The American Thyroid Association risk classification of papillary thyroid cancer according to presurgery cytology.

OBJECTIVE: To compare the American Thyroid Association (ATA) risk staging of histologically proven papillary thyroid cancer (PTC) in patients who received a presurgery cytologic result of either indeterminate thyroid nodules (ITNs, Bethesda III/IV) or suspicious for malignancy/malignant (TIR 4/5, Bethesda V/VI). METHODS: Clinical, ultrasonographic, cytological data from patients with histologically diagnosed PTC were retrospectively collected. RESULTS: Patients were stratified according to the preoperative fine-needle aspiration cytology into 2 groups: 51 ITNs (TIR3A/3B) and 118 suspicious/malignant (TIR 4/5). Male/female ratio, age, and presurgery TSH level were similar between the 2 groups. At ultrasound, TIR 4/5 nodules were significantly more frequently hypoechoic (P = .037), with irregular margins (P = .041), and with microcalcifications (P = .020) and were more frequently classified as high-risk according to the European Thyroid Imaging and Reporting Data System (EU-TIRADS; P = .021). At histology, the follicular PTC subtype was significantly more prevalent among ITNs while classical PTC subtype was more frequent in TIR 4/5 group (P = .002). In TIR 4/5 group, a higher rate of focal vascular invasion (P < .001) and neck lymph node metastasis (P = .028) was observed. Intermediate-risk category according to ATA was significantly more frequent in TIR 4/5 group while low-risk category was more frequently found among ITNs (P = .021), with a higher number of patients receiving radioiodine in TIR 4/5 group (P = .002). At multivariate logistic regression, having a TIR 4/5 cytology was associated with a significant risk of having a higher ATA risk classification as compared to ITN (OR 4.6 [95% CI 1.523-14.007], P = .007), independently from presurgery findings (nodule size at ultrasound, sex, age, and EU-TIRADS score). CONCLUSIONS: Papillary thyroid cancers recorded among ITNs are likely less aggressive and are generally assessed as at lower risk according to ATA classification.

A preliminary study on self-care telemonitoring of dysarthria in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease which may cause impairments in oro-facial musculature. Most of the individuals with SMA present bulbar signs such as flaccid dysarthria which mines their abilities to speak and, as consequence, their psychic balance. To support clinicians, recent work has demonstrated the feasibility of video-based techniques for assessing the oro-facial functions in patients with neurological disorders such as amyotrophic lateral sclerosis. However, no work has so far focused on automatic and quantitative monitoring of dysarthria in SMA. To overcome limitations this work's aim is to propose a cloud-based store-and-forward telemonitoring system for automatic and quantitative evaluation of oro-facial muscles in individuals with SMA. The system integrates a convolutional neural network (CNN) aimed at identifying the position of facial landmarks from video recordings acquired via a web application by an SMA patient.Clinical relevance- The proposed work is in the preliminary stage, but it represents the first step towards a better understanding of the bulbar-functions' evolution in patients with SMA.

Effects of Comano Spring Water-derived Bacterial Lysates on Skin Regeneration: An Ex-vivo Study.

BACKGROUND/AIM: A native non-pathogenic bacterial microflora was identified in Comano (TN, Italy) spring water. The aim of this study was to investigate the regenerative effects of some of the bacterial lysates extracted from this water in a human ex-vivo skin experimental wound model. MATERIALS AND METHODS: Bacterial lysates were extracted from four new isolates: lysate 1 (L1) - closest relative Rudaea cellulosilytica, phylum Proteobacteria; lysate 2 (L2) - closest relative Mesorhizobium erdmanii, phylum Proteobacteria; lysate 3 (L3) - closest relative Herbiconiux ginseng, phylum Actinobacteria; lysate 4 (L4) - closest relative Fictibacillus phosphorivorans, phylum Firmicutes. Their regenerative effects were investigated in a human ex-vivo skin experimental wound healing model at 3 (T1), 5 (T2), and 10 days (T3). RESULTS: The samples cultured with the L2 lysate displayed both an earlier and complete restoration of all the skin layers and their features were the closest to the normal skin. The regenerated epidermis demonstrated a complete maturation as the normal epidermis. The papillary dermis appeared mature, and the reticular dermis displayed both collagen and elastic fibres regularly parallel to the skin surface. An anti-inflammatory effect was displayed by the L1 lysate, but this action did not constitute a regenerative effect, suggesting that pathways for inflammation and regeneration might be different. CONCLUSION: The therapeutic power of spring waters is not exclusively related to their mineral composition, but it may also be attributable to their native non-pathogenic bacterial microflora.

