Surgery for Bismuth-Corlette Type 4 Perihilar Cholangiocarcinoma: Results from a Western Multicenter Collaborative Group

Background Although Bismuth-Corlette (BC) type 4 perihilar cholangiocarcinoma (pCCA) is no longer considered a contraindication for curative surgery, few data are available from Western series to indicate the outcomes for these patients. This study aimed to compare the short- and long-term outcomes for patients with BC type 4 versus BC types 2 and 3 pCCA undergoing surgical resection using a multi-institutional international database. Methods Uni- and multivariable analyses of patients undergoing surgery at 20 Western centers for BC types 2 and 3 pCCA and BC type 4 pCCA. Results Among 1138 pCCA patients included in the study, 826 (73%) had BC type 2 or 3 disease and 312 (27%) had type 4 disease. The two groups demonstrated significant differences in terms of clinicopathologic characteristics (i.e., portal vein embolization, extended hepatectomy, and positive margin). The incidence of severe complications was 46% for the BC types 2 and 3 patients and 51% for the BC type 4 patients (p = 0.1). Moreover, the 90-day mortality was 13% for the BC types 2 and 3 patients and 12% for the BC type 4 patients (p = 0.57). Lymph-node metastasis (N1; hazard-ratio [HR], 1.62), positive margins (R1; HR, 1.36), perineural invasion (HR, 1.53), and poor grade of differentiation (HR, 1.25) were predictors of survival (all p ≤0.004), but BC type was not associated with prognosis. Among the N0 and R0 patients, the 5-year overall survival was 43% for the patients with BC types 2 and 3 pCCA and 41% for those with BC type 4 pCCA (p = 0.60). Conclusions In this analysis of a large Western multi-institutional cohort, resection was shown to be an acceptable curative treatment option for selected patients with BC type 4 pCCA although a more technically challenging surgical approach was required

Recurrence of primary sclerosing cholangitis after liver transplantation – analysing the European Liver Transplant Registry and beyond

Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4–18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9–9.1) and patient survival (HR 2.3; 95% CI 1.5–3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7–4.8). PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival

Anti-tumor activity of recombinant mouse tumor necrosis factor (TNF) on colon cancer in rats is promoted by recombinant rat interferon gamma; toxicity is reduced by indomethacin

The activity and toxlcity of rMuTNF, alone or combined with rat recombinant interferon gamma (rRIFNγ), was tested in inbred WAG rats bearing a weakly immunogenic colon adeno carcinoma (CC531). The tumor was implanted s.c. or under the renal capsule. A single i.v. injection of 10μg of rMuTNF in non‐tumor bearers was lethal in 3 to 5 hr, whereas 2μg was nat. Doses of 1μg rMuTNF were well tolerated when given daily for one week. The most prominent toxic feature was hemorrhagic colitis which could be alleviated when rMuTNF was preceded by i.p. administration of 10mg/kg indomethacin. Three intralesional injections of 10μg rMuTNF on days 0, 10 and 15 into s.c. tumors (diameter 1–1.5cm) led to a moderate retardation of growth in 20% of the cases. Combined with 105 units of rRIFNμ, which on its own had no effect, the overall response rate (arrest of tumor growth or regression) was 50%. Two out of 20 tumors treated intralesionally with rMuTNF and rRlFNγ regressed. The subrenal capsule assay was used to study the possible interference of indomethacin with the anti‐tumor activity of rMuTNF. Tumor cubes of 6–8mg were implanted under the renal capsule; the test was evaluated by weighing. Treatment with 10mg indomethacin alone on days 0, 2 and 4 had no effect (40 ± 8 mg vs. 48 ± 13 mg in controls) whereas 2μg of rMuTNF on the same days resulted in significant tumor inhibition (24 ± 7 mg, p < 0.001). The combined administration of 2μg of rMuTNF and indomethacin had an effect similar to that of rMuTNF alone (25 ± 9 mg). Under protection of indomethacin the rMuTNF dose was increased from 2μg to 10μg. However, this did not lead to further improvement of the results

