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Makuuchi Y, Tanaka S, Koh H, Niki M, Norose K, Nakaya Y, Ido K, Sakatoku K, Kuno M, Harada N, Takakuwa T, Hirose A, Okamura H, Nishimoto M, Nakashima Y, Nakamae M, Hikosaka K, Kakeya H, Ohsawa M, Hino M, Nakamae H. Sinusoidal obstruction syndrome associated with disseminated toxoplasmosis involving the liver after allogeneic hematopoietic stem cell transplantation: A case report. J Infect Chemother 2023:S1341-321X(23)00119-8. [PMID: 37207959 DOI: 10.1016/j.jiac.2023.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 04/11/2023] [Accepted: 05/10/2023] [Indexed: 05/21/2023]
Abstract
Sinusoidal obstruction syndrome (SOS) is a fatal complication after hematopoietic stem cell transplantation (HSCT). Only a few complications after HSCT have been reported as risk factors for SOS, including sepsis. Here, we report the case of a 35-year-old male diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent peripheral blood HSCT from a human leukocyte antigen-matched unrelated female donor in remission. Graft-versus-host disease prophylaxis contained tacrolimus, methotrexate, and low-dose anti-thymoglobulin. The patient was treated with methylprednisolone for engraftment syndrome from day 22. On day 53, he presented worsening fatigue, breathlessness, and abdominal pain in the right upper quadrant that had persisted for 4 days. Laboratory tests showed severe inflammation, liver dysfunction, and positive for Toxoplasma gondii PCR. He died on day 55. An autopsy showed SOS and disseminated toxoplasmosis. Hepatic infection with T. gondii was identified in zone 3 of the liver, which overlapped with the pathological features of SOS. In addition, the timing of the exacerbation of hepatic dysfunction coincided with the onset of systemic inflammatory symptoms and T. gondii reactivation. This rare case of toxoplasmosis is the first to suggest that hepatic infection with T. gondii is strongly associated with SOS after HSCT.
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Affiliation(s)
- Yosuke Makuuchi
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
| | - Sayaka Tanaka
- Department of Diagnostic Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hideo Koh
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan; Department of Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Makoto Niki
- Department of Infection Control and Prevention, Osaka Metropolitan University Hospital, Osaka, Japan
| | - Kazumi Norose
- Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yosuke Nakaya
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kentaro Ido
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuki Sakatoku
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masatomo Kuno
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Naonori Harada
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Teruhito Takakuwa
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Asao Hirose
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroshi Okamura
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Mitsutaka Nishimoto
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Yasuhiro Nakashima
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Mika Nakamae
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan; Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University, Osaka, Japan
| | - Kenji Hikosaka
- Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroshi Kakeya
- Department of Infection Control Science, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masahiko Ohsawa
- Department of Diagnostic Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masayuki Hino
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hirohisa Nakamae
- Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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Yazaki T, Kawashima K, Ishimura N, Kataoka M, Fukunaga M, Hyakudomi R, Tajima Y, Moriyama I, Araki A, Kadota K, Shibagaki K, Tobita H, Ishihara S. Oxaliplatin-related Portal Hypertension Complicated with Esophageal Varices and Refractory Massive Ascites. Intern Med 2022; 61:3225-3231. [PMID: 35370236 PMCID: PMC9683804 DOI: 10.2169/internalmedicine.9266-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/13/2022] [Indexed: 12/17/2022] Open
Abstract
Oxaliplatin, widely used as a chemotherapy drug for colorectal cancer, is known to cause various adverse reactions. In particular, special attention for the development of portal hypertension associated with porto-sinusoidal vascular disease is necessary, as it is a serious adverse life-threating reaction, although rare. We herein report a case of oxaliplatin-related portal hypertension that developed several years after oxaliplatin administration and led to esophageal varices and refractory massive ascites. Clinical physicians should be aware of the possibility of oxaliplatin-induced portal hypertension and its possible development over a long period after discontinuation of the drug.
