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Mihaela Găman,1,2 Ana-Maria Vlădăreanu,1,2 Camelia Dobrea,1 Minodora Onisâi,1,2 Cristina Marinescu,1,2 Diana Cîşleanu,1,2 Cristina Ciufu,1,2 Daniela Vasile,1,2 Horia Bumbea,1,2 Irina Voican2 1Department of Hematology, University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest, Romania; 2Department of Hematology, University Emergency Hospital Bucharest, Bucharest, Romania Abstract: POEMS syndrome (acronym consisting of: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is an uncommon disorder associated with an underlying plasma cell dyscrasia. There is no single specific test for POEMS, and due to its rarity and heterogeneity, patients are often mis- or underdiagnosed. Castleman disease (CD) is a rare lymphoproliferative disorder, closely related to POEMS syndrome; ~11%–30% of POEMS patients are associated with concomitant CD. In contrast to frequently published reports on vascular events in POEMS syndrome affecting coronary arteries or lower limbs, cases of cerebrovascular events are rarely mentioned in literature. We hereby report a patient with POEMS syndrome accompanied by CD who presented recurrent strokes and splenic infarction. Keywords: POEMS, chronic inflammatory demyelinating polyradiculopathy, M protein, thrombotic risk, stroke, recurrent ischemic events

Background. Hepatitis B and C viruses’ infections are often associated with hematological disorders in evolution, suggesting that these viruses have a tropism for peripheral blood and/or bone marrow cells. Aim. To analyze the hematological parameters and bone marrow findings in a group of patients diagnosed with chronic lymphoproliferative disorders (CLD) and hepatitis viruses B, C, D infections, which were included in the research grant (acronym LIMFO-VIR) between December 2007 and May 2010 in the Hematology Department of the Emergency University Hospital of Bucharest. Methods and results. Patients were diagnosed by using immunopathology according to the WHO criteria. The analyzed group included 42 patients (both sexes), with the mean age of 60,35 years. The most frequent hematologic disease was non-Hodgkin’s lymphoma 30/42 (71,42%), followed by chronic lymphocytic leukemia (16,66%) and Hodgkin’s lymphoma (7,14%). Hepatitis viruses were distributed: 17/42 (40,47%) patients with HBV, 22/42 (52,38%) with HCV and 3/42 (7,14%) had a double/triple association of viruses. Most of the patients had an indolent type of disease - 27/42 (64,28%), whereas 15/42 (35,71%) had an aggressive one, pattern found both in the HBV and HCV infected groups. An abnormal bone marrow result was revealed in 32/42 (76,19%) patients, 19 (59,37%) of them being HCV infected. Myelodysplasia was found in 6/42(14,28%) patients, the majority being HCV infected, all having an indolent form of CLD. The antiviral therapy did not influence the hematological parameters (no significant differences were found between the groups with/without an antiviral therapy). Discussions. Patients with hepatitis virus infections may associate neutropenia and thrombocytopenia; the mechanisms are thought to involve hypersplenism, autoimmune processes and antiviral therapy. We excluded the influence of chemotherapy, as the study was performed before the treatment. In our group, patients whether HBV or HCV infected, presented an isolated cytopenia. The abnormal bone marrow cellularity (increased or decreased) and dysplasia were found especially in the HCV group. There are studies showing no association between myelodysplasia and hepatitis viruses; others found a strong relation of these. One of the mechanisms of myelodysplasia could be a dysregulation of the immune system. Conclusions. Bone marrow/peripheral blood features correlate with the type of viral infection and HCV is more prone to develop additional hematological changes than HBV. The degree of bone marrow involvement by CLDs influences these features. We considered mandatory to perform a bone marrow analysis at the diagnosis of CLDs to stage and to establish if other bone marrow changes were present, a crucial aspect for therapy and outcome of the disease. The association between the hepatitis viruses – myelodysplasia- autoimmunity seems to have a role in the lymphoproliferative disorders etiology. Abbreviations: CLD – chronic lymphoproliferative disorders; NHL- non-Hodgkin’s lymphoma, CLL- chronic lymphocytic leukemia, HL- Hodgkin’s lymphoma, MDS – myelodysplastic syndrome, AML – acute myeloid leukemia

