Treatment with Idelalisib in Patients with Relapsed or Refractory Follicular Lymphoma: The Observational Italian Multicenter FolIdela Study

Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years—mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)—were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34+ progenitor cells displayed significantly higher BRCA1 expression (P=0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P=0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P=0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P=0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P=0.0004), and to increased DNA methyltransferase DNMT3A (P=0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis

Oral CorticoSteroid sparing with biologics in severe asthma: A remark of the Severe Asthma Network in Italy (SANI)

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry

Abstract BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs

COVID-19 in Severe Asthma Network in Italy (SANI) patients: Clinical features, impact of comorbidities and treatments

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Severe asthma: One disease and multiple definitions

Introduction: There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients. Methods: Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR. Results: 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values. Conclusions: The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem

Intraepithelial and lamina propria lymphocytes show distinct patterns of apoptosis whereas both populations are active in Fas based cytotoxicity in coeliac disease

BACKGROUND—Lamina propria (LPLs) and intraepithelial (IELs) lymphocytes are markedly increased in coeliac mucosa, and are thought to play a crucial role in the generation of villous atrophy in coeliac disease (CD). However, the mechanisms by which they mediate the killing of enterocytes in this condition are still poorly characterised.
AIM—We investigated Fas mediated cytotoxicity and apoptosis of both LPLs and IELs, isolated from 10 untreated coeliac patients, 10 coeliac patients on a gluten free diet, and 10 biopsied controls.
METHODS—Fas and Fas ligand expression were assessed by flow cytometry and immunocytochemistry. Lymphocyte cytotoxicity against Fas expressing Jurkat cells was determined by the Jam test. The effect of the antagonist ZB4 anti-Fas antibody on apoptotic activity exerted by coeliac lymphocytes against enterocytes was analysed. Lymphocyte apoptosis was assessed by oligonucleosome ELISA.
RESULTS—LPLs and IELs showed increased apoptotic activity and higher levels of Fas ligand expression in untreated CD compared with treated CD patients and controls. Enterocyte apoptosis observed after coculturing coeliac lymphocytes and enterocytes in the presence of ZB4 antibody was reduced. In active CD, LPLs manifested increased apoptosis whereas IELs showed decreased apoptosis.
CONCLUSIONS—Our results support the involvement of the Fas/Fas ligand system in CD associated enterocyte apoptosis. Increased LPL apoptosis is likely to downregulate mucosal inflammation whereas decreased IEL apoptosis could be responsible for autoimmune and malignant complications of CD.


Keywords: apoptosis; coeliac disease; cytotoxicity assay; Fas/Fas ligand system; intraepithelial lymphocytes; lamina propria lymphocyte