ADAMTS13, von Willebrand Factor, Platelet Microparticles, Factor VIII, and Impact of Somatic Mutations in the Pathogenesis of Splanchnic Vein Thrombosis Associated with BCR-ABL-Negative Myeloproliferative Neoplasms.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are often associated with splanchnic vein thrombosis (SVT). Not all the factors involved in the thrombotic tendency are currently known. OBJECTIVES: This study aims to evaluate a possible association between ADAMTS13, von Willebrand factor (VWF), platelet microvesicles (MV), and factor VIII activity (FVIII:C) with thrombotic events in MPN patients. MATERIALS AND METHODS: In total, 36 consecutive MPN patients with SVT were enrolled. The MPNs were diagnosed based on clinical characteristics and one or more gene mutations among JAK-2, CALR, and MPL. As controls, 50 randomly selected patients with MPN without thrombosis, 50 patients with deep vein thrombosis without MPNs, and 50 healthy blood donors were evaluated. Complete blood count, ADAMTS13, VWF, MV, and FVIII:C in plasma were measured in all the subjects. RESULTS: The JAK-2 mutation was found in 94% of the patients with SVT, but none were triple-negative for genetic mutations (JAK2 V617F, CALR, MPL, and exon 12). Compared to the normal subjects, in all the MPN patients (with or without SVT), the levels of ADAMTS13 were found to be significantly lower (p < 0.001) and the MV concentrations were significantly higher (p < 0.001). Among the MPN patients, the VWF and FVIII:C levels were significantly higher in the patients with SVT than those without thrombosis (p = 0.007 and p = 0.04, respectively). Splenomegaly was present in 78% of MPN patients with SVT and in 30% of those without SVT (p < 0.001). The ADAMTS13/VWF ratio was reduced in all the patients, but not in the healthy blood donors (p < 0.001). CONCLUSIONS: The significant increase in circulating MV, VWF, and FVIII:C in the MPN patients and in the patients with thrombosis supports the role of endothelium damage in promoting thrombotic events. In particular, a significant increase in VWF and FVIII:C levels was found in the MPN patients with SVT.

Possible Effect of Polycystic Ovary Syndrome (PCOS) on Cardiovascular Disease (CVD): An Update.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during the fertile period. Women with PCOS have an increased risk of developing major cardiovascular risk factors during the fertile period: obesity, impaired glucose tolerance, diabetes mellitus, dyslipidemia, and metabolic syndrome. The possible effect of PCOS on cardiovascular disease (CVD) has been reported in different studies, but the results are not clear for several reasons. Indeed, most of the studies analyzed a cohort of fertile women who, given their relatively young age, have a low frequency of cardiovascular diseases. In addition, longitudinal studies have a short follow-up period, insufficient to draw firm conclusions on this topic. Finally, pharmacological treatment is limited by the lack of specific drugs available to specifically treat PCOS. In this review, we report on studies that analyzed the possible effect of PCOS on the most common CVD (hypertension, arterial stiffness, atherosclerosis, and cardiovascular event) and available drugs used to reduce CVD in PCOS women.

Platelet Microvesicles, Inflammation, and Coagulation Markers: A Pilot Study.

BACKGROUND: Platelet "Microvesicles" (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. METHODS: We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor ß (TGF-ß), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. RESULTS: A total of 246 individuals (median age 65 years ("IQR"54-72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-ß, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. CONCLUSIONS: To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested.

Endocrine Side Effects in Patients Treated with Immune Checkpoint Inhibitors: A Narrative Review.

Checkpoint inhibitors are monoclonal antibodies that elicit an anti-tumor response by stimulating immune system. Their use has improved the treatment of different types of cancer such as melanoma, breast carcinoma, lung, stomach, colon, liver, renal cell carcinoma, and Hodgkin's lymphoma, but several adverse events have been reported. Although the etiology of these effects is not completely understood, an uncontrolled activation of the immune system has been postulated. Indeed, some studies showed a cross reactivity of T cells, which acted against tumor antigens as well as antigens in the tissues of patients who developed immune-related adverse events. Despite the known possibility of developing immune-related adverse events, early diagnosis, monitoring during therapy, and treatment are fundamental for the best supportive care and administration of immune checkpoint inhibitors. The aim of this review is to guide the clinician in early diagnosis, management, and treatment of the endocrinological adverse effects in the major endocrine glands (thyroid, pituitary, adrenal, endocrine pancreas, and parathyroid).

Esophageal Fully-Covered Metal Stent as a Rescue Therapy for a Strasberg Type A Biliary Leak in a Huge Common Bile Duct Dilation.