Introduzione: i disturbi psichiatrici subiscono frequentemente un ritardo nella diagnosi e nel trattamento e le cause che maggiormente influenzano tali variabili rimangono in gran parte sconosciute, non essendovi strumenti specificamente volti a indagare tale fenomeno (1) (2). A tal proposito, il nostro Dipartimento ha recentemente sviluppato un questionario focalizzato sull’esordio e sulla latenza ai trattamenti: il questionario sull’esordio psicopatologico (QEP). Scopo del presente studio è stato analizzare le principali variabili cliniche e socio-demografiche correlate all’esordio psicopatologico e alla latenza al trattamento, confrontandole tra gruppi diagnostici. Metodi: il questionario è stato somministrato a 256 pazienti, affetti da qualsiasi disturbo psichiatrico e suddivisi in: Disturbi dell’Umore (n=135), Disturbi d’Ansia (n=83), Disturbi Psicotici (n=38). Sono state successivamente effettuate analisi statistiche demografiche e di confronto tra gruppi tramite SPSS. Risultati: il campione di pazienti con Disturbi dell’Umore ha mostrato le seguenti variabili: età d’esordio 33.2 anni ±15.8, eventi stressanti precedenti l’esordio nel 67%, latenza alla prima visita>6 mesi nel 41% dei casi. Il campione dei Disturbi d’Ansia ha riportato invece: età d’esordio 29.6 anni ±14.7, eventi stressanti precedenti l’esordio nel 66%, una latenza alla prima visita>6 mesi nel 47%. Infine, i Disturbi Psicotici hanno mostrato: esordio 29.5 anni±12.9, eventi stressanti precedenti l’esordio nel 54, latenza alla prima visita>6 mesi nel 48% dei casi. Sono emerse differenze significative tra gruppi, in termini di motivazione alla prima visita: più della metà dei pazienti con Disturbi dell’umore (55%) e la maggior parte dei pazienti con Disturbi Psicotici (72%) sono stati inviati su consiglio dei familiari, percentuale ridotta al 39% nei pazienti con Disturbi d’Ansia, nei quali, invece, sembrerebbe prevalere una decisione autonoma. In tutti i gruppi, la familiarità psichiatrica è risultata positiva in circa il 50% dei casi. In tutti i gruppi diagnostici, il primo contatto è stato individuato nella maggior parte dei casi in uno psichiatra e il trattamento in una farmacoterapia. È emerso un trend di significatività (p=0.07) in riferimento alla DUI, maggiore nei Disturbi d’Ansia (6.4 anni ± 8.6) e minore in quelli Psicotici (1.9 anni ± 3.9), assumendo, nel gruppo dell’Umore, un valore intermedio (4.85 anni ±10.9). Conclusione: il QEP si è rivelato uno strumento utile e attendibile nella raccolta di informazioni sull’esordio e la latenza al trattamento in diverse categorie di disturbi psichiatrici. Bibliografia (1) Altamura AC, Buoli M, Albano A, et al. Age at onset and latency to treatment (duration of untreated illness) in patients with mood and anxiety disorders: a naturalistic study. Int Clin Psychopharmacol 2010;25:172-9. (2) Bechard-Evans L, Schmitz N, Abadi S, et al. Determinants of help- seeking and system related components of delay in the treatment of first-episode psychosis. Schizophrenia Research 2007;96:206-14. (3) Dell’Osso B, Palazzo MC, Arici C, et al. Sviluppo di un questiona- rio per la valutazione dell’esordio psicopatologico e della latenza ai trattamenti (QEP-LAT). Presented at the XV National Congress of the Società Italiana di Psicopatologia (SOPSI) 2011.

We present the case of a 37-year-old male, admitted to our clinic with abdominal tenderness, right supraclavicular tumour, and ascites. The presence of ascites was incidentally reported 6 years before, but no other evaluation was done at that moment or during this period. Abdominal ultrasound and CT scan revealed moderate ascites, perivascular adenopathies, and multiple abdominal cystic lesions, while thoracic CT scan revealed the same lesions in mediastinum. Laboratory data were within normal limits, including the tumoral markers, and the tests for hydatid cysts. A biopsy from the right supraclavicular nodule was performed, and based on usual and immunohistochemical stains (calretinin, mesotheline, CK 5/6, CK 7, CK18 diffusely positive in mesothelial cells, and CEA -M, bcl-2 and vimentin negative), suggested the diagnosis of mesothelioma. Based on these results, the diagnosis of "multicystic mesothelioma" was made. The patient was referred for surgery.

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique that modifies cortical excitability in a polarity-dependent way that has been increasingly investigated for the treatment of major depression (MD) during recent years. Stimulation for few minutes can induce plastic alterations of cortical excitability and improve cognitive performance. Even if the available evidence, including randomized clinical trials, has generally reported encouraging results in treatment of major depression and treatment-resistant depression, the use of tDCS in mood disorders should still be considered experimental. In fact, further research is needed to better define the optimal stimulation parameters, duration of treatment, durability of clinical effect and predictors of response. Nevertheless, to date, tDCS has shown a favourable tolerability profile, is easy to apply, portable and inexpensive. Taken together, increased use of the technique in the treatment of depressive disorders may be expected in the near future.

