Juliana F Fernandes

Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study

BACKGROUNDnIn chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients.nnnMETHODSnThis prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/Lu2008×u2008h). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up.nnnFINDINGSn56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients.nnnINTERPRETATIONnThis reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease.nnnFUNDINGnNone.

Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?

Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4(+) and CD3(+) cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

Second transplant with two unrelated cord blood units for early graft failure after haematopoietic stem cell transplantation

Graft failure (GF) can be a fatal complication following haematopoietic stem cell transplantation (HSCT). We report four patients who developed early GF after unrelated HSCT and who subsequently received a double unrelated cord blood transplant (dUCBT) after reduced‐intensity conditioning, at a median 15u2003d after the decision to perform a second transplant. Neutrophil recovery was observed in all four patients between day +15 and +31 with full donor chimaerism of one unit. Acute GVHD grades II–IV was observed in three patients. Three are alive, between 12 and 25u2003months after dUCBT. In conclusion, dUCBT is a promising procedure to treat early GF.

Engraftment kinetics and graft failure after single umbilical cord blood transplantation using a myeloablative conditioning regimen

Umbilical cord blood transplant recipients are exposed to an increased risk of graft failure, a complication leading to a higher rate of transplant-related mortality. The decision and timing to offer a second transplant after graft failure is challenging. With the aim of addressing this issue, we analyzed engraftment kinetics and outcomes of 1268 patients (73% children) with acute leukemia (64% acute lymphoblastic leukemia, 36% acute myeloid leukemia) in remission who underwent single-unit umbilical cord blood transplantation after a myeloablative conditioning regimen. The median follow-up was 31 months. The overall survival rate at 3 years was 47%; the 100-day cumulative incidence of transplant-related mortality was 16%. Longer time to engraftment was associated with increased transplant-related mortality and shorter overall survival. The cumulative incidence of neutrophil engraftment at day 60 was 86%, while the median time to achieve engraftment was 24 days. Probability density analysis showed that the likelihood of engraftment after umbilical cord blood transplantation increased after day 10, peaked on day 21 and slowly decreased to 21% by day 31. Beyond day 31, the probability of engraftment dropped rapidly, and the residual probability of engrafting after day 42 was 5%. Graft failure was reported in 166 patients, and 66 of them received a second graft (allogeneic, n=45). Rescue actions, such as the search for another graft, should be considered starting after day 21. A diagnosis of graft failure can be established in patients who have not achieved neutrophil recovery by day 42. Moreover, subsequent transplants should not be postponed after day 42.

Avaliação do concreto reforçado com baixos teores de fibras para fins estruturais segundo a norma EN 14651-2007

RESUMO Dentre os diversos metodos de avaliacao do comportamento mecânico de concreto reforcado com fibras (CRF), o ensaio proposto pela norma EN 14651-2007 e um dos mais promissores. Isto ocorre porque o mesmo e base da nova proposta do fib Model Code para o dimensionamento de estruturas utilizando o CRF. Dado que nao ha normas tecnicas brasileiras abordando esse tipo de ensaio, e necessario empregar este metodo de ensaio na avaliacao do CRF. Para tal, um estudo experimental foi desenvolvido focando o uso deste metodo de ensaio para a qualificacao e dosagem de concretos reforcados com baixos teores de fibras de aco e de macrofibras polimericas. Foram realizados ensaios de flexao de corpos-de-prova prismaticos com entalhe na face inferior, cuja funcao e induzir o posicionamento da fissura. Foram estudados tres tipos de fibra, duas compostas de polipropileno (nas dosagens de 3,0, 4,5 e 6,0kg/m 3 – correspondentes a 0,33, 0,50 e 0,66% em volume, respectivamente) e uma de aco (nas dosagens de 15, 25 e 35 kg/m 3 – correspondentes a 0,19, 0,32 e 0,45% em volume, respectivamente) em uma matriz de concreto de resistencia a compressao media de 35MPa. Verificou-se grande estabilidade nos resultados dos ensaios, com baixa dispersao nos resultados. Foi comprovado que e possivel dosar as fibras de modo a atender diferentes niveis de requisitos estabelecidos no fib Model Code para o CRF destinado a aplicacoes estruturais quando sao considerados os valores medios dos resultados de ensaio. Esta situacao pode nao se repetir quando os resultados caracteristicos sao considerados. Palavras-chave: concreto reforcado com fibras, estruturas de concreto, metodo de ensaio, resistencia residual.

Concreto submetido a vibrações nas primeiras idades

Este artigo traz informacoes sobre o comportamento nas primeiras idades de um concreto de alta resistencia, produzido com cimento de alta resistencia inicial, lancado e adensado em ambientes submetidos a vibracoes, como em obras de pontes de rodovias. Apresenta-se o programa experimental desenvolvido, descrevendo desde a moldagem dos corpos-de-prova, sob acao de vibracoes similares as induzidas pelo trafego, ate os ensaios de caracterizacao mecânica e de aderencia aco-concreto. Os resultados experimentais indicam que o concreto submetido a vibracao nas primeiras idades pode sofrer perdas na resistencia a tracao e no modulo de elasticidade. A reducao dessas propriedades pode comprometer a utilizacao da estrutura devido ao aparecimento de flechas e fissuras acima dos limites de norma. A reducao da resistencia a tracao do concreto deve ser considerada, tambem, na aplicacao de pavimentos rigidos, onde essa propriedade e fundamental para garantir a durabilidade do sistema. Nao foi observada nenhuma reducao na resistencia a compressao ou na capacidade de aderencia devido a introducao de vibracoes nas primeiras idades do concreto.

Lomentospora prolificans fungemia in hematopoietic stem cell transplant patients: First report in South America and literature review

Lomentospora prolificans is a filamentous fungus and an emerging pathogen in immunocompromised patients. It is encountered most commonly in Australia, Spain, and USA. We described the first case of Lomentospora prolificans fungemia in South America. The patient was a hematopoietic stem cell transplantation (HSCT) recipient who developed the infection 37 days after stem cells infusion. In addition, we performed a literature review of invasive lomentosporiosis in HSCT patients.