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The MTM-HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. (Hepatology 2018;68:103-112).

ICC of thyroid FNAs with cytokeratin 19 and HBME1 antibodies can reduce the false-positive and false-negative results of single morphological analyses. It can increase the sensitivity and specificity of diagnosis, thus improving diagnostic accuracy and reducing the need for surgical controls.

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Pancreatic adenocarcinoma is one of the deadliest malignancies worldwide, mainly due to frequent diagnosis at an advanced stage and its strong chemoresistance. Tumor heterogeneity is evident at the histological level, both between tumors and even within a tumor. Recent high-throughput analyses have confirmed that intertumor heterogeneity is greater than intratumor heterogeneity that is mostly driven by successive catastrophic genetic events in the early stage and by epigenetic modifications in the metastatic stage. While this heterogeneity may complicate the search for a universal cure, these analyses have distinguished several subtypes at the genomic, transcriptomic, and metabolomic levels that offer, for some, new therapeutic opportunities.

Microvascular invasion (MiVI) is a major risk factor in postoperative tumor recurrence and mortality in hepatocellular carcinoma (HCC). Unfortunately, this histological feature is usually missed by liver biopsy because of limited sampling, and MiVI is commonly detected only after surgery and examination of the full resected specimen. To date, there exists no reliable tool for identifying MiVI prior to surgical procedures. This study aimed to compare the proteome of HCC with and without MiVI in order to identify surrogate biomarkers of MiVI. A training cohort comprising surgically resected primary HCC with MiVI (n 5 30) and without MiVI (n 5 26) was subjected to matrixassisted laser desorption ionization imaging mass spectrometry (MALDI IMS). Comparative analysis of acquired mass spectra of the two groups yielded 30 differential protein peaks, among which 28 were more strongly expressed in HCC with MiVI. Among these, two peaks were identified as N-term acetylated histone H4 dimethylated at lysine (K) 20, and N-term acetylated histone H4 dimethylated at K20 and acetylated at K16. Both peaks were validated in the training cohort and in an independent validation cohort (n 5 23) by immunohistochemistry and western blot. Conclusion: These results demonstrate the potential of MALDI IMS for uncovering new relevant biomarkers of MiVI in HCC, and highlight the role of epigenetic modifications in the prognosis of HCC. Preoperative detection of modified forms of histone H4 expression in tumor biopsies would be helpful in management of patients with HCC. (HEPATOLOGY 2013;58:983-994) H epatocellular carcinoma (HCC) is the main primary malignancy of the liver, and ranks as the third most common cause of cancerrelated death worldwide, despite significant efforts made in follow-up of cirrhosis patients and screening of HCC.1 HCC prognosis remains poor, mainly related to a high rate of tumor recurrence following surgical treatment that attains 70% at 5 years after liver resection and 15%-30% after liver transplantation (LT).2 Microvascular invasion (MiVI) is a major risk factor for recurrence and mortality in HCC.3-6 Importantly, MiVI, defined as malignant cells in peritumoral vessels, can only be assessed after careful histological assessment of the whole surgical specimen. Thus, there Abbreviations: ACN, acetonitrile; H4K16ac, histone H4 acetylated at lysine 16; H4K20me2, histone H4 dimethylated at lysine 20; HCC, hepatocellular carcinoma; HCC/MiVI1, hepatocellular carcinoma with microvascular invasion; HCC/MiVI2, hepatocellular carcinoma without microvascular invasion; LT, liver transplantation; LTQ, linear trap quadrupole; K, lysine; MALDI IMS, matrix-assisted laser desorption ionization imaging mass spectrometry; MiVI, microvascular invasion; MS, mass spectrometry; MS/MS, tandem mass spectrometry; nano-LC-ESI-MS/MS, nano-liquid chromatography, electrospray ionization, tandem mass spectrometry; PTMs, posttranslational modifications; RP-micro-LC, reverse-phase micro-liquid chromatography; SA, sinapinic acid; TFA, trifluoroa...

SUMMARY The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and “browning” of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.