulfilling 4 criteria: patients ≤67 years of age, with colorectal metastases, without simultaneous abdominal procedures, and centers having performed ≥30 cases. Benchmark values, defined as the 75th percentile of the median outcome parameters of the centers, were established for 10 clinically relevant domains.

RESULTS: The benchmark values were completion of stage 2: ≥96%, postoperative liver failure (ISGLS-criteria) after stage 2: ≤5%, ICU stay after ALPPS stages 1 and 2: ≤1 and ≤2 days, respectively, interstage interval: ≤16 days, hospital stay after ALPPS stage 2: ≤10 days, rates of overall morbidity in combining both stage 1 and 2: ≤65% and for major complications (grade ≥3a): ≤38%, 90-day comprehensive complication index was ≤22, the 30-, 90-day, and 6-month mortality was ≤4%, ≤5%, and 6%, respectively, the overall 1-year, recurrence-free, liver-tumor-free, and extrahepatic disease-free survival was ≥86%, ≥50%, ≥57%, and ≥65%, respectively.

CONCLUSIONS: This benchmark analysis sets key reference values for ALPPS, indicating similar outcome as other types of major hepatectomies. Benchmark cutoffs offer valid tools not only for comparisons with other procedures, but also to assess higher risk groups of patients or different indications than colorectal metastases.

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Intraoperative fluorescence angiography and cholangiography with indocyanine green in hepatobiliary surgery.

Oldhafer KJ, Reese T, Fard-Aghaie M, Strohmaier A, Makridis G, Kantas A, Wagner KC.; Chirurg. 2019 Nov;90(11):880-886. doi: 10.1007/s00104-019-01035-3.

Intraoperative fluorescence angiography and cholangiography with indocyanine green (ICG) are increasingly used in routine hepatobiliary surgery. Its usage is manifold. It improves and facilitates navigation especially in minimal invasive and robotic surgery and therefore increases the safety of the surgical intervention. In laparoscopic cholecystectomy for example, the bileduct anatomy can be easily visualized, even in complicated cholecystitis or anatomical variants without being too time consuming. ICG fluorescence also enables the visualization of vascular structures and perfusion. Anatomical liver resections, for example in hepatocellular carcinoma (HCC), can be performed easily as liver segments and territories can be identified. Anatomical resection is becoming more important, e.g. in the treatment of HCC. Another useful application is the intraoperative detection of bile leakages after liver resection. In particular, the intraoperative control of a biliodigestive anastomosis is possible with ICG fluorescence cholangiography and therefore reduces morbidity. Even primary and secondary liver tumors can be detected with ICG fluorescence. Whereas well-differentiated HCCs homogeneously take up ICG, poorly differentiated HCCs and metastases do not: however, in these cases the adjacent liver parenchyma stores ICG more intensively than healthy liver tissue, which creates a ring-like fluorescence pattern. To conclude, the use of ICG fluorescence in hepatobiliary surgery is diverse but in Germany it is still at the beginning compared to other countries.

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ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry.

Linecker M, Kambakamba P, Raptis DA, Malagó M, Ratti F, Aldrighetti L, Robles-Campos R, Lehwald-Tywuschik N, Knoefel WT, Balci D, Ardiles V, De Santibañes E, Truant S, Pruvot FR, Stavrou GA, Oldhafer KJ, Voskanyan S, Mahadevappa B, Kozyrin I, Low JK, Ferrri V, Vicente E, Prachalias A, Pizanias M, Clift AK, Petrowsky H, Clavien PA, Frilling A.; HPB (Oxford). 2019 Sep 17. pii: S1365-182X(19)30701-4. doi: 10.1016/j.hpb.2019.08.011.

BACKGROUND: Surgery is the most effective treatment option for neuroendocrine liver metastases (NELM). This study investigated the role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a novel strategy in treatment of NELM.

METHODS: The International ALPPS Registry was reviewed to study patients who underwent ALPPS for NELM.

