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1.
Rinsho Ketsueki ; 62(8): 1256-1264, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497214

RESUMO

Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD) of the liver, is one of the most relevant complications of hepatic sinusoidal endothelial origin that appears early after hematopoietic cell transplantation (HCT). Despite its relatively low incidence and the spontaneous resolution of most SOS/VOD cases, severe SOS/VOD evolved to multi-organ failure with an >80% mortality rate and represents one of the major clinical problems after HCT. The sinusoidal endothelial cells and hepatocytes are damaged by toxic metabolites generated by the conditioning regimen in these patients. Several risk factors have been identified for SOS/VOD development. Although defibrotide is recommended for both prevention and treatment, no satisfactory therapy exists for managing severe SOS/VOD. Thus, this review describes the new definition of SOS/VOD diagnosis and the severity grading of suspected SOS/VOD from the European Society for Blood and Marrow Transplantation. Furthermore, it describes the results of current treatment including the Japanese therapeutic use program, defibrotide treatment protocol.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Células Endoteliais , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos/uso terapêutico , Condicionamento Pré-Transplante
2.
Bone Marrow Transplant ; 56(10): 2454-2463, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34059801

RESUMO

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos , Estudos Prospectivos , Sistema de Registros
3.
Front Immunol ; 12: 641427, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093530

RESUMO

Endothelial cell (EC) dysfunction causes a number of early and life-threatening post hematopoietic stem cell transplant (HCT) complications that result in a rapid clinical decline. The main early complications are graft-vs.-host disease (GVHD), transplant associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome (SOS). Post-HCT endothelial dysfunction occurs as a result of chemotherapy, infections, and allogeneic reactivity. Despite major advances in transplant immunology and improvements in supportive care medicine, these complications represent a major obstacle for successful HCT. In recent years, different biomarkers have been investigated for early detection of post-transplant endothelial cell dysfunction, but few have been validated. In this review we will define GVHD, TA-TMA and SOS, summarize the current data available in HCT biomarker research and identify promising biomarkers for detection and diagnosis of early HCT complications.


Assuntos
Biomarcadores/sangue , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva/sangue , Microangiopatias Trombóticas/sangue , Aloenxertos , Animais , Doença Enxerto-Hospedeiro/etiologia , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Microangiopatias Trombóticas/etiologia
4.
Medicine (Baltimore) ; 100(25): e26463, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160449

RESUMO

RATIONALE: Veno-occlusive disease (VOD) is characterized by painful hepatomegaly, ascites, weight gain, and jaundice with nonthrombotic, fibrous obliteration of the centrilobular hepatic veins. VOD after liver transplantation is a rare complication, with an incidence of approximately 2%; however, it can be life-threatening in severe cases. The precise etiology and mechanism of VOD after liver transplantation remains unclear. Acute cellular rejection, antibody-mediated rejection, and treatment with tacrolimus or azathioprine may be associated with the development of VOD after liver transplantation. Additionally, the optimal treatment of VOD after liver transplantation has not yet been established and focuses on supportive care. Defibrotide is an anti-ischemic and antithrombotic drug with no systemic anticoagulant effects. Moreover, only a few reports have investigated the use of defibrotide for VOD after liver transplantation, which has shown promising results. PATIENT CONCERNS: A 39-year-old woman with primary biliary cholangitis underwent living-donor liver transplantation at our center. She experienced right upper quadrant pain with increased ascites, pleural effusion, and weight gain on postoperative day 14. DIAGNOSES: Imaging and pathological tests showed no evidence of rejection or vessel complications. VOD was diagnosed clinically based on the findings of weight gain, ascites, jaundice, and pathological biopsy. INTERVENTIONS: Defibrotid, 25 mg/kg/day, was administered intravenously for 21 days. OUTCOMES: She showed complete clinical resolution of the VOD. LESSONS: Herein, we report a case of successful defibrotide treatment of VOD after living-donor liver transplantation.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Cirrose Hepática Biliar/cirurgia , Transplante de Fígado/efeitos adversos , Polidesoxirribonucleotídeos/uso terapêutico , Adulto , Aloenxertos/patologia , Biópsia , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Fígado/patologia , Doadores Vivos , Resultado do Tratamento
5.
J Med Econ ; 24(1): 628-636, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33858278