A deep learning-based telemonitoring application to automatically assess oral diadochokinesis in patients with bulbar amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: Timely identification of dysarthria progression in patients with bulbar-onset amyotrophic lateral sclerosis (ALS) is relevant to have a comprehensive assessment of the disease evolution. To this goal literature recognized the utmost importance of the assessment of the number of syllables uttered by a subject during the oral diadochokinesis (DDK) test. METHODS: To support clinicians, this work proposes a remote deep learning-based system, which consists (i) of a web application to acquire audio tracks of bulbar-onset ALS patients and healthy control subjects while performing the oral DDK test (i.e., repeating the /pa/, /pa-ta-ka/ and /oo-ee/ syllables) and (ii) a DDK-AID network designed to process the acquired audio signals which have different duration and to output the number of per-task syllables repeated by the subject. RESULTS: The DDK-AID network overcomes the comparative method achieving a mean Accuracy of 90.23 in counting syllables repeated by the eleven bulbar-onset ALS-patients while performing the oral DDK test. CONCLUSIONS: The proposed remote monitoring system, in the light of the achieved performance, represents an important step towards the implementation of self-service telemedicine systems which may ensure customised care plans.

A store-and-forward cloud-based telemonitoring system for automatic assessing dysarthria evolution in neurological diseases from video-recording analysis.

BACKGROUND AND OBJECTIVES: Patients suffering from neurological diseases may develop dysarthria, a motor speech disorder affecting the execution of speech. Close and quantitative monitoring of dysarthria evolution is crucial for enabling clinicians to promptly implement patients' management strategies and maximizing effectiveness and efficiency of communication functions in term of restoring, compensating or adjusting. In the clinical assessment of orofacial structures and functions, at rest condition or during speech and non-speech movements, a qualitative evaluation is usually performed, throughout visual observation. METHODS: To overcome limitations posed by qualitative assessments, this work presents a store-and-forward self-service telemonitoring system that integrates, within its cloud architecture, a convolutional neural network (CNN) for analyzing video recordings acquired by individuals with dysarthria. This architecture - called facial landmark Mask RCNN - aims at locating facial landmarks as a prior for assessing the orofacial functions related to speech and examining dysarthria evolution in neurological diseases. RESULTS: When tested on the Toronto NeuroFace dataset, a publicly available annotated dataset of video recordings from patients with amyotrophic lateral sclerosis (ALS) and stroke, the proposed CNN achieved a normalized mean error equal to 1.79 on localizing the facial landmarks. We also tested our system in a real-life scenario on 11 bulbar-onset ALS subjects, obtaining promising outcomes in terms of facial landmark position estimation. DISCUSSION AND CONCLUSIONS: This preliminary study represents a relevant step towards the use of remote tools to support clinicians in monitoring the evolution of dysarthria.

Patients with Whipple's disease have a high prevalence of Helicobacter pylori infection.