RESULTS: From 2010 to 2017, 954 ALPPS procedures from 135 international centers were recorded in the International ALPPS Registry. Of them, 24 (2.5%) were performed for NELM. Twenty-one patients entered the final analysis. Overall grade ≥3b morbidity was 9% after stage 1 and 27% after stage 2. Ninety-day mortality was 5%. R0 resection was achieved in 19 cases (90%) at stage 2. Median follow-up was 28 (19-48) months. Median disease free survival (DFS) was 17.3 (95% CI: 7.1-27.4) months, 1-year and 2-year DFS was 73.2% and 41.8%, respectively. Median overall survival (OS) was not reached. One-year and 2-year OS was 95.2% and 95.2%, respectively.

CONCLUSIONS: ALPPS appears to be a suitable strategy for inclusion in the multimodal armamentarium of well-selected patients with neuroendocrine liver metastases. In light of the morbidity in this initial series and a high rate of disease-recurrence, the procedure should be taken with caution.

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Mortality after liver surgery in Germany.

Filmann N, Walter D, Schadde E, Bruns C, Keck T, Lang H, Oldhafer K, Schlitt HJ, Schön MR, Herrmann E, Bechstein WO, Schnitzbauer AA.; Br J Surg. 2019 Oct;106(11):1523-1529. doi: 10.1002/bjs.11236. Epub 2019 Jul 24.

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.

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Correlation between SACE (Subjective Angiographic Chemoembolization Endpoint) score and tumor response and its impact on survival after DEB-TACE in patients with hepatocellular carcinoma.

Habbel VSA, Zeile M, Stavrou GA, Wacker F, Brüning R, Oldhafer KJ, Rodt T.; Abdom Radiol (NY). 2019 Oct;44(10):3463-3479. doi: 10.1007/s00261-019-02128-7.

PURPOSE: To asses angiographic and computed tomographic success criteria during and after transcatheter arterial drug-eluting bead chemoembolization (DEB-TACE) in patients with hepatocellular carcinoma (HCC) and its impact on progression-free survival (PFS) and overall survival (OS).

METHODS: In this retrospective single-center study, 50 patients with unresectable HCC having undergone DEB-TACE from January 2010 to July 2015 were assessed. The angiographic endpoint was classified by Subjective Angiographic Chemoembolization Endpoint (SACE) scale. Relative tumor density in arterial (DArt) and portal venous phase (DPV) computed tomography post- versus pre-DEB-TACE were calculated, respectively. Tumor response according to modified Response Criteria in Solid Tumors (mRECIST) was assessed. Univariate Kaplan-Meier and Cox regression analysis were carried out.

RESULTS: SACE scores I, II, III, and IV were found in 1 (2%), 20 (40%), 15 (30%), and 14 (28%) patients, respectively. Median OS and PFS were 14.2 and 5.5 months, respectively. Death rates at 6 months, 1 year and 2 years were 24%, 38%, and 52%, respectively. SACE score during DEB-TACE significantly correlated with local and overall mRECIST results (local: p < 0.001, r = 0.49, overall: p = 0.042, r = 0.29) and inversely correlated with DPV (p = 0.005, r = - 0.40). In univariate analysis, progressive disease (PD) according to mRECIST and increase of DArt and DPV were associated with significantly shorter PFS. Modified RECIST independently predicted OS (hazard ratio for complete remission vs. PD = 0.15, 95% confidence interval 0.03-0.68, p = 0.014).

CONCLUSIONS: A direct impact of SACE on PFS or OS could not be shown. However, SACE significantly correlated with local and overall mRECIST tumor response that again significantly predicted OS. We therefore postulate an indirect impact of SACE on OS. Consequently, complete embolization should be attempted.

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ASO Author Reflections: Revival of the In-Situ Hypothermic Perfusion? The Role of Complex Liver Surgery in the Modern Era.

Fard-Aghaie MH, Oldhafer KJ.; Ann Surg Oncol. 2019 Dec;26(Suppl 3):653. doi: 10.1245/s10434-019-07521-6. Epub 2019 Jun 26.

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CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans.

Martrus G, Goebels H, Langeneckert AE, Kah J, Flomm F, Ziegler AE, Niehrs A, Löbl SM, Russu K, Hess LU, Salzberger W, Poch T, Nashan B, Schramm C, Oldhafer KJ, Dandri M, Koch M, Lunemann S, Altfeld M.; Front Immunol. 2019 Jun 7;10:1247. doi: 10.3389/fimmu.2019.01247. eCollection 2019.