RESUMO

AIMS: This study evaluated cost-effectiveness of defibrotide vs best supportive care (BSC) for the treatment of hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) with multiorgan dysfunction (MOD) post-hematopoietic cell transplantation (HCT) in Spain. MATERIALS AND METHODS: A two-phase Markov model, comprising a 1-year acute phase with daily cycles and a lifetime long-term phase with annual cycles, was adapted to the Spanish setting. The model included a cohort of patients with severe VOD/SOS (defined as VOD/SOS with MOD) post-HCT. For the acute phase, efficacy and VOD/SOS-related length of stay were obtained from a phase 3 defibrotide study (NCT00358501). VOD/SOS-related hospital stays were 7.5 and 23.2 days in defibrotide-treated and BSC patients, respectively. Defibrotide-treated patients spent 30% of their stay in the intensive care unit vs 60% in BSC patients. Assumptions for the long-term phase and utility values were obtained from the literature. Costs were from the Spanish Health System perspective (€2019). Defibrotide cost was based on 25 mg/kg/day over 17.5 days, using local expert opinion. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were estimated over a lifetime horizon, applying a 3% discount rate for costs and outcomes. Sensitivity analyses assessed the robustness of the results. RESULTS: Defibrotide produced an additional 1.214 QALYs and 1.348 LYs vs BSC, with a total cost of €33,708 more than BSC alone. However, defibrotide resulted in savings up to €16,644/patient for cost of hospital stay. Difference between costs and effective measures led to ratios of €27,757/QALY and €25,007/LY gained. Additional hospital stays had the greatest influence on base-case results. Probabilistic analysis confirmed the robustness of the deterministic results. LIMITATIONS: Limitations include use of historical controls and assumptions extrapolated from the literature. CONCLUSIONS: This cost-effectiveness model, adapted to the Spanish setting, showed that defibrotide is a cost-effective alternative to BSC alone in patients with severe VOD/SOS post-HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Análise Custo-Benefício , Fibrinolíticos/uso terapêutico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos/uso terapêutico , Espanha
6.
Int J Hematol ; 114(1): 94-101, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33763826

RESUMO

Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). We previously reported the efficacy of the Hokkaido Ultrasonography (US)-based scoring system (HokUS-10) for US findings. To establish easier-to-use criteria, we retrospectively evaluated US findings from 441 patients, including 30 patients with SOS using the HokUS-10 scoring system. Using logistic regression analysis, we established the novel diagnostic criteria HokUS-6. In the presence of ascites, US diagnosis was made in the presence of two of the following 6 parameters: moderate amount of ascites, the appearance of a paraumbilical vein blood flow signal, gallbladder wall thickening, portal vein dilatation, portal vein velocity decrease, and hepatic artery resistive index increase. The AUC, sensitivity, and specificity of HokUS-6 were 0.974 (95% confidence interval 0.962-0.990), 95.2%, and 96.9%, respectively. The scores were significantly higher in patients with severe SOS than in those with non-severe SOS (p = 0.013). Furthermore, the scores before HSCT were significantly higher in patients who developed SOS than in controls (p = 0.001). The HokUS-6 is an easy and useful way to diagnose and identify the risk of SOS.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico por imagem , Hepatopatia Veno-Oclusiva/etiologia , Fígado/diagnóstico por imagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia , Adulto Jovem
7.
Zhonghua Gan Zang Bing Za Zhi ; 29(1): 92-96, 2021 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-33541030

RESUMO

Hepatic sinusoidal obstruction syndrome (HSOS) is the most common early complication in patients with hematopoietic stem cell transplantation (HSCT). According to reports, the average incidence of HSOS post-HSCT is 13.7% (0~62%). HSOS may be accompanied by multiple organ failure, and the mortality rate can exceed 80% at 100 days of onset. Defibrotide is currently the safest and most effective drug used to prevent and treat HSOS post-HSCT. It is currently the only drug approved in the United States for the treatment of HSOS with lung/renal dysfunction post-HSCT. In addition, it has been approved in the European Union for the treatment of severe HSOS cases post-HSCT. This article briefly describes and summarizes the research progress, clinical application, pharmacokinetics, efficacy, safety, dose and treatment of defibrotide in HSOS post-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Fibrinolíticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos/uso terapêutico , Estados Unidos
8.
Br J Haematol ; 193(1): 43-51, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538335
9.
Bone Marrow Transplant ; 56(7): 1603-1613, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33526915

