RESUMO
Sirolimus-based graft vs. host disease (GVHD) prophylaxis is associated with higher incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after allogeneic hematopoietic cell transplantation (HCT). However, whether the clinical manifestations and prognosis of VOD/SOS differs when diagnosed in the setting of sirolimus-based GVHD prophylaxis is not well studied. To address this question, we examined presenting features and treatment outcome of VOD/SOS cases identified in a large retrospective cohort of consecutive HCT procedures (n = 818 total, sirolimus (SIR)/tacrolimus (TAC) n = 308, and methotrexate (MTX) or mycophenolate mofetil (MMF)/TAC n = 510). In multivariate analysis, sirolimus-based GVHD prophylaxis (p = 0.006, HR 3.33, 1.94-5.7) increased risk for VOD/SOS. A total of 58 patients were clinically diagnosed with VOD/SOS (SIR/TAC 38/308, 12.3%, vs. MTX or MMF/TAC 20/510, 3.9%). VOD/SOS diagnosed following SIR/TAC prophylaxis demonstrated later time of onset (median 39 vs. 26 days; p = 0.005), less severe hyperbilirubinemia (Bili > 2, 65% vs. 90% p = 0.04), lesser degree of weight gain (weight gain > 5%, 52% vs 80%, p = 0.04), and more frequent complete resolution of hepatic injury (79% vs. 55%, p = 0.05). Presenting features and natural history of VOD/SOS in the context of SIR/TAC GVHD prophylaxis differ and thus warrant particular clinical attention to later hepatic injury in these patients.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Sirolimo/efeitos adversos , Adulto , Idoso , Aloenxertos , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Hepatopatia Veno-Oclusiva/sangue , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sirolimo/administração & dosagemRESUMO
The pathologic interpretation of gut biopsies in hematopoietic cell transplant recipients to assess graft-versus-host disease (GVHD) is well accepted and supplements clinical and endoscopic findings. However, the histologic activity grading of GVHD is controversial, with attempts to predict prognosis or response to treatment largely unsuccessful. GVHD is being diagnosed earlier in its course, raising the possibility that the pathologic grading system can be profitably modified. We developed a histologic activity grading system designed to replace the commonly used modified Lerner grading systems. Our system stratifies the low-level Lerner grade I category into 4 activity grade categories, based on the average frequency of apoptotic cells. The results are expressed as ordinal categories: GVHD of minimal, mild, moderate, severe histologic activity, or severe histologic activity with destruction (activity grades 1 to 5). In a retrospective study, we studied 87 consecutive cases with 201 post-transplantation specimens (median, 48 days; range, 18 to 1479 days) of stomach, duodenum, and colorectum, which had been activity graded at the time of the original diagnosis. Most of the biopsies diagnosed as GVHD were low grade-minimal (11%) or mild (71%) histologic activity. We hypothesized that the higher activity grades would be associated with more therapeutic intervention. The odds of increased therapy in the combined all-site specimens were increased as activity grade increased (odds ratio, 2.9 [95% confidence interval {CI}, 1.9 to 4.5]; P = < .0001). Thus, our grading system was validated. To investigate whether the activity grade was associated with therapy within the formerly undivided Lerner grade I category, the analysis was restricted to these 174 all-site specimens. The validation result was similar (odds ratio, 3.1 [95% CI, 1.3 to 7.2]; P = .009). This result interestingly suggests that there is useful information hidden in the Lerner grade I category, which could potentially guide immediately actionable treatment decisions. This histologic activity grade system has been in use at our institution for over 2 years with good acceptance.