The provision of a particle and power exhaust solution which is compatible with first-wall components and edge-plasma conditions is a key area of present-day fusion research and mandatory for a successful operation of ITER and DEMO. The work package plasma-facing components (WP PFC) within the European fusion programme complements with laboratory experiments, i.e. in linear plasma devices, electron and ion beam loading facilities, the studies performed in toroidally confined magnetic devices, such as JET, ASDEX Upgrade, WEST etc. The connection of both groups is done via common physics and engineering studies, including the qualification and specification of plasma-facing components, and by modelling codes that simulate edge-plasma conditions and the plasma-material interaction as well as the study of fundamental processes. WP PFC addresses these critical points in order to ensure reliable and efficient use of conventional, solid PFCs in ITER (Be and W) and DEMO (W and steel) with respect to heat-load capabilities (transient and steady-state heat and particle loads), lifetime estimates (erosion, material mixing and surface morphology), and safety aspects (fuel retention, fuel removal, material migration and dust formation) particularly for quasi-steady-state conditions. Alternative scenarios and concepts (liquid Sn or Li as PFCs) for DEMO are developed and tested in the event that the conventional solution turns out to not be functional. Here, we present an overview of the activities with an emphasis on a few key results: (i) the observed synergistic effects in particle and heat loading of ITER-grade W with the available set of exposition devices on material properties such as roughness, ductility and microstructure; (ii) the progress in understanding of fuel retention, diffusion and outgassing in different W-based materials, including the impact of damage and impurities like N; and (iii), the preferential sputtering of Fe in EUROFER steel providing an in situ W surface and a potential first-wall solution for DEMO.

Background: Chronic lymphoproliferative disorders (CLD) are frequently found in patients with hepatitis viral infections, which can lead to changes in pathogenesis. Hepatitis viruses are hepatotrope viruses, potentially lymphotrope and also potentially oncogenic (hepatocellular carcinoma) viruses. HBV and HCV are involved in autoimmune disorders and in the ethiopathogeny of chronic lymphoproliferative disorders. Aim: Detection of immunophenotype changes of malignant lymphocytes in CLD – especially CLL – associated with hepatitis viral infections. Materials and methods: Bone marrow aspirate, peripheral blood samples on EDTA were available for analysis from 58 patients from a follow–up schedule of the Department of Hematology SUUB from March 2008 until June 2009. The patients were diagnosed with chronic lymphoproliferative disorders associated with hepatitis virus B/C/D infections. A group of 28 consecutive unselected patients with CLL who met the diagnostic criteria of the National Cancer Institute–Working Group (NCI NCIWG), and associated hepatitis viral infection (v–CLL) were studied for the expression of several immunophenotypical markers, in comparison to CLL patients without viral infection (control group). Immunophenotyping analysis was performed on a FACS Calibur flowcytometer with a large panel according to EGIL/WHO recommendations. The diagnosis was completed after the histological and immunochemical analysis from tumoral lesions. Results: demographics characteristics – male/female ratio 1/2, average age 64 years. Disease type: 90% B–CLD, 5% T–CLD, 5% Hodgkin's disease. The viral infections: 58,53% HCV, 34,41Z% HBV, 2,43% HBV+HDV, 2,43% HCV+HDV, 2,43% HBV+HCV+HDV. We found in CLL with viral coinfection (v–CLL) cases an elevated expression of B–cell markers – CD19 (Md95/92), CD20 (Md 90/39), CD79b (Md58/31), CD23 (Md67/37). Poor prognosis markers have a higher expression in v–CLL: CD38 (Md49/24), Bcl2 (Md 46/5), cyclin D19 (Md 11/0,5). No change in ZAP–70 expression was observed: Md 59,5/59,1. Discussions: Hepatitis viruses could be involved in the pathogenesis of CLD, but as a trigger for a more aggressive outcome. Higher expression of B–cell markers CD19, CD20 in CLL with viral infection suggests a change to atypical CLL, sustained by elevated expression of known poor prognosis markers bcl–2, cyclin D1 and CD38. Lack of ZAP–70 expression could be explained by a strong correlation with a basic unmutated IgVH status, not related to the viral infection. We found a higher frequency of HCV infection in patients with CLD and especially in CLL patients, which were analyzed extensively for immunophenotypical changes. In the present study, we demonstrated that this CD5+ B cell population with clonal expansion, defining CLL patients, has a different immunophenotype, probably related to the hepatitis viral infection.