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Affiliation(s)
- Tomotaka Yazaki
- Department of Hepatology, Shimane University Faculty of Medicine, Japan
| | - Kousaku Kawashima
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan
| | - Norihisa Ishimura
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan
| | - Masatoshi Kataoka
- Department of Hepatology, Shimane University Faculty of Medicine, Japan
| | - Mai Fukunaga
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan
| | - Ryoji Hyakudomi
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Japan
| | - Yoshitsugu Tajima
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Japan
| | - Ichiro Moriyama
- Division of Innovative Cancer Center, Shimane University Hospital, Japan
| | - Asuka Araki
- Department of Pathology, Shimane University Faculty of Medicine, Japan
| | - Kyuichi Kadota
- Department of Pathology, Shimane University Faculty of Medicine, Japan
| | | | - Hiroshi Tobita
- Department of Hepatology, Shimane University Faculty of Medicine, Japan
| | - Shunji Ishihara
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan
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Retrospective Application of Sinusoidal Obstruction Syndrome/Veno-occlusive Disease Diagnostic Criteria in a Pediatric Hematopoietic Stem Cell Transplant Cohort. J Pediatr Hematol Oncol 2022; 44:e343-e348. [PMID: 35200220 DOI: 10.1097/mph.0000000000002267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/10/2021] [Indexed: 11/26/2022]
Abstract
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) posthematopoietic stem cell transplantation (HSCT) is often diagnosed using the modified Seattle (MS) or European Society for Blood and Marrow Transplantation (EBMT) criteria. We hypothesized that strict application of these criteria could affect the timing of diagnosis and incidence of SOS/VOD. We collected data on 215 transplants performed in 184 patients at a single pediatric hematopoietic stem cell transplantation center, which were divided into 3 cohorts. Clinical diagnosis and treatment of SOS/VOD was documented in 13% of transplants (cohort 1). On retrospective review, 49% of transplant events met either MS and/or EBMT criteria, however, were not diagnosed with SOS/VOD (cohort 2); remaining 38% of transplant events did not meet MS or EBMT criteria and were not diagnosed with SOS/VOD (cohort 3). Day+100 overall survival was significantly inferior for cohort 1 (78%) compared with cohorts 2 or 3 (92% and 95%, P=0.01) with no difference between cohorts 2 and 3 (P=0.5). Patients diagnosed with SOS/VOD >day+13 had worse day+100 overall survival when compared with those diagnosed ≤day13 (64.3% and 100%, respectively, P=0.02). This study highlights the value of careful clinical assessment to guide diagnosis and the need to refine diagnostic criteria for SOS/VOD in children.
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Hoeben BAW, Wong JYC, Fog LS, Losert C, Filippi AR, Bentzen SM, Balduzzi A, Specht L. Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions. Front Pediatr 2021; 9:774348. [PMID: 34926349 PMCID: PMC8678472 DOI: 10.3389/fped.2021.774348] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 11/03/2021] [Indexed: 12/13/2022] Open
Abstract
Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.
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Affiliation(s)
- Bianca A. W. Hoeben
- Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
| | - Jeffrey Y. C. Wong
- Department of Radiation Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, United States
| | - Lotte S. Fog
- Alfred Health Radiation Oncology, The Alfred Hospital, Melbourne, VIC, Australia
| | - Christoph Losert
- Department of Radiation Oncology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Andrea R. Filippi
- Department of Radiation Oncology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy
| | - Søren M. Bentzen
- Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Adriana Balduzzi
- Stem Cell Transplantation Unit, Clinica Paediatrica Università degli Studi di Milano Bicocca, Monza, Italy
| | - Lena Specht
- Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Kloehn J, Brodt G, Ernst J, Gruhn B. Analysis of risk factors for hepatic sinusoidal obstruction syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients. J Cancer Res Clin Oncol 2021; 148:1447-1455. [PMID: 34255148 PMCID: PMC9114040 DOI: 10.1007/s00432-021-03732-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/07/2021] [Indexed: 01/19/2023]
Abstract
Purpose Hepatic sinusoidal obstruction syndrome (SOS) represents a serious complication following hematopoietic stem cell transplantation (HSCT). Our study aimed to investigate important risk factors of SOS in a pediatric population. Methods This retrospective study analyzed 105 children, adolescents and young adults who underwent allogeneic HSCT at our pediatric HSCT center in Jena. The observation period was 12 years and SOS was defined by the pediatric criteria of the European Society for Blood and Marrow Transplantation (EBMT). Results 15 out of all 105 patients developed SOS (14.3%). The median time from HSCT to SOS diagnosis was 12 days. The mortality rate of SOS was 20.0%. In univariate analyses, we identified the significant risk factors of patient age < 1 year [odds ratio (OR) = 7.25, p = 0.037], prior treatment with gemtuzumab ozogamicin (OR = 11.00, p = 0.020), high pretransplant ferritin levels above 1500 ng/mL (OR = 4.00, p = 0.033), 2000 ng/mL (OR = 4.69, p = 0.016), and 2400 ng/mL (OR = 5.29, p = 0.005) as well as international normalized ratio (INR) ≥ 1.3 (OR = 5.91, p = 0.009). The following risk factors could be confirmed in multivariate analysis: treatment with gemtuzumab ozogamicin (OR = 9.24, p = 0.048), ferritin > 2400 ng/mL (OR = 5.74, p = 0.023), and INR ≥ 1.3 (OR = 8.02, p = 0.007). Conclusion Our study confirms several risk factors from the current literature. Additionally, this is the first report on the risk factor of high pretransplant INR.
