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Background: Antitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumorinfiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis. Methods: CD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells. Results: Low ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICSlow subgroup. Conclusion: Identifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Aim: We aimed to assess management, comorbidities, biliary histopathology and outcomes of choledochal malformations (CM) in adults. Methods: All adult CM patients managed during 1987–2021 at the Helsinki University Hospital were retrospectively reviewed. Results: Of the 39 patients (females 79%) identified, 19 (49%) underwent surgery, 5 (13%) therapeutic ERCP with papillotomy for type 3 CM and 15 (38%) were managed conservatively. Twenty-five (66%) patients had ≥1 comorbidity, and five (13%) patients had associated inflammatory bowel disease (IBD); ulcerative colitis (n = 3) and Crohn's disease (n = 2). Most surgically treated patients underwent hepaticojejunostomy (n = 13) or pancreaticoduodenectomy (n = 3) and they were younger at presentation than other patients [29 (21 – 48) vs. 59 (41 – 71), p = 0.001]. Three patients (23%) suffered from pancreatitis following diagnostic ERCP. Early surgical complications occurred in six (32%) patients, including one anastomotic leakage. Biliary epithelial dysplasia was found in three (15%) patients in resected specimens, while no neoplastic changes were observed. Nine patients (47%) had long-term postoperative complications, cholangitis (n = 5) and anastomotic stricture (n = 3) being the most common ones. No evidence of malignant change was observed after median follow-up of 2.3 (0.60 − 4.5) years included all patient cohorts. Conservatively managed patients remained symptomless with unprogressive biliary tract imaging findings and normal liver biochemistry values during follow-up. Nearly half of operated patients developed long-term postoperative complications. A novel association between CMs and IBD was observed. Although no hepatobiliary malignancies regardless of treatment modality were encountered, the number of patients and length of follow-up remained limited. [ABSTRACT FROM AUTHOR]

Introduction: Simultaneous pancreas‐kidney transplantation (SPK) is an option for patients with type 1 diabetes (T1D) and kidney failure but can be associated with a high complication rate. Here we describe our 10‐year experience since the launch of the SPK program. Methods: This retrospective study included consecutive patients with T1D receiving SPK from March 14, 2010 to March 14, 2020 at Helsinki University Hospital. Portocaval anastomosis (i.e., systemic venous drainage) and enteric exocrine drainage were used. A specific team was trained for both pancreas retrieval and transplantation, postoperative care was standardized to include somatostatin analogues, antimicrobial treatment, and preoperatively initiated chemothrombopropylaxis. During program maturation donor criteria were expanded and logistical processes improved to minimize cold ischemia time. Clinical data were collected from a nationwide transplantation registry and patient records. Results: A total of 166 SPKs were performed (median 2 per year in the first 3 years, 17.5 per year for the following 4 years, and 23 per year for the past 3 years). Seven patients (4.1%) died with a functioning graft with a median 43 months follow‐up. One‐year pancreas graft survival was 97.0%, 3‐year pancreas graft survival was 96.1% and 5‐year was 96.1%. Mean HbA1c was 36 mmol/mol (SD 5.57) and creatinine was 107 μmol/L (SD 34.69) at 1‐year after transplantation. All kidney grafts were functioning at the end of follow‐up. Complications required re‐laparotomy in 39 (23%) patients, mostly due to a pancreas graft related problem (N = 28). No pancreas or kidney graft failure from thrombosis occurred. Conclusion: A planned, step‐wise development of an SPK program offers a safe and effective treatment for patients with T1D and kidney failure. [ABSTRACT FROM AUTHOR]

Liver-transplantation activity is limited by the shortage of grafts. Donor-liver macrovesicular steatosis predisposes to ischemia-reperfusion injury and is associated with reduced graft survival. The increasing prevalence of fatty-liver disease underlines the importance of identifying macrovesicular steatosis in potential donor livers. We analyzed liver grafts discarded for transplantation, and particularly the role of gamma-glutamyltransferase (GGT) in predicting graft steatosis. One-hundred sixty rejected cadaveric-donor liver grafts were studied. Donor selection was based on clinical data, and macroscopic graft inspection. Discarded grafts were biopsied at procurement of non-liver organs. The most common reasons for discarding the graft were abnormal liver tests, ultrasound-verified steatosis and history of harmful alcohol use. GGT correlated moderately with macrovesicular steatosis (r = 0.52, p < 0.001), but poorly with microvesicular steatosis (r = 0.36, p < 0.001). Increased correlation between GGT and macrovesicular steatosis was observed among alcohol abusers (r = 0.67, p < 0.001). Area under the curve (AUC) of GGT for predicting >30% macrovesicular steatosis was 0.79 (95% CI 0.71–0.88), and for >60% steatosis, 0.79 (95% CI 0.68–0.90). The optimal GGT-cut off for detecting >30% and >60% macrovesicular steatosis were, respectively, 66 U/L (sensitivity 76% and specificity 68%) and 142 U/L (sensitivity 66% and specificity 83%). Among alcohol users, a GGT value >90 U/L showed 100% sensitivity for >60% macrovesicular steatosis. AUC for GGT in predicting fibrosis Stages 2–4 was 0.82 (95% CI 0.71–0.92, p < 0.001, optimal cut off 68, sensitivity 92%, specificity 61%). Abnormal liver values, steatosis and harmful alcohol use were the main reasons for discarding liver-graft offers in Finland. GGT proved useful in predicting moderate and severe liver graft macrovesicular steatosis. [ABSTRACT FROM AUTHOR]