RESUMO

We attempted to identify the incidence and survival outcome of hepatic sinusoidal obstruction syndrome/veno-occlusive disease (VOD/SOS) after hematopoietic cell transplantation (HCT) under strategy of prophylactic ursodiol and intravenous heparin or prostaglandin E1 (PGE1). From 2009 to 2018, 2572 consecutive allogeneic-HCT cases were reviewed. We used oral ursodiol for all transplants, and most were administered low-dose heparin, while PGE1 in selected cases with low platelet count at the time of preconditioning. Diagnosis and severity grades were reassessed by revised EBMT criteria. The overall incidence of hepatic VOD/SOS was 3.4% (Mild 0.9%, Moderate 0.6%, Severe 0.7%, Very severe 1.2%) after allogeneic-HCT under strategy of intravenous prophylaxis. The 1-year overall survival of VOD/SOS was 41.4% which was divided into 73.9% for mild, 66.7% for moderate, 38.9% for severe, and 6.5% for very severe grade. Very high disease risk index, male gender, donor other than matched sibling donor, and busulfex > 9 mg/kg were affecting factors for development of VOD/SOS. For severe to very severe VOD/SOS, history of pre-HCT liver dysfunction was an additionally affecting factor. Allogeneic-HCT using ursodiol and intravenous prophylaxis was considered safe without significant bleeding complications and should be evaluated in future clinical trials. For those with high-risk of VOD/SOS, early intervention and management is important.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Adulto , Alprostadil , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Heparina , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/prevenção & controle , Humanos , Incidência , Masculino , Fatores de Risco , Ácido Ursodesoxicólico
10.
Bone Marrow Transplant ; 56(7): 1635-1641, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33608657

RESUMO

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present prospective study, we aimed to investigate the incidence, management, and outcome of VOD/SOS in patients with thalassemia major (TM) who received allo-HSCT. VOD/SOS was diagnosed and classified based on the modified Seattle criteria. The prophylactic regimen for VOD/SOS was a combination treatment of dalteparin and lipo-PGE1. VOD/SOS was managed through an approach consisting of adequate supportive measures, short-term withdrawal of calcineurin inhibitors (CNIs), and the use of methylprednisolone and basiliximab for graft-versus-host disease prophylaxis. VOD/SOS was found in 54 of 521 patients (10.4%) at a median time of 12 days after allo-HSCT. The cumulative incidence of all-grade and moderate VOD/SOS was 10.4% and 4.2%, respectively. Among the 54 VOD/SOS patients, no patient developed severe grade and died from VOD/SOS. Besides, the cumulative incidence of transplant-related mortality on day 100 for patients with or without VOD/SOS was 0% vs. 4.0% (P = 0.187), respectively, and the 3-year overall survival rates were 94.3% vs. 93.2% (P = 0.707), respectively. Collectively, we concluded that appropriate symptomatic therapy and short-term withdrawal of CNIs safely mitigated the mortality of VOD/SOS in TM patients who underwent allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Talassemia beta , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Incidência , Polidesoxirribonucleotídeos/uso terapêutico , Estudos Prospectivos
11.
Anticancer Res ; 41(1): 391-402, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419836

RESUMO

BACKGROUND/AIM: Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS). PATIENTS AND METHODS: We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients. RESULTS: SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX. CONCLUSION: S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hepatopatia Veno-Oclusiva/etiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Adulto , Biomarcadores , Capecitabina/administração & dosagem , Gerenciamento Clínico , Combinação de Medicamentos , Feminino , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/terapia , Humanos , Incidência , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Ácido Oxônico/administração & dosagem , Estudos Retrospectivos , Baço/patologia , Esplenectomia , Tegafur/administração & dosagem , Resultado do Tratamento
12.
J Med Ultrason (2001) ; 48(1): 45-52, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33398544

