The importance of MHC class II in allogeneic bone marrow transplantation and chimerism-based solid organ tolerance in a rat model.

Mixed hematopoietic chimerism enables donor-specific tolerance for solid organ grafts. This study evaluated the influence of different serological major histocompatibility complex disparities on chimerism development, graft-versus-host disease incidence and subsequently on solid organ tolerance in a rat model. For bone marrow transplantation conditioning total body irradiation was titrated using 10, 8 or 6 Gray. Bone marrow transplantation was performed across following major histocompatibility complex mismatched barriers: complete disparity, MHC class II, MHC class I or non-MHC mismatch. Recipients were clinically monitored for graft-versus-host disease and analyzed for chimerism using flow cytometry. After a reconstitution of 100 days, composition of peripheral leukocytes was determined. Mixed chimeras were challenged with heart grafts from allogeneic donor strains to define the impact of donor MHC class disparities on solid organ tolerance on the basis of stable chimerism. After myeloablation with 10 Gray of total body irradiation, chimerism after bone marrow transplantation was induced independent of MHC disparity. MHC class II disparity increased the incidence of graft-versus-host disease and reduced induction of stable chimerism upon myelosuppressive total body irradiation with 8 and 6 Gray, respectively. Stable mixed chimeras showed tolerance towards heart grafts from donors with MHC matched to either bone marrow donors or recipients. Isolated matching of MHC class II with bone marrow donors likewise led to stable tolerance as opposed to matching of MHC class I. In summary, MHC class II disparity was critically associated with the onset of graft-versus host disease and was identified as obstacle for successful development of chimerism after bone marrow transplantation and subsequent donor-specific solid organ tolerance

Extended hepatic metastasectomy for renal cell carcinoma—new aspects in times of targeted therapy: a single-center experience over three decades

Purpose!#!Despite the introduction of novel targeted therapies on patients with renal cell carcinoma, syn- and metachronous metastases (including hepatic lesions) are observed frequently and significantly influence patient survival. With introduction of targeted therapies as an effective alternative to surgery, therapeutical strategies in stage IV disease must be reevaluated.!##!Methods!#!This is a retrospective analysis of 40 patients undergoing hepatic resection of histologically confirmed RCC metastases at our institution between April 1993 and April 2017.!##!Results!#!The interval between nephrectomy for renal cell carcinoma and hepatic metastasectomy was 44.0 months (3.3-278.5). Liver resections of different extents were performed, including multivisceral resections. The median follow-up was 37.8 months (0.5-286.5). Tumor recurrence after resection of hepatic metastases occurred in 19 patients resulting in a median disease-free survival of 16.2 months (0.7-265.1) and a median overall survival of 37.8 months (0.5-286.5). Multivariable analysis identified multivisceral resection as an independent risk factor for disease-free and overall survival (p = 0.043 and p = 0.001, respectively). A longer interval between nephrectomy and hepatic metastasectomy was identified as an independent significant protective factor for overall survival (p < 0.001). Patients undergoing metastasectomy after introduction of sunitinib in Europe in 2006 (n = 15) showed a significantly longer overall survival (45.2 (9.1-111.0) versus 27.5 (0.5-286.52) months in the preceding era; p = 0.038).!##!Conclusion!#!Hepatic metastasectomy, including major and extended resections, on patients with metastasized renal cell carcinoma can be performed safely and may facilitate long-term survival. Due to significant morbidity and increased mortality, multivisceral resections must be weighed against other options, such as targeted therapy

Repeated resection for recurrent intrahepatic cholangiocarcinoma: A retrospective German multicentre study

Background Tumour recurrence is common after resection of intrahepatic cholangiocarcinoma (ICC). Repeated resection is a potential curative treatment, but outcomes are not well-defined thus far. The aim of this retrospective multicentre cohort study was to show the feasibility and survival of repeated resection of ICC recurrence. Methods Data were collected from 18 German hepato-pancreatico-biliary centres for patients who underwent repeated exploration of recurrent ICC between January 2008 and December 2017. Primary end points were overall (OS) and recurrence-free survival from the day of primary and repeated resection. Results Of 156 patients who underwent repeated exploration for recurrent ICC, 113 underwent re-resection. CA19-9 prior to primary resection, R status of first liver resection and median time to recurrence were significant determinants of repeated resectability. Median OS in the repeated resection group was 65.2 months, with consecutive 1-, 3- and 5-year OS of 98%, 78% and 57% respectively. After re-exploration, median OS from primary resection was 46.7 months, with a consecutive 1-, 3- and 5-year OS of 95%, 55% and 22% respectively. From the day of repeated resection, the median OS was 36.8 months, with a consecutive 1-, 3- and 5-year OS of 86%, 51% and 34% respectively. Minor morbidity (grade I+II) was present in 27%, grade IIIa-IVb morbidity in 20% and mortality in 3.5% of patients. Conclusion Repeated resection of ICC has acceptable morbidity and mortality and seems to be associated with improved long-term survival. Structured follow-up after resection of ICC is necessary for early identification of these patients