Brain death-induced cytokine storm is thought to harm transplantable organs. However, longer procurement times have been associated with non-inferior or better outcomes in kidney, heart, and lung transplants, while optimal procurement time for liver allografts is unknown. Our aim was to analyze the association of time interval from brain death to organ procurement with liver allograft outcomes in two nationwide cohorts. The association of procurement interval with graft survival and short-term complications was analysed in multivariable models. Altogether 643 and 58,017 orthotopic liver transplantations from brain-dead donors were included from Finland between June 2004 and December 2017 and the US between January 2008 and August 2018, respectively. Median time from brain death to organ procurement was 10.5 h in Finland and 34.6 h in the US. Longer interval associated with better graft survival (non-linearly, p = 0.016) and less acute rejections (OR 0.935 95% CI 0.894–0.978) in the US cohort, and better early allograft function (p = 0.005; Beta −0.048 95% CI −0.085 −(−0.011)) in the Finnish cohort, in multivariable models adjusted with Donor Risk Index, recipient age, Model for End-Stage Liver Disease and indication for transplantation. Progressive liver injury after brain death is unlikely. Rushing to recover seems unnecessary; rest and repair might prove beneficial. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is a rare malignancy in Western population with poor prognosis. This study aimed to investigate the trends in GBC incidence, treatment pattern, and survival in Finland. Patients diagnosed with primary GBC in a geographically defined area (Southern Finland Regional Cancer Center) during 2006–2017 were identified. Final cohort included 270 patients with GBC. The incidence was 1.32/100,000 persons, and it decreased 6.8 cases per million personyears during the study period. One hundred fifty-one (56%) patients were diagnosed at Stage IV. Fifty-one patients (19%) underwent curative-intent resection with 96% R0-resection rate. The median overall survival was 7.1 months and 5-year overall survival 11.6% for all patients, and 67.7 months and 56.8% after curative-intent resection, respectively. No improvement was noted over time in overall survival in patients with GBC, or in subgroups of different stages of GBC. The incidence of GBC is slightly decreasing in Southern Finland, but survival has not improved over time. [ABSTRACT FROM AUTHOR]

Introduction: Recently new standards for reporting outcomes of bile duct injury (BDI) have been proposed. It is unclear how these treatment outcomes are reflected in quality of life (QOL). The aim of this study was to report outcomes and QOL after repair of major BDI and compare repairs by hepatobiliary surgeon to repairs by non-hepatobiliary surgeons.Methods: This was a retrospective study of patients treated for major (Strasberg E-type) BDI after cholecystectomy at a tertiary hepatobiliary center. Outcomes were assessed using Cho-Strasberg proposed standards. QOL was assessed using Short Form Health Survey (SF-36) and the gastrointestinal QOL-index (GIQLI). Patients undergoing uneventful cholecystectomy matched by age, urgency, and duration of follow-up were used as controls.Results: Fifty-two patients with major BDI treated between 2000 and 2016 were included (42% male, median age 53 years). Thirty-seven (71%) patients attained primary patency (29 (83%) if primarily operated by a hepatobiliary surgeon). Actuarial primary patency rate (grade A result) at 1, 3, and 5 years was 58%, 56%, and 53% in the whole cohort, and 83%, 80%, and 80% in patients primary treated by a hepatobiliary surgeon, respectively. At 3-year follow-up 6 (11.5%) patients obtained grade B, 10 (19.2%) grade C, and 7 (13.5%) grade D result. QOL was similar in patients with BDI and controls (median SF-36 physical component 51.7 and 53.6, p = 1.0, mental component 53.3 and 53.4, p = 1.0, GIQLI 109.0 and 123.0, p = 0.174, respectively) at median 90 (IQR 70-116) months from cholecystectomy. QOL was similar regardless of outcome grade.Conclusion: First attempt to repair a severe BDI should be undertaken by a hepatobiliary surgeon. However, long-term QOL is not affected even by severe BDI, and QOL is not associated with the grade of the outcome. [ABSTRACT FROM AUTHOR]

In acute portal vein thrombosis (PVT), a six-month anticoagulation treatment achieves complete recanalization in only 35%–45% of patients, but the predictors of poor treatment responses are unclear. We examined treatment outcomes in PVT and aimed to identify predictors of incomplete recanalization and portal hypertensive complications. This retrospective study comprised patients diagnosed with PVT between 2006 and 2015. Key exclusion criteria were liver cirrhosis, malignancy, and age <18. The final cohort comprised 145 patients, of whom 132 (92%) were primarily treated with anticoagulation. The 5-year cumulative incidence of complete recanalization was 42% and of portal hypertensive complications, 31%. Independent predictors of insufficient recanalization were sub-acute or chronic thrombosis (hazard ratio (HR) 3.1, 95% CI 1.6–5.8), while acute pancreatitis was a protective factor (HR 0.3, 95% CI 0.2 − 0.7). Independent predictors of incident portal hypertensive complications were as cites at baseline (HR 3.3, 95% CI 1.7–6.7), sub-acute or chronic thrombosis (HR 2.9, 95% CI 1.6–5.3), extension of thrombosis to the splenic or mesenteric vein (HR 2.6, 95% CI 1.2–5.7), myeloproliferative disease (HR 3.0, 95% CI 1.4–6.5), and anemia (HR 2.1, 95% 1.1–3.9), while acute pancreatitis was a protective factor (HR 0.1, 95% CI 0.03–0.5). Etiology and age of thrombosis are associated with treatment responses in PVT. The presence of ascites at baseline, etiology, and extent of thrombosis, a non-acute thrombosis and anemia, are associated with the risk of portal hypertensive complications. Etiology and extent of thrombosis should be taken into account when determining the treatment (method) for PVT. [ABSTRACT FROM AUTHOR]

