Death following cylindrical battery ingestion associated with toxic manganese levels.

Cases of battery ingestion are well documented in the scientific literature, especially concerning button cell battery ingestion in children. In this instance, the authors present an atypical case of a young man who voluntarily ingested a cylindrical alkaline battery containing manganese. The patient died approximately a week later, despite not exhibiting any specific symptoms. The battery was found in the cecum during the autopsy, showing deterioration at its positive pole. The cecal mucosa exhibited two ulcerations without perforation. Histological analysis revealed intestinal ischemia in the cecum, with no microscopic lesions in other organs. Toxicology reports indicated high levels of manganese in both cardiac and peripheral blood. Considering all the results from the additional analyses, the experts concluded that the death was likely of multifactorial origin, associated with a toxic blood concentration of manganese. To the best of our knowledge, this is the first recorded death following the ingestion of a cylindrical battery, and the first instance of manganese intoxication resulting from the ingestion of an alkaline battery. The authors will present the case and provide a literature review to assess the extent to which the presence of manganese may have contributed to the fatality.

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

BACKGROUND: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-ß-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING: Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

Molecular Networking for Drug Toxicities Studies: The Case of Hydroxychloroquine in COVID-19 Patients.

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient's plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ.

[Reforming Biosciences and Health Research: Part I, Funding]. / Rapport 21-06. Réformer la recherche en sciences biologiques et en santé : partie I, le financement.

The COVID-19 pandemic occurred in the context of a dramatic decline in support for biological and health research in France. An analysis of resources allocated to this sector shows that the credits in 2020 correspond to only 17.2 % of the total credits allocated to research, the lowest ratio inat least 15 years. Another weakness in the system of support for hospital research is the way funds from the health insurance system are allocated. To bring it into line with international best practices, the task of allocating these funds should be entrusted to a "Hospital Research Orientation Council", which should also be involved in the implementation of national research programming. Another article deals with the organization of research. Recommendations are also made to improve the functioning of the research system at the local level, particularly in university hospitals, and at the national level.

Molecular profiling of stroma highlights stratifin as a novel biomarker of poor prognosis in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer worldwide, as a result of a late diagnosis and limited therapeutic options. Tumour microenvironment (or stroma) plays a key role in cancer onset and progression and constitutes an intrinsic histological hallmark of PDAC. Thus we hypothesised that relevant prognostic biomarkers and therapeutic targets can be identified in the stroma. METHODS: Laser microdissection of the stroma from freshly frozen PDAC was combined to gene expression profiling. Protein expression of candidate biomarkers was evaluated by immunohistochemistry on tissue microarrays (n = 80 tumours) and by ELISA in plasma samples (n = 51 patients). RESULTS: A signature made of 1256 genes that significantly discriminate the stroma from the non-tumour fibrous tissue was identified. Upregulated genes were associated with inflammation and metastasis processes and linked to NF-Kappa B and TGFß pathways. TMA analysis validated an increased expression of SFN, ADAMTS12 and CXCL3 proteins in the stroma of PDAC. Stromal expression of SFN was further identified as an independent prognostic factor of overall (p = 0.003) and disease-free survival (DFS) (p = 0.034). SFN plasma expression was significantly associated with reduced DFS (p = 0.006). CONCLUSIONS: We demonstrated that gene expression changes within the stroma of PDAC correlate with tumour progression, and we identified Stratifin as a novel independent prognostic biomarker.

The bidirectional crosstalk between metastatic uveal melanoma cells and hepatic stellate cells engenders an inflammatory microenvironment.