Macrophages play central roles in inflammatory reactions and initiation of immune responses during infections. More than 80% of total tissue macrophages are described to be located in the liver as liver-resident macrophages, also named Kupffer cells (KCs). While studies in mice have established a central role of liver-resident KCs in regulating liver inflammation, their phenotype and function are not well-characterized in humans. Comparing paired human liver and peripheral blood samples, we observed significant differences in the distribution of macrophage (Mφ) subsets, with lower frequencies of CD14hiCD16lo and higher frequencies of CD14int-hiCD16int Mφ in human livers. Intrahepatic Mφ consisted of diverse subsets with differential expression of CD49a, a liver-residency marker previously described for human and mice NK cells, and VSIG4 and/or MARCO, two recently described human tissue Mφ markers. Furthermore, intrahepatic CD49a+ Mφ expressed significantly higher levels of maturation and activation markers, exhibited higher baseline levels of TNF-α, IL-12, and IL-10 production, but responded less to additional in vitro TLR stimulation. In contrast, intrahepatic CD49a- Mφ were highly responsive to stimulation with TLR ligands, similar to what was observed for CD49a- monocytes (MOs) in peripheral blood. Taken together, these studies identified populations of CD49a+, VSIG4+, and/or MARCO+ Mφ in human livers, and demonstrated that intrahepatic CD49a+ Mφ differed in phenotype and function from intrahepatic CD49a- Mφ as well as from peripheral blood-derived monocytes.

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Accuracy of estimated total liver volume formulas before liver resection.

Olthof PB, van Dam R, Jovine E, Campos RR, de Santibañes E, Oldhafer K, Malago M, Abdalla EK, Schadde E.; Surgery. 2019 Sep;166(3):247-253. doi: 10.1016/j.surg.2019.05.003. Epub 2019 Jun 14.

BACKGROUND: Future remnant liver volume is used to predict the risk for liver failure in patients who will undergo major liver resection. Formulas to estimate total liver volume based on biometric data are widely used to calculate future remnant liver volume; however, it remains unclear which formula is most accurate. This study evaluated published estimate total liver volume formulas to determine which formula best predicts the actual future remnant liver volume based on measurements in a large number of patients who underwent associating liver partition and portal vein ligation for staged hepatectomy surgery.

METHODS: All patients with complete liver volume data in the associating liver partition and portal vein ligation for staged hepatectomy registry were included in this study. Estimate total liver volume and estimated future remnant liver volume were calculated for 16 published formulas. The median over- or underestimation compared with actual measured volumes were determined for estimate total liver volume and future remnant liver volume. The proportion of patients with an under- or overestimated future remnant liver volume for each formula were compared with each other using a 25% cut-off for each formula.

RESULTS: Among 529 studied patients, the formulas ranged from a 19% underestimation to a 63% overestimation of estimate total liver volume. Estimation of future remnant liver volume lead to a 10% underestimation to a 5% overestimation among the formulas. Of all studied formulas, the Vauthey1 formula was the most accurate, generating underestimation of future remnant liver volume in 20% and overestimation of future remnant liver volume in 6% of patients.

CONCLUSION: Validation of 16 published total liver volume formulas in a multicenter international cohort of 529 patients that underwent staged hepatectomy revealed that the Vauthey formula (estimate total liver volume = 18.51 × body weight + 191.8) provides the most accurate prediction of the actual future remnant liver volume.

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Critical appraisal of the modified ante situm liver resection: Is the original method the better choice?

Fard-Aghaie MH, Kantas A, Makridis G, Reese T, Wagner KC, Oldhafer KJ.; Langenbecks Arch Surg. 2019 Aug;404(5):647. doi: 10.1007/s00423-019-01794-x. Epub 2019 Jun 10.

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Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice.

Ravichandran G, Neumann K, Berkhout LK, Weidemann S, Langeneckert AE, Schwinge D, Poch T, Huber S, Schiller B, Hess LU, Ziegler AE, Oldhafer KJ, Barikbin R, Schramm C, Altfeld M, Tiegs G.; J Hepatol. 2019 Oct;71(4):773-782. doi: 10.1016/j.jhep.2019.05.023. Epub 2019 Jun 5.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC, yet their functional role remains to be determined.