Treatment of biliary leaks is challenging and complex. Even if endoscopic sphincterotomy with biliary stenting is usually resolutive in restoring the original bile flow, common bile duct (CBD) diameter is crucial in defining the size and features of the stent. Additional factors, such as uncommon anatomical reconstructions due to a previous abdominal surgery, could make the endoscopic approach more difficult, therefore increasing the risk of failure. Many articles deal with uncommon technique adopted to allow an optimal healing of biliary leaks but, thus far, only two reports of biliary stent using an esophageal through-the-scope (TTS), partially-covered, self-expandable metal stent (SEMS) exist in the current literature. This article describes the deployment of an esophageal SEMS into the CBD for a refractory type A Strasberg fistula in a Billroth-II reconstruction. To our knowledge, this is the first report concerning the use of an esophageal stent for CBD drainage in a Billroth-II reconstruction.

A Diagnostic of Acquired Hemophilia Following PD1/PDL1 Inhibitors in Advanced Melanoma: The Experience of Two Patients and a Literature Review.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against factor VIII (FVIII). Immunotherapy is a recent therapeutic option that targets the patient's self-tolerance against tumor cells. Because therapeutic effects of the immune checkpoint inhibitors (ICIs) are mediated by enhancing the immune response to restore antitumor immunity, autoimmune-related adverse effects can be seen in up to 80% of patients during treatment and after treatment. A rare hematologic ICIs-related adverse event is AHA. Hereafter we report two cases of AHA developed during anti-PD-1 immunotherapy for advanced melanoma: one secondary to treatment with nivolumab and one secondary to pembrolizumab. Both patients were treated with activated FVII (Novoseven®, Novo Nordisk, Bagsværd, Denmark) as hemostatic treatment combined with the eradication of antibodies anti-FVIII obtained with rituximab. In the last few years these drugs have significantly improved the therapeutic armamentarium for the management of AHA. Indeed, while FVIIa has proven to be an effective and safe tool for the treatment of acute bleeding related to FVIII autoantibodies, rituximab is a promising alternative for the autoantibodies' elimination and the restoration of normal hemostasis. Our finding supports the use of this combination even in AHA secondary to ICIs treatment.

Contrast-enhanced ultrasound Liver Imaging Reporting and Data System: Lights and shadows in hepatocellular carcinoma and cholangiocellular carcinoma diagnosis.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) is considered a secondary examination compared to computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of hepatocellular carcinoma (HCC), due to the risk of misdiagnosing intrahepatic cholangiocarcinoma (ICC). The introduction of CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS) might overcome this limitation. Even though data from the literature seems promising, its reliability in real-life context has not been well-established yet. AIM: To test the accuracy of CEUS LI-RADS for correctly diagnosing HCC and ICC in cirrhosis. METHODS: CEUS LI-RADS class was retrospectively assigned to 511 nodules identified in 269 patients suffering from liver cirrhosis. The diagnostic standard for all nodules was either biopsy (102 nodules) or CT/MRI (409 nodules). Common diagnostic accuracy indexes such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for the following associations: CEUS LR-5 and HCC; CEUS LR-4 and 5 merged class and HCC; CEUS LR-M and ICC; and CEUS LR-3 and malignancy. The frequency of malignant lesions in CEUS LR-3 subgroups with different CEUS patterns was also determined. Inter-rater agreement for CEUS LI-RADS class assignment and for major CEUS pattern identification was evaluated. RESULTS: CEUS LR-5 predicted HCC with a 67.6% sensitivity, 97.7% specificity, and 99.3% PPV (P < 0.001). The merging of LR-4 and 5 offered an improved 93.9% sensitivity in HCC diagnosis with a 94.3% specificity and 98.8% PPV (P < 0.001). CEUS LR-M predicted ICC with a 91.3% sensitivity, 96.7% specificity, and 99.6% NPV (P < 0.001). CEUS LR-3 predominantly included benign lesions (only 28.8% of malignancies). In this class, the hypo-hypo pattern showed a much higher rate of malignant lesions (73.3%) than the iso-iso pattern (2.6%). Inter-rater agreement between internal raters for CEUS-LR class assignment was almost perfect (n = 511, k = 0.94, P < 0.001), while the agreement among raters from separate centres was substantial (n = 50, k = 0.67, P < 0.001). Agreement was stronger for arterial phase hyperenhancement (internal k = 0.86, P < 2.7 × 10-214; external k = 0.8, P < 0.001) than washout (internal k = 0.79, P < 1.6 × 10-202; external k = 0.71, P < 0.001). CONCLUSION: CEUS LI-RADS is effective but can be improved by merging LR-4 and 5 to diagnose HCC and by splitting LR-3 into two subgroups to differentiate iso-iso nodules from other patterns.

Ferric Carboxymaltose and Erythropoiesis-Stimulating Agent Treatment Reduces the Rate of Blood Transfusion in Refractory Anemia.