INTRODUCTION: Whipple's disease is a rare systemic infection due to an impaired immunological response against T. whipplei in genetically predisposed individuals. Since we previously noted development of H. pylori related complications in some patients with Whipple's disease, our aim was to study the prevalence of H. pylori infection and H. pylori related disorders in Whipple's disease. METHODS: Whipple's disease patients diagnosed from Jan-2002 to Dec-2021 and two controls per patient, matched for age, gender, ethnicity and year of H. pylori testing were enrolled. RESULTS: 34 patients with Whipple's disease and 68 controls were enrolled. H. pylori infection (13/34 vs 8/68, p<0.01), H. pylori-related gastritis (p<0.01) and gastric atrophy (p = 0.01) were significantly more common in patients with Whipple's disease than controls. H. pylori infection and Whipple's disease were diagnosed synchronously in 6/13 patients, and during follow-up in the remaining 7. Interestingly, these last 7 patients were all on trimethoprim-sulfamethoxazole long-term therapy. Two patients developed H. pylori-related gastric malignancies during follow-up. No patients on doxycycline developed H. pylori infection. CONCLUSIONS: H. pylori infection and related disorders are common in patients with Whipple's disease and should always be excluded both at time of diagnosis and during follow-up. These findings should be taken into account when selecting antibiotics for Whipple's disease long-term prophylaxis.

Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS.

There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1-30 µM) and exposure times (24-48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs.

Clonal Megakaryocyte Dysplasia with Isolated Thrombocytosis Is a Distinct Myeloproliferative Neoplasm Phenotype.

INTRODUCTION: About 15% of people with a myeloproliferative neoplasm (MPN) are identified as MPN, unclassifiable using the 2016 WHO classification. METHODS: We tested whether persons with platelet concentration ≥450 × 10E+9/L, bone marrow megakaryocyte morphology typical of prefibrotic/early myelofibrosis (pre-MF), and no minor criteria of pre-MF should be classified as a distinct MPN subtype, clonal megakaryocyte dysplasia with isolated thrombocytosis (CMD-IT). RESULTS: 139 subjects meet these criteria who we compared with primary myelofibrosis (PMF) including 402 with pre-MF and 521 with overt myelofibrosis. CMD-IT subjects were more likely female and younger. They had lower frequencies of JAK2V617F compared with persons with PMF (55% vs. 70%; p < 0.001) and higher frequencies of CALR mutations (37% vs. 17%; p < 0.001). They also had lower frequency of variations associated with JAK2V617F susceptibility, JAK2 46/1 (35% vs. 47%; p = 0.021), and VEGFA rs3025039 (12% vs. 17%; p = 0.030). Subjects with CMD-IT had lower incidences of thrombotic events compared with those with pre-MF (9.7% vs. 26%; p < 0.001) and longer survival (median, not reached vs. 23 years; HR = 0.34 (0.10, 0.30); p < 0.001). CONCLUSION: Our data indicate CMD-IT is a distinct MPN subtype and should be included in the classification of myeloid neoplasms.

Extensive Intraductal Component in Breast Cancer: What Role in Disease-Free Survival?

INTRODUCTION: Extensive intraductal component (EIC) associated to early breast cancer could increase the risk locoregional recurrence, but its impact on distant metastases is still unclear. The aim of the present study was to assess the role of EIC on 5-year survival outcomes in patients affected by early breast cancer treated with breast-conserving surgery. METHODS: A total of 414 consecutive patients with a minimum follow-up of 60 mo were collected from January 2007 to December 2015. Disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival at 5 y were assessed considering the presence or absence of EIC and other clinical and pathological features. RESULTS: Absence of EIC was independently associated with worse 5-year DFS (hazard ratio [HR] 1.68, P = 0.008) and 5-year DMFS (HR 1.93, P = 0.007), whereas 5-year locoregional recurrence-free survival was not affected (HR 1.50, P = 0.16). Five-year DFS was increased by EIC in T1 patients (P = 0.03) but not in T2 stage. Moreover, EIC was associated to better DFS in G2 (P = 0.03) and G3 patients (P = 0.01) but not in G1 cases. CONCLUSIONS: Our results suggest that EIC is independently correlated with increased 5-year DFS and in particular with 5-year DMFS.