Aims Alcohol-related hangover symptoms: nausea, headache, stress and anxiety cause globally considerable amount of health problems and economic losses. Many of these harmful effects are produced by alcohol and its metabolite, acetaldehyde, which also is a common ingredient in alcohol beverages. The aim of the present study is to investigate the effect of the amino acid L-cysteine on the alcohol/acetaldehyde related aftereffects. Methods Voluntary healthy participants were recruited through advertisements. Volunteers had to have experience of hangover and/or headache. The hangover study was randomized, double-blind and placebo-controlled. Nineteen males randomly swallowed placebo and L-cysteine tablets. The alcohol dose was 1.5 g/kg, which was consumed during 3 h. Results The primary results based on correlational analysis showed that L-cysteine prevents or alleviates hangover, nausea, headache, stress and anxiety. For hangover, nausea and headache the results were apparent with the L-cysteine dose of 1200 mg and for stress and anxiety already with the dose of 600 mg. Conclusions L-cysteine would reduce the need of drinking the next day with no or less hangover symptoms: nausea, headache, stress and anxiety. Altogether, these effects of L-cysteine are unique and seem to have a future in preventing or alleviating these harmful symptoms as well as reducing the risk of alcohol addiction. [ABSTRACT FROM AUTHOR]

Background: The risk of invasive pneumococcal disease is significant among solid organ transplant (SOT) recipients. The optimal pneumococcal vaccination strategy for SOT patients is not known. Methods: The potential kidney transplant recipients in dialysis were randomized into two arms: to receive a 23‐valent pneumococcal polysaccharide vaccine (PPV23) before transplantation or to receive a 13‐valent pneumococcal conjugate vaccine (PCV13) before transplantation and a second dose of PCV13 six months after the transplantation. Serotype‐specific antibody concentrations and opsonophagocytic activity (OPA) were measured before and after the first vaccination (visits V1,V2) and six and seven months after the transplantation, for example, before and after the second PCV13 (visits V3,V4). Results: Out of 133 participants, 48 (PCV13 arm) and 46 (PPV23 arm) received a kidney transplant, and 37 + 37 in both arms completed the study. After the first vaccination, the geometric mean concentrations (GMCs) in the PCV13 arm were significantly higher for 9/13 serotypes and the OPA geometric mean titers (GMTs) were significantly higher for 4/13 serotypes. At V3, the antibody levels had declined but OPA remained significantly higher for 7/13 (PCV13) vs 4/13 (PPV23) serotypes. At V4, the GMCs for 9/13 serotypes and the GMTs for 12/13 serotypes were significantly higher in the PCV13 arm. The GMCs but not GMTs were lower than at V2. There was no difference in adverse effects. No vaccine‐related allograft rejection was detected. Conclusions: The immunogenicity of PCV13 was better in dialysis patients, and revaccination with PCV13 was immunogenic and safe. [ABSTRACT FROM AUTHOR]

Aim: To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017.Methods: Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method.Results: During follow-up, liver malignancy incidence remained stable at 1.1:106 . Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged ≥ 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1).Conclusion: Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality. [ABSTRACT FROM AUTHOR]

Objective: Ischaemia/reperfusion-injury degrades endothelial glycocalyx. Graft glycocalyx degradation was studied in human liver transplantation. Methods: To assess changes within the graft, blood was drawn from portal and hepatic veins in addition to systemic samples in 10 patients. Plasma syndecan-1, heparan sulfate and chondroitin sulfate, were measured with enzyme-linked immunosorbent assay. Results: During reperfusion, syndecan-1 levels were higher in graft caval effluent [3118 (934–6141) ng/ml, P = 0.005] than in portal venous blood [101 (75–121) ng/ml], indicating syndecan-1 release from the graft. Concomitantly, heparan sulfate levels were lower in graft caval effluent [96 (32–129) ng/ml, P = 0.037] than in portal venous blood [112 (98–128) ng/ml], indicating heparan sulfate uptake within the graft. Chondroitin sulfate levels were equal in portal and hepatic venous blood. After reperfusion arterial syndecan-1 levels increased 17-fold (P < 0.001) and heparan sulfate decreased to a third (P < 0.001) towards the end of surgery. Conclusion: Syndecan-1 washout from the liver indicates extensive glycocalyx degradation within the graft during reperfusion. Surprisingly, heparan sulfate was taken up by the graft during reperfusion. Corroborating previous experimental reports, this suggests that endogenous heparan sulfate might be utilized within the graft in the repair of damaged glycocalyx. [ABSTRACT FROM AUTHOR]

