Bone marrow megakaryocytic activation predicts fibrotic evolution of Philadelphia-negative myeloproliferative neoplasms

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have been traditionally considered as indistinctly slowly progressing conditions; recent evidence proves that a subset of cases have a rapid evolution, so that MPNs' prognosis needs to be personalized. We identified a new morphological parameter, defined as Megakaryocytic Activation (M-ACT) based on the coexistence of megakaryocytic emperipolesis, megakaryocytes (MK) clusters formation and evidence of arrangement of collagen fibers around the perimeter of MK. We retrospectively analyzed the bone marrow biopsy of two MPNs cohorts of patients with polycythemia (PV) (n=64) and non-PV patients [including essential thrombocythemia (ET), and early/prefibrotic primary myelofibrosis (PMF)] (n=222). M-ACT showed a significant correlation with splenomegaly, white blood cell (WBC) count, and LDH serum levels in both groups, with JAK2 V617F allele burden in PV patients, and with CALR mutations, and platelet count in non-PV patients. Progression-free survival, defined as PV-to-secondary MF progression and non-PV-to-overt PMF, was worse in both PV and early/prefibrotic PMF patients with M-ACT in comparison to those without M-ACT (P<.0001). Interestingly, M-ACT was not found in the subgroup of ET patients. In conclusion, M-ACT can be helpful in the differential diagnosis of MPNs and can represent a new morphologic parameter with a predictive value for progression of MPNs

Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1

Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p < 0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells

Circulating hematopoietic stem cells and putative intestinal stem cells in coeliac disease

Background: The intestinal stem cells (ISC) modulation and the role of circulating hematopoietic stem cells (HSC) in coeliac disease (CD) are poorly understood. Our aim was to investigate the longitudinal modifications in peripheral blood HSC traffic and putative ISC density induced by gluten-free diet (GFD) in CD. Methods: Thirty-one CD patients and 7 controls were enrolled. Circulating CD133+ and CD34+ HSC were measured by flow cytometry, at enrolment and after 7 days and 1, 3, 6, 12, and 24 months of GFD. Endoscopy was performed at diagnosis and repeated at 6, 12, and 24 months following GFD. We used the Marsh-Oberhuber score to evaluate the histological severity of duodenal damage; immunohistochemistry was employed to measure the intraepithelial lymphoid infiltrate (IEL, CD3+ lymphoid cells) and the putative ISC compartment (CD133+ and Lgr5+ epithelial cells). Results: At enrolment, circulating HSCs were significantly increased in CD patients and they further augmented during the first week of GFD, but progressively decreased afterwards. CD patients presented with villous atrophy, abundant IEL and rare ISC residing at the crypt base. Upon GFD, IEL progressively decreased, while ISC density increased, peaking at 12 months. After 24 months of GFD, all patients were asymptomatic and their duodenal mucosa was macroscopically and histologically normal. Conclusions: In active CD patients, the ISC niche is depleted and there is an increased traffic of circulating HSC versus non-coeliac subjects. GFD induces a precocious mobilization of circulating HSC, which is followed by the expansion of the local ISC compartment, leading to mucosal healing and clinical remission

Riabilitazione ed Educazione: integrazioni possibili di soggetti adulti con danno cerebrale

Numero monografic

A New Operative Telesurgical System: Telelap Alf-X - Experimental Study on Animal Model

Objective: To report the first surgical thoracic major procedure performed using a new robotic telesurgical device (TELE-LAP ALF-X) in the ovine model.Materials: The new operative-system has two innovative peculiarities: tactile perception (similar to tactile feedback of thoracoscopy) and eye tracking (the immediate and perfect synchronization between the surgeon eyes and the Robot-camera).Results: After a careful setting of the robotic device, we have performed a lower-right lobectomy under complete robotic-assistance. The operative time was similar to the traditional thoracoscopy. In particular after the resection of inferior pulmonary ligament, we have isolated and closed firstly the lower pulmonary vein, then the bronchus followed by the arterial branches. The vascular and bronchial resections as well as the completion of the fissure were performed with standard endoscopic staplers introduced through an utility 4cm-sized incision. The specimen was placed in an endoscopic retrieval-bag and removed through the minithoracotomy. Finally, albeit the limitations due to different anatomical landmarks, a mediastinal lymph nodal dissection was also completed. Overall operation time was 180 minutes (with estimated blood loss of 100ml). The cooperation between the “first-operator†(placed at computer-console) and the “second-operator†(placed at the surgical-theatre) was optimal and no technical difficulties occurred.Conclusions: According to this first experimental experience, we may assume that robotic thoracic procedures, using Tele-Lap Alf-X system, could be technical feasible in the ovine model. Although more “in vivo†experimental data are needed, we believe that robot-assisted telesurgery approach could be reasonable an innovative contribution in the near future also in human model

L’EMPIEMA PLEURICO NEI PAZIENTI HIV-NEGATIVI CON DIPENDENZA DA SOSTANZE E/O ALCOOL: CARATTERISTICHE, TRATTAMENTO E RISULTATI IN UN SINGOLO CENTRO.

