Geographic variation in the prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly: a comparative analysis of a Mexican and a German population.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma of the elderly was included as a provisional entity in the 2008 WHO lymphoma classification. Most reports of this disease come from Asia and little is known about it in other regions of the world, including Latin America. Therefore, in this study, 305 diffuse large B-cell lymphomas in patients above 50 years were analyzed, 136 from Mexico and 169 from Germany. EBV was detected by Epstein-Barr early RNA (EBER) in situ hybridization. Only cases with EBER+ in the majority of tumor cells were regarded as EBV+ diffuse large B-cell lymphoma. The prevalence of EBV+ diffuse large B-cell lymphoma in Mexican patients was found to be 7% (9 of 136), whereas only 2% (4 of 169) of the German cases were positive. The median age at diagnosis was 66 years in the Mexican cohort, as opposed to 77 years in the German group. The site of presentation was in both groups predominantly nodal in nine cases (70%) and extranodal in four cases (30%). Of the 13 EBV+ cases, 10 (77%) were classified as polymorphic and 3 (23%) as monomorphic type. The polymorphic cases showed a non-germinal center B-cell immunophenotype (CD10- MUM1+). Twelve cases (92%) were LMP1 positive and two (15%) expressed EBNA2. An interesting finding was the high frequency of EBV type B with the LMP1 30 bp deletion found in the Mexican cases (50%). Eight of the 11 evaluable cases were B-cell monoclonal by polymerase chain reaction. In summary, we found a similar prevalence of EBV+ diffuse large B-cell lymphoma of the elderly in a Mexican population compared with what has been reported in Asian countries, and in contrast to the low frequency in Western populations (1-3%). However, compared with the Asian series, the Mexican patients were younger at diagnosis, presented predominantly with nodal disease and rarely expressed EBNA2 protein.

PAR1 is selectively over expressed in high grade breast cancer patients: a cohort study.

BACKGROUND: The protease-activated receptor (PAR1) expression is correlated with the degree of invasiveness in cell lines. Nevertheless it has never been directed involved in breast cancer patients progression. The aim of this study was to determine whether PAR1 expression could be used as predictor of metastases and mortality. METHODS: In a cohort of patients with infiltrating ductal carcinoma studied longitudinally since 1996 and until 2007, PAR1 over-expression was assessed by immunoblotting, immunohistochemistry, and flow citometry. Chi-square and log rank tests were used to determine whether there was a statistical association between PAR1 overexpression and metastases, mortality, and survival. Multivariate analysis was performed including HER1, stage, ER and nodes status to evaluate PAR1 as an independent prognostic factor. RESULTS: Follow up was 95 months (range: 2-130 months). We assayed PAR1 in a cohort of patients composed of 136 patients; we found PAR1 expression assayed by immunoblotting was selectively associated with high grade patients (50 cases of the study cohort; P = 0.001). Twenty-nine of 50 (58%) patients overexpressed PAR1, and 23 of these (46%) developed metastases. HER1, stage, ER and PAR1 overexpression were robustly correlated (Cox regression, P = 0.002, P = 0.024 and P = 0.002 respectively). Twenty-one of the 50 patients (42%) expressed both receptors (PAR1 and HER1 P = 0.0004). We also found a statistically significant correlation between PAR1 overexpression and increased mortality (P = 0.0001) and development of metastases (P = 0.0009). CONCLUSION: Our data suggest PAR1 overexpression may be involved in the development of metastases in breast cancer patient and is associated with undifferentiated cellular progression of the tumor. Further studies are needed to understand PAR1 mechanism of action and in a near future assay its potential use as risk factor for metastasis development in high grade breast cancer patients.

Atypical chronic myeloid leukemia as defined in the WHO classification is a JAK2 V617F negative neoplasm.

Atypical chronic myeloid leukemia (aCML) as defined by the WHO classification is a rare hematopoietic stem cell disorder, which shows both myeloproliferative as well as myelodysplastic features. Because of the presence of neutrophilic leukocytosis, aCML may resemble chronic myelogenous leukemia. However, in contrast with the latter, aCML lacks a Philadelphia chromosome or the BCR/ABL fusion gene. The molecular pathogenesis of aCML and its relationship to other myeloproliferative neoplasms is unknown. To clarify these points, the presence of JAK2 V617F was examined by a retrospective analysis of archival specimens obtained from two large medical institutions. Paraffin-embedded bone marrow (BM) trephines and clot sections were examined by an allele-specific TaqMan PCR suitable for use with decalcified tissue. Fifty-nine cases of Philadelphia (Ph) chromosome negative chronic myeloproliferative neoplasms (CMPN) and normal bone marrows (BM) served as controls. None of the nine amplifiable cases of aCML and none of the normal BM controls showed a JAK2 V617F mutation, in contrast to 45/59 (76%) of the Ph chromosome negative CMPN cases. Atypical CML should therefore be considered as a JAK2 negative chronic myeloid neoplasm that remains properly categorized, alongside chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, within the WHO group of myelodysplastic/myeloproliferative neoplasms.

A proof-of-principle study of epigenetic therapy added to neoadjuvant doxorubicin cyclophosphamide for locally advanced breast cancer.

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1-2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.

Guías de práctica clínica de la Sociedad Española de Cardiología sobre conducción de vehículos, pilotaje de aviones y actividades subacuáticas en cardiópatas / Guidelines of the Spanish Society of Cardiology for Airplane Piloting, Car Driving and Underwater Activities in Subjects with Heart Disease

La conducción de vehículos, el pilotaje de aviones y las actividades subacuáticas plantean para el cardiópata el riesgo de sufrir episodios de incapacidad transitoria, posiblemente súbita, que le impidan mantener el margen de seguridad necesario para evitar accidentes. En el caso de la conducción de automóviles y el pilotaje de aviones el riesgo abarca al cardiópata conductor, pero también a sus pasajeros y a los habitantes o viandantes de una posible zona de acidnete. En el caso del buceo el riesgo fundamental es el de perder control de los mecanismos de apoyo vital e un medio muy hostil. Se revisan en este documento las causas de incapacidad transitoria, con y sin pérdida de conciencia, y otras situaciones de limitación funcional, partiendo de las alteraciones fisiopatológicas producidas por el estrés, la fatiga, la hipoxia o el barotrauma en cada caso. Se hacen a continuación de estas actividades, incluyendo una referencia detallada a la normativa legal vigente o de aprobación inminente en España y en Europa y se aportan direcciones de centros especializados para consultas sobre el tema. El documento incluye algunas recomendaciones para los cardiópatas que hayan de viajar en avión (AU)

Car driving, airplane piloting and underwater activities by subjects with heart disease may cause sudden incapacitation leading to the 1055of the safety margins necessary to avoid accidents. In the case of car driving and airplane piloting the risk affects, not only the driver or pilot, but also passengers and/or bystanders within an accident zone. In the case of diving the risk resides basically in the loss of control of the vital support mechanisms necessary in a very hostile medium. This document reviews the possible causes of unexpected incapacitation, with or without loss of consciousness, in the light of the pathophysiologic consequences of fatigue, hypoxia, stress or barotrauma posed by each activity. Detailed recommendations are made for limiting driving, piloting and diving, based on official Spanish and European regulations and the addresses of specialized centers are provided for consultation. Moreover, recommendations for airplane travel for patients with heart disease are indicated (AU)

Guías de práctica clínica de la Sociedad Española de Cardiología sobre conducción de vehículos, pilotaje de aviones y actividades subacuáticas en cardiópatas / Guidelines of the Spanish Society of Cardiology for Airplane Piloting, Car Driving and Underwater Activities in Subjects with Heart Disease

La conducción de vehículos, el pilotaje de aviones y las actividades subacuáticas plantean para el cardiópata el riesgo de sufrir episodios de incapacidad transitoria, posiblemente súbita, que le impidan mantener el margen de seguridad necesario para evitar accidentes. En el caso de la conducción de automóviles y el pilotaje de aviones el riesgo abarca al cardiópata conductor, pero también a sus pasajeros y a los habitantes o viandantes de una posible zona de accidente. En el caso del buceo el riesgo fundamental es el de perder control de los mecanismos de apoyo vital en un medio muy hostil. Se revisan en este documento las causas de incapacidad transitoria, con y sin pérdida de conciencia, y otras situaciones de limitación funcional, partiendo de las alteraciones fisiopatológicas producidas por el estrés, la fatiga, la hipoxia o el barotrauma en cada caso. Se hacen a continuación recomendaciones en cuanto a la limitación de estas actividades, incluyendo una referencia detallada a la normativa legal vigente o de aprobación inminente en España y en Europa y se aportan direcciones de centros especializados para consultas sobre el tema. El documento incluye algunas recomendaciones para los cardiópatas que hayan de viajar en avión (AU)