Small bowel villous atrophy due to immune-checkpoint inhibitors: report of two cases and literature review.

The differential diagnosis of non-coeliac enteropathies (NCEs) is challenging and includes a wide range of aetiologies. Drug-induced NCEs are relatively common and characterized by duodenal villous atrophy, which resolves upon suspension of the offending drug. Immune-checkpoint inhibitors (ICIs), targeting molecules involved in the activation of cytotoxic T cells by targeting, for example, PD-1, PD-L1 and CTLA4, are increasingly used for many types of cancers. Adverse events occurring in the gastrointestinal tract have been described, predominantly in the form of immune-mediated colitis mimicking inflammatory bowel disease. Small bowel involvement whilst on ICI therapy is also possible, though less well described. Herein, we describe two cases of enteropathy with villous atrophy and negative coeliac serology due to ICIs: a 65-year-old man affected by stage IV pulmonary adenocarcinoma under treatment with pembrolizumab and an 18-year-old woman affected by stage IV auricular melanoma who was treated with nivolumab. We also provide a review of the current literature describing small bowel involvement during therapy with ICIs, alone or in combination, for different types of solid tumours. Implications for clinical practice include considering the possibility of small bowel involvement in oncological patients treated with ICIs and the inclusion of ICIs amongst the iatrogenic causes of NCE with villous atrophy. Enteropathies due to ICIs may also represent a pathogenetic model for the understanding of the molecular mechanisms leading to villous atrophy in NCE.

Clonal Megakaryocyte Dysplasia with Normal Blood Values Is a Distinct Myeloproliferative Neoplasm.

INTRODUCTION: In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. METHODS: This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. RESULTS: Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41-54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. JAK2V617F was present in 10 subjects and CALR mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40-160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5-4.0) and 5.0 events (4.6-5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. CONCLUSION: Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.

VEGFA rs3025020 Polymorphism Contributes to CALR -Mutation Susceptibility and Is Associated with Low Risk of Deep Vein Thrombosis in Primary Myelofibrosis.

Background Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A ( VEGFA ) are associated with susceptibility to several diseases including cancer. Correlations between VEGFA rs3025020 genotypes with clinical and laboratory features of primary myelofibrosis (PMF) are unstudied. Methods DNA was analyzed by real-time polymerase chain reaction for VEGFA rs3025020 genotypes in a cohort of 844 subjects with PMF and in two cohorts of normal subjects ( N = 247 and N = 107). Results Frequency of rs3025020 minor allele (T) was not significantly different in subjects with PMF compared with normals; however, the T-allele was more frequent in PMF subjects with a calreticulin ( CALR )-mutated genotype compared with normals (35 vs. 27%; OR = 1.47 [95% CI, 1.09, 1.98] p = 0.011), especially in subjects with a CALR- type 2/type 2-like mutation (43 vs. 27%; OR = 2.01 [1.25, 3.24] p = 0.004). CALR mutants with the rs3025020 TT genotype had higher CXCR4 expression on CD34-positive blood cells, and those who carried CT/TT genotypes had lower platelet concentrations compared with other genotypes at diagnosis. Overall, subjects with the rs3025020 CT/TT genotype had a lower cumulative incidence of deep vein thrombosis in typical sites (1.6 vs. 4.2%; OR = 0.37 [0.15, 0.90] p = 0.029) and longer interval from diagnosis to first thrombosis (HR = 0.37 [0.14, 0.95] p = 0.039). Conclusion Persons with PMF and the VEGFA rs3025020 minor T-allele are more likely to have a CALR mutation compared with other somatic driver mutations and lower cumulative incidence and hazard for deep vein thrombosis in typical sites.

Ultrastructural analysis of breast cancer patient-derived organoids.