Uveal melanoma is the most common primary ocular neoplasm in adults. It is peculiar for its hematogenous dissemination and its high propensity to spread to the liver. Current treatments rarely prolong patient survival. We hypothesized that metastatic uveal melanoma cells modulate the function of surrounding hepatic stellate cells to facilitate their own growth and survival. This study was conducted to investigate the role of the hepatic microenvironment on uveal melanoma aggressiveness. We demonstrated that the paracrine signaling of surrounding hepatic stellate cells have more transcriptional impact on metastatic uveal melanoma cells. Upregulated transcripts were linked to inflammation and included several interleukins. The uveal melanoma-stellate cell crosstalk induced as well the expression of transmembrane integrins. In addition, the interleukin-6 receptor inhibitor Tocilizumab did not reduce the growth of uveal melanoma cells. Our results provide evidence that inflammatory mediators are key players in the homing of uveal melanoma cells to the liver. The bidirectional crosstalk between uveal melanoma cells and hepatic stellate cells involved pro-fibrogenic interleukins. The inflammatory characteristics of the metastatic microenvironment might offer relevant therapeutic opportunities in uveal melanoma.

Urinary TIMP-2 and MMP-2 are significantly associated with poor bladder compliance in adult patients with spina bifida.

AIMS: To assess the predictive values of six urinary markers (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], matrix metalloproteinase 2 [MMP-2], tissue inhibitor metalloproteinase 2 [TIMP-2], transformation growth factor ß-1 [TGF-B1], and prostaglandin 2 [PGE2]) for adverse urodynamic features and for upper urinary tract damage in adult patients with spina bifida. MATERIALS AND METHODS: A single-center prospective trial was conducted from March 2015 to March 2017 including all consecutive adult patients with spina bifida seen for urodynamic testing. The urine was collected and stored at -80°C. A urodynamic and an upper urinary tract were systematically performed. At the end of the inclusion period, urines were defrosted and urinary nerve growth factor, BDNF, TIMP-2, and TGF-B1 were assessed using validated ELISA kits. The urinary markers levels were adjusted on the urinary creatinine level. Urinary MMP-2 levels were assessed by zymography. RESULTS: Fourty patients were included. Only TIMP-2 and MMP-2 were significantly associated with poor bladder compliance (P = .043 and P = .039, respectively). TIMP-2 was also the only urinary marker significantly associated with upper urinary tract damage on imaging (OR = 19.81; P = .02). Of all urodynamic parameters, bladder compliance and maximum detrusor pressure were the only ones associated with upper urinary tract damage on imaging (P = .01 and P = .02), The diagnostic performances of urinary TIMP-2 for upper urinary tract damage were slightly superior to PdetMax and bladder compliance with an area under the curve of 0.72. CONCLUSION: Urinary TIMP-2 and MMP-2 were significantly associated with poor bladder compliance and urinary TIMP-2 was significantly associated with upper urinary tract damage. These findings support a pathophysiological role of extracellular matrix remodeling in poor bladder compliance of adult patients with spina bifida.

[Tumor banks and complex data management: Current and future challenges]. / Biobanques tumorales et gestion des données complexes : enjeux actuels et futurs.

Tumor banks are asked to clinical and translationnal research project development in oncology. They strongly participate to the assessment, then to the validation of diagnostic, prognostic and predictive biomarkers. The progressive change of these structures leads to induce a professionalization of their functioning and to identify them as key actors in oncology by the stakeholders of the public and private worlds. The progresses made in biotechnologies and therapeutics are rapidly modifying the impact and the proper functioning of the biobanks. These latter are now facing different challenges, in particular for their sustainability. Among the major issues, the integration of the clinical and biological data becoming increasingly complex leads to urgently consider an optimization of the role of different biobanks in France. Their goal is to be an attractive counterpart face to the international competition. The purpose of this review is to briefly describe the current evolution of the biobanks, then their present and future challenges, and finally the role made by the pathologists in these new issues in oncology field.

Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection.

Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (<2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% ß-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type ß-catenin) and perivenous-type (mutant ß-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was down-regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. CONCLUSION: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection. (Hepatology 2017;66:1502-1518).