Assuntos
Tomada de Decisão Clínica/métodos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Colo/cirurgia , Duodeno/efeitos dos fármacos , Duodeno/imunologia , Duodeno/patologia , Duodeno/cirurgia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Reto/efeitos dos fármacos , Reto/imunologia , Reto/patologia , Reto/cirurgia , Estudos Retrospectivos , Índice de Gravidade de Doença , Estômago/efeitos dos fármacos , Estômago/imunologia , Estômago/patologia , Estômago/cirurgia , Transplante HomólogoRESUMO
PURPOSE: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. RESULTS: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. CONCLUSIONS: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Rituximab/uso terapêutico , Esclerose/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto JovemRESUMO
Graft versus host disease (GvHD) is a clinically important complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its diagnosis relies on clinical and histopathological findings. In order to evaluate and improve inter-institutional diagnostic agreement on histological diagnosis and grading of acute gastrointestinal GvHD, we conducted a round robin test, which included 33 biopsies from 23 patients after HSCT. Five pathologists from different institutions independently evaluated the original sections from the biopsies submitted for diagnosis. Based on their results, consensus qualitative criteria for the assessment of typical histological features of GvHD (e.g., apoptosis, crypt destruction, mucosa denudation) were proposed, including detailed descriptions as well as histological images. In a second round robin test with involvement of the same pathologists, the reproducibility of both diagnosis and grading had improved. Remaining differences were mostly related to differential diagnostic considerations, including viral infection or toxic side effects of medication, which should be resolved by integrating histopathological findings with proper clinical information.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Adulto , Idoso , Aloenxertos , Consenso , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do ObservadorRESUMO
The 2005 National Institute of Health (NIH) Consensus Conference outlined histopathological diagnostic criteria for the major organ systems affected by both acute and chronic graft-versus-host disease (GVHD). The 2014 Consensus Conference led to this updated document with new information from histopathological studies of GVHD in the gut, liver, skin, and oral mucosa and an expanded discussion of GVHD in the lungs and kidneys. The recommendations for final histological diagnostic categories have been simplified from 4 categories to 3: no GVHD, possible GVHD, and likely GVHD, based on better reproducibility achieved by combining the previous categories of "consistent with GVHD" and "definite GVHD" into the single category of "likely GVHD." Issues remain in the histopathological characterization of GVHD, particularly with respect to the threshold of histological changes required for diagnostic certainty. Guidance is provided for the incorporation of biopsy information into prospective clinical studies of GVHD, particularly with respect to biomarker validation.
Assuntos
Ensaios Clínicos como Assunto , Doença Enxerto-Hospedeiro , Enteropatias , Hepatopatias , Doenças da Boca , Dermatopatias , Biomarcadores/metabolismo , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Humanos , Enteropatias/metabolismo , Enteropatias/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Doenças da Boca/metabolismo , Doenças da Boca/patologia , Dermatopatias/metabolismo , Dermatopatias/patologiaRESUMO
Development of liver disease after hematopoietic cell transplantation is common and the causes diverse. Infection by hepatitis C virus (HCV) can be seen in patients who are chronically infected before transplant or from passage of virus from an infected donor; the normal 10-year course of hepatitis C after transplant is one of waxing and waning of serum aminotransferase enzymes, with little morbidity. In the series of 3 patients reported here, the course of hepatitis C was rapidly fatal, with the onset of jaundice at day 60 to 80 after transplant and liver histology typical of fibrosing cholestatic hepatitis (marked bile ductular proliferation, ballooned hepatocytes, and associated collagenous fibrosis centered around ductules). The bile ductular reaction pattern varied from elongated structures without a recognizable lumen to a pattern of cuboidal cells with a clear lumen. There was significant cholestasis with bile within hepatocytes and canalicular bile plugs. In situ HCV RNA hybridization studies from 1 patient showed a robust infection with high levels of HCV-infected hepatocytes and active viral replication. All 3 patients were on immunosuppressive drugs after transplant, including mycophenolate mofetil (MMF), which irreversibly inhibits inosine monophosphate dehydrogenase, on which T and B lymphocytes are dependent. We speculate that fatal fibrosing cholestatic hepatitis C in these cases was related to the immunosuppressive effects of MMF, as we had not recognized this presentation of HCV infection before the introduction of MMF.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatite C/etiologia , Hepatite C/patologia , Hospedeiro Imunocomprometido , Adulto , Colestase/etiologia , Colestase/imunologia , Evolução Fatal , Fibrose/etiologia , Fibrose/imunologia , Hepatite C/imunologia , Humanos , Imunossupressores/efeitos adversos , Leucemia/cirurgia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/análogos & derivadosRESUMO
