Philippos Klonizakis

Helicobacter pylori Infection Might Contribute to Esophageal Adenocarcinoma Progress in Subpopulations With Gastroesophageal Reflux Disease and Barrett's Esophagus

To the Editor, Fischbach et al. [1] concluded that estimates for the effect of Helicobacter pylori (H. pylori) on Barrett’s esophagus (BE) were heterogenous across studies; although overall H. pylori, and particularly cagA cytotoxin, tended to be protective for BE in most studies, H. pylori effect on BE varied by geographic location. Barrett’s esophagus is a complication of long-standing gastroesophageal reflux disease (GERD) and wellrecognized premalignant condition playing a pivotal role in the development of esophageal adenocarcinoma (EA), the most common esophageal malignancy in Western countries with increasing faster incidence than any other cancer [2]; GERD plays a crucial role in the pathophysiology and the clinical identification of BE [2]. In this regard, our data show that H. pylori infection (H. pylori-I) is frequent in Greek patients with GERD and even with nonendoscopical reflux disease [2], and H. pylori eradication leads to better control of GERD symptoms and improves esophagitis [2,3]. Moreover, consistent associations with the Greek data were shown by others [3] also reporting improvement in reflux symptoms following H. pylori treatment. It is important to note that some other authors, usually prior supporters of the theory that H. pylori “protects” against GERD, relented their initial findings, claiming that H. pylori eradication does not cause or protect against GERD and, moreover, recommending H. pylori eradication in GERD [4]. Additionally, although epidemiologic studies do not suggest causality with H. pylori, however, such studies support our and others’ findings; for instance, a large study (~21,000 cases) showed that the decrease in H. pylori-I parallels the decrease in peptic ulcer prevalence, and the increase in GERD and reappearance of GERD after H. pylori eradication is rare. Moreover, contrary to expectation, patients hospitalized with duodenal ulcers (61,548 cases), obviously attributed to H. pylori-I, had a significant 70% excess risk of EA. Much evidence further potentiates the concern that H. pylori is not “protective” against GERD [5] and its complications including BE and EA. The interplay between H. pylori and host factors plays an important role in the pathogenesis of GERD. Specifically, H. pylori may contribute to GERD pathogenesis by several mechanisms including release of several mediators, cytokines, and nitric oxide, which may adversely affect the lower esophageal sphincter (LES); direct damage of the esophageal mucosa by bacterial products; increased production of prostaglandins that sensitize afferent nerves and reduce LES pressure; and augmented acidity (by gastrin release) that exacerbate GERD [3]. The authors considered some putative pathways involving H. pylori and a decreased risk of BE [1]. However, these pathways might represent the one BE pathogenic “coin’s” side. Regarding the other alternative side, gastrin, induced by H. pylori-I, is an oncogenic growth factor contributing to esophageal, gastric, and colon carcinogenesis and, in particular, playing a potential causal effect on neoplastic progression in BE; gastrin stimulates proliferation via JAK2and Akt-dependent NF-kappaB (NF-jB) activation in Barrett’s EA cells, shows antiapoptotic activity through upregulation of Bcl-2 and survivin, and upregulates cyclooxygenase (COX)-2 expression [2]. In this regard, H. pylori-I activates NF-jB, an oxidantsensitive transcription regulator of inducible expression of inflammatory genes such as COX-2, which regulates gastrointestinal cancer cell growth and proliferation. In particular, H. pylori-I induced NF-jB and COX-2 expression in esophageal epithelial cells, playing a role in inflammation associated with BE and tumorigenesis in the esophagus [2]; upon colonizing esophagus, H. pylori increases the severity of esophageal inflammation and the incidence of BE and EA [6]. Moreover, recent evidence indicates that 1, H. pylori-I prevalence is high in BE; 2, neither H. pylori-I nor H. pylori-I by CagA+ strains reduce the risk of BE in certain populations with high prevalence of H. pylori-I; 3, the expected incidence of EA with persistent H. pylori-I is higher than that of EA after eradication of infection [5]; H. pylori-I may affect specific molecular alterations (genetic instability, E-cadherin methylation, and monoclonal antibody Das-1) associated with the pathogenesis of BE; and 4, H. pylori induces

Pure Red Cell Aplasia and Lymphoproliferative Disorders: An Infrequent Association