Local Anesthetics Inhibit the Growth of Human Hepatocellular Carcinoma Cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapeutic options. Retrospective studies have shown that the administration of local anesthetics (LAs) during cancer surgery could reduce cancer recurrence. Besides, experimental studies reported that LAs could inhibit the growth of cancer cells. Thus, the purpose of this study was to investigate the effects of LAs on human HCC cells. METHODS: The effects of 2 LAs (lidocaine and ropivacaine) (10 to 10 M) were studied after an incubation of 48 hours on 2 HCC cell lines, namely HuH7 and HepaRG. Cell viability, cell cycle analysis, and apoptosis and senescence tests were performed together with unsupervised genome-wide expression profiling and quantitative real-time polymerase chain reaction for relevant genes. RESULTS: We showed that LAs decreased viability and proliferation of HuH7 cells (from 92% [P < .001] at 5 × 10 M to 40% [P = .02] at 10 M with ropivacaine and from 87% [P < .001] to 37% [P = .02] with lidocaine) and HepaRG progenitor cells (from 58% at 5 × 10 M [P < .001] to 29% at 10 M [P = .04] with lidocaine and 59% [P < .001] with ropivacaine 5 × 10 M) in concentration-dependent manner. LAs have no effect on well-differentiated HepaRG. Ropivacaine decreased the mRNA level of key cell cycle regulators, namely cyclin A2, cyclin B1, cyclin B2, and cyclin-dependent kinase 1, and the expression of the nuclear marker of cell proliferation MKI67. Lidocaine had no specific effect on cell cycle but increased by 10× the mRNA level of adenomatous polyposis coli (P < .01), which acts as an antagonist of the Wnt/ß-catenin pathway. Both LAs increased apoptosis in Huh7 and HepaRG progenitor cells (P < .01). CONCLUSIONS: The data demonstrate that LAs induced profound modifications in gene expression profiles of tumor cells, including modulations in the expression of cell cycle-related genes that result in a cytostatic effect and induction of apoptosis.

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis.

PURPOSE: Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or (90)Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. METHODS: We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. RESULTS: A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. CONCLUSION: SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials.

Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability.

Synergy between yttrium-90 (90Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI < 1 denoting synergy and CI > 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with 90Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with 90Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with 90Y radioembolization for treatment of liver cancer.

Stellate cells and the development of liver cancer: therapeutic potential of targeting the stroma.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common types of primary tumors in the liver. Although major advances have been made in understanding the cellular and molecular mechanisms underlying liver carcinogenesis, HCC and ICC are still deadly cancers worldwide waiting for innovative therapeutic options. Growing evidence from the literature highlight the critical role of the tumor cell microenvironment in the pathogenesis of cancer diseases. Thus, targeting the microenvironment, particularly the crosstalk between tumor cells and stromal cells, has emerged as a promising therapeutic strategy. This strategy would be particularly relevant for liver cancers which frequently develop in a setting of chronic inflammation and microenvironment remodeling associated with hepatic fibrosis and cirrhosis, such processes in which hepatic stellate cells (HSC) greatly contribute. This review brings a genomic point of view on the alterations of the cellular microenvironment in liver cancers, particularly the stromal tissue within tumor nodules, emphasizing the importance of the crosstalk between tumor cells and stromal cells, notably activated HSC, in tumor onset and progression. Furthermore, potential therapeutic modalities of targeting the stroma and HSC are discussed.

Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma.

UNLABELLED: Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well-established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFß) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFß2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFß2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease-free survival. CONCLUSION: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression.

Epithelial cell adhesion molecule is a prognosis marker for intrahepatic cholangiocarcinoma.