Cord colitis syndrome after umbilical cord blood transplantation (UCBT) involves late-onset diarrhea, absence of infection or GVHD, chronic active colitis, and granulomatous inflammation that responds to antibiotics. We tested the hypothesis that Seattle recipients of UCBT had late-occurring colitis distinct from GVHD and colitis in other allograft recipients. We conducted a blinded histological review of 153 colon biopsy specimens from 45 UCBT recipients and 45 matched allografted controls obtained between day +70 and day +365 post-transplantation. Diarrhea was the primary indication for biopsy in 10 UCBT recipients and 11 controls. No histological differences were seen between UCBT recipients and controls with diarrhea or between the entire cohort of UCBT recipients and their controls. Distorted mucosal architecture and apoptotic crypt cells typical of GVHD were common in both groups; Paneth cell metaplasia and granulomas were rare findings. Chronic active colitis was present in 58% of the UCBT recipients and in 62% of controls. No UCBT recipient with diarrhea was treated with antibiotics, and all recipients responded to systemic corticosteroids. Colitis occurring after day +70 in allografted controls was related to acute GVHD, independent of the source of donor cells. We could not identify a histologically distinct cord colitis syndrome in either the UCBT or the non-cord blood allograft recipients.
Assuntos
Colite/etiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Colite/patologia , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
After allogeneic hematopoietic cell transplantation (alloHCT) liver biopsy is performed for enigmatic liver disorders when noninvasive diagnostic steps have failed in establishing a definitive diagnosis. This document provides an updated consensus on the prerequisites for proper evaluation of liver biopsies in alloHCT patients and the histological diagnostic criteria for liver graft-versus-host disease (GvHD). The Working Group's recommendations for the histological diagnosis of liver GvHD were derived from the peer-reviewed literature and from the consensus diagnosis of a total of 30 coded liver biopsies. Acceptance of the recommendations was tested by a survey distributed to all HCT centers in Austria, Germany and Switzerland. Consensus was achieved for biopsy indications, methods of sample acquisition and processing, reporting and interpretation of biopsy findings. As GvHD is variably treated and the treatment modalities have changed over time, the panel endorses the use of more frequent biopsies in clinical studies in order to improve the present challenging clinical and diagnostic situation.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fígado/patologia , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto JovemRESUMO
Clonal cytogenetic abnormalities are a major risk factor for relapse after hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). We determined the impact of the recently established 5-group cytogenetic classification of MDS on outcome after HCT. Results were compared with the impact of the International Prognostic Scoring System (IPSS) 3 cytogenetic risk groups, and the additional effect of a monosomal karyotype was assessed. The study included data on 1007 patients, 1-75 years old (median 45 years), transplanted from related (n = 547) or unrelated (n = 460) donors. Various conditioning regimens were used, and marrow, peripheral blood, or cord blood served as stem cell source. Both IPSS and 5-group cytogenetic risk classifications were significantly associated with post-HCT relapse and mortality, but the 5-group classification discriminated more clearly among the lowest- and highest-risk patients. A monosomal karyotype tended to further increase the rates of relapse and mortality, even after considering the IPSS or 5-group classifications. In addition, the pathologic disease category correlated with both relapse and mortality. Mortality was also impacted by patient age, donor type, conditioning regimen, platelet count, and etiology of MDS. Although mortality declined significantly in recent years, novel strategies are needed to overcome the barrier of high-risk cytogenetics.
Assuntos
Análise Citogenética , Transplante de Células-Tronco Hematopoéticas , Cariótipo , Leucemia Mieloide Aguda/classificação , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto JovemRESUMO
Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.