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Affiliation(s)
- Jaspar Kloehn
- Department of Pediatrics, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany
| | - Grit Brodt
- Department of Pediatrics, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany
| | - Jana Ernst
- Department of Pediatrics, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany
| | - Bernd Gruhn
- Department of Pediatrics, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.
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Hepatic veno-occlusive disease development in the hematopoietic stem cell transplantation patients: incidence and associated risk factors, a meta-analysis. Eur J Gastroenterol Hepatol 2021; 33:872-884. [PMID: 32639417 DOI: 10.1097/meg.0000000000001802] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Now there are no efficient prophylactic or treatment strategies for hepatic veno-occlusive disease (VOD). Therefore, it is critical to early identify patients at high risk of VOD. AIM To analyze the risk factors of VOD in the hematopoietic stem cell transplantation (HSCT) patients. METHODS A comprehensive search of the population was conducted. RESULTS Twenty-one studies with 27 679 HSCT patients were eligible. The incidence of VOD was 15% [95% confidence interval (CI) 13-17%]. The following were the risk factors for VOD: mismatched HLA [odds ratio (OR) 2.34, 95% CI 1.20-4.57, P = 0.01], history of liver disease (OR 2.72, 95% CI 2.03-3.64, P < 0.00001), elevated AST before transplant (OR 2.49, 95% CI 1.49-4.15, P = 0.0005), months from diagnosis to HSCT > 12 months (OR 1.76, 95% CI 1.15-2.69, P = 0.009), previous radiation (OR 1.86, 95% CI 1.49-2.31, P < 0.00001), busulphan (OR 3.69, 95% CI 2.58-5.29, P < 0.00001) and MTX (OR 1.81, 95% CI 1.22-2.69, P = 0.003). There were no significant differences for VOD presentation in the patients with regards to sex, number of HSCT, Karnofsky score <90%, unrelated donor, autologous HSCT, CYA and heparin prophylaxis. CONCLUSION Mismatched HLA, liver disease (history of liver disease, elevated AST), months from diagnosis to HSCT >12 months, previous radiation and use of hepatotoxic drugs (BU and MTX) are the independent risk factors for VOD in the HSCT patients.
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Shin J, Yoon H, Cha YJ, Han K, Lee MJ, Kim MJ, Shin HJ. Liver stiffness and perfusion changes for hepatic sinusoidal obstruction syndrome in rabbit model. World J Gastroenterol 2020; 26:706-716. [PMID: 32116418 PMCID: PMC7039830 DOI: 10.3748/wjg.v26.i7.706] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/08/2020] [Accepted: 01/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatic sinusoidal obstruction syndrome (SOS) is caused by damage to hepatic sinusoidal endothelial cells that results in fibrous obliteration of intrahepatic venules and necrosis of hepatocytes. Currently the diagnosis is primarily based on nonspecific clinical features and invasive liver biopsy. Therefore, noninvasive imaging methods are required for the early diagnosis and severity assessment of hepatic SOS.
AIM To determine the effectiveness of supersonic shear wave imaging (SSI) and dual energy computed tomography (DECT) for diagnosing hepatic SOS using a rabbit model.
METHODS Among nine New Zealand white rabbits (3-4 kg, male), three in control group ingested normal saline for 20 d and six in the SOS group ingested 6-thioguanine (5 mg/kg/d) for 20 d. Liver stiffness was measured using SSI on days 0, 3, 10, and 20. On the same days, liver perfusion was evaluated from virtual monochromatic images of 55 keV and iodine map using DECT. Morphologic changes in the liver were assessed using CT. Final pathology scores were compared between the two groups. Liver stiffness and perfusion parameters were compared according to the groups, days, and pathology scores.