Pure red cell aplasia (PRCA) is a rare bone marrow failure syndrome defined by a progressive normocytic anaemia and reticulocytopenia without leukocytopenia and thrombocytopenia. Secondary PRCA can be associated with various haematological disorders, such as chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma (NHL). The aim of the present review is to investigate the infrequent association between PRCA and lymphoproliferative disorders. PRCA might precede the appearance of lymphoma, may present simultaneously with the lymphoid neoplastic disease, or might appear following the lymphomatic disorder. Possible pathophysiological molecular mechanisms to explain the rare association between PRCA and lymphoproliferative disorders are reported. Most cases of PRCA are presumed to be autoimmune mediated by antibodies against either erythroblasts or erythropoietin, by T-cells secreting factors selectively inhibiting erythroid colonies in the bone marrow or by NK cells directly lysing erythroblasts. Finally, focus is given to the therapeutical approach, as several treatment regimens have failed for PRCA. Immunosuppressive therapy and/or chemotherapy are effective for improving anaemia in the majority of patients with lymphoma-associated PRCA. Further investigation is required to define the pathophysiology of PRCA at a molecular level and to provide convincing evidence why it might appear as a rare complication of lymphoproliferative disorders.

High Prevalence of Helicobacter pylori Infection in Greek Patients with Myelodysplastic Syndromes

Background/Aims/Methods: To determine the frequency of Helicobacter pylori infection (Hp-I) in 73 patients with myelodysplastic syndromes (MDS) and 40 controls, serologic analyses of Hp and 13C-urease breath tests (INFAI) were performed. Gastric mucosal biopsy specimens were obtained to determine the presence of Hp-I using a rapid urease test, i.e. the Campylobacter-like organism (CLO) test, and cresyl violet staining. Peripheral blood (PB) flow cytometry for CD3, CD4, CD8, CD14, CD19 and CD34 was conducted in 35 patients and in controls. Results:Hp-I was detected by: (a) serology in 75.34% of patients (p = 0.000), (b) INFAI in 57.69% of patients, (c) CLO in 60.71% of patients and (d) histological confirmation in 80.36% of patients (p = 0.001). No correlation between Hp-I and CD3, CD4, CD8, CD14, CD19 expression, leukemic transformation or death was observed. However, in 20 cases, significant variation in the PB lymphocytic proportion possibly attributable to Hp-I was ascertained, in contrast to the expected MDS ratio. Conclusion: Although there is no evidence for a causal relationship between Hp-I and MDS, the increased prevalence of Hp-I among the MDS patients is an interesting finding that deserves further investigation as it may indicate a common factor causing susceptibilities to both MDS and Hp-I or that Hp might influence the pathophysiology of MDS.

Multiple sclerosis and seizures: possible role of Helicobacter pylori

We have read with interest the proposition by Anderson and Rodriguez [1] that an increase in interleukin (IL)-18, and its associated induction of indoleamine 2, 3-dioxygenase (IDO) and quinolinic acid, mediates seizure activity in multiple sclerosis (MS) at least partly via an increase in interferon-gamma (IFN-c), accompanied by blood–brain barrier (BBB) permeability. Recent studies showed an association between Helicobacter pylori infection (Hp-I) and epilepsy, especially with poor prognosis [2]. Moreover, using histology, the practical gold standard for current Hp-I diagnosis, we showed a strong association between Hp-I and MS in a Greek cohort [3]. In this respect, we proposed that Hp-I, by inducing pro-inflammatory cytokine production and BBB disruption [4], may lead to neuroinflammation and neuronal damage in epilepsy, thereby triggering seizures induction and epilepsy progression [5]. Specifically, a series of factors have been implicated in inducing BBB disruption, including inflammatory mediators (e.g. cytokines and chemokines induced by Hp-I) and oxidative stress [5,6]. Hp could indirectly affect the brain through the release of numerous pro-inflammatory cytokines, such as IL-1b, IL-18, IFN-c [7] mentioned by the authors, or tumor necrosis factor (TNF)-a acting at a distance. TNF-a may contribute to BBB disruption and pathogenesis of neuronal inflammatory damage in neurodegenerative diseases and epilepsy; IL-1b, IL-6, and TNF-a influence the pathogenesis of seizures and course of epilepsy, and the primary BBB lesion is involved in seizures induction/epileptogenesis [8]. Likewise, an influx of Hp-infected monocytes, owing to defective autophagy resulting in Hp replication in autophagic vesicles, through the disrupted BBB might lead to brain degeneration and epilepsy development partially by potential activation of natural killer cells and IFN-c production, detrimental for MS; Hp VacA cytotoxin promotes intracellular survival of the bacterium and modulates host immune responses. Of note, Hp is known to be associated with the increase in IDOdependent mechanisms. Viewing the aforementioned data and because half of the world s population is infected withHp, it would be interesting to know whether the authors have considered Hp-I as a potential confounder involved in the pathophysiology of MS-associated increased seizure activity and therefore its management.

