Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease.

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Extremes of baseline cognitive function determine the severity of delirium: a population study.

Although delirium is a significant clinical and public health problem, little is understood about how specific vulnerabilities underlie the severity of its presentation. Our objective was to quantify the relationship between baseline cognition and subsequent delirium severity. We prospectively investigated a population-representative sample of 1510 individuals aged ≥70 years, of whom 209 (13.6%) were hospitalized across 371 episodes (1999 person-days assessment). Baseline cognitive function was assessed using the modified Telephone Interview for Cognitive Status, supplemented by verbal fluency measures. We estimated the relationship between baseline cognition and delirium severity [Memorial Delirium Assessment Scale (MDAS)] and abnormal arousal (Observational Scale of Level of Arousal), adjusted by age, sex, frailty and illness severity. We conducted further analyses examining presentations to specific hospital settings and common precipitating aetiologies. The median time from baseline cognitive assessment to admission was 289 days (interquartile range 130 to 47 days). In admitted patients, delirium was present on at least 1 day in 45% of admission episodes. The average number of days with delirium (consecutively positive assessments) was 3.9 days. Elective admissions accounted for 88 bed days (4.4%). In emergency (but not elective) admissions, we found a non-linear U-shaped relationship between baseline global cognition and delirium severity using restricted cubic splines. Participants with baseline cognition 2 standard deviations below average (z-score = -2) had a mean MDAS score of 14 points (95% CI 10 to 19). Similarly, those with baseline cognition z-score = + 2 had a mean MDAS score of 7.9 points (95% CI 4.9 to 11). Individuals with average baseline cognition had the lowest MDAS scores. The association between baseline cognition and abnormal arousal followed a comparable pattern. C-reactive protein ≥20 mg/l and serum sodium <125 mM/l were associated with more severe delirium. Baseline cognition is a critical determinant of the severity of delirium and associated changes in arousal. Emergency admissions with lowest and highest baseline cognition who develop delirium should receive enhanced clinical attention.

Distal Pancreatectomy With En Bloc Celiac Axis Resection (DP-CAR) for Locally Advanced Pancreatic Cancer: A Safe and Effective Procedure.

OBJECTIVE: To determine perioperative and oncologic outcomes after distal pancreatectomy with en bloc resection of the celiac axis (DP-CAR). BACKGROUND: DP-CAR can be used in a selective group of patients to resect locally advanced pancreatic cancer involving the celiac axis or common hepatic artery without arterial reconstruction by preserving retrograde blood flow via the gastroduodenal artery to the liver and stomach. METHODS: We analyzed all consecutive patients who had undergone DP-CAR between May 2003 and April 2022 at a tertiary hospital specialized in pancreatic surgery and present one of the largest single-center studies. RESULTS: A total of 71 patients underwent DP-CAR. Additional venous resection (VR) of the mesenterico-portal axis was performed in 31 patients (44%) and multivisceral resection (MVR) in 42 patients (59%). Margin-free (R0) resection was achieved in 40 patients (56%). The overall 90-day mortality rate was 8.4% for the entire patient cohort. After a cumulated experience of 16 cases, the 90-day mortality dropped to 3.6% in the following 55 patients. Extended procedures with (+) additional MVR with or without (+/-) VR resulted in higher major morbidity (Clavien-Dindo ≥IIIB; standard DP-CAR: 19%; DP-CAR + MVR +/- VR: 36%) and higher 90-day mortality (standard DP-CAR: 0%; DP-CAR + MVR +/- VR: 11%). Median overall survival after DP-CAR was 28 months. CONCLUSIONS: DP-CAR is a safe and effective procedure but requires experience. Frequently, surgical resection has to be extended with MVR and VR to accomplish tumor resection, which results in promising oncologic outcomes. However, extended resections were associated with increased morbidity and mortality.

Celiac Axis Stenosis is an Underestimated Risk Factor for Increased Morbidity After Pancreatoduodenectomy.