Objective: Spontaneous hepatic tumor hemorrhage is a rare but challenging emergency especially among cirrhotic patients with poor hepatic function. This study aimed at analyzing the safety, efficacy and feasibility of transcatheter arterial embolization (TAE) in the treatment of hepatic tumor hemorrhage. Methods: This retrospective study included all patients undergoing embolization attempt for hepatic tumor hemorrhage in the Helsinki University Hospital during 2004–2017. Electronic medical records provided the study data. Outcomes included the 30-day rebleeding, complication and mortality rates, need for blood transfusions, durations of intensive care unit and hospital admissions, estimates of overall survival, and analysis of factors associated with 30-day mortality. Results: During the study period, 49 patients underwent angiography for hepatic tumor hemorrhage. TAE was technically feasible in 45 patients (92%), and controlled the bleeding with the first attempt in 84%. The 30-day complication and mortality rates were 57 and 33%, respectively. Major complications occurred in 33% of patients. In-hospital mortality was higher among cirrhotic than non-cirrhotic patients (55 versus 7%, p <.001). Patients with bleeding hepatic metastases, but no cirrhosis, had an in-hospital mortality of 0% with no major complications. Patients with benign etiology had a good prognosis and no bleeding- or tumor-related mortality. Discussion: TAE is an effective method in controlling the bleeding in spontaneous hepatic hemorrhage. Underlying pathology determines the prognosis that is poor especially in cirrhotic patients with bleeding hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background Three new parvoviruses of Protoparvovirus genus, bufavirus (BuV), tusavirus (TuV), and cutavirus (CuV), have recently been discovered in diarrheal stools. CuV was further detected in a proportion of cutaneous T-cell lymphoma (CTCL)/mycosis fungoides skin samples and in one melanoma. Patients and Methods With novel multiplex quantitative polymerase chain reaction and antibody assays, we studied 3 patient groups for BuV, TuV, and CuV DNA and immunoglobulin G (IgG): CTCL patients, immunosuppressed solid-organ transplant recipients, and immunocompetent healthy adults. Results CuV DNA was detected in skin biopsies of 4/25 (16.0%) CTCL and 4/136 (2.9%) transplant patients but not in any of 159 skin samples of 98 healthy adults. The dermal CuV-DNA prevalence was significantly higher in CTCL patients than in the other subjects. CuV DNA was further detected in healthy skin of 4 organ transplant recipients, 2 of whom also had CuV-positive skin carcinomas. One CTCL patient harbored CuV DNA in both malignant (CTCL, melanoma) and nonmalignant skin and sentinel lymph nodes but not in his prostate. The CuV IgG seroprevalences were among CTCL patients 9.5% (4/42), transplant recipients 6.5% (8/124), and healthy adults 3.8% (3/78). BuV and TuV DNAs were absent and antibodies infrequent in all cohorts. Parvoviral antibodies were shown to persist for ≥20 years and dermal CuV DNA for 4 years. All 3 CuV-DNA-positive patients, with both biopsies and sera available, were CuV-IgG positive. Conclusion Our results suggest that dermal CuV DNA carriage is associated with CTCL. Any putative roles of CuV in the carcinogenesis must be determined in forthcoming studies. [ABSTRACT FROM AUTHOR]

Summary: To date 14 human polyomaviruses (HPyVs) have been identified. The newly found HPyVs have not been examined with regard to post‐transplant skin carcinogenesis. To determine the occurrences in skin and possible pathological associations of the HPyVs, we studied their genoprevalences in squamous cell carcinoma (SCC) in situ or actinic keratosis and benign skin in liver transplant recipients (LiTRs); and of healthy skin in immunocompetent adults. We used highly sensitive and specific HPyV PCRs of two types. Overall, Merkel cell polyomavirus (MCPyV), human polyomavirus 6 (HPyV6), human polyomavirus 7 (HPyV7), trichodysplasia spinulosa polyomavirus (TSPyV), and Lyon IARC polyomavirus (LIPyV) were found in 58/221 (26.2%) skin biopsies. MCPyV DNA was detected in 5/14 (35.7%) premalignant vs. 32/127 (25.2%) benign skin of LiTRs, and in 12/80 (15%) healthy skin of immunocompetent adults, with no statistically significant difference in viral DNA prevalence or load. TSPyV DNA was found in a single skin lesion. LIPyV, HPyV6 and HPyV7 DNAs occurred exclusively in benign skin. Overall, the viral findings in premalignant versus benign skin were alike. The occurrences of HPyVs in skin of LiTRs and immunocompetent individuals speak against a role for any of the 14 HPyVs in SCC development. [ABSTRACT FROM AUTHOR]

Key Clinical Message: In an intestinal transplant patient under triple immunosuppression therapy with tacrolimus levels >10 ng/L, a 2‐day oral immunoglobulin therapy given as treatment for chronic norovirus infection was temporally closely associated with the development of severe steroid‐resistant acute graft rejection, thus suggesting that oral immunoglobulin might be able to promote a rejection response. [ABSTRACT FROM AUTHOR]