BACKGROUND: Recently, we identified a gene signature of intrahepatic cholangiocarcinoma (ICC) stroma and demonstrated its clinical relevance for prognosis. The most upregulated genes included epithelial cell adhesion molecule (EpCAM), a biomarker of cancer stem cells (CSC). We hypothesized that CSC biomarkers could predict recurrence of resected ICC. METHODS: Both functional analysis of the stroma signature previously obtained and immunohistochemistry of 40 resected ICC were performed. The relationships between the expression of CSC markers and clinicopathologic factors including survival were assessed by univariate and multivariable analyzes. RESULTS: Gene expression profile of the stroma of ICC highlighted embryonic stem cells signature. Immunohistochemistry on tissue microarray showed at a protein level the increased expression of CSC biomarkers in the stroma of ICC compared with nontumor fibrous liver tissue. The overexpression of EpCAM in the stroma of ICC is an independent risk factor for overall (hazard ratio = 2.6; 95% confidence interval, 1.3-5.1; P = 0.005) and disease-free survival (hazard ratio = 2.2; 95% confidence interval, 1.2-4.2; P = 0.012). In addition, the overexpression of EpCAM in nontumor fibrous liver tissue is closely correlated with a worst disease-free survival (P = 0.035). CONCLUSIONS: Our findings provide new arguments for a potential role of CSC on ICC progression supporting the idea that targeting CSC biomarkers might represent a promise personalized treatment.

SARS-CoV-2 receptor ACE2 is upregulated by fatty acids in human MASH.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) results in steatosis, inflammation (steatohepatitis), and fibrosis. Patients with MASLD more likely develop liver injury in coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As viral RNA has been identified in liver tissues, we studied expression levels and cellular sources of the viral receptor angiotensin-converting enzyme 2 (ACE2) and coreceptors in MASLD and fibroinflammatory liver diseases. Methods: We built a transcriptomic MASLD meta-dataset (N = 243) to study SARS-CoV-2 receptor expression and verified results in 161 additional cases of fibroinflammatory liver diseases. We assessed the fibroinflammatory microenvironment by deconvoluting immune cell populations. We studied the cellular sources of ACE2 by multiplex immunohistochemistry followed by high-resolution confocal microscopy (N = 9 fatty livers; N = 7 controls), meta-analysis of two single-cell RNA sequencing datasets (N = 5 cirrhotic livers; N = 14 normal livers), and bulk transcriptomics from 745 primary cell samples. In vitro, we tested ACE2 mRNA expression in primary human hepatocytes treated with inflammatory cytokines, bacterial lipopolysaccharides, or long-chain fatty acids. Results: We detected ACE2 at the apical and basal poles of hepatocyte chords, in CLEC4M+ liver sinusoidal endothelial cells, the lumen of ABCC2+ bile canaliculi, HepPar-1+-TMPRSS2+ hepatocytes, cholangiocytes, and CD34+ capillary vessels. ACE2 steeply increased between 30 and 50 years of age; was related to liver fat area, inflammation, high immune reactivity, and fibrogenesis; and was upregulated in steatohepatitis. Although ACE2 mRNA was unmodified in alcoholic or viral hepatitis, it was upregulated in fibroinflammatory livers from overweight patients. In vitro, treatment of primary human hepatocytes with inflammatory cytokines alone downregulated but long chain fatty acids upregulated ACE2 mRNA expression. Conclusions: Lipid overload in fatty liver disease leads to an increased availability of ACE2 receptors. Impact and implications: COVID-19 can be a deadly disease in vulnerable individuals. Patients with fatty liver disease are at a higher risk of experiencing severe COVID-19 and liver injury. Recent studies have indicated that one of the reasons for this vulnerability is the presence of a key cell surface protein called ACE2, which serves as the main SARS-CoV-2 virus receptor. We describe the cellular sources of ACE2 in the liver. In patients with fatty liver disease, ACE2 levels increase with age, liver fat content, fibroinflammatory changes, enhanced positive immune checkpoint levels, and innate immune reactivity. Moreover, we show that long chain fatty acids can induce ACE2 expression in primary human hepatocytes. Understanding the cellular sources of ACE2 in the liver and the factors that influence its availability is crucial. This knowledge will guide further research and help protect potentially vulnerable patients through timely vaccination boosters, dietary adjustments, and improved hygiene practices.

Volumetric changes after (90)y radioembolization for hepatocellular carcinoma in cirrhosis: an option to portal vein embolization in a preoperative setting?