OBJECTIVE: To assesses the prevalence and severity of CAS in patients undergoing PD/total pancreatectomy and its association with major postoperative complications after PD. SUMMARY OF BACKGROUND DATA: CAS may increase the risk of ischemic complications after PD. However, the prevalence of CAS and its relevance to major morbidity remain unknown. METHODS: All patients with a preoperative computed tomography with arterial phase undergoing partial PD or TP between 2014 and 2017 were identified from a prospective database. CAS was assessed based on computed tomography and graded according to its severity: no stenosis (<30%), grade A (30%-<50%), grade B (50%-≤80%), and grade C (>80%). Postoperative complications were assessed and uni- and multivariable risk analyses were performed. RESULTS: Of 989 patients, 273 (27.5%) had CAS: 177 (17.9%) with grade A, 83 (8.4%) with grade B, and 13 (1.3%) with grade C. Postoperative morbidity and 90-day mortality occurred in 278 (28.1%) patients and 41 (4.1%) patients, respectively. CAS was associated with clinically relevant pancreatic fistula ( P =0.019), liver perfusion failure ( P =0.003), gastric ischemia ( P =0.001), clinically relevant biliary leakage ( P =0.006), and intensive care unit ( P =0.016) and hospital stay ( P =0.001). Multivariable analyses confirmed grade B and C CAS as independent risk factors for liver perfusion failure; in addition, grade C CAS was an independent risk factor for clinically relevant pancreatic fistula and gastric complications. CONCLUSIONS: CAS is common in patients undergoing PD. Higher grade of CAS is associated with an increased risk for clinically relevant complications, including liver perfusion failure and postoperative pancreatic fistula. Precise radiological assessment may help to identify CAS. Future studies should investigate measures to mitigate CAS-associated risks.

Completion Pancreatectomy After Pancreatoduodenectomy: Who Needs It?

OBJECTIVE: The objective of this study was to identify the indications for and report the outcomes of completion pancreatectomy (CPLP) in the postoperative course after pancreatoduodenectomy (PD). BACKGROUND: CPLP may be considered or even inevitable for damage control after PD. METHODS: A prospectively maintained database of all patients undergoing PD between 2001 and 2019 was searched for patients who underwent CPLP in the postoperative course after PD. Baseline characteristics, perioperative details, and outcomes of CPLP patients were analyzed and specific indications for CPLP were identified. RESULTS: A total of 3953 consecutive patients underwent PD during the observation period. CPLP was performed in 120 patients (3%) after a median of 10 days following PD. The main indications for CPLP included postpancreatectomy acute necrotizing pancreatitis [n=47 (39%)] and postoperative pancreatic fistula complicated by hemorrhage [n=41 (34%)] or associated with uncontrollable leakage of the pancreatoenteric anastomosis [n=23 (19%)]. The overall 90-day mortality rate of all 3953 patients was 3.5% and 37% for patients undergoing CPLP. CONCLUSIONS: Our finding that only very few patients (3%) need CPLP suggests that conservative, interventional, and organ-preserving surgical measures are the mainstay of complication management after PD. Postpancreatectomy acute necrotizing pancreatitis, uncontrollable postoperative pancreatic fistula, and fistula-associated hemorrhage are highly dangerous and represent the main indications for CPLP after PD.

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

Comparison of transection techniques in pediatric major hepatectomy: a matched pair analysis.

BACKGROUND: Evidence on safety and efficacy of different liver transection techniques in pediatric major hepatectomy is completely lacking, as no study has been conducted so far. The use of stapler hepatectomy has never before been reported in children. METHODS: Three liver transection techniques were compared: (1) ultrasonic dissector (CUSA), (2) tissue sealing device (LigaSure™), and (3) stapler hepatectomy. All pediatric hepatectomies performed at a referral center in a 12-year study period were analyzed, patients were pair-matched in a 1:1:1-fashion. Intraoperative weight-adjusted blood loss, operation time, use of inflow occlusion, liver injury (peak-transaminase levels), postoperative complications (CCI), and long-term outcome were compared. RESULTS: Of 57 pediatric liver resections, 15 patients were matched as triples based on age, weight, tumor stage, and extent of resection. Intraoperative blood loss was not significantly different between the groups (p = 0.765). Stapler hepatectomy was associated with significantly shorter operation time (p = 0.028). Neither postoperative death nor bile leakage occurred, and no reoperation due to hemorrhage was needed in any patient. CONCLUSION: This is the first comparison of transection techniques in pediatric liver resection and the first report on stapler hepatectomy in children. All three techniques can be safely applied and may harbor individual advantages in pediatric hepatectomy each.

Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis.

OBJECTIVE: A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options. DESIGN: We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling. RESULTS: Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin. CONCLUSION: Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.