SCOPO DEL LAVORO L’empiema pleurico è una patologia temibile per gravità e frequenza che a volte è sottovalutata nei pazienti che abusano di sostanze stupefacenti e/o di alcool. Scopo del lavoro è studiare caratteristiche e trattamento di un gruppo di pazienti HIV-negativi con dipendenza patologica. MATERIALI E METODI Da Gennaio 2004 ad Aprile 2019 sono stati trattati chirurgicamente per empiema pleurico 121 pazienti (M/F: 81/40; età media 65 anni; range 21-83 anni) presso la nostra Unità Operativa. L’eziologia è stata principalmente parapneumonica con 103 casi (85%) e post-traumatica con 18 casi (15%). I pazienti sono stati retrospettivamente stratificati in due gruppi a seconda che avessero o no una dipendenza da sostanze e/o alcool fino a due anni prima (43 vs 78 pazienti – 36% vs 64%). Le caratteristiche dei pazienti con dipendenza sono state poi approfondite mediante analisi statistica univariata. Sono stati infine esclusi dallo studio i pazienti con empiema post-chirurgico e i casi dovuti a fistola bronco-pleurica. RISULTATI I casi di empiema pleurico parapneumonico sono stati 33 (77%; p=0,1) e post-traumatico 10 (23%; p=0,1) tra i pazienti con dipendenza patologica. L’età media era di 43 anni (range 21-56 anni) con un rapporto M/F di 28/15 (p=0,2). Ventiquattro pazienti (56%) sono stati sottoposti all’ingresso a posizionamento di drenaggio pleurico (p&lt;0,05) e tutti i pazienti sono stati poi sottoposti, con buon esito, a intervento di empiemectomia e decorticazione (p&lt;0,05) per persistenza di febbre e/o dispnea nonostante la terapia sistemica. La via di accesso finale è stata in tutti i casi la toracotomia (p&lt;0,05), indipendentemente dallo stadio dell’empiema, a causa dell’estensione della flogosi. In 6 casi (14%, p=0,07) è stato necessario eseguire anche una lobectomia o wedge resection per la presenza di ascesso polmonare/micetoma (5 casi, 12%; p&lt;0,05) o bronchiectasie (1 caso, 2%; p=1,00). All’analisi dei fattori di rischio la malnutrizione (BMI&lt;19) è emersa come principale fattore con 15 pazienti (35%, p&lt;0,05). Anche il diabete con 12 pazienti (28%, p&lt;0,05) e la flebite con 4 pazienti (9%, p&lt;0,05), associata o no ad ascesso nel sito d’iniezione della sostanza, rappresentano le comorbilità più frequenti in questo gruppo omogeneo di pazienti. È stato segnalato inoltre un caso di endocardite della valvola tricuspide (2%, p=0,4) e 4 pazienti erano HCV-positivi (9%, p=0,05) in assenza di cirrosi. CONCLUSIONI I pazienti con empiema pleurico e dipendenza presentano caratteristiche cliniche e comorbilità peculiari. L’intervento chirurgico di empiemectomia/decorticazione, più impegnativo in questi pazienti, è necessario per la persistenza di segni di sepsi anche dopo il posizionamento del drenaggio pleurico. La possibile spiegazione potrebbe essere, secondo noi, la presenza di malnutrizione e diabete oltre al già noto effetto immunosoppressore esercitato dagli oppiacei (eroina in primo luogo) e dall’alcool

Radiocarbon Dating the Exploitation Phases of the Grotta della Monaca Cave in Calabria, Southern Italy: A Prehistoric Mine for the Extraction of Iron and Copper

Grotta della Monaca is a karstic cave in Calabria (southern Italy) that plays an important role in reconstructing the oldest strategies for the acquisition of mineral resources in the Mediterranean. In fact, systematic archaeological excavations carried out by the University of Bari allowed the identification of intense prehistoric mining activities aimed at the exploitation of iron and copper ores. Archaeological evidence suggests different phases of frequentation of the cave spanning from the Upper Paleolithic, Neolithic, Copper and Bronze ages up to the Middle Ages. In order to establish an absolute timeframe for the different phases, a radiocarbon dating campaign was carried out and the results presented in this paper