BACKGROUND: Breast cancer Patient Derived Organoids (PDO) have been demonstrated to be a reliable model to study cancer that promised to replace and reduce the use of animals in pre-clinical research. They displayed concordance with the tissue of origin, resuming its heterogenicity and representing a good platform to develop approaches of personalized medicines. Although obtain PDOs from mammary tumour, was a very challenging process, several ongoing studies evaluated them as a platform to study efficacy, sensitivity and specificity of new drugs and exploited them in personalized medicine. Despite tissue organization represented a crucial point to evaluate in a 3-dimensional model, since it could influence drug penetration, morphology of breast cancer PDOs has not been analysed yet. Here, we proposed a complete ultrastructural analysis of breast PDOs obtained from tumour and healthy tissues to evaluate how typical structures observed in mammary gland were resumed in this model. METHODS: 81 samples of mammary tissue (healthy or tumour) resulting from surgical resections have been processed to obtain PDO. The resulting PDOs embedded in matrigel drop have been processed for transmission electron microscopy and analysed. A comparison between ones from healthy and ones from cancerous tissue has been performed and PDOs derived from tumour tissue have been stratified according to their histological and molecular subtype. RESULT: The morphological analysis performed on 81 PDO revealed an organized structure rich in Golgi, secretion granules and mitochondria, which was typical of cells with a strong secretory activity and active metabolism. The presence of desmosomes, inter and intracellular lumens and of microvilli and interdigitations signified a precise tissue-organization. Each PDO has been classified based on whether or not it possessed (i) peripheral ridges in mitochondria, (ii) intracellular lumens, (iii) intercellular lumens, (iv) micro-vesicles, (v) open desmosomes, (vi) cell debris, (vii) polylobed nuclei, (viii) lysosomes and (ix) secretion granules, in order to identify features coupled with the cancerous state or with a specific histological or molecular subtype. CONCLUSION: Here we have demonstrated the suitability of breast cancer PDO as 3-dimensional model of mammary tissue. Besides, some structural features characterizing cancerous PDO have been observed, identifying the presence of distinctive traits.

Clinical Relevance of VEGFA (rs3025039) +936 C>T Polymorphism in Primary Myelofibrosis: Susceptibility, Clinical Co-Variates, and Outcomes.

We evaluated the association of VEGFA rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with JAK2V617F compared with those without JAK2V617F (18% vs. 13%; p = 0.014). In subjects with JAK2V617F, the TT genotype was associated at diagnosis with lower platelet concentrations (p = 0.033), higher plasma LDH concentration (p = 0.005), higher blood CD34-positive cells (p = 0.027), lower plasma cholesterol concentration (p = 0.046), and higher concentration of high-sensitivity C-reactive protein (p = 0.018). These associations were not found in subjects with PMF without JAK2V617F. In subjects with the TT genotype, risk of death was higher compared with subjects with CC/CT genotypes (HR = 2.12 [1.03, 4.35], p = 0.041). Finally, the TT genotype was associated with higher frequency of deep vein thrombosis in typical sites (12.5% vs. 2.5%; OR = 5.46 [1.51, 19.7], p = 0.009). In conclusion, in subjects with PMF, the VEGFA rs3025039 CT or TT genotypes are more common in those with JAK2V617F than in those without JAK2V67F mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis.

Modulation of ACE-2 mRNA by inflammatory cytokines in human thyroid cells: a pilot study.

