Portomesenteric vein thrombosis following sleeve gastrectomy: Case report focusing on the role of pathogenetic factors.

INTRODUCTION: Sleeve gastrectomy has currently become the most commonly performed bariatric. procedure worldwide according to the last IFSO survey, overtaking gastric bypass with. a share of more than 50% of all primary bariatric-metabolic surgery. Gastric leak, intraluminal bleeding, bleeding from the staple-line and strictures are the most common complications. Portomesenteric vein thrombosis (PMVT)after sleeve gastrectomy is. another complication that has been increasingly reported in case-series in recent.years, although it remains uncommon. In this case report is described an extended portomesenteric vein thrombosis after. sleeve gastrectomy interesting splenic vein too with a favorable course and an. uneventful follow-up. We try to search in this case for pathogenetic factors involved in. this complication. CASE REPORT: A 42-year old man, with a body mass index (BMI) of 45 kg/m2, with a medical history of Obstructive Sleep Apnea Sindrome (OSAS) underwent laparoscopic sleeve gastrectomy. Early postoperative course was uneventful. Six days after discharge he complained abdominal pain and was admitted at the Emergency Department. A CT scan with intravenous contrast showed an occlusion of the portal vein, of the intrahepatic major branches and an extension to the superior mesenteric vein and the splenic vein. The patient received heparin and oral anticoagulation together with intravenous hydration and proton pump inhibitors. Considering the favourable course the patient was discharged after six days with long-term oral anticoagulation therapy. Anticoagulation with acenocumarol was continued for six months after a CT scan showed resolution of the PMVT without cavernoma. He had no recurrence of symptoms. DISCUSSION: Porto-mesenteric thrombosis after sleeve gastrectomy is a rare complication but it has been increasingly reported over the last 10 years along with the extensive use of sleeve gastrectomy. Because PMVT is closely associated with sleeve gastrectomy in comparison with other bariatric procedures, we need to investigate what pathogenetic factors are involved in sleeve gastrectomy. Thrombophylic state, prolonged duration of surgery, high levels of pneumoperitoneum, thermal injury of the gastroepiploic vessels during greater curvature dissection, high intragastric pressure, inadequate antithrombotic prophylaxis and delayed mobilization of the patient after surgery have been reported as pathogenetic factors of portmesenteric vein thrombosis. Most of the cases presented in the literature such as our clinical case resolve with medical therapy, although portal vein thrombus extends into the superior mesenteric vein and the splenic vein. CONCLUSION: Portomesenteric venous thrombosis is a rare but serious complication of bariatric surgery, especially associated with sleeve gastrectomy. Diagnosis is based on CT examination with intravenous contrast, and initial therapy is anticoagulation. Etiologic factors reported in the literature include a long duration of surgery, a high degree of pneumoperitoneum, high intragastric pressure after sleeve gastrectomy and thermal injury to the short gastric vessels and gastroepiploic arcade. Limited operative time, controlled values of pneumoperitoneum, careful dissection with energy device of gastric greater curvature, appropriate prophylaxis with low molecular weight heparin may be useful tools to prevent and limit this complication. Nonetheless we have to search which factors may condition the evolution of an extended PMVT as that described in this case towards resolution or to a further worsening clinical state. Early diagnosis? Correct treatment? Undiscovered patientrelated factors?

[Management of myelodysplastic syndromes in 2019: An update]. / Prise en charge des syndromes myélodysplasiques en 2019 : mise au point.

Myelodysplastic syndromes are a heterogeneous group of clonal myeloid disorders characterized by peripheral cytopenias and an increased risk of progression to acute myeloid leukemia. Inflammatory, auto-immune or syndromic symptoms can make the diagnosis difficult. Diagnosis is currently based on bone marrow cytology but cytogenetics and molecular features are currently overpassing their initial prognostic function (allowing early diagnosis and prediction of therapeutic response). The prognostic classification is based on the Revised International Prognostic Scoring System, which also provides guidance for therapeutic management. The treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias (erythropoiesis stimulating agents, transfusions, lenalidomide, etc.), whereas in high-risk group, the goal is the control of the leukemic clone (hypomethylating agents, allograft of hematopoietic stem cell transplantation). Other molecules are used to manage complications of cytopenias or transfusion (anti-infectious prophylaxis and treatments, martial chelation). New molecules are being studied with some interesting results (luspatercept, venetoclax). This article aims to provide an update on the knowledge that an internist should know for the practical management of myelodysplastic syndromes in 2019.

Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia.

In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is required. Here, we found that FLT3-ITD expression increased basal autophagy in AML cells, and that both pharmacological and genetic inhibition of the receptor reduced autophagy in primary AML samples and cell lines. Conditional expression of shRNAs against key autophagy proteins demonstrated that autophagy is required for AML cell proliferation in vitro and for leukemic cells survival in a mouse model of xenograft. Importantly, autophagy inhibition also overcame FLT3 inhibitor resistance both in vitro and in vivo. The transcription factor ATF4 was identified as an essential actor of FLT3-ITD-induced autophagy. Cellular levels of ATF4 were highly dependent on FLT3-ITD activity, and downregulation of ATF4 inhibited autophagy-dependent AML cell proliferation and improved overall mouse survival similarly to autophagy inhibition. These results suggest that targeting autophagy or ATF4 in patients expressing FLT3 mutations may represent a novel promising and innovative therapeutic strategy for AML.

Pim kinases phosphorylate Chk1 and regulate its functions in acute myeloid leukemia.

Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN-/- cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3- and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies.

The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors.

Several receptor tyrosine kinases (TKs) are involved in the pathogenesis of acute myeloid leukemia (AML). Here, we have assessed the expression of the Recepteur d'Origine Nantais (RON) in leukemic cell lines and samples from AML patients. In a series of 86 AML patients, we show that both the full length and/or the short form (sf) of RON are expressed in 51% and 43% of cases, respectively. Interestingly, sfRON is not expressed in normal CD34+ hematopoietic cells and induces part of its oncogenic signaling through interaction with the Src kinase Lyn. sfRON-mediated signaling in leukemic cells also involves mTORC1, the proapoptotic bcl2-family member, BAD, but not the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, the expression of sfRON was specifically downregulated by 5-azacytidine (AZA). Conversely, AZA could induce the expression of sfRON in sfRON-negative leukemic cells suggesting that the activity of this drug in AML and myelodysplastic syndromes could involve modulation of TKs. cMET/RON inhibitors exhibited an antileukemic activity exclusively in AML samples and cell lines expressing sfRON. These results might support clinical trials evaluating cMET/RON inhibitors in AML patients expressing sfRON.

Spontaneous hypoglycemia in patients with cystic fibrosis.

OBJECTIVE: Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear. DESIGN AND METHODS: A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed. RESULTS: FPG < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (P = 0.002) and lower Shwachman scores (P = 0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia. CONCLUSIONS/INTERPRETATION: Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

Is ghrelin a signal of decreased fat-free mass in elderly subjects?

OBJECTIVE: Aging is associated with appetite decline, weight loss, reduced fat-free mass (FFM), and increased fat mass (FM). Ghrelin and leptin are short- and long-term determinants of energy balance respectively, whose dysregulation could alter food intake. We evaluate the relationship of circulating ghrelin and leptin responses to standardized oral mixed nutrient load (SOMNL) with body composition, daily food intake, and insulin sensitivity in healthy elderly subjects (ES). DESIGN AND METHODS: Twenty-six ES (12/14 M/F, 69+/-4 years) and ten young healthy controls (LY) (5/5 M/F, 27+/-3 years) were studied at the International Center for the Assessment of Nutritional Status (Milan, Italy) with air plethysmography, dual energy X-ray absorptiometry, indirect calorimetry, and dietary intake assessment. Basal and postprandial ghrelin, leptin, testosterone, glucose, insulin and C-peptide concentrations, and insulin resistance (homeostasis model assessment (HOMA-R)) and sensitivity (quantitative insulin-sensitivity check index (QUICKI)) were evaluated. RESULTS: Basal ghrelin levels were similar in ES and LY, whereas leptin was higher in ES than LY, in agreement with the higher amount of FM. Basal and percentage change in ghrelin were inversely related to FFM, appendicular skeletal muscle mass (SMM), and QUICKI, but not to FM. Basal and percentage change in leptin were directly related to FM and not to FFM indexes. Ghrelin basal concentration was negatively correlated with energy and protein intake and with QUICKI. Percentage change in Ghrelin after SOMNL correlated negatively with protein intake, but positively with resting energy expenditure and energy intake, and glucose, insulin, C-peptide basal concentrations, and HOMA-R. CONCLUSION: In ES, basal and postprandial ghrelin increases with FFM, specifically SMM, reduction, whereas leptin increases with relative FM increases.