New insights in the management of Hepatocellular Adenoma

International audienceHepatocellular adenoma (HCA) are benign liver tumours that may be complicated by haemorrhage or malignant transformation to hepatocellular carcinoma. Epidemiological data are fairly outdated, but it is likely to assume that the incidence has increased over the past decades as HCA are more often incidentally found due to the more widespread use of imaging techniques and the increased incidence of obesity. Various molecular subgroups have been described. Each of these molecular subgroups are defined by specific gene mutations and pathway activations. Additionally, they are all related to specific risk factors and show a various biological behaviour. These molecular subgroups may be identified using immunohistochemistry and molecular characterization. Contrast-enhanced MRI is the recommended imaging modality to analyse patients with suspected hepatocellular adenoma allowing to determine the subtype in up to 80%. Surgical resection remains to be the golden standard in treating HCA, although resection is deemed unnecessary in a large number of cases, as studies have shown that the majority of HCA will regress over time without complications such as haemorrhage or malignant transformation occurring. It is preferable to treat patients with suspected HCA in high volume centres with combined expertise of liver surgeons, hepatologists, radiologists and (molecular) pathologists.Key points- Epidemiological data on HCA are fairly outdated but it is likely to assume that the incidence has increased over the past decades as HCA are more often incidentally found due to the more widespread use of imaging techniques and the increased incidence of obesity.- Various molecular subgroups of HCA have been described with varying biological behaviour.- These molecular subgroups may be identified using contrast-enhanced MRI, immunohistochemistry and molecular characterization.- Surgical resection remains to be the golden standard in treating HCA, although resection is deemed unnecessary in a large number of cases.- As HCA may be considered a rare disease, it is preferable to treat patients with suspected HCA in high volume centres with combined expertise of liver surgeons, hepatologists, radiologists and (molecular) pathologists

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting.

Background: Irinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue. Experimental approach: Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses. Key results: The AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals. Conclusions: Transcriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients

Low skeletal muscle mass as a risk factor for postoperative delirium in elderly patients undergoing colorectal cancer surgery

Christina Alexa Mosk,1 Jeroen LA van Vugt,2 Huub de Jonge,1 Carlijn DM Witjes,2 Stefan Buettner,2 Jan NM Ijzermans,2 Lijckle van der Laan11Department of Surgery, Amphia Hospital, Breda, the Netherlands; 2Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the NetherlandsBackground: Both low skeletal muscle mass (LSMM) and delirium are frequently seen in elderly patients. This study aimed to investigate the association between preoperative LSMM and postoperative delirium (POD) in elderly patients undergoing colorectal cancer (CRC) surgery and to design a model to predict POD. Patients and methods: This is a retrospective observational cohort study. Patients aged 70 years or older undergoing CRC surgery from January 2013 to October 2015 were included in this study. The cross-sectional skeletal muscle area at the level of the third lumbar vertebra using computed tomography was adjusted for patients&rsquo; height, resulting in the skeletal muscle index. The lowest quartile per sex was defined as LSMM. Short Nutritional Assessment Questionnaire for Residential Care and KATZ-Activities of Daily Living were used to define malnourishment and physical dependency, respectively. POD was diagnosed using the Delirium Observational Screening Scale and geriatricians&rsquo; notes. Results: Median age of the 251 included patients was 76 years (IQR, 73&ndash;80 years), of whom 56% of patients were males, 24% malnourished, and 15% physically impaired. LSMM and POD were diagnosed in 65 and 33 (13%) patients, respectively. POD occurred significantly more in patients with LSMM (25%) compared with patients without LSMM (10%), P=0.006. In the multivariate analysis, age, history of delirium, and LSMM were significantly associated with POD. In addition, this effect increased in patients with LSMM and malnourishment (P=0.019) or physical dependency (P=0.017). Conclusion: Age, history of delirium, LSMM, and malnourishment or physical dependency were independently associated with POD. Our nomogram could be used to identify patients at an increased risk for delirium. These patients may benefit from intensive monitoring to prevent POD.Keywords: skeletal muscle mass, sarcopenia, colorectal surgery, postoperative delirium, elderly, nomogra