The role of donor-specific HLA antibodies ( DSAs) after pediatric liver transplantation ( LT) is inadequately established. We conducted a cross-sectional study on the prevalence of DSAs and their association with liver histology and biochemical variables after pediatric LT. Serum samples were drawn for HLA antibody analyses from 50 patients (76% of 66 eligible patients) operated on at age <18 years between 1987 and 2007 with a median of 10.0 (interquartile range 4.0-16.4) years after deceased donor LT. Mixed and single-antigen beads with Luminex were used for HLA antibody screening and detection. A mean fluorescence intensity ( MFI) value of 1000 was used for positive cutoff. Twenty-six patients (52%; 95% confidence interval ( CI) 39% to 65%) had DSAs. In 22 (85%) patients, DSAs were against class II HLA antigens with a mean (standard deviation) MFI of 13 481 (4727). The unadjusted prevalence ratio for portal inflammation in DSA-positive compared to DSA-negative patients ( n = 47; 9/24 vs. 1/23) was 8.6 (95% CI 1.6 to 50.9). Laboratory values at the time of study were comparable between DSA-positive and DSA-negative patients. In conclusion, approximately half of patients studied had DSAs after pediatric LT. Portal inflammation was associated with DSA positivity although the wide confidence interval around the ratio estimate warrants cautious interpretation. [ABSTRACT FROM AUTHOR]

Objective. Thresholds for when a patient should be considered too healthy or too sick to undergo liver transplantation (LT) have been pursued, but have undergone little external validation and may differ between centers and countries. Material and methods. We investigated the ability of the Model for End-stage Liver Disease (MELD), D-MELD, Donor Risk Index (DRI) and Balance of Risk (BAR) scores to predict 1-year graft survival, and determined the 1-year survival-benefit of LT, compared with conservative management, according to MELD score and graft quality among 538 adult LT recipients with underlying chronic non-malignant liver disease. Results. One-year graft survival rates showed small, but statistically significant variation according to MELD ( p = 0.002) and D-MELD score ( p = 0.04), and among LTs after year 2000 also according to BAR score ( p = 0.01), but not according to DRI. Diagnostic accuracy of these scores was poor; area under the curve was 0.50-0.65 depending on the score. A 1-year survival-benefit of LT emerged at MELD scores ≥15, but also at lower MELD scores when using high-quality grafts (DRI <1.075). Conclusions. The performance of various prognostic scores in the Finnish setting was poor. Careful clinical evaluation is imperative when deciding on the timing of LT in the course of chronic liver disease. [ABSTRACT FROM AUTHOR]

Objective. Intestinal and multivisceral transplantation have gained acceptance as treatment modalities for patients with: intestinal failure and life-threatening complications of parenteral nutrition (PN), rare cases of vascular abdominal catastrophes and selected cases of low-grade neoplastic tumors such as neuroendocrine pancreatic tumors and desmoids involving the mesenteric root. The aim was to describe the survival and nutritional outcome in the transplanted Nordic patients and the complications attributed to this procedure. Method. The authors included all Nordic patients transplanted between January 1998 and December 2013. Information on patients transplanted outside the Nordic region was collected through questionnaires. Results. A total of 34 patients received different types of intestinal allografts. Currently, there are two Nordic transplant centers ( n = 29) performing these procedures (Gothenburg, Sweden n = 24, Helsinki, Finland n = 5). The remaining five patients were transplanted in the USA ( n = 3) and the UK ( n = 2). Most patients were transplanted for life-threatening failure of PN (70%) caused primarily by intestinal motility diseases (59%). Allograft rejection was the most common complication and occurred in 79% of the patients followed by post-transplantation lymphoproliferative disorders (21%) and graft-versus-host disease (18%). The 1- and 5-year survival was 79% and 65% respectively for the whole cohort and nutritional autonomy was achieved in 73% of the adults and 57% of the children at 1 year after transplantation. Conclusion. This collective Nordic experience confirms that intestinal transplantation is a complex procedure with many complications, yet with the possibility to provide long-term survival in selected conditions previously considered untreatable. [ABSTRACT FROM AUTHOR]

Aims. This is a descriptive study aiming to compare outcomes of intestinal rehabilitation surgery among pediatric and adult intestinal failure (IF) patients with either primary intestinal motility disorders or short bowel syndrome (SBS) treated by our nationwide program. Methods. Medical records of IF patients ( n = 31, 71% children) having undergone autologous intestinal reconstructions (AIR) ( n = 25), intestinal transplantation (ITx) ( n = 5), or being listed for ITx ( n = 2) between 1994 and 2014 were reviewed. Results. At surgery, median age was 3.4 (interquartile range, 1.0-22.1) in SBS ( n = 22) and 16.5 (3.2-26.7) years in dysmotility patients ( n = 9) who received median 60% and 83% of energy requirement parenterally, respectively. Median small bowel length was shorter in SBS than dysmotility patients (34 versus 157 cm, p < 0.001). Following AIR, none of the dysmotility patients achieved permanent intestinal autonomy, whereas 68% of SBS patients weaned off parenteral nutrition (PN) ( p = 0.022) and none required listing for ITx. Five dysmotility patients who underwent ITx achieved intestinal autonomy. Regarding both AIR and ITx procedures, no significant difference in PN weaning was observed between the two subgroups. At last follow-up, 3.3 (0.6-8.0) years postoperatively, median plasma bilirubin was 6 (4-16) µmol/l, while liver biopsy showed fibrosis (Metavir stage 1-2) in 50% and cholestasis in 8%. Proportion of PN energy requirement had reduced significantly ( p = 0.043) among PN-dependent SBS ( n = 7) but not among dysmotility patients ( n = 5). Overall survival was 90%. Conclusion. AIR surgery was beneficial among selected SBS patients, whereas in intestinal dysmotility disorders, permanent PN weaning was only achieved by ITx. [ABSTRACT FROM AUTHOR]

