Molecular perspectives for the treatment of hepatocellular carcinoma.

Major advances have been performed in the understanding of genomic dysregulation of hepatocellular carcinoma. A median of 40 to 60 somatic mutations in coding sequence per tumor was identified including 2 to 6 mutations per tumor in genes driving liver carcinogenesis. The main genetic alterations target the key signaling pathways of liver carcinogenesis : telomere maintenance, cell cycle gene, Wnt/beta-catenin pathway, epigenetic modifier gene, oxidative stress pathway, AKT/mTOR and Ras/Raf MAP kinase pathways. A genotype/phenotype classification between these genetic drivers the tumor and patient's features have been also described and was correlated with transcriptomic profiling. These data will be helpful to identify subgroups of HCC that will respond or resist to systemic treatments already used in clinical practice such as tyrosine kinase inhibitors, anti-VEGFR antibody or checkpoint inhibitors and will be useful to identify new therapeutic targets tested in future clinical trials.

Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis.

Lymphangiogenesis is a novel prognostic parameter for several cancers that is preferentially quantified by immunohistochemistry of the lymphatic endothelium-specific hyaluronan receptor LYVE-1. Recently, the specificity of LYVE-1 was challenged by serendipitous observations of LYVE-1 expression in rare tissue macrophages. As expression of the hyaluronan receptor-like molecule stabilin-1 is shared by sinusoidal endothelium and macrophages, a thorough analysis of LYVE-1 expression was performed using macrophage-specific markers in vivo and in vitro. In murine tumour models and excisional wound healing, LYVE-1 expression occurred in a subset of CD11b(+), F4/80(+) tissue macrophages that preferentially co-expressed stabilin-1. Upon comparison of single- and double-labelling immunofluorescence, it became apparent that LYVE-1(+) macrophages mimic sprouting and collapsed lymphatic vessels. In vitro, LYVE-1 expression was induced in 25-40% of murine bone marrow-derived macrophages upon exposure to B16F1 melanoma-conditioned medium and IL-4/dexamethasone. By FACS analysis, 11.5% of bone marrow-derived macrophages were LYVE-1(+), stabilin-1(+) double-positive, while 9.9% were LYVE-1(+), stabilin-1(-) and 33.5% were LYVE-1(-), stabilin-1(+). Northern and western analyses confirmed expression of LYVE-1 mRNA and protein in bone marrow-derived macrophages. In the light of the current debate about true endothelial trans-differentiation versus endothelial mimicry of monocytes/macrophages, LYVE-1(+), stabilin-1(+) non-continuous endothelial-like macrophages will require further developmental and functional analyses. In conclusion, the findings imply that LYVE-1 staining must be supplemented by double labelling with macrophage markers in order to differentiate clearly between LYVE-1(+) lymphatics and LYVE-1(+) tumour-infiltrating macrophages. This improved approach will help to clarify the prognostic significance of lymphangiogenesis in malignant tumours.

Hypocalcemia in end-stage renal disease: a consequence of spontaneous parathyroid gland infarction.

Advances over the last several years have led to a better understanding of the etiology of hyperparathyroidism in renal disease and to more effective means of medical prevention and therapy. Thus, in most dialysis populations, many of the serious complications, such as bone fractures, refractory hypercalcemia, and hyperphosphatemia with vascular and other extraskeletal calcifications, have diminished. Furthermore, more aggressive medical management has decreased the requirement for parathyroidectomy. Unfortunately, not all patients respond to medical management and few still develop refractory hyperparathyroidism with associated morbidity. Of the many complications of refractory hyperparathyroidism in dialysis patients, the development of life-threatening hypocalcemia has not been described. We describe a patient with severe secondary hyperparathyroidism who presented with the acute development of hypocalcemia. To our knowledge, this represents the fourth case, the first reported in a patient with end-stage renal disease, of parathyroid autoinfarction presenting as acute hypocalcemia.

Diurnal changes in thermoregulatory behavior in rats with medial preoptic lesions.

Rats with medial preoptic area (MPOA) damage lack adequate autonomic thermoregulatory reflexes but can behaviorally regulate their body temperatures (Tb) in the cold and heat. We examined the performance of such rats on 90-min behavioral thermoregulatory tests. Tests were conducted during the day and night to determine the preferred Tb at different phases of the circadian Tb rhythm. The amplitude of this rhythm was exaggerated after electrolytic MPOA lesions; differences of 3-4 degrees C between daily peaks and troughs were seen (from 37 degrees C during day to 40-41 degrees C at night) compared with control variations of only 1.5-2.0 degrees C (from 36.0-36.5 degrees C during day to 38 degrees C at night). When escaping cold during the day or night or when escaping heat at night, both MPOA-damaged and control rats maintained Tb within +/- 0.5 degrees C of initial values. When escaping heat during the day, control and MPOA-damaged rats allowed their TbS at the end of the 90-min behavioral tests to rise to normal night levels (38 degrees C for controls and 40-41 degrees C for MPOA rats). These results demonstrate that rats with MPOA damage behaviorally defend the different phases of their exaggerated Tb rhythm in a manner similar to that of controls. Therefore the exaggerated swings in Tb seen in these preparations have an active regulated component and are not simply passive results of an excessive rhythm in heat production or heat conservation.