Helicobacter pylori might be a potential therapeutic target in epilepsy

predict AIS development. Cartilage oligomeric matrix protein (COMP) is essential for the normal development of cartilage and for its conversion to bone during growth. It is expressed at high levels during skeletal development and long bone growth. Mutations in COMP produce clinical phenotypes of pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) [2,3]. These disorders are characterized by disproportionate short stature, brachydactyly, joint hypermobility, earlyonset osteoarthritis, and scoliosis [4]. Interestingly, the phenotypes in PSACH/MED cartilage disorders is not caused by the reduced amount of COMP but rather due to dysfunctional mutated COMP. Abnormal COMP protein cannot be transported out of the cell but rather builds up inside the chondrocyte and it ultimately leads to early chondrocytes death preventing normal bone growth [5]. Recently, in a microarray approach evaluating primary human osteoblasts, we found that COMP is one of the most differentially regulated genes in AIS compared to unaffected individuals [6]. COMP was found to be significantly down-regulated by 4-fold in AIS [6]. Consistent with the microarray analysis, relatively low levels of COMP mRNA transcripts in AIS were detected by RT-qPCR analysis. Altogether, these data suggest that low expression of COMP is associated with AIS. This is the first down-regulated gene described in AIS. Thus, we hypothesized COMP down-regulation would result to a low COMP serum level in AIS patients and this could be an important and novel biomarker in predicting scoliosis development. Supported by The Yves Cotrel Foundation, Institut de France.

Five Years of Deferasirox Therapy for Cardiac Iron in β-Thalassemia Major

Abstract Myocardial siderosis in β-thalassemia major (β-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with β-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30 mg/kg/day and never increased to more than 40 mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82 ± 10.86 ms, and after 32.13 ± 7.74 ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23 ms). The mean LVEF value was 68.43 ± 7.08% before treatment with DFX and 67.95 ± 5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.

Helicobacter pylori infection might protect from the leukaemic transformation of myelodysplastic syndromes.

MDD. Another recent study analyzed data from about 7000 members of the Vietnam Era Twin Registry [4]. This study is the first to use a twin design to quantify the degree to which a common genetic vulnerability explains the etiology of the association between PTSD and MDD. The authors found substantial genetic overlap between PTSD and MDD and suggested that genes implicated in the etiology of MDD are strong candidates for PTSD and vice versa. This observation supports the idea that comorbid PTSD and MDD may be a distinct neurobiological condition that can be named ‘‘post-traumatic mood disorder.’’ Post-traumatic mood disorder is associated with greater symptom severity and higher risk for suicidal behavior compared to PTSD [1,2]. Traumatic experiences are common, if we consider the preponderance of individuals exposed to sexual or non-sexual assault, natural disasters (e.g. flooding), accidents (e.g. work, motor vehicle), and war [5]. Many individuals exposed to traumas may have post-traumatic mood disorder. Studies of PTSD and PTSD with symptoms of major depression are merited. References

Fatal chylous ascites, pericarditis and extensive venous thrombosis, due to an aggressive T cell non-Hodgkin lymphoma.