Proposal of a New Definition of “Very Early” Intrahepatic Cholangiocarcinoma—A Retrospective Single-Center Analysis

Intrahepatic cholangiocarcinoma (ICC) is a rare disease with poor outcome, despite advances in surgical and non-surgical treatment. Recently, studies have reported a favorable long-term outcome of “very early” ICC (based on tumor size and absence of extrahepatic disease) after hepatic resection and liver transplantation, respectively. However, the prognostic value of tumor size and a reliable definition of early disease remain a matter of debate. Patients undergoing resection of histologically confirmed ICC between February 1996 and January 2021 at our institution were reviewed for postoperative morbidity, mortality, and long-term outcome after being retrospectively assigned to two groups: “very early” (single tumor ≤ 3 cm) and “advanced” ICC (size > 3 cm, multifocality or extrahepatic disease). A total of 297 patients were included, with a median follow-up of 22.8 (0.1–301.7) months. Twenty-one (7.1%) patients underwent resection of “very early” ICC. Despite the small tumor size, major hepatectomies (defined as resection of ≥3 segments) were performed in 14 (66.7%) cases. Histopathological analyses revealed lymph node metastases in 5 (23.8%) patients. Patients displayed excellent postoperative outcome compared to patients with “advanced” disease: intrahospital mortality was not observed, and patients displayed superior long-term survival, with a 5-year survival rate of 58.2% (versus 24.3%) and a median postoperative survival of 62.1 months (versus 25.3 months; p = 0.013). In conclusion, although the concept of a “very early” ICC based solely on tumor size is vague as it does not necessarily reflect an aggressive tumor biology, our proposed definition could serve as a basis for further studies evaluating the efficiency of either surgical resection or liver transplantation for this malignant disease

Resection of intrahepatic cholangiocarcinoma in octogenarians: a single-center analysis

Abstract The rapidly aging population in industrialized countries comes with an increased incidence of intrahepatic cholangiocarcinoma (iCC) which presents new challenges for oncological treatments especially in elderly patients. Thus, the question arises to what extent the benefit of surgical resections, as the only curative treatment option, outweighs possible perioperative risks in patients ≥ 80 years of age (octogenarians). We therefore retrospectively analyzed 311 patients who underwent resection for iCC at Hannover Medical School between January 1996 and December 2022. In total, there were 11 patients older than 80 years in our collective. Despite similar tumor size, octogenarians underwent comparatively less extensive surgery (54.5% major resections in octogenarians vs. 82.7% in all other patients; p = 0.033) with comparable rates of lymphadenectomy and tumor-free resection margins. Furthermore, we did not observe increased major postoperative morbidity (Clavien-Dindo ≥ IIIa complications: 27.3% vs. 34.3% in all other patients; p = 0.754) or mortality (estimated 1-year OS of 70.7% vs. 72.5% in all other patients, p = 0.099). The length of intensive care unit (ICU) or intermediate care unit (IMC) stay was significantly longer in octogenarians, however, with a comparable length in total hospital stay. The estimated overall survival (OS) did also not differ significantly, although a trend towards reduced long-term survival was observed (14.5 months vs. 28.03 months in all other patients; p = 0.099). In conclusion, primary resection is a justifiable and safe therapeutic option even in octogenarians but requires an even more thorough preoperative patient selection

Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma

Purpose!#!The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. Despite advances in surgical and non-surgical treatment, reported outcomes are still poor and surgical resection remains to be the only chance for long-term survival of affected patients. The identification and validation of prognostic factors and scores, such as the recently introduced resection severity index, for postoperative morbidity and mortality are essential to facilitate optimal therapeutic regimens.!##!Methods!#!This is a retrospective analysis of 269 patients undergoing resection of histologically confirmed intrahepatic cholangiocarcinoma between February 1996 and September 2018 at a tertiary referral center for hepatobiliary surgery. Regression analyses were performed to evaluate potential prognostic factors, including the resection severity index.!##!Results!#!Median postoperative follow-up time was 22.93 (0.10-234.39) months. Severe postoperative complications (≥ Clavien-Dindo grade III) were observed in 94 (34.9%) patients. The body mass index (p = 0.035), the resection severity index (ASAT in U/l divided by Quick in % multiplied by the extent of liver resection graded in points; p = 0.006), additional hilar bile duct resection (p = 0.005), and number of packed red blood cells transfused during operation (p = 0.036) were independent risk factors for the onset of severe postoperative complications. Median Kaplan-Meier survival after resection was 27.63 months. Preoperative leukocytosis (p = 0.003), the resection severity index (p = 0.005), multivisceral resection (p = 0.001), and T stage ≥ 3 (p = 0.013) were identified as independent risk factors for survival.!##!Conclusion!#!Preoperative leukocytosis and the resection severity index are useful variables for preoperative risk stratification since they were identified as significant predictors for postoperative morbidity and mortality, respectively

CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans

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

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study

Background: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. Methods: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. Results: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. Conclusion: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure