Resection of hepatocellular carcinoma with tumor thrombus in the major vasculature. A European case-control series

Tumor thrombus in major vasculature is a frequent finding with a poor long-term prognosis in patients with hepatocellular carcinoma (HCC). The utility of surgical resection is still controversial. This study compared morbidity and survival after resection for HCC with and without tumor thrombus. Data of 108 patients who underwent major hepatic resection for HCC were prospectively recorded. Patients were divided into two groups. The venous thrombectomy (VT) group included 26 patients who had HCC with tumor thrombus in the portal or hepatic veins. The matched control group included 82 patients who had HCC without tumor thrombus. Surgical technique, early outcome, and late survival were analyzed in each group. Multivariate analysis was performed to assess the prognostic value of this feature. Surgical technique was comparable in the VT and control group with regard to extent of hepatectomy, procedure duration, and transfusion requirements. Early postoperative outcome was also comparable. Actuarial survival at 1, 3, and 5 years was 38%, 20%, and 13%, respectively, in the VT group (median: 9 months) versus 74%, 56%, and 33%, respectively, in the control group (median: 41 months). In the subgroup of patients with tumor thrombus limited to the portal vein, actuarial survival at 1, 3, and 5 years was 50%, 26%, and 17%, respectively, (median: 12 months) and two patients lived longer than 5 years. Multivariate analysis showed that incomplete resection, alphafetoprotein level greater than 100 N, more than two tumor nodules, and tumor thrombus in major vasculature were independent factors of poor prognosis. Survival after resection for HCC with tumor thrombus in the major vasculature is poorer than after resection for HCC without tumor thrombus. However, an aggressive surgical strategy can provide significant survival with comparable morbidity in selected cases, that is, tumor thrombus located in the portal vein only and expected complete resection of the lesions.     

Optimal donation of kidney transplants after controlled circulatory death

Controlled donation after circulatory death (cDCD) is used for “extended criteria” donors with poorer kidney transplant outcomes. The French cDCD program started in 2015 and is characterized by normothermic regional perfusion, hypothermic machine perfusion, and short cold ischemia time. We compared the outcomes of kidney transplantation from cDCD and brain-dead (DBD) donors, matching cDCD and DBD kidney transplants by propensity scoring for donor and recipient characteristics. The matching process retained 442 of 499 cDCD and 809 of 6185 DBD transplantations. The DGF rate was 20% in cDCD recipients compared with 28% in DBD recipients (adjusted relative risk [aRR], 1.43; 95% confidence interval [CI] 1.12–1.82). When DBD transplants were ranked by cold ischemia time and machine perfusion use and compared with cDCD transplants, the aRR of DGF was higher for DBD transplants without machine perfusion, regardless of the cold ischemia time (aRR with cold ischemia time <18 h, 1.57; 95% CI 1.20–2.03, vs aRR with cold ischemia time ≥18 h, 1.79; 95% CI 1.31–2.44). The 1-year graft survival rate was similar in both groups. Early outcome was better for kidney transplants from cDCD than from matched DBD transplants with this French protocol.     

Intracellular Phosphate and ATP Depletion Measured by Magnetic Resonance Spectroscopy in Patients Receiving Maintenance Hemodialysis

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��-Cell Failure in Diet-Induced Obese Mice Stratified According to Body Weight Gain: Secretory Dysfunction and Altered Islet Lipid Metabolism Without Steatosis or Reduced ��-Cell Mass

OBJECTIVE

C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about β-cell failure in these mice.

RESEARCH DESIGN AND METHODS

DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced β-cell mass or function and studied islet metabolism and signaling.

RESULTS

HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced β-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca²⁺ was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets.