RESUMO

PURPOSE: Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a fatal complication after hematopoietic stem cell transplantation. We previously reported the usefulness of an ultrasonographical (US) scoring system, the Hokkaido US-based scoring system consisting of ten parameters (HokUS-10): (1) hepatomegaly in the left lobe and (2) right lobe, (3) dilatation of the main portal vein (PV), (4) hepatofugal flow in the main PV, (5) decreased velocity of the PV, (6) dilatation of the para-umbilical vein (PUV), (7) appearance of blood flow signal in the PUV, (8) gallbladder (GB) wall thickening, (9) ascites, and (10) increased resistive index of the hepatic artery, for the diagnosis of SOS/VOD. However, the reliability of this system among operators remains elusive. Therefore, we prospectively evaluated the reliability of HokUS-10. METHODS: Twenty-four healthy volunteers and 40 patients with liver dysfunction were enrolled. Inter- and intra-operator reliabilities were analyzed using three sonographers. RESULTS: The median concordance rate of HokUS-10 among three sonographers and intra-operator in 24 volunteers was 92% (95% CI: 73-98%) and 98% (95% CI: 92-100%), respectively. In all 64 cases, in terms of the reliability between two sonographers for three representative US parameters (amount of ascites, GB wall thickening, and appearance of PUV blood flow signal), the median concordance rate was more than 98% (95% CI: 86-106%). CONCLUSION: The inter- and intra-reliabilities of HokUS-10 were excellent. Thus, US might be a reliable tool for SOS/VOD diagnosis.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico por imagem , Hepatopatia Veno-Oclusiva/etiologia , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Artéria Hepática/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Veia Porta/diagnóstico por imagem , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto Jovem
13.
BMC Gastroenterol ; 21(1): 26, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33423668

RESUMO

BACKGROUND: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) on hepatic sinusoidal obstruction syndrome (HSOS) associated with consumption of Gynura segetum (GS). METHODS: We retrospectively reviewed 9 consecutive patients with GS-related HSOS who were refractory to supportive treatment and underwent TIPS at our institution between January 2014 and September 2019. The patients were evaluated for safety and efficacy, including TIPS complications and changes in portosystemic pressure gradient (PPG), ascites, total bilirubin, liver size and portal vein diameter. RESULTS: TIPS procedures were performed successfully in the 9 patients, and no technically-related complications due to the TIPS procedure were recorded. The PPG was improved by TIPS in all patients (mean PPG before TIPS, 30.4 ± 5.2 vs. 13.0 ± 4.1 mm Hg post-TIPS, P = 0.008). One patient who was lost to follow-up, whereas the remaining 8 patients survived with a median follow-up period of 12 months (range 5-39 months). Although the total bilirubin was significantly increased 5-7 days after TIPS compared with that before the procedure (3.57 ± 1.58 vs. 4.82 ± 2.06 mg/dl, P = 0.017), it returned to baseline levels at 1-month follow-up (3.53 ± 2.72 vs. 4.82 ± 2.06 mg/dl, P = 0.401). The patients experienced complete resolution or noticeable reduction of ascites (P < 0.001), significant reduction of liver size (16.7 ± 2.2 vs. 13.7 ± 1.7 cm, P = 0.018), and significant enlargement of the portal trunk (10.7 ± 2.5 vs. 13.4 ± 2.4 mm, P = 0.017) after TIPS compared to the pre-TIPS state. CONCLUSION: TIPS may offer a potentially useful treatment for the GS-related HSOS.


Assuntos
Hepatopatia Veno-Oclusiva , Derivação Portossistêmica Transjugular Intra-Hepática , Medicamentos de Ervas Chinesas , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Estudos Retrospectivos , Resultado do Tratamento
14.
Bone Marrow Transplant ; 56(2): 411-418, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32839533

RESUMO

Hepatic veno-occlusive disease (VOD) is a serious systemic endothelial complication after stem cell transplantation. Defibrotide is under investigation as a prophylactic agent for VOD; however, high costs limit its utility. We evaluated the prophylactic efficacy of a low-dose defibrotide regimen for VOD. We retrospectively enrolled 147 paediatric patients who underwent autologous haematopoietic stem cell transplantation (HSCT; 69 with defibrotide prophylaxis and 78 historical controls) at the Yonsei Cancer Center in Seoul, Korea, between March 2013 and Feb 2020. Low-dose defibrotide (12.5 mg/kg/day) was administered from D-3 to D+10 after HSCT. The most common diagnosis in the cohort was brain tumour (N = 86). VOD developed in 10 (12.8%) and 3 (4.3%) patients in the control and prophylaxis groups, respectively (P = 0.071). In the second HSCT group, VOD incidence was significantly lower in the prophylaxis group [2.9% (1/35)] than in the control group (28.6%, 6/21, P = 0.005). VOD severity was significantly higher in the control group than in the prophylaxis group (P = 0.006). Three VOD-related mortalities occurred in the control group, whereas no VOD-related mortality occurred in the prophylaxis group. In conclusion, low-dose defibrotide prophylaxis is a promising and economical strategy for preventing VOD, especially in second-round HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/prevenção & controle , Humanos , Polidesoxirribonucleotídeos , República da Coreia , Estudos Retrospectivos
15.
Bone Marrow Transplant ; 56(1): 121-128, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32623447