METHODS: Liver tissue samples were collected from patients with PSC. The contribution of lymphocytes to liver pathology was assessed in Mdr2-/- x Rag1-/- mice, which lack T and B cells, and following depletion of CD90.2+ or natural killer (NK)p46+ cells in Mdr2-/- mice. Liver pathology was also determined in Mdr2-/- x Ifng-/- mice and following anti-IFNγ antibody treatment of Mdr2-/- mice. Immune cell composition was analysed by multi-colour flow cytometry. Liver injury and fibrosis were determined by standard assays.

RESULTS: Patients with PSC showed increased IFNγ serum levels and elevated numbers of hepatic CD56bright NK cells. In Mdr2-/- mice, hepatic CD8+ T cells and NK cells were the primary source of IFNγ. Depletion of CD90.2+ cells reduced hepatic Ifng expression, NK cell cytotoxicity and liver injury similar to Mdr2-/- x Rag1-/- mice. Depletion of NK cells resulted in reduced CD8+ T cell cytotoxicity and liver fibrosis. The complete absence of IFNγ in Mdr2-/-x Ifng-/- mice reduced NK cell and CD8+ T cell frequencies expressing the cytotoxic effector molecules granzyme B and TRAIL and prevented liver fibrosis. The antifibrotic effect of IFNγ was also observed upon antibody-dependent neutralisation in Mdr2-/- mice.

CONCLUSION: IFNγ changed the phenotype of hepatic CD8+ T cells and NK cells towards increased cytotoxicity and its absence attenuated liver fibrosis in chronic sclerosing cholangitis. Therefore, unravelling the immunopathogenesis of PSC with a particular focus on IFNγ might help to develop novel treatment options.

LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis, whose current medical treatment is hardly effective. We observed an increased interferon (IFN)-γ response in patients with PSC and in a mouse model of sclerosing cholangitis. IFNγ changed the phenotype of hepatic CD8+ T lymphocytes and NK cells towards increased cytotoxicity, and its absence decreased liver cell death, reduced frequencies of inflammatory macrophages in the liver and attenuated liver fibrosis. Therefore, IFNγ-dependent immune responses may disclose checkpoints for future therapeutic intervention strategies in sclerosing cholangitis.

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Liver Resection with In Situ Hypothermic Perfusion: An Old but Effective Method.

Oldhafer KJ, Stavrou GA, Wagner KC, Fard-Aghaie MH.; Ann Surg Oncol. 2019 Jun;26(6):1859. doi: 10.1245/s10434-019-07232-y. Epub 2019 Feb 24.

BACKGROUND: More than 40 years ago, patients with tumors infiltrating the confluence of the hepatic veins were deemed unresectable; however, in situ hypothermic perfusion, first described by Fortner et al. (Ann Surg 180(4):644-652, 1974), allowed resection of these tumors. In order to prevent liver ischemia after total vascular exclusion, the liver was flushed with a cooled organ preservation solution. The surgeon was able to resect the tumor and reconstruct the hepatic veins with occlusion of the hepatic inflow and outflow.

METHODS: A 55-year-old female suffering from a leiomyosarcoma of the inferior vena cava (IVC) presented to our clinic. Three years ago, the IVC was replaced with a synthetic graft. During the patient's follow-up, a computed tomography (CT) scan revealed three hepatic metastases of the sarcoma. A central metastasis in Segment 8 infiltrated the right hepatic vein (RHV), and two additional metastases were located in the left lateral segments. We used Fortner's technique to resect these tumors.

RESULTS: The postoperative course of the patient was prolonged due to a hematoma that partially compressed the new RHV graft. A re-laparotomy was performed and drains were placed. On the 15th postoperative day, the patient was discharged in good health.

CONCLUSIONS: Although nowadays patients with these unfortunate tumor locations can, to some extent, be managed non-operatively, surgery remains an option with a chance of cure. Azoulay et al. (Ann Surg 262(1):93-104, 2015) were able to show satisfactory 5-year-survival in 77 patients (30.4%), however 90-day mortality was high (19.5%). Therefore, patients need to be selected carefully. In the era of minimally invasive liver surgery, these old techniques should not vanish from the armamentarium of liver surgeons.

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CCL21-expression and accumulation of CCR7+ NK cells in livers of patients with primary sclerosing cholangitis.