Dear Editor, Chylous ascites or chyloperitoneum is the extravasation of milky peritoneal fluid rich in triglycerides in the abdominal cavity, because of lymphatic obstruction or trauma. Cirrhosis, malignancies and infectious agents are frequent etiologies, whereas congenital, inflammatory, post-operative and traumatic causes have been described [1]. The incidence of chylous ascites is between 1 in 50,000 and 1 in 187,000 hospital admissions. Neoplasms are mainly responsible for chyloperitoneum, with lymphomas predominating among malignant causes in young patients [2]. We report a case of a young patient presenting with chylous ascites, chylothorax, pericarditis and venous thrombosis in several anatomic regions, due to an aggressive T cell non-Hodgkin lymphoma (T-NHL). To the best of our knowledge, this is the first case of such co-existing pathologic features, revealing a T-NHL. The need for effective treatment is essential in such medical incidents, especially when young patients suffer from aggressive neoplasms. However, rarity of such cases and lack of guidelines concerning therapeutic options impede the task of haematologists. Therefore, reporting lymphomas combined with chyloperitoneum facilitates the choice of appropriate treatment and the outcome comparison between similar incidents. A 38-year-old man with 3-month recurrent effusive right pleuritis, after being initially treated for presumed tuberculosis, was referred to our centre. The patient had increasing abdominal distention and shortness of breath. Physical examination revealed ascites, left axillary lymphadenopathy and upper limb oedema. Lymph node biopsy was diagnostic of peripheral T-NHL, unspecified. There was complete effacement of the nodal architecture, along with infiltration by neoplasmatic, lymphoid cells with abundant mitotic figures. They were medium-sized or enlarged with slightly eosinophilic cytoplasm and irregular-shaped nuclei. Immunohistochemically, tumour cells were strongly positive for CD5, mildly positive for CD3 and negative for CD20, CD79a, CD30, CD56, CD23 and cyclin D1 (Fig. 1). Peripheral, unspecified T-NHLs derive from post-thymic T cells at various differentiative stages. Computed tomography (CT) scan revealed ascites, ambilateral pleuritic fluid causing mediastinal compression, pericarditis and excessive left axillary, mediastinal, mesenteric and retroperitoneal lymphadenopathy (Fig. 2). Enlarged lymph nodes surrounding the thymus were traced. The presence of pericardial fluid was confirmed by an echocardiogram. Paracentesis elicited chylous-effusive pleuritic fluid and creamy white ascetic fluid with elevated triglycerides (1,212 mg/dl), low protein (2.6 g/dl) and cell count (550 cells per decilitre) with lymphocytic predominance. Moreover, thrombosis was detected in the left brachiocephalic, subclavian and internal jugular veins, as a result Ann Hematol (2009) 88:371–373 DOI 10.1007/s00277-008-0570-0

Rivaroxaban Use in Patients with Hemoglobinopathies

Abstract The use of rivaroxaban in patients with hemoglobinopathies and thrombotic events has not been studied extensively. Here we present eight cases of such patients, five receiving rivaroxaban for stroke and systemic embolism prevention due to non-valvular atrial fibrillation and three for deep vein thrombosis treatment. The follow-up period ranged from 6 to 34 months. During this period none of the patients experienced any thrombotic or bleeding event.There were no other adverse events reported. Further studies with larger numbers of patients with hemoglobinopathies are needed to determine the use of rivaroxaban and ensure its safety in this patient setting.

Presence of the IVS-I-6-Mutated Allele in Beta-Thalassemia Major Patients Correlates with Extramedullary Hematopoiesis Incidence

Extramedullary hematopoiesis (EMH) results from the extension of hematopoietic tissue beyond the confines of the bones. Since the initiation of regular transfusion programs from an early age for all thalassemia major (ΤΜ) patients, EMH has not been considered a clinical issue anymore. The present study aims to record the prevalence of EMH in chronically transfused ΤΜ patients followed at our institution and to investigate possible risk factors associated with its occurrence. The project was designed as a retrospective, nonexperimental, descriptive, exploratory study. In total, the study enrolled 104 patients. EMH was revealed in 15/104 (14%) patients. The presence of intravening sequence (IVS)-I-6 was significantly related with the development of EMH (p < 0.05). No other demographic or biological factor studied was found to be related with the presence of EMH. The study stresses a profound incidence of asymptomatic EMH in a solid group of well-transfused ΤΜ patients. Given the high incidence of the IVS-I-6 allele in the Mediterranean and Middle Eastern region, high-quality, prospective, multicenter studies could confirm the association of EMH occurrence with the presence of the IVS-I-6 mutation and further evaluate the exact role of this mutation in the EMH process.