Diagnosis of acute graft-versus-host disease in the gastrointestinal tract of patients undergoing allogeneic hematopoietic stem cell transplantation. A descriptive and critical study of diagnostic tests

ABSTRACT Introduction: Acute graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT) and has become the subject of several studies to understand and treat it. Objective: This study does a descriptive analysis of the apoptotic index (AI) evaluation and intestinal permeability (IP) alterations in association with the clinical, endoscopic and histopathological data on patients undergoing AHSCT, with emphasis on acute intestinal graft-versus-host disease (GVHD) diagnosis. Methods: Thirty-one patients were divided into two groups—one of patients with a clinical GVHD diagnosis and one of those without GVHD diagnosis. Results: Thirteen deaths (41.9%) occurred during the study period, thereby reaffirming the severity of the alterations found in the patients. Fifteen patients subjected to 21 esophagogastroduodenoscopy procedures prior to D + 90 post-transplant had visible endoscopic alterations and 19 biopsies revealed histological alterations to the stomach and duodenum. Higher apoptotic indices, not reaching statistical significance, were observed in patients who died of graft versus host disease (GVHD), in the more acute forms of GVHD and where clinical GVHD was present. The intestinal permeability evaluation was performed on nine patients able to undergo it in the three proposed study periods, which showed alterations, some of which were pronounced even during pre-transplant and, therefore, the pre-conditioning phase. Conclusion: Clinical judgment remains a fundamental tool in the diagnosis of GVHD. This study points to the known limitations of traditional diagnostic aids (endoscopy and histology) and points to new methods not usually employed in clinical practice.

FLT3 Mutations: Significance in Paediatric AML

Patients with acute myeloid leukaemia (AML) who have FMS-like tyrosine kinase 3 (FLT3) mutations are a concern for haematologists. Many studies indicate that these patients have poor prognosis. Due to the dearth of research in this area, the role of allogeneic transplantation as a therapy is still controversial. But the available limited data suggest that transplantation in first remission is possibly the first choice. As FTL3 mutations in AML result in poor patient outcomes, different FLT3 inhibitors are used as specific targeted therapy.

Comportamento dos enxertos alógenos em bloco na reconstrução alveolar maxilar antes e após a instalação de implantes: análise tomográfica, histológica e imunohistoquímica da incorporação e remodelação / Behavior of bone block allografts in the maxillary alveolar reconstruction before and after implants placement: tomographic, histological and immunohistochemical analysis of the incorporation and remodeling

Rebordos alveolares extensamente reabsorvidos podem levar a um volume ósseo insuficiente para a instalação de implantes osseointegrados, assim como comprometer as restaurações definitivas no ponto de vista estético e funcional.Na última década, diversos estudos têm demonstrado a aplicação de enxertos alógenos como substitutos ósseos nareconstruçãoalveolar.Apesar de bem documentado em relatos e séries de casos, o uso do tecido alógeno ainda requer estudos mais bem desenhados para a orientação da prática clínica e das condutas na sua utilização. O objetivo do presente estudo foi avaliar o comportamento clínico dos aloenxertos ósseos em bloco antes e após a instalação dos implantes, além de investigar sua incorporação e remodelação. Em um período de 53 meses, pacientes que tivessem indicação para reconstrução maxilar óssea em bloco foram consecutivamente incluídos no estudo. O trabalho foi dividido em 4 estudos para a investigação dos parâmetros separadamente: a incorporação e remodelação; a prevalência de complicações e taxade sobrevivência dos implantes;dados histológicos e tomográficos de longo prazo; além de um ensaio piloto.Os enxertos apresentaram taxas de reabsorção entre 13,98% (4 meses) e 31,52% (6 meses); neoformação óssea entre 20,79% (4 meses) e 27,2% (6 meses);presença de células ósseas e ausência de infiltrado inflamatório histologicamente; intensa positividade para um marcador de atividade óssea fisiológica; prevalência de complicações de 22,14%; além demonstrar uma taxa de sobrevivência dos implantes instalados de 94,03%. Após 4 anos de acompanhamento com implantes em carga, demonstram uma reabsorção entre 2,1 a 7,7%. Histologicamente, foram encontrados remanescentes do tecido alógeno juntamente com um número abundante de osteócitos, osteoblastos e vasos.Os parâmetros avaliados apresentam-se similares aos de outras modalidades reconstrutivas, demonstrando a viabilidade dos enxertos em bloco alógenos como uma opção para o aumento ósseo maxilar com fins de instalação de implantes dentais.