RESUMO

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12-58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21-30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57-8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Sirolimo/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo
16.
Am J Transplant ; 21(2): 864-869, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33037770

RESUMO

Classical veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication post allogeneic hematopoietic stem cell transplantation (HSCT). Before the recently revised EBMT criteria, the Baltimore and modified Seattle criteria failed to recognize the syndrome of late-onset VOD. We present real-world experience from a large UK transplant center reporting on VOD/SOS in consecutive HSCT adult patients (n = 530), transplanted for hematological cancers. We identified 27 patients treated with Defibrotide for VOD/SOS diagnosis, where detailed data were available for final analysis. Using standard definitions including EBMT criteria, around 30% (n = 8/27) of cases classified as late-onset VOD presenting at median of 46 (22-93) days but with D100 survival (63% vs 58%, Log-rank; P = 0.81) comparable to classical VOD. Hazard ratio for D100 mortality was 2.82 (95% CI: 1.74-4.56, P < .001, Gray test) with all VOD/SOS events. Twenty percent (n = 2/8) of late-onset VOD patients were anicteric and 42% (n = 8) classical VOD patients presented with refractory thrombocytopenia, while less than half met EBMT criteria for classical VOD in adults, highlighting gaps in real-world diagnostic limitations using EBMT criteria. However, challenges remain about underrecognition and difficulties related to early defibrotide access for treatment of late-onset VOD in current treatment guidelines. Our report strongly supports early Defibrotide for the treatment of severe VOD/SOS in adults regardless of time of onset.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Adulto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos , Reino Unido
17.
Int J Hematol ; 113(1): 34-44, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32902759

RESUMO

Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.


Assuntos
Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/terapia , Neoplasias Hematológicas/complicações , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Trombomodulina/uso terapêutico , Antitrombina III/análise , Biomarcadores/análise , Biomarcadores/sangue , Coagulação Intravascular Disseminada/diagnóstico , Fibrina/análise , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Peptídeo Hidrolases/análise , Proteínas Recombinantes/uso terapêutico , Solubilidade , Microangiopatias Trombóticas/etiologia
18.
Haematologica ; 106(2): 446-453, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31974195

RESUMO

No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Biomarcadores , Endotélio , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Fatores de Risco
19.
Anticancer Res ; 40(12): 6817-6833, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288574

RESUMO

BACKGROUND: In patients with colorectal liver metastases, the possibility for radical liver resection can be limited by oxaliplatin-induced sinusoidal obstruction syndrome (SOS). This study investigates the potential of mesenchymal stem cells (MSC) to improve the outcome of liver resections in pigs with SOS. MATERIALS AND METHODS: SOS was induced in all animals (n=20) on day 0. Animals in the experimental group (n=8) received allogeneic MSC on day 7. Liver resection was performed in all animals on day 14 and the animals were observed until day 28. Ultrasound volumetry, biochemical analysis and histological examination of liver parenchyma was performed during the follow-up period. RESULTS: Six animals from the control group died prematurely, while all animals survived in the experimental group. According to histology, biochemical analysis and ultrasound volumetry, there were no significant differences between the groups documenting the effect of MSC. CONCLUSION: Single dose allogeneic MSC administration improved survival of animals with SOS undergoing partial liver resection. Further experiments with different timing of liver resection and MSC administration should be performed to investigate the effect of MSC in more detail.


Assuntos
Hepatectomia , Hepatopatia Veno-Oclusiva/patologia , Hepatopatia Veno-Oclusiva/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Biomarcadores , Neoplasias Colorretais/patologia , Terapia Combinada , Modelos Animais de Doenças , Feminino , Hepatectomia/métodos , Hepatopatia Veno-Oclusiva/etiologia , Imuno-Histoquímica , Imunofenotipagem , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/secundário , Masculino , Células-Tronco Mesenquimais/citologia , Suínos , Resultado do Tratamento
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