Assuntos
Fibrinolíticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacocinética , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/metabolismo , Hepatopatia Veno-Oclusiva/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Polidesoxirribonucleotídeos/efeitos adversos , Polidesoxirribonucleotídeos/farmacocinética , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Many patients who undergo hematopoietic cell transplantation (HCT) present with anemia and have received red blood cell transfusions before HCT. As a result, iron overload is frequent and appears to be particularly prominent in patients with myelodysplastic syndromes. There is evidence that peritransplant events contribute to further iron accumulation, although the mechanism that disrupts normal iron homeostasis remains to be determined. Recent studies suggest that iron overload, as determined by ferritin levels, a surrogate marker for iron, is a risk factor for increased non-relapse mortality after HCT. Iron overload is associated with an increased rate of infections, in particular with fungal organisms. Furthermore anecdotal data suggest that increased hepatic iron may mimic the clinical picture of (chronic) graft-versus-host-disease (GVHD). Whether excess iron contributes to GVHD and whether iron depletion, be it by phlebotomy or chelation, reduces the post-transplantation complication rate and improves transplant outcome is yet to be determined.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Sobrecarga de Ferro/etiologia , Complicações Pós-Operatórias/etiologia , Anemia/etiologia , Anemia/terapia , Animais , Apoptose , Terapia por Quelação , Diagnóstico Diferencial , Transfusão de Eritrócitos/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/fisiopatologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Infecções/etiologia , Absorção Intestinal , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/terapia , Ferro da Dieta/farmacocinética , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/cirurgia , Flebotomia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/terapia , Transferrina/metabolismo , Transferrina/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversosRESUMO
BACKGROUND: The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD) resembles the appearance of fibrosis in scleroderma (SSc). Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed skin biopsies of normal controls (n = 24), patients with SSc (n = 30) and c-GVHD with dermal fibrosis (n = 133)). Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001) average vessels in SSc biopsies (9.8) when compared with c-GVHD (16.5). Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05), respectively). In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies. CONCLUSIONS/SIGNIFICANCE: The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.
Assuntos
Endotélio/patologia , Doença Enxerto-Hospedeiro/patologia , Escleroderma Sistêmico/patologia , Dermatopatias/patologia , Doença Crônica , Humanos , FenótipoRESUMO
Iron overload is common in patients undergoing allogeneic hematopoietic cell transplantation (HCT), but the mechanisms leading to overload are unknown. Here, we determined iron levels and the expression of iron regulatory proteins in the liver and gut of nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice that underwent transplantation with syngeneic (histocompatible) or allogeneic (histoincompatible) T lymphocytes. Infusion of histoincompatible T cells resulted in a significant rise in serum iron levels and liver iron content. Iron deposition was accompanied by hepatocyte injury and intestinal villous damage. Feeding of low- or high-iron diet was associated with appropriate ferroportin 1 and hepcidin responses in mice given histocompatible T cells, whereas mice given histoincompatible T cells showed inappropriate up-regulation of duodenal ferroportin 1 and a loss of expression of hepatic hepcidin. These findings suggest that alloreactive T cell-dependent signals induced dysregulation of intestinal iron absorption, which contributed to liver iron overload after HCT.
Assuntos
Transferência Adotiva/efeitos adversos , Homeostase/imunologia , Sobrecarga de Ferro/imunologia , Ferro/metabolismo , Linfócitos T/transplante , Animais , Apoproteínas/metabolismo , Sobrecarga de Ferro/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Linfócitos T/metabolismo , Transferrina/metabolismo , Transplante HomólogoRESUMO
BACKGROUND: Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal. CONCLUSION/SIGNIFICANCE: These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.