Extremely resorbed alveolar ridges may lead to insufficient bone volume for dental implants placement, as well as jeopardize the final prosthesis in the aesthetic and functional standpoints. In the last decade, several studies have demonstrated the application of allogeneic grafts as bone substitutes in the alveolar reconstruction. Although case reports and case series are well documented in the literature, the use of the allograft bone requires more well-designed studies to guide the clinical practice. The aim of this study was to evaluate the clinical behavior of bone allograft blocks before and after implant placement and to investigate its incorporation and remodeling. In a 53-months period, patients who had indication for maxillary bone block reconstruction were consecutively included in the study. The trial was divided into four studies to investigate the following parameters separately: the incorporation and remodeling; the prevalence of complications and the survival rate of the implants; histological and tomographic long-termdata; and a pilotstudy. The grafts showed resorption rates from 13.98% (4 months) to 31.52% (6 months); new bone formation from 20.79% (4 months) to 27.2% (6 months); presence of bone cells and absence of inflammatory infiltratehistologically; intense positivity for a physiological bone activitymarker; 22.14% prevalence of complications; and a implants survival rate of 94.03%. After a 4 years follow-up with loaded implants, the grafts demonstrated a reabsorption rate from 2.1 to 7.7%. Histologically, remnants of allograft tissue were found along with an abundant number of osteocytes, osteoblasts and vessels. The evaluated parameters showed to be similar to other reconstructive procedures, demonstrating the viability of allogeneic bone block grafts as an option to augment thealveolar ridgefor dental implants placement

Effect of FK506 nanospheres on regeneration of allogeneic nerve after transplant

OBJECTIVE@#To discuss effect of FK506 nanospheres used at different time on the regeneration of allogeneic nerve after transplant.@*METHODS@#Single emulsion-solvent evaporation method (O/W) was adopted to prepare the FK506 nanospheres and the tibial nerve of rats after allogeneic transplantation. FK506 nanospheres were used in group A after operation immediately, in group B in 24 h after operation, and in group C in 3 d after operation while FK506 nanospheres were not used in group D; in the 4th, 8th and 12th week after operation respectively, general observation of transplanted nerves, histological examination, image analysis of myelinated fibers, wet-weight determination of musculi triceps surae, retrogradely labeling of neurons by the fluorescein and electrophysiological comparison of bilateral tibial nerve were carried out.@*RESULTS@#FK506 nanospheres can be degraded and absorbed quickly. The neural regenerations in group A and B were similar, which were both much better than those in group C and D. The difference was statistically significant and so was the difference between group C and D.@*CONCLUSIONS@#Drug release rate of FK506 nanospheres is accordant with the regeneration law of damaged nerves and the local application can promote the regenerations of nerves. The effect would be better if the drug is used in earlier period (within 24 h).

Efficacy of imatinib mesylate-based front-line therapy in pediatric chronic myelogenous leukemia / 소아과

PURPOSE: Despite the established role of imatinib (IM) in chronic myelogenous leukemia (CML) in adults, there are few reports on its efficacy in children. In this study, we compared the outcomes of children with CML before and after the advent of IM-based treatment. METHODS: The study cohort consisted of 52 patients treated for CML at the Department of Pediatrics, The Catholic University of Korea from January 1995 to October 2010. Patients were divided and analyzed according to the preImatinib group (pre-IMG) and imatinib group (IMG). RESULTS: Median age at diagnosis for the overall cohort (pre-IMG, n=27; IMG, n=25) was 9 years, with a median follow-up duration of survivors of 84 months. Except for 5 patients in the IMG, all were diagnosed in chronic phase (CP). The overall survival (OS) of patients diagnosed in CP was 45.7% and 89.7% for pre-IMG and IMG, respectively (P=0.025). The OS of hematopoietic stem cell transplantation (HSCT) recipients in the 2 groups was similar, but the OS of patients diagnosed in CP who did not receive HSCT was superior in IMG (91.7% vs. 16.7%, P=0.014). Of the 12 patients in IMG who remained on IM without HSCT, 2 showed disease progression, compared to 11 of 12 in pre-IMG. No difference was observed in the progression free survival (PFS) of matched donor HSCT recipients and IM-based treatment recipients. CONCLUSION: Similar PFS of patients treated with IM and those who received matched donor HSCT underscore the potential of IM as effective first-line treatment in childhood CML.