Langeneckert AE, Lunemann S, Martrus G, Salzberger W, Hess LU, Ziegler AE, Poch T, Ravichandran G, Matschl U, Bosse JB, Tiegs G, Fischer L, Koch M, Herkel J, Oldhafer KJ, Schramm C, Altfeld M.; Eur J Immunol. 2019 May;49(5):758-769. doi: 10.1002/eji.201847965. Epub 2019 Feb 27.

The pathogenesis of primary sclerosing cholangitis (PSC), an autoimmune liver disease, remains unknown. The aim of this study was to characterize peripheral blood and intrahepatic NK cells from patients with PSC. Peripheral blood samples from patients with PSC, other autoimmune liver diseases, and from healthy control individuals were used, as well as liver tissues from PSC patients undergoing liver transplantation. Multiparameter flow cytometry showed that peripheral blood NK cells from PSC patients were significantly enriched for CCR7+ and CXCR3+ cells, and CCR7+ but not CXCR3+ cells were also significantly increased within intrahepatic NK cells. PSC patients undergoing liver transplantation furthermore had significantly higher plasma levels of the CCR7-ligand CCL21, and the CXCR3-ligands CXCL10 and CXCL11, and significantly higher levels of CCL21, but not CXCL10, were detected in liver tissues. CCR7+ and CXCR3+ NK cells from PSC patients exhibited significantly higher functional capacity in peripheral blood, but not liver tissues, consistent with chronic activation of these NK cells in the inflamed liver. These data show that PSC is characterized by intrahepatic CCL21 expression and accumulation of CCR7+ NK cells in the inflamed liver tissue.

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Human liver-derived CXCR6+ NK cells are predominantly educated through NKG2A and show reduced cytokine production.

Lunemann S, Langeneckert AE, Martrus G, Hess LU, Salzberger W, Ziegler AE, Löbl SM, Poch T, Ravichandran G, Sauter J, Schmidt AH, Schramm C, Oldhafer KJ, Altfeld M, Körner C.; J Leukoc Biol. 2019 Jun;105(6):1331-1340. doi: 10.1002/JLB.1MA1118-428R. Epub 2019 Feb 19.

NK cells have been implicated to affect the outcome of numerous liver diseases. In particular, members of the killer-cell Ig-like receptor (KIR) family, predominantly expressed by NK cells, have been associated with the outcome of hepatitis C virus infection and clearance of hepatocellular carcinoma. Inhibitory KIRs tune NK cell function through interaction with HLA class I, a process termed education. Nevertheless, the impact of the hepatic environment on NK cell education is incompletely understood. Therefore, we investigated the composition and function of hepatic KIR-expressing NK cells. Matched PBMC and hepatic lymphocytes were isolated from 20 individuals undergoing liver surgery and subsequently phenotypically analyzed for expression of KIRs and markers for tissue residency using flow cytometry. NK cell function was determined by co-culturing NK cells with the target cell line 721.221 and subsequent assessment of CD107a, IFN-γ, and TNF-α expression. Liver-resident CXCR6+ /CD56Bright NK cells lacked KIRs and were predominantly educated through NKG2A, while CXCR6- /CD16+ NK cells expressed KIRs and resembled peripheral blood NK cells. Hepatic NK cells showed lower response rates compared to peripheral blood NK cells; in particular, CXCR6+ NK cells were hyporesponsive to stimulation with target cells. The high proportion of educated NK cells in both subsets indicates the importance of self-inhibitory receptors for the balance between maintenance of self-tolerance and functional readiness. However, the reduced functionality of hepatic NK cells may reflect the impact of the tolerogenic hepatic environment on NK cells irrespective of NK cell education.

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Liver resection in octogenarians: are the outcomes worth the risk? The Hamburg Barmbek experience.

Makridis G, Reese T, Kantas A, Fard-Aghaie MH, Oldhafer KJ.; ANZ J Surg. 2019 Jan;89(1-2):131-132. doi: 10.1111/ans.14937.

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Avoiding postoperative mortality after ALPPS-development of a tumor-specific risk score for colorectal liver metastases.

Huiskens J, Schadde E, Lang H, Malago M, Petrowsky H, de Santibañes E, Oldhafer K, van Gulik TM, Olthof PB.; HPB (Oxford). 2019 Jul;21(7):898-905. doi: 10.1016/j.hpb.2018.11.010. Epub 2019 Jan 2.