Characterization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Clusters Based on Integrated Genomic Surveillance, Outbreak Analysis and Contact Tracing in an Urban Setting.

BACKGROUND: Tracing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission chains is still a major challenge for public health authorities, when incidental contacts are not recalled or are not perceived as potential risk contacts. Viral sequencing can address key questions about SARS-CoV-2 evolution and may support reconstruction of viral transmission networks by integration of molecular epidemiology into classical contact tracing. METHODS: In collaboration with local public health authorities, we set up an integrated system of genomic surveillance in an urban setting, combining a) viral surveillance sequencing, b) genetically based identification of infection clusters in the population, c) integration of public health authority contact tracing data, and d) a user-friendly dashboard application as a central data analysis platform. RESULTS: Application of the integrated system from August to December 2020 enabled a characterization of viral population structure, analysis of 4 outbreaks at a maximum care hospital, and genetically based identification of 5 putative population infection clusters, all of which were confirmed by contact tracing. The system contributed to the development of improved hospital infection control and prevention measures and enabled the identification of previously unrecognized transmission chains, involving a martial arts gym and establishing a link between the hospital to the local population. CONCLUSIONS: Integrated systems of genomic surveillance could contribute to the monitoring and, potentially, improved management of SARS-CoV-2 transmission in the population.

Is metabolic syndrome a risk factor in hepatectomy? A meta-analysis with subgroup analysis for histologically confirmed hepatic manifestations.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor in surgery. MetS can progress to metabolic (dysfunction)-associated fatty liver disease (MAFLD), a vast-growing etiology of primary liver tumors which are major indications for liver surgery. The aim of this meta-analysis was to investigate the impact of MetS on complications and long-term outcomes after hepatectomy. METHODS: The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science, and Cochrane Library were searched for publications on liver resections and MetS. Comparative studies were included. Outcomes encompassed postoperative complications, mortality, and long-term oncologic status. Data were pooled as odds ratio (OR) with a random-effects model. Risk of bias was assessed using the Quality in Prognostic Studies tool (QUIPS), and the certainty of the evidence was evaluated with GRADE. Subgroup analyses for patients with histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) versus controls were performed. RESULTS: The meta-analyses included fifteen comparative studies. Patients with MetS suffered significantly more overall complications (OR 1.55; 95% CI [1.05; 2.29]; p=0.03), major complications (OR 1.97 95% CI [1.13; 3.43]; p=0.02; I2=62%), postoperative hemorrhages (OR 1.76; 95% CI [1.23; 2.50]; p=0.01) and infections (OR 1.63; 95% CI [1.03; 2.57]; p=0.04). There were no significant differences in mortality, recurrence, 1- or 5-year overall or recurrence-free survivals. Patients with histologically confirmed NAFLD did not have significantly more overall complications; however, PHLF rates were increased (OR 4.87; 95% CI [1.22; 19.47]; p=0.04). Recurrence and survival outcomes did not differ significantly. The certainty of the evidence for each outcome ranged from low to very low. CONCLUSION: Patients with MetS that undergo liver surgery suffer more complications, such as postoperative hemorrhage and infection but not liver-specific complications-PHLF and biliary leakage. Histologically confirmed NAFLD is associated with significantly higher PHLF rates, yet, survivals of these patients are similar to patients without the MetS. Further studies should focus on identifying the tipping point for increased risk in patients with MetS-associated liver disease, as well as reliable markers of MAFLD stages and early markers of PHLF. TRIAL REGISTRATION: PROSPERO Nr: CRD42021253768.