Expression of SOCS1 and SOCS3 genes in human graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

BACKGROUND: Suppressor of cytokine signaling genes (SOCS) are regarded as pivotal negative feedback regulators of cytokine signals, including the interferon-gamma (IFN-gamma), granulocyte-colony stimulating factor, and interleukin families, released by T cells. A detailed understanding of the involvement of SOCS genes in graft-versus-host disease (GVHD) is critical to effectively manage GVHD, yet their expression patterns among recipients remain largely unexplored. METHODS: Expression levels of SOCS1 and SOCS3 were determined by real-time quantitative reverse transcription PCR (qRT-PCR) in patients with acute GVHD (aGVHD) and chronic GVHD (cGVHD), in a severity-dependent manner, after allogeneic hematopoietic stem cell transplantation (HSCT). A total of 71 recipients with AML (N=40), ALL (N=12), myelodysplastic syndromes (MDS; N=10), chronic myelogenous leukemia (CML; N=2), severe aplastic anemia (SAA; N=5), or others (N=2), who received allogeneic HSCT from human leukocyte antigen-identical siblings or unrelated donors between 2009 and 2011, were included in the present study. RESULTS: Overall, the expression levels of SOCS1 decreased in recipients with grade II to IV aGVHD and cGVHD when compared to normal donors and non-GVHD recipients. Interestingly, the expressions of SOCS1 decreased significantly more in cGVHD than in aGVHD recipients (P=0.0091). In contrast, SOCS3 expressions were similarly reduced in all the recipients. CONCLUSION: This is the first study to show that SOCS1 and SOCS3 are differentially expressed in recipients following allogeneic HSCT, suggesting a prognostic correlation between SOCS genes and the development of GVHD. This result provides a new platform to study GVHD immunobiology and potential diagnostic and therapeutic targets for GVHD.

Expression of SOCS1 and SOCS3 genes in human graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

BACKGROUND: Suppressor of cytokine signaling genes (SOCS) are regarded as pivotal negative feedback regulators of cytokine signals, including the interferon-gamma (IFN-gamma), granulocyte-colony stimulating factor, and interleukin families, released by T cells. A detailed understanding of the involvement of SOCS genes in graft-versus-host disease (GVHD) is critical to effectively manage GVHD, yet their expression patterns among recipients remain largely unexplored. METHODS: Expression levels of SOCS1 and SOCS3 were determined by real-time quantitative reverse transcription PCR (qRT-PCR) in patients with acute GVHD (aGVHD) and chronic GVHD (cGVHD), in a severity-dependent manner, after allogeneic hematopoietic stem cell transplantation (HSCT). A total of 71 recipients with AML (N=40), ALL (N=12), myelodysplastic syndromes (MDS; N=10), chronic myelogenous leukemia (CML; N=2), severe aplastic anemia (SAA; N=5), or others (N=2), who received allogeneic HSCT from human leukocyte antigen-identical siblings or unrelated donors between 2009 and 2011, were included in the present study. RESULTS: Overall, the expression levels of SOCS1 decreased in recipients with grade II to IV aGVHD and cGVHD when compared to normal donors and non-GVHD recipients. Interestingly, the expressions of SOCS1 decreased significantly more in cGVHD than in aGVHD recipients (P=0.0091). In contrast, SOCS3 expressions were similarly reduced in all the recipients. CONCLUSION: This is the first study to show that SOCS1 and SOCS3 are differentially expressed in recipients following allogeneic HSCT, suggesting a prognostic correlation between SOCS genes and the development of GVHD. This result provides a new platform to study GVHD immunobiology and potential diagnostic and therapeutic targets for GVHD.

Treatment of Acute Myocardial Infarction by Allogeneic Transplantation of Rat Bone Marrow Mesenchymal Stem Cells / 中国康复理论与实践

@#Objective To investigate the feasibility of acute myocardial infarction(AMI)treated with transplantation of bone marrow mesenchymal stem cells(MSCs).Methods Fifty female Wistar rats were randomly divided into the transplant group and control group with 25 animals in each group.The AMI animal model was made by liquid nitrogen freezing.Rat MSCs cultured and induced repeatedly was prepared for transplantation and injected into the infarcted parts of the transplant group.The same volume of DMEM solution was injected into the infarcted parts of the control group.Echocardiography was applied one day preoperation,and one week and four weeks postoperation to evaluate cardiac function.The animals of the transplanted group were executed in the fourth week after operation and the tissues of transplant part were examined by BrdU immunofluorescent stain.Results Some transplant cells expressed the cardiac-specific proteins,α-actin and troponin T.The cardiac function of the transplant group had better than that of the control group(P>0.05)in the fourth week postoperation.The BrdU-labeled cells were found in the histological sections of the transplant parts.Conclusion Rat MSCs cultured generation by generation and repeatedly induced by 5-aza in vitro can differentiate into cardiomyocyte-like cells,which if transplanted into the rat infarcted cardiac muscles will survive and help to improve the host's cardiac function.