Measurement of salicylic acid in human serum using stable isotope dilution and gas chromatography-mass spectrometry.

A simple, highly selective, and sensitive method using stable isotope dilution and gas chromatography-mass spectrometry has been developed to quantify salicylic acid (SA) at concentrations naturally occurring in biological fluids, such as in the serum of subjects not taking aspirin. After extraction of liquid-liquid with diethyl ether and ethyl acetate and preparation of the tert-butyldimethylsilyl derivative, SA content was detected using deuterated SA as internal standard. The mean recovery of SA from serum was 85 +/- 6%. Intra- and interday precision and % relative error were <15% in all cases. With a detection limit of 0.6 ng and a quantification limit of 2 ng, the method is therefore also adequate for population studies because of the small amount of blood necessary to perform the analyses.

[From the Mailing List SIN: Therapy and prevention of peritoneal sclerosis]. / Dalla Mailing-List soci SIN (ML-SIN). La sclerosi peritoneale: terapia e prevenzione.

Recently, in the Mailing List of the Italian Society of Nephrology (ML-SIN), a message asking for opinions on the diagnosis and treatment of peritoneal sclerosis gave rise to an extensive debate on this interesting clinical topic. The discussion evidenced significant differences both in the reported onset of clinical manifestations, emphasizing the difficulty in obtaining a definite early diagnosis, and in therapy approaches. Occasionally, this is limited to medical treatment, but surgery, although burdened with elevated complexity and high mortality rates due to post-operative complications, is usually advocated for intestinal obstruction. This is the second issue reserved for the review of the ML-SIN concerning this topic, following that dedicated to definition, etiology, pathology and clinical characteristics. In this section, two expert colleagues complete the analysis of the different aspects of peritoneal sclerosis, discussing the therapy and the prevention of this serious complication of peritoneal dialysis.

[From the Mailing List SIN: peritoneal sclerosis]. / Dalla Mailing-List soci SIN (ML-SIN): la sclerosi peritoneale.

In the course of previous months, in the Mailing List of the Italian Society of Nephrology (ML-SIN), a message asking for opinions on the diagnosis and treatment of peritoneal sclerosis, gave rise to an extensive debate concerning this clinically interesting topic. The discussion evidenced significant differences both in the reported onset of clinical manifestations, emphasizing the difficulty in obtaining a definite early diagnosis, and in therapy approaches. This is sometimes limited to medical treatment, but surgery, although burdened with elevated complexity and a high mortality rate, mainly due to post-operative complications, is usually advocated for intestinal obstruction. In this issue of the review dedicated to the ML-SIN, two expert colleagues will analyze the different aspects of peritoneal sclerosis. The argument is developed in two sections: the first section is dedicated to the discussion of definition, etiology, pathology and clinical characteristics of this serious complication in peritoneal dialysis (PD).

Histological and functional characteristics of peritoneal membrane in peritoneal sclerosis of PD patients.

BACKGROUND: Function and structure of peritoneal membrane (PM) are impaired on peritoneal dialysis (PD). Peritoneal sclerosis is a common finding in peritoneal biopsies (PB) of PD patients. The aim of this study was to examine the impact of peritoneal sclerosis on peritoneal function and clinical parameters in PD patients submitted to peritoneal biopsy. METHODS: A PB was performed on 31 PD patients during catheter removal due to malfunction or after drop-out from treatment. For each patient PM transport was evaluated by the last peritoneal equilibration test before PB. Each daily glucose load was calculated. Tissue was formalin-embedded and stained for histological and immunohistochemical studies. RESULTS: Patients with submesothelial sclerosis and those with impairment of submesothelial basement membrane and subendothelial vascular membrane were submitted to a larger daily glucose load. Peritoneal sclerosis > 50 microns was more frequent in high transporters, who were exposed to larger daily glucose load compared to medium-high transporters. Mesothelial loss is correlated to peritoneal sclerosis and vascular injuries. CONCLUSIONS: Peritoneal sclerosis is not constant in PD patients: it is related to the loss of mesothelium integrity, to the daily glucose load of PD treatment and to vascular injuries, but apparently not to the presence of inflammatory infiltrate. It remains a matter of debate how much the peritoneal sclerosis modifies the function of PM and how new more biocompatible PD solutions could reduce PM injury.