Background: Erythropoiesis-stimulating agents (ESAs) are used to treat refractory anemia (RA). Guidelines suggest iron supplementation for unresponsive patients, regardless of iron deficiency. The primary aim of this study was to evaluate the effect of iron supplementation with ferric carboxymaltose (FCM) on the reduction of red blood cell transfusion (RBCT) rate in transfusion-dependent RA patients. Methods: This was a prospective quasi-randomized study, wherein patients were randomly assigned into three groups: (A) ESAs alone, (B) ferric gluconate (FG) and ESAs, and (C) FCM and ESAs. Hemoglobin and ferritin levels, as well as the number of RBCTs at 4 and 28 weeks were compared. Economic evaluation was also performed. Results: A total of 113 RA patients were enrolled. In total, 43 were treated with intravenous FG and ESAs, 38 with FCM and ESAs, and 32 with ESAs alone. At both follow-ups, erythropoietic response was increased in those receiving iron as compared with those with ESAs alone (p = 0.001), regardless of the type of iron. At one month, ferritin levels were higher in the FCM and ESA groups (p = 0.001). RBCTs were lower in both iron groups. The less costly treatment strategy was FCM, followed by FG, and lastly ESAs. Conclusions: Addition of iron to ESAs in RA reduced RBCT requirement and improved hemoglobin values.

Rendezvous endoscopy using a transillumination fashion as a feasible and safe alternative to endoscopic ultrasound-guided recanalization in case of complete anastomotic stricture.

Complete colorectal anastomotic strictures are rare and difficult to solve surgical complications. In case of failure of endoscopic ultrasound-guided recanalization (usually the first choice treatment), rendezvous maneuver using a transillumination fashion represents a feasible and safe procedure to reconstitute the completely obstructed colonic lumen.

Incidence of Venous Thromboembolism in Multiple Myeloma Patients across Different Regimens: Role of Procoagulant Microparticles and Cytokine Release.

Introduction: Multiple myeloma (MM) is characterized by a high prevalence of thrombotic complications. Microvesicles (MVs) are small membrane vesicles released from activated cells, and they may potentially contribute to thrombosis. Methods: We have evaluated the plasma levels of MVs and cytokines (IL-10, IL-17, and TGF-ß in MM and Watch and Wait Smoldering MM (WWSMM) from patients and related them to thrombotic complications. The secondary aim was to assess the impact of ongoing therapy on MV and on cytokine levels. Result: 92 MM and 31 WWSMM were enrolled, and 14 (12%) experienced a thrombotic episode. Using univariate analysis, TGF-ß and MV were significantly higher in patients with thrombotic events (p = 0.012; p = 0.008, respectively). Utilizing a Cox proportional hazard model, we confirmed this difference (TGF-ß p = 0.003; Odds ratio 0.001, 95% CI 0−0.003 and MV p = 0.001; Odds ratio 0.003, 95% CI 0.001−0.005). Active treatment management displayed higher levels of MV (p < 0.001) and lower levels of glomerular filtration-rate (p < 0.001), IL-17 (p < 0.001) as compared to the WWSMM group. The TGF-ß values of immunomodulatory derivatives patients were lower in the WWSMM (p < 0.001) and Dexamethasone/Bortezomib subgroup (p < 0.001). Conclusion: The increased levels of MVs in active regimens add insight into the mechanisms of hypercoagulation in MM. In addition, a role for cytokine-related thrombosis is also suggested.

Nuclear localization dictates hepatocarcinogenesis suppression by glycine N-methyltransferase.

BACKGROUND: GNMT (glycine N-methyltransferase) is a tumor suppressor gene, but the mechanisms mediating its suppressive activity are not entirely known. METHODS: We investigated the oncosuppressive mechanisms of GNMT in human hepatocellular carcinoma (HCC). GNMT mRNA and protein levels were evaluated by quantitative RT-PCR and immunoblotting. GNMT effect in HCC cell lines was modulated through GNMT cDNA induced overexpression or anti-GNMT siRNA transfection. RESULTS: GNMT was expressed at low level in human HCCs with a better prognosis (HCCB) while it was almost absent in fast-growing tumors (HCCP). In HCCB, the nuclear localization of the GNMT protein was much more pronounced than in HCCP. In Huh7 and HepG2 cell lines, GNMT forced expression inhibited the proliferation and promoted apoptosis. At the molecular level, GNMT overexpression inhibited the expression of CYP1A (Cytochrome p450, aromatic compound-inducible), PREX2 (Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2), PARP1 [Poly (ADP-ribose) polymerase 1], and NFKB (nuclear factor-kB) genes. By chromatin immunoprecipitation, we found GNMT binding to the promoters of CYP1A1, PREX2, PARP1, and NFKB genes resulting in their strong inhibition. These genes are implicated in hepatocarcinogenesis, and are involved in the GNMT oncosuppressive action. CONCLUSION: Overall, the present data indicate that GNMT exerts a multifaceted suppressive action by interacting with various cancer-related genes and inhibiting their expression.