BACKGROUND: ALPPS is a two-stage hepatectomy that induces more rapid liver growth compared to conventional strategies. This report aims to establish a risk-score to avoid adverse outcomes of ALPPS only for patients with colorectal liver metastases (CRLM) as primary indication for ALPPS.

METHODS: All patients with CRLM included in the ALPPS registry were included. Risk score analysis was performed for 90-day mortality after ALPPS, defined as death within 90 days after either stage. Two risk scores were generated i.e. one for application before stage-1, and one for application before stage-2. Logistic regression analysis was performed to establish the risk-score.

RESULTS: In total, 486 patients were included, of which 35 (7%) died 90 days after stage-1 or 2. In the stage-1 risk score, age ≥67 years (OR 3.7), FLR/BW ratio <0.40 (OR 2.9) and total center-volume (OR 2.4) were included. For the stage-2 score age ≥67 years (OR 3.7), FLR/BW ratio <0.40 (OR 2.8), bilirubin 5 days after stage-1 >50 μmol/L (OR 2.4), and stage-1 morbidity grade IIIA or higher (OR 6.3) were included.

CONCLUSIONS: The CRLM risk-score to predict mortality after ALPPS demonstrates that older patients with small remnant livers in inexperienced centers, especially after experiencing morbidity after stage-1 have adverse outcomes. The risk score may be used to restrict ALPPS to low-risk patient populations.

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Performance validation of the ALPPS risk model.

Linecker M, Kuemmerli C, Kambakamba P, Schlegel A, Muiesan P, Capobianco I, Nadalin S, Torres OJ, Mehrabi A, Stavrou GA, Oldhafer KJ, Lurje G, Balci D, Lang H, Robles-Campos R, Hernandez-Alejandro R, Malago M, De Santibanes E, Clavien PA, Petrowsky H.; HPB (Oxford). 2019 Jun;21(6):711-721. doi: 10.1016/j.hpb.2018.10.003. Epub 2018 Nov 24.

BACKGROUND: Based on the International ALPPS registry, we have recently proposed two easily applicable risk models (pre-stage1 and 2) for predicting 90-day mortality in ALPPS but a validation of both models has not been performed yet.

METHODS: The validation cohort (VC) was composed of subsequent cases of the ALPPS registry and cases of centers outside the ALPPS registry.

RESULTS: The VC was composed of a total of 258 patients including 70 patients outside the ALPPS registry with 32 cases of early mortalities (12%). Development cohort (DC) and VC were comparable in terms of patient and surgery characteristics. The VC validated both models with an acceptable prediction for the pre-stage 1 (c-statistic 0.64, P = 0.009 vs. 0.77, P < 0.001) and a good prediction for the pre-stage 2 model (c-statistic 0.77, P < 0.001 vs. 0.85, P < 0.001) as compared to the DC. Overall model performance measured by Brier score was comparable between VC and DC for the pre-stage 1 (0.089 vs. 0.081) and pre-stage 2 model (0.079 vs. 0087).

CONCLUSION: The ALPPS risk score is a fully validated model to estimate the individual risk of patients undergoing ALPPS and to assist clinical decision making to avoid procedure-related early mortality after ALPPS.

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Extending resectability of hilar cholangiocarcinomas: how can it be assessed and improved?

Donati M, Stang A, Stavrou GA, Basile F, Oldhafer KJ.; Future Oncol. 2019 Jan;15(2):193-205. doi: 10.2217/fon-2018-0413. Epub 2018 Oct 31. Review.

Until the 1980's, Klatskin tumors were considered 'desperate cases' and most of them were not resected; almost no oncologic concept was available. After many improvements, today, extended hepatectomy, including caudate lobe resection and lymphoadenectomy, have become a standard of care for oncologicaly radical resection of Klatskin tumors. Portal vein en bloc resection, if necessary, is a diffused standard assuring R0-resection without any improvement of survival in most series. Arterial resection remains episodical and controversial in its oncologic impact. Arterial resection-reconstruction was demonstrated to be feasible with many different technical possibilities. Neoadjuvant chemotherapy, refinement of associating liver partition and portal vein ligation for staged hepatectomy and liver transplantations are some possible future resources for treatment of those aggressive tumors that could be able to expand the pool of treatable patients.

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