Genetic and phenotypic attributes of splenic marginal zone lymphoma.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Rates of Symptomatic SARS-CoV-2 Infection in Patients With Autoimmune Liver Diseases in Northern Italy: A Telemedicine Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus responsible for a variety of clinical manifestations that, besides the lungs, can involve several other organs, leading to both mild and severe complications.1-3.

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis.

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment.

Spleen stiffness measurement predicts decompensation and rules out high-risk oesophageal varices in primary biliary cholangitis.

Background & Aims: Primary biliary cholangitis (PBC) may lead to portal hypertension (PH). Spleen stiffness measurement (SSM) by vibration-controlled transient elastography accurately predicts PH. We aimed to assess SSM role in stratifying the risk of liver decompensation in PBC. Methods: In this monocentric, prospective, cross-sectional study, we included 114 patients with PBC who underwent liver stiffness measurement (LSM) and SSM. In total, 78 and 33 patients underwent two and three sequential vibration-controlled transient elastography examinations, respectively (longitudinal study). Screening for high-risk oesophageal varices by oesophagogastroduodenoscopy was performed according to guidelines and proposed to all patients with SSM >40 kPa. Results: Among the 114 patients, 20 (17%) had LSM ≥10 kPa, whereas 17 (15%) had SSM >40 kPa. None of the patients with SSM ≤40 kPa had high-risk oesophageal varices, compared with three of 14 patients with SSM >40 kPa (21%; three refused endoscopy); any-size oesophageal varices were found in nine of 14 patients (64%). During a median follow-up of 15 months (IQR 10-31 months), five (4%) patients developed liver decompensation. The probability of liver decompensation was significantly higher among patients with both LSM ≥10 kPa and SSM >40 kPa: 41% at 24 months vs. 0% in other patient groups (i.e. LSM <10 kPa and SSM ≤40 kPa, or LSM ≥10 kPa and SSM ≤40 kPa, or LSM <10 kPa and SSM >40 kPa) (p <0.0001). Among the 78 patients undergoing longitudinal evaluation, four of nine patients (44%) with SSM increase during follow-up experienced liver decompensation, whereas none of those with stable LSM and SSM had liver decompensation. Conclusions: Both LSM and SSM predict liver decompensation in patients with PBC. SSM ≤40 kPa rules out high-risk oesophageal varices and might be used in combination with LSM to improve the prediction of PH-related complications. Impact and implications: Spleen stiffness measurement by vibration-controlled transient elastography accurately predicts portal hypertension in patients with chronic viral hepatitis. The present study is the first to demonstrate that in primary biliary cholangitis the combination of liver stiffness and spleen stiffness measurement can significantly improve risk stratification by predicting liver decompensation. Moreover, when spleen stiffness is combined with liver stiffness measurement and platelet count, it aids in identifying individuals with a low probability of having high-risk oesophageal varices, thereby allowing the avoidance of unnecessary endoscopy examinations. Further validation of our results in larger cohorts of patients with primary biliary cholangitis is needed to implement spleen stiffness measurement in clinical practice.

Excellent outcome in patients with primary biliary cholangitis in Northwest Italy followed up for up to 30†years.

OBJECTIVE: Primary biliary cholangitis (PBC) is a rare chronic autoimmune cholangiopathy, characterized by a variable course and response to treatment. We aimed to describe long-term outcomes of PBC patients referred to three academic centres in Northwest Italy. METHODS: This is an ambispective cohort study of PBC patients (retrospective component: diagnosis before 1 January 2019; prospective component: thereafter), including 302 patients: 101 (33%) followed up in Novara, 86 (28%) in Turin, 115 (38%) in Genoa. Clinical features at diagnosis, biochemical response to therapy and survival were analyzed. RESULTS: Among the 302 patients (88% women, median age 55 years, median follow-up 75 months), alkaline phosphatase (ALP) levels significantly decreased during treatment with ursodeoxycholic acid (UDCA, P < 0.0001) and obeticholic acid (P < 0.0001). At multivariate analysis, ALP at diagnosis was predictive of 1-year biochemical response to UDCA [odds ratio 3.57, 95% confidence interval (CI) 1.4-9, P < 0.001]. Estimated median survival free of liver transplantation and hepatic complications was 30 years (95% CI 19-41). Bilirubin level at diagnosis was the only independent risk factor for the combined outcome of death, transplantation or hepatic decompensation (hazard ratio, 1.65, 95% CI 1.66-2.56, P = 0.02). Patients presenting with total bilirubin at diagnosis ≥0.6 times the upper normal limit (ULN) had a significantly lower 10-year survival compared to those with bilirubin <0.6 times ULN (63% vs. 97%, P < 0.0001). CONCLUSION: In PBC, both short-term response to UDCA and long-term survival can be predicted by simple conventional biomarkers of disease severity, obtained at diagnosis.

