Impaired repair properties of endothelial colony-forming cells in patients with granulomatosis with polyangiitis.

In patients with ANCA-associated vasculitis, interactions between neutrophils and endothelial cells cause endothelial damage and imbalance. Endothelial colony-forming cells (ECFCs) represent a cellular population of the endothelial lineage with proliferative capacity and vasoreparative properties. This study aimed to evaluate the angiogenic capacity of ECFCs of patients with granulomatosis with polyangiitis (GPA). The ECFCs of 13 patients with PR3-positive GPA and 14 healthy controls were isolated and characterized using fluorescence-activated cell sorting, capillary tube formation measurement, scratching assays and migration assays with and without plasma stimulation. Furthermore, three patients with active disease underwent post-treatment recollection of ECFCs for longitudinal evaluation. The ECFCs from the patients and controls showed similar capillary structure formation. However, the ECFCs from the patients with inactive GPA exhibited early losses of angiogenic capacity. Impairments in the migration capacities of the ECFCs were also observed in patients with GPA and controls (12th h, p = 0.05). Incubation of ECFCs from patients with GPA in remission with plasma from healthy controls significantly decreased migration capacity (p = 0.0001). Longitudinal analysis revealed that treatment significantly lowered ECFC migration rates. This study revealed that ECFCs from the patients with PR3-positive GPA in remission demonstrated early losses of tube formation and reduced migration capacity compared to those of the healthy controls, suggesting impairment of endothelial function.

Longitudinal sequencing of RUNX1 familial platelet disorder: new insights into genetic mechanisms of transformation to myeloid malignancies.

The mechanisms by which patients with RUNX1 familial platelet disorder with propensity to myeloid malignancies (FPDMM) develop myeloid malignancies (MM) are not fully understood. We report the results of targeted next-generation sequencing on three patients with RUNX1 FPDMM who developed acute myeloid leukaemia or myelodysplastic syndromes (AML/MDS). DNA samples were collected from bone marrow, peripheral blood and buccal swabs at different time points. One patient had clonal haematopoiesis, represented by an SRSF2 p.P95R variant, prior to his AML diagnosis, when he developed an additional NRAS p.G12D variant. His sister presented to us with MDS, with a TET2 p.S471fs and identical NRAS p.G12D variant. The third patient, from another family, had an additional RUNX1 p.R204X and an NFE2 p.Q139fs variant at AML diagnosis. This constitutes the first report of NFE2 variants in AML without extramedullary disease and NRAS variants in AML/MDS in the setting of FPDMM. A systematic review of the literature including our findings distinguishes two genetic landscapes at AML transformation from FPDMM characterized by either the presence or absence of somatic abnormalities in RUNX1 with or without variants in genes usually associated with MM. Whether clonal haematopoiesis precedes transformation only in patients without somatic abnormalities in RUNX1 needs further confirmation.

Thalidomide for the Treatment of Gastrointestinal Bleeding Due to Angiodysplasia in a Patient with Glanzmann's Thrombasthenia.

Angiodysplasia is a frequent cause of persistent gastrointestinal (GI) hemorrhage in elderly patients. Although GI bleeding isn't the most common manifestation in patients with bleeding disorders, when present, it represents a challenging complication. We describe a 62-year-old patient with Glanzmann's thrombasthenia, who used thalidomide for severe and recurrent GI bleeding. For 6 months, the patient experienced temporary control of GI bleeding with thalidomide in a daily oral dose of 100 mg. The anti-angiogenic effects of thalidomide have recently been explored by several groups, particularly in the management of bleeding from angiodysplasia, including cases with von Willebrand disease. Here, we review the relevant descriptions of the use of thalidomide in this situation, and also discuss potential reasons why we observed only a temporary control of the GI bleeding in our patient, such as the use of low-dose regimen due to limitations posed by thalidomide side effects.

Deferasirox associated with liver failure and death in a sickle cell anemia patient homozygous for the -1774delG polymorphism in the Abcc2 gene.

This manuscript describes the case of a patient with sickle cell anemia who died of fulminant hepatitis after therapy with the iron chelator Deferasirox. The patient was homozygous for the -1774delG polymorphism in the Abcc2 gene, which raises the concern about the use of hepatotoxic drugs in this specific context.

Brazilian experience using high-dose sequential chemotherapy followed by autologous hematopoietic stem cell transplantation for relapsed or refractory Hodgkin lymphoma.

PURPOSE: We evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma. PATIENTS AND METHODS: We performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide. RESULTS: The majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively. CONCLUSION: Despite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.

Brazilian experience using high-dose sequential therapy (HDS) followed by autologous hematopoietic stem cell transplantation (ASCT) for malignant lymphomas / Experiência brasileira utilizando terapia sequencial de alta dose seguido de transplante autólogo de célula-tronco hematopoética para linfomas malignos

Using the overall survival (OS), disease free survival (DFS) and progression free survival (PFS), as well as associated toxicity, the purpose of this work was to evaluate the effectiveness of HDS followed by ASCT as salvage therapy. A retrospective analysis was performed of 106 patients with high grade non-Hodgkin lymphoma receiving HDS followed by ASCT, between 1998 and 2006. Median age was 45 years (Range: 8-65), with 66 (62 percent) men. Histopathological classification was: 78 percent DLBCL patients, 12 percent T and anaplastic and 9 percent Mantle cell lymphomas; 87 percent had B cell and 12 percent T cell lymphomas; 83 percent were stage III-IV (Ann Arbor Staging), 63 percent had B symptoms, 32 percent had bone marrow involvement, 62 percent bulky disease and 42 percent high-intermediate or high risk IPI. After HDCY, 9 patients died, 7 from toxicity and 2 from sepsis. Eighty patients underwent ASCT, 47 percent were in complete remission (CR) and 15 percent died, all from toxicity. Their OS was 45 percent over 8 years. During the follow-up, another 35 patients died [4 CR, 1 partial response (PR), 2 relapsed disease (RD) and 28 disease progression (DP)], 11 (31 percent) had not performed ASCT. OS was 37 percent; DFS was 49 percent and PFS 28 percent. OS by diagnosis was 42 percent for DLBCL, 40 percent for T-cell (8 y) and 20 percent for Mantle Cell (6 y) (P=NS). OS by B symptom patients was 22 percent vs. 58 percent (P=0.002) and PFS was 23 percent vs. 37 percent (P=0.03). Patients who achieved CR after HDCY (38) had significantly better OS and PFS (38 percent and 17 percent) than patients who remained in DP (P<0.0001). Cox Regression demonstrated therapeutic lines before HDCY (Relative risk - RR = 1.41; CI 95 percent: 1.04-1.90; P= 0.02) and PD both before (RR = 2.70; CI 95 percent: 1.49-4.91, P<0.001) and after HDCY (RR = 5.38; 95 percent CI: 2.93-9.87; P<0.0001). Conclusions: Our study suggests HDS is an efficient treatment to ...

A proposta deste trabalho foi avaliar a eficácia da HDS seguida do transplante autólogo como terapia de salvamento através da sobrevida global, livre de doença e livre de progressão bem como sua toxicidade. Realizou-se estudo retrospectivo com 106 pacientes com LNH de alto grau de malignidade entre 1998 e 2006. A mediana de idade foi 45 anos (8-65); 62 por cento homens; DLBCL, 78 por cento; 12 por cento, T e anaplásico e 9 por cento, linfoma da zona do manto; 87 por cento, células B; 83 por cento estádios III-IV; 63 por cento com sintomas B; 32 por cento com infiltração da medula óssea ao diagnóstico; 62 por cento com grande massa e 42 por cento com IPI de alto risco ou intermediário. Após alta dose de ciclofosfamida (HDCY), nove pacientes faleceram. Oitenta pacientes realizaram o transplante, sendo que 47 por cento estavam em RC e 15 por cento faleceram devido à toxicidade. A sobrevida global foi de 45 por cento em oito anos para estes pacientes. Trinta e cinco pacientes não realizaram o transplante por causas diversas. Sobrevida global para todos os pacientes foi de 42 por cento, DLBCL, 40 por cento; T-cell, 40 por cento e zona do manto, 20 por cento (P=NS). Pacientes que obtiveram RC após HDCY tiveram melhor sobrevida global e livre de progressão (38 por cento e 17 por cento, respectivamente) do que os que permaneceram em PD (P<0.0001). O modelo de Cox resultou que o número de linhas terapêuticas antes da HDCY (RR 1.41 IC 95 por cento: 1.04-1.90, P=0.02) e PD antes da HDCY (RR 2.70, IC 95 por cento: 1.49-4.91, P<0.001) e após HDCY (RR 5.38, IC 95 por cento: 2.93-9.87, P<0.0001). Nosso estudo sugere que HDS é um método eficiente de tratamento para melhorar o status e reduzir a massa tumoral. Em relação à toxicidade, é factível, especialmente em pacientes de prognóstico ruim