Kidney outcomes in early post-liver transplantation ( LT) are crucial for long-term prognosis, but difficult to predict. Among 203 adult LT patients, we studied the value of plasma neutrophil gelatinase-associated lipocalin ( NGAL) measured pre- LT for predicting acute kidney injury ( AKI), kidney-replacement therapy within three months, and kidney dysfunction at three months post- LT. Glomerular filtration rate ( GFR) was estimated by creatinine-based and cystatin C-based equations. Highest NGAL levels were among patients on pre- LT kidney-replacement therapy, whereas NGAL exceeded 200 μg/L in only three (2%) patients with pre- LT GFR >60 mL/min. Pre- LT NGAL >260 μg/L predicted GFR <60 mL/min at three months post- LT ( OR 17.8, 95% CI 2.1-153) independently of 19 other variables reflecting recipient characteristics, liver and kidney function, perioperative hemodynamic stress, and immunosuppression. Of 81 patients with pre- LT GFR <60 mL/min, 48% had GFR <60 mL/min at three months, and an NGAL level >260 μg/L predicted this outcome with 90% specificity and 46% sensitivity. NGAL failed to predict post- LT AKI or need for temporary kidney-replacement therapy. In conclusion, NGAL independently predicted irreversibility of pre-LT kidney dysfunction and could thus help in optimizing patient care and in the decision to perform combined liver-kidney transplantation. Pre- LT NGAL was not useful in patients with preserved pre- LT kidney function or in predicting post- LT AKI. [ABSTRACT FROM AUTHOR]

Aim. Prediction of prognosis in hepatocellular carcinoma (HCC) is difficult. The aim of this study was to evaluate the prognostic value of serum MMP-8, -9, -13, and TIMP-1 in patients with HCC. Methods. Pre-treatment serum samples from 134 patients with HCC were retrospectively analyzed. The serum concentration of MMP-8 was analyzed with immunofluorometric assay (IFMA), and those of MMP-9, MMP-13, and TIMP-1 were determined by enzyme-linked immunosorbent assays (ELISA). Clinical data were retrieved from patient records and survival data obtained from Statistics Finland. Results. The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years, and 33% at 5 years. Kaplan-Meier overall survival analysis showed that patients with low concentrations of serum MMP-8 or TIMP-1 had a statistically significantly better overall survival than patients with high concentrations of serum MMP-8 or TIMP-1 ( P = 0.013 and P = 0.003). Interestingly, the overall survival in patients with high MMP-9/TIMP-1 ratio was statistically significantly better than in those patients with low MMP-9/TIMP-1 ratio ( P = 0.004). Conclusion. Our results suggest that serum MMP-8, TIMP-1, and the ratio of MMP-9/TIMP-1 might be useful adjuncts as predictors of prognosis in patients with HCC. [ABSTRACT FROM AUTHOR]

Aim. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer death worldwide. The aim of this study was to evaluate the prognostic value of serum tumor-associated trypsin inhibitor (TATI) and the free β subunit of human chorionic gonadotropin (hCGβ) in patients with HCC. Methods. The serum concentrations of TATI and hCGβ were determined by time-resolved immunofluorometric assays (IFMA) in pretreatment serum samples from 144 patients with HCC. Clinical data were retrieved from patient records and survival data obtained from Statistics Finland. Results. The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years and 33% at 5 years. Disease-specific median survival time was 26 months. The overall survival in patients with low serum concentrations of TATI or hCGβ was statistically significantly better than in patients with elevated concentrations ( p = 0.003 and 0.003, respectively). In multivariate analysis, both serum TATI and serum hCGβ were independent prognostic markers. Conclusion. The results imply that elevated serum concentrations of TATI and hCGβ are predictors of adverse prognosis in patients with HCC and appear to be useful adjuncts in predicting prognosis in patients with HCC. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5) in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver. [ABSTRACT FROM AUTHOR]

Abstract: In recent years, the use of antibodies against tumor necrosis factor α (TNFα) has expanded in rheumatology, gastroenterology, and dermatology. In addition to the more common side effects such as infections and hypersensitivity reactions, elevations of liver enzymes have been reported during anti-TNFα therapy, although severe liver failure has been extremely uncommon. This report describes a patient with severe liver failure after induction therapy with the TNFα antibody infliximab (Remicade®). A 46-year old female patient received two infusions of infliximab at a dose of 400mg on weeks 0 and 8 for steroid-dependent ulcerative colitis. Eight weeks after the second infusion, she suffered acute liver failure with necrosis, requiring liver transplantation. [Copyright &y& Elsevier]