Repeat liver resection for recurrent intrahepatic cholangiocarcinoma: meta-analysis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a relatively rare malignancy. The aim of this meta-analysis was to evaluate outcomes of repeat liver resection and non-surgical approaches for treatment of recurrent ICC. METHODS: PubMed, Embase, and Web of Science databases were searched from their inception until March 2021 for studies of patients with recurrent ICC. Studies not published in English were excluded. Two meta-analyses were performed: a single-arm meta-analysis of studies reporting pooled short- and long-term outcomes after repeat liver resection for recurrent ICC (meta-analysis A), and a meta-analysis of studies comparing 1-, 3-, and 5-year overall survival (OS) rates after repeat liver resection and non-surgical approaches for recurrent ICC (meta-analysis B). RESULTS: Of 543 articles retrieved in the search, 28 were eligible for inclusion. Twenty-four studies (390 patients) were included in meta-analysis A and nine studies (591 patients) in meta-analysis B. After repeat liver resection, 1-, 3-, and 5-year OS rates were 87 (95 per cent c.i. 81 to 91), 58 (48 to 68), and 39 (29 to 50) per cent respectively. The 1-, 3-, and 5-year OS rates were higher after repeat liver resection than without surgery: odds ratio 2.70 (95 per cent c.i. 1.28 to 5.68), 2.89 (1.15 to 7.27), and 5.91 (1.59, 21.90) respectively. CONCLUSION: Repeat liver resection is a suitable strategy for recurrent ICC in selected patients. It improves short- and long-term outcomes compared with non-surgical treatments.

Pancreatic surgery with or without drainage: propensity score-matched study.

BACKGROUND: A recent RCT has shown that routine intraoperative drain placement after pancreatoduodenectomy (PD) is not necessary. The aim was to confirm this in real-world conditions. METHODS: A propensity score-matched (PSM) analysis of patients with and without drainage after PD or distal pancreatectomy (DP) at a high-volume centre was undertaken. Main outcomes were complications and duration of hospital stay. Multivariable regression analysis was used to assessed which factors led to intraoperative drainage after the standard was changed from drain to no drain. RESULTS: Of 377 patients who underwent PD, 266 were included in PSM analysis. No drain was associated with fewer major complications (42 (31.6 per cent) versus 62 (46.6 per cent); P = 0.017), shorter duration of hospital stay (mean(s.d.) 14.7(8.5) versus 19.6(14.9) days; P = 0.001), and required fewer interventional drain placements (8.4 versus 19.8 per cent; P = 0.013). In PSM analysis after DP (112 patients), no drainage was associated with fewer clinically relevant postoperative pancreatic fistulas (9 versus 18 per cent; P = 0.016), fewer overall complications (mean(s.d.) comprehensive complication index score 15.9(15.4) versus 24.8(20.4); P = 0.012), and a shorter hospital stay (9.3(7.0) versus 13.5(9.9) days; P = 0.011). Multivisceral resection (OR 2.80, 95 per cent c.i. 1.10 to 7.59; P = 0.034) and longer operating times (OR 1.56, 1.04 to 2.36; P = 0.034) influenced the choice to place a drain after PD. Greater blood loss was associated with drainage after DP (OR 1.14, 1.02 to 1.30; P = 0.031). CONCLUSION: Standard pancreatic resections can be performed safely without drainage. Surgeons were more reluctant to omit drainage after complex pancreatic resections.

Pancreatic surgery has traditionally relied on the use of drains placed during surgery that should facilitate outflow of fluids from the operating site. This principle has recently been challenged by specially designed studies showing that patients who do not receive a drain may have fewer complications. The present study has demonstrated that these results also apply to routine clinical settings outside the constraints of surgical trials.

The role of liver resection in metastatic nephroblastoma: a systematic review and Meta-regression analysis.

BACKGROUND: The impact of hepatic resection for liver metastases (LM) on the survival of pediatric patients with Wilms' tumor (WT) is unclear. So far, there is a lack of studies investigating the best suited treatment for patients with WTLM, and the role of liver resection has rarely been investigated. Thus, the development of evidence-based guidelines concerning indications of liver resection for WTLM remains difficult. AIM: To investigate the role of surgery in the therapy of WTLM. All available data on liver resections and subgroup outcomes of patients with WTLM are analyzed. Main research question is whether liver resection improves survival rates of patients with WTLM compared to non-surgical treatment. METHODS: A systematic literature search of MEDLINE, Web of Science, and Central provided the basis for this PRISMA-compliant systematic review. For the main analysis (I), all studies reporting on surgical treatment of pediatric WTLM were included. To provide a representative overview of the general outcome of WTLM patients, in analysis II all studies with cohorts of at least five WTLM patients, regardless of the kind of treatment, were reviewed and analyzed. A Multiple meta-regression model was applied to investigate the impact liver resection on overall survival. RESULTS: 14 studies with reports of liver resection for WTLM were found (Analysis I). They included a total of 212 patients with WTLM, of which 93 underwent a liver resection. Most studies had a high risk of bias, and the quality was heterogenous. For the analysis II, eight studies with subgroups of at least five WTLM patients were found. The weighted mean overall survival (OS) of WTLM patients across the studies was 55% (SD 29). A higher rate of liver resection was a significant predictor of better OS in a multiple meta-regression model with 4 covariates (I2 29.43, coefficient 0.819, p = 0.038). CONCLUSIONS: This is the first systematic review on WTLM. Given a lack of suited studies that specifically investigated WTLM, ecological bias was high in our analyses. Generating evidence is complicated in rare pediatric conditions and this study must be viewed in this context. Meta-regression analyses suggest that liver resection may improve survival of patients with WTLM compared to non-surgical treatment. Especially patients with persisting disease after neoadjuvant chemotherapy but also patients with metachronous LM seem to benefit from resection. Complete resection of LM is vital to achieve higher OS. Studies that prospectively investigate the impact of surgery on survival compared to non-surgical treatment for WTLM are highly needed to further close the current evidence gap. STUDY REGISTRATION: PROSPERO 2021 CRD42021249763  https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249763 .