BACKGROUND: Contralateral hypertrophy after (90)Y radioembolization has been described in case reports, but the incidence and quantitative extent of liver volume modifications after this therapy are unknown. METHODS: This retrospective study examined patients with hepatocellular carcinoma and underlying cirrhosis treated by (90)Y radioembolization. The main inclusion criteria were unilateral treatment, no prior liver surgery, and computed tomographic scans allowing for volumetric assessments. Treated, tumor, and contralateral liver volumes were measured. Whole liver volume and the ratio of contralateral to total functional liver volume after a virtual hepatectomy were calculated. RESULTS: Data of 34 patients were analyzed. Response rates were 26 % according to Response Evaluation Criteria in Solid Tumors (RECIST) and 63 % according to modified RECIST. Median overall survival was 13.5 months. Median treated volume decreased from 938 mL (interquartile range [IQR] = 719) to 702 mL (IQR = 656) (p < 0.001), while median contralateral volume increased from 724 mL (IQR = 541) to 920 mL (IQR = 530) (p < 0.001). The whole liver volume remained stable, with a median volume of 1,702 mL (IQR = 568) versus 1,577 mL (IQR 670), respectively (p = 0.55). The mean maximal increase in contralateral volume was 42 % (95 % confidence interval 16-67). Overall, 13 patients (38.2 %) exhibited increases greater than 30 %, while 13 patients (38.2 %) showed no increase or showed increases less than 10 %. The median ratio of contralateral to total functional liver volume increased from 48.5 to 64.9 % (p < 0.001), with the proportion of patients with a ratio of ≥50 % increasing from 47.1 to 67.6 % (p = 0.013). CONCLUSIONS: (90)Y radioembolization induced frequent and similar increases in functional liver remnant volume compared with portal vein embolization. This technique should be tested in a prospective study phase 2 study before liver resection.

Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFß signaling pathways.

Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFß and Wnt/ß-catenin were identified as the two major signalling pathways activated in cHCC-CC. A ß-catenin signature distinct from that observed in well-differentiated HCC with mutant ß-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFß activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HCC.

Usefulness and pitfalls of MAA SPECT/CT in identifying digestive extrahepatic uptake when planning liver radioembolization.

PURPOSE: Identifying gastroduodenal uptake of (99m)Tc-macroaggregated albumin (MAA), which is associated with an increased risk of ulcer disease, is a crucial part of the therapeutic management of patients undergoing radioembolization for liver tumours. Given this context, the use of MAA single photon emission computed tomography (SPECT)/CT may be essential, but the procedure has still not been thoroughly evaluated. The aim of this retrospective study was to determine the effectiveness of MAA SPECT/CT in identifying digestive extrahepatic uptake, while determining potential diagnostic pitfalls. METHODS: Overall, 139 MAA SPECT/CT scans were performed on 103 patients with different hepatic tumour types. Patients were followed up for at least 6 months according to standard requirements. RESULTS: Digestive, or digestive-like, uptake other than free pertechnetate was identified in 5.7% of cases using planar imaging and in 36.6% of cases using SPECT/CT. Uptake sites identified by SPECT/CT included the gastroduodenal region (3.6%), gall bladder (12.2%), portal vein thrombosis (6.5%), hepatic artery (6.5%), coil embolization site (2.1%) as well as falciform artery (5.0%). For 2.1% of explorations, a coregistration error between SPECT and CT imaging could have led to a false diagnosis by erroneously attributing an uptake site to the stomach or gall bladder, when the uptake actually occurred in the liver. CONCLUSION: SPECT/CT is more efficacious than planar imaging in identifying digestive extrahepatic uptake sites, with extrahepatic uptake observed in one third of scans using the former procedure. However, more than half of the uptake sites in our study were vascular in nature, without therapeutic implications. The risk of coregistration errors must also be kept in mind.

The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor.

Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates signals to Smad proteins, which mediate the activation of TGF-beta target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-beta signaling pathway that acts through association with TbetaRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-beta signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TbetaRII in early endosomal vesicles and stabilizes the TbetaRII protein presumably by suppressing the association of TbetaRII with Smad7. These results define ADAM12 as a new partner of TbetaRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.