Background Detection of biliary dysplasia in PSC is essential for proper timing of liver transplantation to prevent the development of cholangiocancer, which is considered a contraindication for liver transplantation in most centres. In patients with PSC, differential diagnosis of benign, premalignant and malignant biliary strictures is difficult. Aims This prospective study aimed to evaluate the role of DNA analysis in combination with brush cytology, scored ERCP findings, and tumour markers to detect hepatobiliary dysplasia and malignancy. Material and methods Brush samples for cytology and for evaluation of DNA content analysed with flow cytometry came from 102 consecutive PSC patients referred for ERCP. Symptoms, serum Ca19-9 and CEA were determined at the time of index biliary examination. ERCP findings were scored for intra- and extrahepatic changes. The end-points were liver transplantation or diagnosis of malignancy or dysplasia. Results Most of the patients were asymptomatic at the time of ERCP: 73% had no symptoms, and 12% had only mild symptoms. An aneuploid DNA content was evident in 20 (20%) patients, and cells suspected for malignancy in 22 (21%). Seven patients had both aneuploidity and cytology (7%) suspicious for malignancy. An end-point, diagnosis of malignancy or liver transplantation was achieved in 42 patients. Combining DNA ploidity and cytology in patients at the end-point, sensitivity was 72%, specificity 82%, positive predictive value 86% and negative predictive value 67%. Discussion and conclusion In this mostly asymptomatic PSC-patient population, 33% demonstrated abnormal brush cytology or aneuploidity. Determining DNA ploidy and brush cytology during ERCP offers a useful tool for identifying those PSC patients who are at high risk of developing cholangiocancer. [ABSTRACT FROM AUTHOR]

Objective. Anastomotic bile duct complications after liver transplantation (LT) have been treated endoscopically by dilation and plastic tube stenting, with the stent therapy having moved toward using covered, self-expandable metallic stents (cSEMS) in recent years. The aim of this study was to analyze therapy outcome of post-LT anastomotic complications using cSEMS. Material and methods. Seventeen post-LT patients had 29 cSEMS (Allium stent, n == 23; Wallstent®, n == 4; Micro-Tech, n == 2) placed during endoscopic retrograde cholangiopancreatography (ERCP). The fully covered stents (Allium, Micro-Tech) were placed entirely inside the common bile duct. Data were collected and analyzed in a retrospective manner. Results. These 17 patients had 19 stent treatment periods. Resolution was eventually established in all patients. There were four (14%) stent migrations. Pancreatitis was seen after one ERCP procedure, whereas five cases of cholangitis were seen. Conclusion. Treatment of post-LT anastomotic complications with cSEMS seems to be both safe and efficient. Further assessment regarding indications, stent types and stenting time is needed. [ABSTRACT FROM AUTHOR]

In experimental liver transplantation, endogenous protease inhibitors alleviate ischemia–reperfusion (I/R) injury by inhibiting proteolysis and by direct anti-inflammatory actions. We described the kinetics of endogenous protease inhibitors and explored their anti-inflammatory potential during reperfusion and their effects on graft function in human liver transplantation. We measured circulating levels of protease inhibitors (secretory leukocyte proteinase inhibitor, SLPI; tissue inhibitor of metalloproteinases-1, TIMP-1) and proteolytic enzymes (elastase; matrix metalloproteinase-9, MMP-9) with ELISA, and neutrophil and monocyte CD11b and l-selectin expression with flow cytometry during liver transplantation in ten patients. To assess changes within the graft during reperfusion, blood samples from portal and hepatic veins were obtained simultaneously. Circulating SLPI and TIMP-1 levels decreased during surgery. During initial reperfusion, the transhepatic SLPI gradient was −27 (−35 to −22) ng/ml, P = 0.005, and TIMP-1 −510 (−636 to −362) ng/ml, P = 0.005, indicating graft protease inhibitor uptake. Concomitantly, hepatic phagocyte activation and sequestration as well as elastase and MMP-9 release into the circulation occurred. The transhepatic SLPI gradient correlated with postoperative liver enzymes (ALT R = −0.648, P = 0.043; ALP R = −0.661, P = 0.038; bilirubin R = −0.821, P = 0.004; GGT R = −0.648, P = 0.043). The results suggest a relative shortage of protease inhibitors within the liver during reperfusion, which may contribute to the development of graft injury. [ABSTRACT FROM AUTHOR]

Ilmakunnas M, Höckerstedt K, Mäkisalo H, Siitonen S, Repo H, Pesonen EJ. Hepatic IL-8 release during graft procurement is associated with impaired graft function after human liver transplantation. Clin Transplant 2010: 24: 29–35. © 2009 John Wiley & Sons A/S. In experimental models, brain death induces inflammatory cascades, leading to reduced graft survival. Thus far, factors prior to graft preservation have gained less attention in clinical setting. We studied pre-preservation inflammatory response and its effects on graft function in 30 brain dead liver donors and the respective recipients. Before donor graft perfusion, portal and hepatic venous blood samples were drawn for phagocyte adhesion molecule expression and plasma cytokine determinations. Donor intensive care unit stay correlated with donor C-reactive protein ( R = 0.472, p = 0.013) and IL-6 ( R = 0.419, p = 0.026) levels, and donor ( R = 0.478, p = 0.016) and recipient gamma-glutamyl transferase ( R = 0.432, p = 0.019) levels. During graft procurement, hepatic IL-8 release was observed in 17/30 donors. Grafts with hepatic IL-8 release exhibited subsequently higher alkaline phosphatase [319 (213–405) IU/L vs. 175 (149–208) IU/L, p = 0.006] and bilirubin [101 (44–139) μmol/L vs. 30 (23–72) μmol/L, p = 0.029] levels after transplantation. Our findings support the concept that inflammatory response in the brain dead organ donor contributes to the development of graft injury in human liver transplantation. [ABSTRACT FROM AUTHOR]