Body composition assessment in spinal cord injury subjects.

Total and segmental body composition (fat mass, FM; fat-free mass, FFM; bone mineral density, BMD) were evaluated in 13 sedentary spinal cord injury (SCI) subjects and in 13 able-bodied healthy males (control, C) using dual X-ray absorptiometry (DXA) and skinfold methods. In the SCI group, total FM was significantly higher (31.1+/-8.2 vs. 20.8+/-6.9%) and total FFM was significantly lower (62.2+/-8.9 vs. 73.5+/-6.4%) than in C subjects. Total BMD did not differ between the SCI and C groups (1.20+/-0.11 vs. 1.30+/-0.11 g/cm(2)). In the SCI group, segmental FM was higher in the legs and trunk, whereas BMD was lower in legs only. The skinfold method significantly underestimated FM in the SCI group. Body composition is severely modified in paralyzed segments. The predictive equations developed for healthy populations appear to be inapplicable to SCI subjects.

[Morpho-functional study of peritoneum in peritoneal dialysis]. / Studio morfo-funzionale del peritoneo in dialisi peritoneale.

BACKGROUND: Peritoneal dialysis (PD) impairs both structure and function of the peritoneal membrane (PM). Aim of the study is to examine the relationship among dialytic, histological and functional parameters in PD patients. METHODS: Thirty-one PD patients were submitted to peritoneal biopsy (PB) during catheter removal for malfunction or after dropping out of the treatment. For each patient PM transport was evaluated by the last peritoneal equilibration test (PET) prior to PB. Each daily glucose load was calculated. PB was performed at a distance of at least 5 cm from the catheter insertion point. The tissues were promptly embedded in formalin and stained for histological and immunohistochemical studies. RESULTS: 1) Patients with mesothelial impairment had longer treatment time. 2) Patients presenting submesothelial sclerosis (SS) and those with impairment of submesothelial basement membrane and subendothelial vascular membrane (SVM) were submitted to larger daily glucose loads. 3) High transporters were exposed to larger daily glucose loads and presented an SS thickness greater than 50 micron more frequently than medium-high transporters. 4) Mesothelial loss was correlated with SS and vascular alterations. 5) SS and vascular injuries were related to each other and not to inflammatory infiltrate. CONCLUSION: Our study suggests that PD length seems to be mainly involved in mesothelial impairment; glucose load appears to damage mainly the submesothelial layer; SS is not a constant event in PD patients and in itself does not seem to be a decisive factor in PD drop out.

Clinical aspects of peritoneal sclerosis.

Peritoneal sclerosis (PS) occurs in various clinical situations in Peritoneal Dialysis (PD) patients. Some degree of PS is often present in long-term PD patients, generally without clinical or functional consequences. At the other end of the spectrum of PS there is Sclerosing encapsulating peritonitis (SEP). Though infrequent, it is very severe. SEP is not a complication exclusive to PD; it is a syndrome related to many diseases of abdominal organs, some drugs and abdominal surgery. Remarkably, in many cases, the first symptoms of SEP appear months or years after the change from PD to HD has occurred. Today there is no full agreement about the microscopical findings of SEP or about the name of this syndrome: SEP or Encapsulating Peritoneal Sclerosis (EPS). The main etiopathogenetic factor for PS is the poor biocompatibility of PD solutions. In the etiopathogenesis of SEP, other factors in addition to the PD fluids have been suggested as possible causes (peritonitis, drugs, disinfectants, etc.). This paper reviews all the clinical aspects of PS and SEP: pathogenesis, clinical signs, diagnosis and therapy.

Changes in peritoneal membrane after continuous ambulatory peritoneal dialysis--a histopathological study.