CONCLUSIONS

β-Cell failure in HDR mice is not due to reduced β-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca²⁺ and lipid signaling, as well as free cholesterol deposition.While insulin resistance is a common feature in most obese subjects, insulin secretion is increased to compensate for its reduced action and normoglycemia is maintained (1,2). In obese type 2 diabetes subjects, however, β-cell compensation fails due to marked impairment of glucose-stimulated insulin secretion (GSIS), often with reduced β-cell mass (2). The relationship between β-cell function and mass as causative factors in β-cell failure and diabetes progression is debated, with emphasis on the relevance of “functional β-cell mass” rather than total mass (2). Increased adiposity leads to elevated circulating free fatty acids (FFAs) and triglycerides, and in vitro and in vivo studies have indicated a causative role for dyslipidemia in insulin resistance (1,3). Although FFAs are necessary for the amplification of GSIS, their excess supply may also have a role in β-cell failure (4), as prolonged elevation of FFA levels both in vivo and in vitro cause β-cell dysfunction (5,6) and, at least in vitro, apoptosis (7).At least part of the β-cell compensation to insulin resistance is due to an increase in β-cell mass (4). Either long-term high-fat diet (HFD) (8) or a short-term lipid infusion (9) can result in increased β-cell mass without augmentation of GSIS, indicating that β-cell function and mass are not necessarily linked. Rodent studies have indicated that HFD leads to increased β-cell mass (8), which is also observed in normoglycemic obese individuals (10). Unclear at present is the dynamics between the factors driving compensatory increase in β-cell mass and function and those reducing them through the various stages of type 2 diabetes development, particularly as FFA may do both. Genetic islet susceptibility may be a critical determinant of these dynamics, both in humans and animal models (4,11,12).Even though studies employing genetically modified models (e.g., Zucker Diabetic Fatty rats, db/db mice) have helped in understanding some of these pathological processes (13–16), several of these models are of extreme nature, with rapid development of pronounced type 2 diabetes. These models, therefore, differ from human obesity-linked type 2 diabetes, which usually develops more gradually. In an attempt to gain insight into the basis of β-cell failure in a mild model of diabetes, we recently developed a new model of type 2 diabetes, the 60% pancreatectomized obese hyperlipidemic Zucker Fatty rat (14). In this model, severe β-cell dysfunction was found without any evidence of a falling β-cell mass or islet steatosis (14). More detailed examination of the pancreatectomized Zucker Fatty rat islets showed marked depletion of insulin stores and altered glycerolipid metabolism (14). The Zucker Fatty rat, as opposed to the Zucker Diabetic Fatty rat, however, does not have genetic predisposition to diabetes, as it maintains normoglycemia despite severe obesity-related insulin resistance (4). The diet-induced obese (DIO) C57BL/6 mouse gradually develops hyperglycemia (17). This suggests that DIO islets are unable to fully compensate for the obesity-related insulin resistance, as occurs in human type 2 diabetes.In the present study, we investigated β-cell dysfunction in DIO mice stratified into two groups according to the effect of HFD on body weight: the low responders to HFD (LDR) were less obese, developed intermediate severity of insulin resistance, and had only mild impairment in glycemia. The high responders to HFD (HDR) were more obese, insulin resistant, and hyperinsulinemic and were clearly hyperglycemic. Thus, the LDR and HDR groups allowed for analysis and comparison of islet β-cell mass and function in response to different levels of insulin resistance with corresponding very mild perturbation of glucose homeostasis and overt but mild hyperglycemia, respectively. When extended to obese humans, these two groups correspond to the pre-diabetes and early diabetes situations.     

Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant.

Interleukin-10 (IL-10) is constitutively produced by peritoneal B1a lymphocytes, and stromal cell-derived factor-1 (SDF-1) by mesothelial cells. Independent studies have shown that both IL-10 and SDF-1 are involved in the persistence of the peritoneal B-lymphocyte compartment. This study shows that IL-10 and SDF-1 act in synergy on peritoneal B lymphocytes. Indeed, autocrine production of IL-10 was absolutely required for all effects of SDF-1 on these cells, including increased proliferation, survival, and chemotaxis. Moreover, adding IL-10 to peritoneal B lymphocytes increased the effects of SDF-1. Neither IL-5, IL-6, nor IL-9 affected the response of peritoneal B lymphocytes to SDF-1. IL-10 was chemokinetic for peritoneal B lymphocytes, increasing their random mobility. It also potentiated the SDF-1-induced reorganization of the cytoskeleton without affecting CXCR4 gene expression by peritoneal B lymphocytes. Despite its chemokinetic properties, IL-10 abolished the migration of peritoneal B lymphocytes in response to B-lymphocyte chemoattractant (BLC), a chemokine targeting B lymphocytes to lymphoid organ follicles. The ability of B1a lymphocytes to produce IL-10 constitutively, combined with the opposite effects of this cytokine on the responses to SDF-1 and BLC, may account for the selective accumulation of B1 lymphocytes in body cavities.     

Efficacy and safety of low intensity vitamin K antagonists in Western and East-Asian patients with left-sided mechanical heart valves

Journal of Thrombosis and Thrombolysis - The optimal INR target in patients with mechanical heart valves is unclear. Higher INR targets are often used in Western compared with East Asian countries....     

Management of bone marrow biopsy related bleeding risks: a retrospective observational study

Journal of Thrombosis and Thrombolysis - Bone marrow biopsies are largely used for the diagnosis and prognostic of various hematological diseases. Complications are rare but can be as serious as...