INTRODUCTION: Angiotensin-converting-enzyme-2 (ACE-2) was demonstrated to be the receptor for cellular entry of SARS-CoV-2. ACE-2 mRNA was identified in several human tissues and recently also in thyroid cells in vitro. PURPOSE: Aim of the present study was to investigate the effect of pro-inflammatory cytokines on the ACE-2 mRNA levels in human thyroid cells in primary cultures. METHODS: Primary thyroid cell cultures were treated with IFN-γ and TNF-α alone or in combination for 24 h. ACE-2 mRNA levels were measured by RT-PCR. As a control, the levels of IFN-γ inducible chemokine (CXCL10) were measured in the respective cell culture supernatants. RESULTS: The mean levels of ACE-2 mRNA increased after treatment with IFN-γ and TNF-α in all the thyroid cell preparations, while the combination treatment did not consistently synergically increase ACE-2-mRNA. At difference, CXCL10 was consistently increased by IFN-γ and synergically further increased by the combination treatment with IFN-γ + TNF-α, with respect to IFN-γ alone. CONCLUSIONS: The results of the present study show that IFN-γ and, to a lesser extent TNF-α consistently increase ACE-2 mRNA levels in NHT primary cultures. More interestingly, the combined stimulation (proven to be effective according to the synergic effect registered for CXCL10) produces different responses in terms of ACE-2 mRNA modulation. These results would suggest that elevated levels of pro-inflammatory cytokines could facilitate the entering of the virus in cells by further increasing ACE-2 expression and/or account for the different degree of severity of SARS-COV-2 infection. This hypothesis deserves to be confirmed by further specific studies.

Raman analysis of microcalcifications in male breast cancer.

Microcalcifications (MCs) are important disease markers for breast cancer. Many studies were conducted on their characterization in female breast cancer (FBC), but no information is available on their composition in male breast cancer (MBC). Raman spectroscopy (RS) is a molecular spectroscopy that can rapidly explore the biochemical composition of MCs without requiring any staining protocol. In this study, we optimized an algorithm to identify the mineral components present in MCs from Raman images. The algorithm was then used to study and compare MCs identified on breast cancer pieces from male and female patients. In total, we analyzed 41 MCs from 5 invasive MBC patients and 149 MCs from 13 invasive FBC patients. Results show that hydroxyapatite is the most abundant type of calcium both in MBC and FBC. However, some differences in the amount and distribution of calcium minerals are present between the two groups. Besides, we observed that MCs in MBC have a higher amount of organic material (collagen) than FBC. To the best of our knowledge, this study provides the first overview of the composition of MCs present in MBC patients; and suggests that these patients have specific features that differentiate them from the previously studied FBC. Our result support thus the need for studies designed explicitly to the understanding of MBC.

Clinical and gastro-duodenal histopathological features of enteropathy due to angiotensin II receptor blockers.

BACKGROUND: Clinical elements differentiating enteropathy due to angiotensin II-receptor-blockers (ARBs-E) from coeliac disease (CD) are poorly defined. The histopathological features on duodenal and gastric biopsies in these patients still need to be investigated. AIMS: To describe the clinical phenotype of ARBs-E in comparison to CD, and the histological findings of gastric and duodenal biopsies in ARBs-E. METHODS: Clinical data of patients with ARBs-E and CD diagnosed between 2013 and 2020 were retrospectively reviewed. Baseline presenting symptoms and demographics were compared (Fisher's exact test and t-test). Gastric and duodenal histology in ARBs-E were revised by two independent pathologists. RESULTS: 14 ARBs-E and 112 CD patients were enroled. Weight loss (p < 0.01), acute onset of diarrhoea (p < 0.01), hospitalization (p < 0.01), and older age at diagnosis (p < 0.01) were more common in ARBs-E. Duodenal histology in ARBs-E showed intraepithelial lymphocytosis in 71%, increased mucosal eosinophilic count in 57%, with preserved neuroendocrine, Paneth and goblet cells in all patients. Gastric histologic lesions at baseline, including lymphocytic gastritis, eosinophilic gastritis, chronic active gastritis, and metaplastic atrophic gastritis patterns were observed in 73% of patients, without Helicobacter pylori infection. CONCLUSIONS: ARBs-E showed a severe clinical phenotype, often requiring hospital admission. Gastric involvement at diagnosis is very common, and this could further support this diagnosis.

Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis.

Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2-one of the most potent immunomodulatory chemokines-to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.