Assuntos
Capilares/fisiologia , Esclerodermia Difusa/cirurgia , Transplante de Células-Tronco , Humanos , Fenótipo , RegeneraçãoRESUMO
We analyzed outcomes after hematopoietic cell transplantation (HCT) in 257 patients, 3 to 72.7 years old (median, 43 y), with secondary myelodysplastic syndrome (MDS) including those with transformation to acute myeloid leukemia (tAML). Conditioning regimens included high-dose total-body irradiation (TBI)/chemotherapy (n = 83); busulfan (BU)/cyclophosphamide (CY) (BUCY, n = 122; with BU targeting [tBUCY], n = 93); fludarabine (Flu) with tBU (FLUtBU; n = 12); Flu plus 200 cGy TBI (n = 26); and miscellaneous regimens (n = 14). Donors were HLA-identical or partially mismatched family members in 135 and unrelated individuals in 122 patients. Five-year relapse-free survival was highest (43%) and nonrelapse mortality lowest (28%) among tBUCY-conditioned patients. Outcomes were compared with results in 339 patients who received transplants for de novo MDS/tAML, and a multivariate analysis failed to show significant differences in outcome between the 2 cohorts. Relapse probability and relapse-free survival correlated significantly with disease stage (P < .001) and karyotype (P < .001). Relapse incidence was lower (P = .003) and relapse-free survival superior (P = .02) with unrelated donor transplants. The data suggest that overall inferior outcome in patients with secondary MDS/tAML was related to the frequency of high-risk cytogenetics. For both cohorts, transplantation outcomes improved over the time interval studied.
Assuntos
Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Segunda Neoplasia Primária/terapia , Neoplasias/complicações , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Prognóstico , Taxa de Sobrevida , Condicionamento Pré-Transplante , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal TotalRESUMO
This consensus document provides an update for pathologists and clinicians about the interpretation of biopsy results and use of this information in the management of hematopoietic cell transplantation patients. Optimal sampling and tissue preparation are discussed. Minimal criteria for the diagnosis of graft-versus-host disease (GVHD) are proposed, together with specific requirements for the diagnosis of chronic GVHD. Four final diagnostic categories (no GVHD, possible GVHD, consistent with GVHD, and definite GVHD) reflect the integration of histopathology with clinical, laboratory, and radiographic information. Finally, the Working Group developed a set of worksheets to facilitate communication of clinical information to the interpreting pathologist and to aid in clinicopathologic correlation studies. Forms are available at . The recommendations of the Working Group represent a consensus opinion supplemented by evaluation of available peer-reviewed literature. Consensus recommendations and suggested data-capture forms should be validated in prospective clinicopathologic studies.
Assuntos
Ensaios Clínicos como Assunto/normas , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Biópsia , Doença Crônica , Gerenciamento Clínico , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , National Institutes of Health (U.S.) , Patologia/normas , Guias de Prática Clínica como Assunto , Estados UnidosRESUMO
Recent studies in lymphohemopoietic cells show that transferrin (Tf), a pivotal component of iron transport and metabolism, also exerts cytoprotective functions. We show here in a murine model that Tf interferes with Fas-mediated hepatocyte death and liver failure. The mechanism involves the downregulation of apoptosis via BID, cytochrome c, caspase-3 and caspase-9, and upregulation of antiapoptotic signals via Bcl-xL. The results obtained with iron-saturated Tf, Apo-Tf and the iron-chelator salicylaldehyde isonicotinoyl hydrazone indicate that the observed antiapoptotic effect of Tf was not mediated by iron alone. In conclusion, the data suggest that Tf has broader functions than previously recognized and may serve as a cytoprotective agent.
Assuntos
Falência Hepática/prevenção & controle , Transferrina/farmacologia , Receptor fas/fisiologia , Animais , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3 , Proteínas de Transporte/metabolismo , Caspase 3 , Caspase 9 , Caspases/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Citoproteção , Ativação Enzimática/efeitos dos fármacos , Feminino , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Ferro/metabolismo , Falência Hepática/etiologia , Falência Hepática/patologia , Falência Hepática/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína bcl-XRESUMO
Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fígado/lesões , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Hiperbilirrubinemia/etiologia , Lactente , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Transplante HomólogoRESUMO
This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 microg/kg per day; 10 microg/kg per day; 20 microg/kg per day) for 7 days to determine the optimal dose. The dose of 10 microg/kg per day of rhTPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/microL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/microL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/microL or in the time to recover neutrophil counts >500/microL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.