Background: Patients with Myeloproliferative Neoplasms–(MPN) have a high risk of thrombotic complications. Portal vein thrombosis is a severe complication, which in many cases, appears at the onset of the disease; the risk factors are related to the presence of qualitatively altered thrombocytes and leucocytes, leading to their activation and appearance of leukocytes–platelet–aggregates; anomalies of portal vein endothelial cells are also implicated. The presence of JAK2V617F mutation increases the risk for splahnic thrombosis. Methods and results: We present three patients with portal vein thrombosis and Budd Chiari syndrome, who were further diagnosed with MPN–the thrombosis was the onset event of the disease Conclusion: Patients were diagnosed with thrombosis of the portal vein before being diagnosed with MPN. Splenectomy was not associated with risk of thrombosis for the two cases in which it was performed; for one case, splenectomy was a therapeutic method to resolve portal hypertension. All patients had homozygous JAK2 mutation, which is associated in recent studies with increased risk of portal, mesenteric thrombosis. The high number of platelet was difficult to control for all patients. Bone marrow biopsy and determination of JAK status are valuable investigations for patients who have splenoportal thrombosis, with no apparent identifiable cause.

Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance.

Anxiety disorders are common, comorbid, and disabling conditions, often underdiagnosed and under-treated, typically with an early onset, chronic course, and prolonged duration of untreated illness. The present study aimed to explore the influence of sociodemographic and clinical factors in relation to onset and latency to treatment in patients with generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD). A total of 157 patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM-IVTR) diagnosis of PD (n=49), GAD (n=68), and OCD (n=40) were recruited, and epidemiological and clinical variables were collected through a specific questionnaire. Statistical analyses were carried out to compare variables across diagnostic groups. PD, GAD, and OCD patients showed a duration of untreated illness of 53.9 ±81.5, 77.47 ±95.76, and 90.6± 112.1 months, respectively. Significant differences between groups were found with respect to age, age of first diagnosis, age of first treatment, family history of psychiatric illness, onset-related stressful events, benzodiazepine prescription as first treatment, antidepressant prescription as first treatment, and helpseeking (self-initiated vs. initiated by others). Patients with GAD, PD, and OCD showed significant differences in factors influencing onset and latency to treatment, which may, in turn, affect condition-related outcome and overall prognosis. Further studies with larger samples are warranted in the field.

Latency to first pharmacological treatment [duration of untreated illness (DUI)] in psychiatric disorders can be measured in years, with differences across diagnostic areas and relevant consequences in terms of socio-occupational functioning and outcome. Within the psychopathological onset of a specific disorder, many factors influence access and latency to first pharmacotherapy and the present study aimed to investigate such factors, through an ad-hoc developed questionnaire, in a sample of 538 patients with diagnoses of schizophrenia-spectrum disorder (SZ), mood disorder (MD), and anxiety disorder (AD). Patients with SZs showed earlier ages at onset, first diagnosis and treatment, as well as shorter DUI compared with other patients (43.17 months vs. 58.64 and 80.43 months in MD and AD; F=3.813, P=0.02). Patients with MD and AD reported more frequently onset-related stressful events, benzodiazepines as first treatment, and autonomous help seeking compared with patients with SZs. In terms of first therapist, psychiatrist referral accounted for 43.6% of the cases, progressively decreasing from SZ to MD and AD (57.6, 41.8, and 38.3%, respectively). The opposite phenomenon was observed for nonpsychiatrist clinician referrals, whereas psychologist referrals remained constant. The present findings confirm the presence of a relevant DUI in a large sample of Italian patients with different psychiatric disorders (5 years, on average), pointing out specific differences, in terms of treatment access and latency, between psychotic and affective patients. Such aspects are relevant for detection of at-risk patients and implement early intervention programs.

Transcranial direct current stimulation (tDCS) is a selective, painless, brain stimulation technique that allows the electric stimulation of specific cortical regions. TDCS has been recently used as investigational intervention for major depression and treatment resistant depression (TRD) with encouraging results. The present study was aimed to investigate the efficacy and tolerability of tDCS in major depressives with poor response to pharmacological treatment. Twenty-three depressed patients, with a diagnosis of major depressive disorder or bipolar disorder, were treated with augmentative tDCS for 5 days, two sessions per day in a blind-rater trial. The course of depressive symptoms was analyzed using repeated measures ANOVA for HAM-D and MADRS total scores. A qualitative analysis on the basis of the HAM-D response was performed as well. Both analyses were conducted at three time-points: T0 (baseline), T1 (endpoint tDCS) and T2 (end of the first week of follow-up). All patients completed the trial without relevant side-effects. A significant reduction of HAM-D and MADRS total scores was observed during the study (P