Peritoneal membrane changes in continuous ambulatory peritoneal dialysis (CAPD) patients have been widely described but poorly classified. Our aim was to identify the morphological changes occurring after CAPD treatment. To this end, 17 biopsies of parietal peritoneum (1 cm in diameter) were withdrawn at least 5 cm from the catheter entry hole and stained with Van Gieson, hematoxylin-eosin, trichrome, and some immunohistochemical stains: keratin, vimentin, CD34, CD20, CD4, CD8, desmin, and collagen IV. The morphology of mesothelium, vessels, and basement membrane (BM) of mesothelium and vessels, the presence of inflammatory cells, fibrin, and calcifications, and the distribution and thickness of submesothelial tissue were evaluated. Patients were divided into three groups according to the thickness of the sclerotic band replacing mesothelium: group 1, band up to 40 microns; group 2, band less than 40 microns; group 3, no sclerotic band. The main histopathological alterations noted were: loss of mesothelium; sclerotic alteration of vessels or duplication of BM; presence of myofibroblasts; and presence of inflammatory cells (sparse, focal, or perivascular), mainly represented by macrophages and CD4+ lymphocytes. No significant qualitative differences were observed between the three groups. In conclusion, the variable histological changes in peritoneal membrane suggest a routine peritoneal biopsy in any surgical procedure to better understand pathological changes in the course of CAPD treatment.

Absence of HIV antigens in renal tissue from patients with HIV-associated nephropathy.

HIV-associated nephropathy (HIV-N) is considered a distinctive disease, the pathogenesis of which is still undefined. Direct virus-induced renal cell damage has been postulated. The numerous cytolytic ultrastructural changes and a few studies by immunoperoxidase support this hypothesis, but there has been no demonstration of virus by electron-microscopy (EM) or by tissue culture. In seven out of 12 cases with histological characteristics of HIV nephropathy, with proteinuria (five cases) or with nephrotic syndrome (two cases), we tested renal tissue for HIV antigens: core p18 and p25; envelope gp45 and gp110, by means of immunoperoxidase avidin-biotin complex monoclonal antibodies (MoAbs). Light-microscopy (LM) showed in five patients a focal and segmental glomerular sclerosis, and in two a mesangial hyperplasia with vacuolisation of visceral epithelium and protein inclusions. Electron-microscopy, performed in five of seven patients, showed several protein inclusions in podocyte cytoplasm, tubuloreticular inclusions in endothelial cell cytoplasm in all cases, nuclear degranulation of tubular cells in four cases and nuclear bodies in two. HIV antigens by MoAbs on renal tissue were negative in all cases, in both glomeruli and tubules. These results do not confirm the presence of HIV proteins in renal tissue of patients with HIV nephropathy. A possible explanation, apart from no direct HIV in the disease, may be the low viral load in tissues, because of the early phases of renal damage in most cases.

HIV-associated nephropathy: a new entity. A study of 12 cases.

The existence of an HIV-related nephropathy as a distinct disease entity is controversial. Twelve patients affected by HIV infection (eight drug-abusers, three homosexuals and one black heterosexual) who showed nephrotic syndrome (five patients) or urinary abnormalities (seven patients), four with renal insufficiency, were submitted to renal biopsy. Six patients were in pre-AIDS, six had AIDS. Light microscopy, performed in all cases, showed focal segmental glomerular sclerosis in nine patients, a moderate hypercellularity in six, vacuolisation of visceral epithelium in ten, focal collapsed tuft in seven, and tubular microcystic dilatation with large dense protein casts in lumina in seven. Immunofluorescence, available in 11 patients, showed small deposits in mesangium or mesangial and subendothelial spaces. IgG, IgM, and C3 were more frequently found, while three cases were negative. Electron-microscopy (five patients), besides confirming light-microscopy changes, showed several tubuloreticular inclusions (four patients), nuclear bodies (mainly complex) in nuclei of tubular cells (three patients), and nuclear granulofibrillary transformation of tubular cells. Various histological aspects and clinical data confirm the hypothesis that HIV nephropathy can be considered as a separate entity, different from heroin nephropathy and idiopathic focal glomerulosclerosis.