Integrated genomic surveillance enables tracing of person-to-person SARS-CoV-2 transmission chains during community transmission and reveals extensive onward transmission of travel-imported infections, Germany, June to July 2021.

BackgroundTracking person-to-person SARS-CoV-2 transmission in the population is important to understand the epidemiology of community transmission and may contribute to the containment of SARS-CoV-2. Neither contact tracing nor genomic surveillance alone, however, are typically sufficient to achieve this objective.AimWe demonstrate the successful application of the integrated genomic surveillance (IGS) system of the German city of Düsseldorf for tracing SARS-CoV-2 transmission chains in the population as well as detecting and investigating travel-associated SARS-CoV-2 infection clusters.MethodsGenomic surveillance, phylogenetic analysis, and structured case interviews were integrated to elucidate two genetically defined clusters of SARS-CoV-2 isolates detected by IGS in Düsseldorf in July 2021.ResultsCluster 1 (n = 67 Düsseldorf cases) and Cluster 2 (n = 36) were detected in a surveillance dataset of 518 high-quality SARS-CoV-2 genomes from Düsseldorf (53% of total cases, sampled mid-June to July 2021). Cluster 1 could be traced back to a complex pattern of transmission in nightlife venues following a putative importation by a SARS-CoV-2-infected return traveller (IP) in late June; 28 SARS-CoV-2 cases could be epidemiologically directly linked to IP. Supported by viral genome data from Spain, Cluster 2 was shown to represent multiple independent introduction events of a viral strain circulating in Catalonia and other European countries, followed by diffuse community transmission in Düsseldorf.ConclusionIGS enabled high-resolution tracing of SARS-CoV-2 transmission in an internationally connected city during community transmission and provided infection chain-level evidence of the downstream propagation of travel-imported SARS-CoV-2 cases.

Specific Changes in OCT Imaging Associated with a Novel Mutation of the RS1 Gene in X-Linked Retinoschisis. / Spezifische OCT-Veränderungen bei einer neuen Mutation im RS1-Gen bei X-chromosomal-rezessiver Retinoschisis.

X-linked retinoschisis (XLRS) is a rare vitreoretinal dystrophy caused by molecular genetic changes in the RS1 gene. It usually manifests itself at a young age with symmetrical splitting within different layers of the retina and leads to a significant reduction in visual acuity. Correct diagnosis at older ages is difficult due to nonspecific changes in OCT scans. We report the morphological changes in OCT scans at different stages of life in a family with XLRS and a novel mutation in the RS1 gene. Our 78-year-old index patient presented with visual disturbances that he had experienced since his childhood. After a detailed anamnesis, complete clinical examination and measurement with SD-OCT, we performed germline genetic testing using whole blood DNA on the index patient, his clinically unaffected daughter and her clinically affected son. The OCT examination of the index patient showed nonspecific atrophic macular changes on both sides. A fundoscopy of the 8-year-old grandson showed the typical macular star pattern. The OCT scan showed the typical retinoschisis of the macula. The genetic analysis revealed the previously undescribed pathogenic variant c.487T>G; p.Trp163Gly in the RS1 gene in all 3 patients. The typical fundus image and OCT pattern, which are absent in the 78-year-old patient, are also present in childhood with the novel RS1 mutation. Our case shows that even with nonspecific changes in the OCT scans, a detailed family history can provide important information on X-linked recessive inheritance and thus for an appropriate molecular genetic diagnosis, so that rare retinal diseases can be diagnosed even at an advanced age.