Prothrombotic and Inflammatory Markers in Elderly Patients with Non-Alcoholic Hepatic Liver Disease before and after Weight Loss: A Pilot Study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a pathological condition, ranging from fatty liver to chronic steatohepatitis (NASH), liver cirrhosis, and eventually to hepatocellular carcinoma. Recent findings suggest that patients with NAFLD have an increased risk of cardiovascular events and thromboembolism, which is independent of metabolic diseases that are frequently associated with NAFLD, such as diabetes, hyperlipidemia, and obesity. METHODS: We evaluated 30 NAFLD patients, before and after weight loss. Plasma levels of C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, coagulation protein S, Thrombin activable fibrinolysis inhibitor (TAFI), and factor VII (FVII) were assessed to evaluate whether they should be responsible of the prothrombotic state of NAFLD after weight loss. RESULTS: At baseline, patients affected by NAFLD had a significantly higher levels of CRP, fibrinogen, PAI-1, VWF antigen, and FVII levels. After weight reduction, we observed a significant drop of inflammatory and prothrombotic markers, as well as glucometabolic, lipid profile. CONCLUSION: These findings provide evidence for a link between NAFLD/NASH and thromboembolism. The association seems to be linked with primitive thrombotic state and hypercoagulation due to increased levels of coagulation factors and reduced levels of PAI-1. This hypercoagulation state might explain increased levels of thrombosis and splanchnic thrombosis observed in NASH correlated cirrhosis.

Rescheduling/scheduling of endoscopic procedures during "Phase-Two: which precautions should be taken?" Experience and results of a single Italian Endoscopic Unit.

Not required.

Impact of implementing a Choosing Wisely educational intervention into clinical practice: The CW-SIMI study (a multicenter-controlled study).

OBJECTIVES: To evaluate the impact of an educational intervention based on the Italian Society of Internal Medicine Choosing Wisely (CW-SIMI) recommendations. DESIGN: Multicenter, interventional, controlled study. SETTING: Twenty-three acute-care hospital wards in Italy. PARTICIPANTS: 303 Physicians working in internal medicine wards. INTERVENTION: An online educational course. MAIN OUTCOMES: The rate of proton pump inhibitor (PPI) prescriptions, the number of days of central venous catheter (CVC) usage, and the duration of intravenous (IV) antibiotic prescriptions evaluated at one month (T1) and at six months (T2) after course completion. Patients admitted and discharged during a 30-day period before the educational intervention (T0, one year before T2) were considered the comparison group. RESULTS: A total of 232 physicians completed the course, while 71 did not attend the course. Data from 608, 662, and 555 patients were analyzed at T0, T1, and T2, respectively. The rate of PPI prescriptions declined at one month (RR: 0.67, 95% CI: 0.52-0.87, p = 0.0005) and at six months (RR: 0.62, 95% CI: 0.46-0.84, p = 0.003), and the number of days of CVC usage was reduced at six months (9.13 days at T0 vs. 5.52 days at T2, p = 0.007). The duration of IV antibiotic prescriptions displayed a decreasing trend (7.94 days at T0 vs. 7.42 days at T2, p = 0.081). CONCLUSIONS: A simple online educational intervention based on the CW-SIMI recommendations was associated with a clinically relevant reduction in the usage of PPIs and CVCs. Further studies are needed to confirm these findings and a possible benefit on patients' outcomes.

HERV-K Modulates the Immune Response in ALS Patients.

Human endogenous retrovirus (HERV)-K env-su glycoprotein has been documented in amyotrophic lateral sclerosis (ALS), where HERV-K env-su 19-37 antibody levels significantly correlated with clinical measures of disease severity. Herein, we investigated further the humoral and cell-mediated immune response against specific antigenic peptides derived from HERV-K in ALS. HERV-K env glycoprotein expression on peripheral blood mononuclear cells (PBMCs) membrane and cytokines and chemokines after stimulation with HERV-K env 19-37 and HERV-K env 109-126 were quantified in patients and healthy controls (HCs). HERV-K env glycoprotein was more expressed in B cells and NK cells of ALS patients compared to HCs, whereas HERV-K env transcripts were similar in ALS and HCs. In ALS patients, specific stimulation with HERV-K env 109-126 peptide showed a higher expression of IL-6 by CD19/B cells. Both peptides, however, were able to induce a great production of IFN-γ by stimulation CD19/B cells, and yielded a higher expression of MIP-1α and a lower expression of MCP-1. HERV-K env 19-37 peptide induced a great production of TNF-α in CD8/T cells. In conclusion, we observed the ability of HERV-K to modulate the immune system, generating mediators mainly involved in proinflammatory response.

Diagnosis and management of intraductal papillary mucinous neoplasms of the pancreas. An Useful Update with a Noteworthy Tip.

Not requested.