Pre-transplant Disease Status is Important for an Improved Outcome of the Second Stem Cell Transplantation in the Myeloma Patients Receiving the First Autologous Stem Cell Transplantation

BACKGROUND: Double autologous stem cell transplantation (ASCT) seems to be superior to a single ASCT, at least in the patients who did not achieve a 90% response after the first transplant. An allogeneic SCT with a dose-reduced conditioning regimen after ASCT and as part of the initial therapy, might be a feasible and highly effective approach. The aim of this study was to determine the prognostic factors that are associated with the outcome of multiple myeloma (MM) patients who had received a second transplant. METHODS: From April 1996 to December 2004, 38 MM patients, who had previously received high-dose melphalan (200 mg/m2) with autologous stem cell support, underwent a second transplant. Following the 1(st) ASCT, 24 patients received a second ASCT and 14 received a tandem reduced-intensity conditioning allogeneic stem cell transplantation (RIST) from their HLA-matched siblings. RESULTS: The 3-year estimated PFS and overall survival (OS) from the time of the first ASCT were 25.2% and 77.6%, respectively. The median PFS and OS were 26 months (95% CI, 23~29) and 60 months (95% CI, 44~76), respectively. The disease status (a CR vs. PR or less) at the second transplant was be the most powerful factor for improving the PFS (P=0.001, hazard ratio 5.8, 95% CI 2.1~16.1). CONCLUSION: Patients whose disease is sensitive to chemotherapy and who obtain a CR after a single transplantation might benefit the most from a second transplant.

Regulatory T Cells and Allogeneic Transplantation / 소아과

Allogeneic organ or hematopoietic stem cell transplantation(HSCT) is the treatment of choice for end-stage organ diseases or various hematologic disorders. The induction of alloantigen specific T cell tolerance and its maintenance are critical for preventing immune responses, including graft rejection or graft-versus-host disease(GVHD) in allogeneic transplantation. CD4+ T cells are classified as immune functions : Th1 CD4+ cells for cellular immunity, Th2 for humoral immunity, Th3 for suppressive effect against activated T cells, Tr1 for regulation of immune response. Some CD4+ regulatory T cells have a major role in controlling immune response to alloantigen. A minor population of CD4+ T cells, which co-express the interleukin-2 receptor(IL-2R) alpha-chain(CD25), is crucial for the control of autoreactive T cells and for peripheral tolerance in allogeneic transplantation. CD4+CD25+ regulatory T cells express high level of cytotoxic T lymphocyte associated antigen 4(CTLA 4), as cell-contact mechanism, and secret immunomodulating cytokines, as IL-10 or TGF-beta, as independent cell contact. High expression of CTLA 4 on CD4+CD25+ T cells may contribute to deliver suppressive signals into T cells via CD28. Immature dendritic cells have low expression of major histocompatibility(MHC) and co-stimulatory signals, and few secretion of IL-12. CD4+CD25+ T cells are developed by immature myeloid dendritic cells, which are controlled under vitamin D3 or IL-10. In kidney transplantation, graft survival in recipients with donor specific transfusion(DST) showed longer than without DST. DST may induce antigen specific CD4+CD25+ T cells, and these cells play a role for central or peripheral tolerance against immune cells. In allogeneic HSCT, donor CD4+CD25+ T cells suppress lethal GVHD in MHC mismatched pairs, and also may possess graft-versus-leukemia effect in early infusion with HSC. We need more study for cytotoxic effect of CD4+CD25+ T cells, which have Fas-FasL interaction, although these cells in cancer patients suppress autoreactive T cells against tumor. Recently, many trials have investigated treatment for intractable disease using various types of cells, including mesenchymal stem cells, dendritic cells. We have to consider ex vivo expansion of CD4+CD25+ T cells for induction of immune tolerance in allogeneic transplantation. Now, we have to study or understand immunoregulatory cells for allogeneic transplantation or immune control.

Study on the inhibition of allogeneic transplantation rejection by the B7 antisense peptide / 中国免疫学杂志

95%,WT= 1 271 6 .Lymphoproliferation reaction of the splenocytes derived from BALB/C mice was inhibited by stimulating with the antisense peptide pre treatment of allogeneic splenic cells and cardiac cells of C57 mice.The inhibition rates up to 38 4% and 36 6%.Pre treatment of allogeneic cardiac grafts resulted in prolonging the survival of cardiac transplantation 5 4 days more than the control group(n=6,P

New developments in allogeneic blood stem cell transplantation / Novos avanços no transplante alogênico de células progenitoras periféricas

Over the past three decades stem cell transplantation was considered solely a rescue treatment that enables patients to undergo myeloablative chemo/radiotherapy. Recent experimental and clinical data indicate that, in addition to the cytotoxic effect of high-dose chemo/radiotherapy, an immune-mediated effect significantly contributes to the therapeutic benefit of allogeneic stem cell transplantation on disease-free survival.

Nas últimas tres décadas o transplante de células progenitoras foi considerado como forma de tratamento a pacientes em condições de submeter-se previamente a mieloablação quimio/radioterapia. Experimentos recentes, no entanto, indicam que adicionalmente ao efeito citotóxico da quimio/radioterapia, o efeito imunoterápico do transplante de células progenitoras exerce um real benefício terapêutico.