Pushing the limit of liver regeneration - Safety and survival after monosegment-ALPPS: systematic review and individual patient data meta-analysis.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has expanded and spearheaded development in hepatobiliary surgery. Monosegment-ALPPS tests liver regeneration limits and may present as the last feasible curative treatment option. METHODS: Electronic databases (MEDLINE, Web of Science, Google Scholar, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on mono-ALPPS using a predefined strategy without date or language restrictions. Individual patient data was extracted and analyzed. RESULTS: 237 publications were identified. 19 patients were identified to have undergone mono-ALPPS. Primarily, mono-ALPPS has been utilized as curative treatment for CRLM (17 of 19 cases). Successful mono-ALPPS was possible in FLR above 8% SLV. All patients received either chemotherapy alone or in combination with radiotherapy prior to surgery. 8 of 19 patients experienced PHLF grade A or B. There was no in-hospital mortality described. Recurrent disease has occurred in 7 of 19 patients and 3 have died during follow-up. CONCLUSION: Mono-ALPPS is an experimental procedure that provides a reasonably safe opportunity to curatively treat extensive liver malignancies in patients with FLR as low as 8% SLV. PHLF is the most prevalent complication in mono-ALPPS. Mono-ALPPS should be evaluated in a multicentral study setting.

Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNα signal response.

Communication of Bichromophore Emission upon Aggregation - Aroyl-S,N-ketene Acetals as Multifunctional Sensor Merocyanines.

Aroyl-S,N-ketene acetal-based bichromophores can be readily synthesized in a consecutive three-component synthesis in good to excellent yields by condensation of aroyl chlorides and an N-(p-bromobenzyl) 2-methyl benzothiazolium salt followed by a Suzuki coupling, yielding a library of 31 bichromophoric fluorophores with substitution pattern-tunable emission properties. Varying both chromophores enables different communication pathways between the chromophores, exploiting aggregation-induced emission (AIE) and energy transfer (ET) properties, and thus, furnishing aggregation-based fluorescence switches. Possible applications range from fluorometric analysis of alcoholic beverages to pH sensors.

miRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis.

Distal cholangiocarcinoma (dCCA) is a biliary tract cancer with a dismal prognosis and is often preceded by biliary intraepithelial neoplasia (BilIN), representing the most common biliary non-invasive precursor lesion. BilIN are histologically well defined but have not so far been characterised systematically at the molecular level. The aim of this study was to determine miRNA-regulated genes in cholangiocarcinogenesis via BilIN. We used a clinicopathologically well-characterised cohort of 12 dCCA patients. Matched samples of non-neoplastic biliary epithelia, BilIN and invasive tumour epithelia of each patient were isolated from formalin-fixed paraffin-embedded tissue sections by laser microdissection. The resulting 36 samples were subjected to total RNA extraction and the expression of 798 miRNAs was assessed using the Nanostring® technology. Candidate miRNAs were validated by RT-qPCR and functionally investigated following lentiviral overexpression in dCCA-derived cell lines. Potential direct miRNA target genes were identified by microarray and prediction algorithms and were confirmed by luciferase assay. We identified 49 deregulated miRNAs comparing non-neoplastic and tumour tissue. Clustering of these miRNAs corresponded to the three stages of cholangiocarcinogenesis, supporting the concept of BilIN as a tumour precursor. Two downregulated miRNAs, i.e. miR-451a (-10.9-fold down) and miR-144-3p (-6.3-fold down), stood out by relative decrease. Functional analyses of these candidates revealed a migration inhibitory effect in dCCA cell lines. Activating transcription factor 2 (ATF2) and A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) were identified as direct miR-451a target genes. Specific ATF2 inhibition by pooled siRNAs reproduced the inhibitory impact of miR-451a on cancer cell migration. Thus, our data support the concept of BilIN as a direct precursor of invasive dCCA at the molecular level. In addition, we identified miR-451a and miR-144-3p as putative tumour suppressors attenuating cell migration by inhibiting ATF2 in the process of dCCA tumorigenesis. © The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence.

Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are rescued by expressing wild-type Nup88 but not the disease-linked mutant forms of Nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.