Background. The risk factors for Merkel cell carcinoma (MCC), a rare type of skin cancer, are poorly understood. Some evidence suggests that MCC is more common in individuals with abnormal immune function resulting from viral infection, autoimmune disease or organ trans- plantation. [ABSTRACT FROM PUBLISHER]

The role of adjuvant systemic chemotherapy in liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial. Here, we report the results of a Nordic prospective, randomized, multi-centre trial of systemic low-dose doxorubicin in patients with HCC. Between February 1996 and April 2004, 46 patients were randomized to receive either neoadjuvant doxorubicin in combination with LT (chemo group; n = 19) or LT alone (control group; n = 27). In the chemo group, doxorubicin was administered intravenously, 10 mg/m2 weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m2 was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m2, depending on the clinical course, up to a cumulative dose of 400 mg/m2. Actuarial, 3-year overall survival (OS) and disease-free survival (DFS) in the control group were 70% and 50%, respectively. In the chemo group, both OS and DFS were 63%. Freedom from recurrence at 3 years was 55% in the control group and 74% in the chemo group. None of the differences was statistically significant. Neoadjuvant treatment with systemic low-dose doxorubicin seems not to improve either survival or freedom from recurrence in patients with HCC undergoing LT. [ABSTRACT FROM AUTHOR]

Hepatobiliary cystadenomas and cystadenocarcinomas are rare tumors. Differentiating between these tumors and benign hepatic cysts may be difficult. Because of their rarity, diagnosis is often delayed and may result in inaccurate treatment, resulting in unnecessary morbidity and mortality. The purpose of this report is to draw attention to these entities and their complications. We report on two cases with spontaneous rupture of hepatobiliary cystadenoma and cystadenocarcinoma cysts, initially treated as simple hepatic cysts by aspiration, or by aspiration combined with sclerotherapy. The spontaneous rupture of the cysts appeared years after the initial treatment of the cysts, leading in one case to a prolonged stay in an intensive care unit. In both cases, a formal liver resection was carried out and microscopic investigations revealed a mucinous cystadenocarcinoma and cystadenoma. In conclusion, although hepatobiliary cystadenomas and cystadenocarcinomas are rare findings, they should not be forgotten in the diagnostic workshop when examining patients with hepatic cysts. If hepatobiliary cystadenomas and cystadenocarcinomas cannot be excluded following radiological imaging, surgery is recommended. [ABSTRACT FROM AUTHOR]

Healthy, premenopausal women completed the Buss-Perry Aggression Questionnaire. Venous blood samples were taken at the mid-cycle phase of the menstrual cycle to determine plasma androgen levels. Total and free testosterone, 5α-dihydrotestosterone, androstenedione, and dehydroepiandrosterone were assessed. Path analyses were aimed at finding out which of the five circulating hormones might best predict a latent aggression construct derived from the four subscales of the Aggression Questionnaire. A significant correlation was found between free testosterone and physical and verbal aggression subscales. In addition, the results demonstrate for the first time in women a significant link between 5α-dihydrotestosterone and anger. Thus, both testosterone and 5α-dihydrotestosterone may affect, by separate pathways, the basal regulation of aggression-proneness in women. Aggr. Behav. 28:273–280, 2002. © 2002 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effect of alcohol on androgen levels among premenopausal women. Eighty-seven women in the mid-cycle phase of the menstrual cycle, 47 of whom used oral contraceptives (OC+), were included in the study. The range for reported alcohol consumption was 0–4 drinks/day. The total testosterone levels were significantly higher after alcohol intake (0.5 g/kg) than after placebo at 45 min and 90 min from the start of drinking among both OC– and OC+ subjects. This effect was also seen in the free testosterone fraction. The effect on testosterone was more prominent among OC+ subjects. Androstenedione levels were significantly lowered and the testosterone:androstenedione ratio significantly elevated by alcohol among both OC– and OC+ subjects. No effect of alcohol on dehydroepiandrosterone or dihydrotestosterone levels was observed. A positive correlation was observed between the change in testosterone levels and the change in androstenedione levels during placebo conditions. The correlation was significantly reduced during alcohol conditions among OC+ subjects, indicating an increased androstenedione to testosterone conversion. No significant dose (0.34, 0.68 and 1.02 g/kg) or time (45, 90 and 150 min) effects on total testosterone were observed in a substudy involving 10 OC+ subjects. The present results suggest that the testosterone effect is related to the zero-order mechanism of ethanol oxidation. The observed testosterone and androstenedione effects are suggested to be the result of an increased androstenedione to testosterone conversion in the liver caused by the alcohol-mediated elevation in the [NADH]:[NAD+] ratio. The present findings may be relevant in the development of hyperandrogenism and loss of female sexual characteristics associated with heavy alcohol consumption. [ABSTRACT FROM PUBLISHER]