High reproducibility of spleen stiffness measurement by vibration-controlled transient elastography with a spleen-dedicated module.

Spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is a noninvasive technique for estimating portal hypertension in patients with chronic liver disease (CLD), with its reproducibility yet to be established and its feasibility still unknown beyond CLD. We have studied 420 participants from two tertiary referral centers for liver diseases (Novara, Milan): 297 patients with CLD (32% with cirrhosis) of different etiology (Group A), 63 Philadelphia-negative myeloproliferative neoplasms (Group B), and 60 heathy volunteers (Group C). All underwent SSM by VCTE with a spleen-dedicated module (SSM@100 Hz) and liver stiffness measurement (LSM), blindly performed by 2 different operators. In total, 1680 VCTE examinations for SSM were performed (1000 in Novara, 680 in Milan), with an overall 3.2% failure rate. Median SSM was 26.5 kPa (interquartile range [IQR] 20.0-42.3) in Group A, 26.3 kPa (IQR 22.3-33.6) in Group B, and 16.1 kPa (IQR 14.6-18.7) in Group C. In Group A, the median LSM was 6.8 kPa (IQR 4.9-11.3) in Novara and 8.3 kPa (IQR 7.1-10.8) in Milan, the proportion of patients with cirrhosis being 34% in Novara and 31% in Milan. The Group A interobserver agreement ICC was 0.90 (0.88-0.92), significantly lower in the absence of splenomegaly (ICC 0.87 vs. 0.91) and in absence of cirrhosis (ICC 0.84 vs. 0.90); overweight slightly, but not significantly reduced the interobserveragreement. The intra-observer agreement ICC ranged from 0.91 to 0.96 for the four operators. The Group B interobserver agreement ICC was 0.90 (0.83-0.94). In conclusion, SSM measured by the new spleen-dedicated VCTE module is a feasible, reliable, and highly reproducible tool in patients with CLD and hematological disorders, and in healthy volunteers.

Stiffer Spleen Predicts Higher Bone Marrow Fibrosis and Higher JAK2 Allele Burden in Patients With Myeloproliferative Neoplasms.

A total of 63 myeloproliferative neoplasms [MPN; 9 polycythemia vera (PV), 32 essential thrombocythemia (ET), and 22 myelofibrosis (MF)] underwent spleen stiffness (SS) measurement by vibration-controlled transient elastography equipped with a novel spleen-dedicated module. Higher SS values significantly correlated with grade 2-3 bone marrow (BM) fibrosis (p=0.035), with hemoglobin level <10 g/dl (p=0.014) and with white blood cells ≥10,000/µl (p=0.008). Median SS was significantly higher in MF patients compared to ET and PV (p=0.015). SS also correlated with higher JAK2 variant allele frequency (p=0.02). This study identifies SS as a potential noninvasive tool that reflects BM fibrosis and the mutational burden in MPN.

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19.

INTRODUCTION: The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. MATERIALS AND METHODS: In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients (F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. RESULTS: At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) (χ 2 10.4; p < 0.001), neutrophil-to-lymphocyte (NL) ratio (χ 2 7.6; p = 0.006), and platelet count (χ 2 5.39; p = 0.02), along with age (χ 2 87.6; p < 0.001) and gender (χ 2 17.3; p < 0.001), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality (OR) = 3.40 (2.40-4.82), while the OR for a RDW > 13.7% was 4.09 (2.87-5.83); a platelet count > 166,000/µL was, conversely, protective (OR: 0.45 (0.32-0.63)). CONCLUSION: Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.

A Case of Blastic Plasmacytoid Dendritic Cell Neoplasm Extensively Studied by Flow Cytometry and Immunohistochemistry.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with aggressive clinical course and poor prognosis. Diagnosis is based on detection of CD4+ CD56+, CD123high, TCL-1+, and blood dendritic cell antigen-2/CD303+ blasts, together with the absence of lineage specific antigens on tumour cells. In this report we present a case of BPDCN presenting with extramedullary and bone marrow involvement, extensively studied by flow cytometry and immunohistochemistry, who achieved complete remission after acute lymphoblastic leukemia like chemotherapy and allogeneic hematopoietic stem cell transplantation.