RESULTS Final pathology scores were significantly higher in the SOS than the control group (median 22 vs 2, P = 0.024). No gross morphologic changes were seen in livers. Liver stiffness, Hounsfield Unit values, and iodine concentrations were higher in the SOS compared to the control group on days 10 and 20 (all, P ≤ 0.007). Compared to day 0, liver stiffness and perfusion parameters were higher on day 20 in the SOS group (all, P ≤ 0.001). Correlation coefficients for liver stiffness (r = 0.635), Hounsfield Unit values (r = 0.587), and iodine concentration (r = 0.611) with final pathology scores were positive without significance (all, P > 0.05).
CONCLUSION Liver stiffness and perfusion parameters were significantly increased in the livers of a rabbit SOS model. SSI and DECT might aid in early diagnosis of hepatic SOS.
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Affiliation(s)
- Jaeseung Shin
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Haesung Yoon
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Yoon Jin Cha
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea
| | - Kyunghwa Han
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Seoul 03722, South Korea
| | - Mi-Jung Lee
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Myung-Joon Kim
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hyun Joo Shin
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul 03722, South Korea
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Duncan C, Kahn J, Grupp SA, Richardson PG. Recent developments with defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Expert Opin Orphan Drugs 2019. [DOI: 10.1080/21678707.2019.1651641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Christine Duncan
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Justine Kahn
- Columbia University Irving Medical Center, New York, NY, USA
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Spectral Doppler Ultrasound Can Help Diagnose Children With Hepatic Sinusoidal Obstructive Syndrome After Hematopoietic Stem Cell Transplantation. Ultrasound Q 2019; 36:6-14. [PMID: 30921102 DOI: 10.1097/ruq.0000000000000441] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Hepatic sinusoidal obstruction syndrome (SOS) is a potentially fatal complication after hematopoietic stem cell transplantation (HSCT). Current clinical guidelines state that spectral Doppler changes occur late in the disease, and imaging is only useful for confirming SOS diagnosis. OBJECTIVE Our primary objective was to examine abdominal ultrasound variables as predictors of development of SOS in pediatric HSCT patients. MATERIALS AND METHODS A single-center cohort retrospective study was conducted on patients aged 0 to 21 years who underwent HSCT between September 2001 and May 2017 at our institution. Patients were excluded if they did not have abdominal ultrasounds after HSCT. Clinical, demographic, grayscale, and spectral Doppler liver ultrasound findings were evaluated. We modeled the odds of SOS diagnosis within 100 days after HSCT as a function of each of the 15 ultrasound variables. RESULTS A total of 333 patients received an HSCT. One hundred forty subjects had ultrasound data available. Thirty-two patients developed SOS, and 9 of these patients died. Sinusoidal obstruction syndrome odds more than double per 1-SD increase in peak systolic velocity in common hepatic artery or left hepatic artery and more than triple per 1-SD decrease in main portal vein velocity or change in ascites severity. Several ultrasound variables were statistically significant predictors in the Cox models for time to SOS diagnosis. CONCLUSION Several ultrasound variables can be used as predictors for a patient's risk of developing SOS. The strongest predictors are ascites severity, main portal vein velocity, common hepatic artery peak systolic velocity, and left hepatic artery peak systolic velocity.
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Ní Chonghaile M, Wolownik K. Identification and Management: Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Eelated to Hematopoietic Stem Cell Transplantation
. Clin J Oncol Nurs 2019; 22:E7-E17. [PMID: 29350698 DOI: 10.1188/18.cjon.e7-e17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Sinusoidal obstruction syndrome (SOS), also called hepatic veno-occlusive disease (VOD), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) that affects about 1 in 7 patients undergoing this procedure. SOS/VOD is caused by the conditioning regimens administered prior to HSCT; in some cases, SOS/VOD results from chemotherapy alone. SOS/VOD usually develops within three weeks following HSCT; however, it can have later onset.
. OBJECTIVES Clearly understanding how SOS/VOD develops may support prompt detection and treatment when the condition arises.
. METHODS Research on identification and management of SOS/VOD is summarized, and data from clinical trials are reviewed.
. FINDINGS This article describes the syndrome, risk factors, signs and symptoms, and appropriate supportive care and treatment. The authors also offer some practical tips for detecting SOS/VOD and providing patient care, as well as the latest information on treating and preventing this condition.
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11
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The incidence and risk factors of hepatic veno-occlusive disease after hematopoietic stem cell transplantation in Taiwan. Ann Hematol 2019; 98:745-752. [DOI: 10.1007/s00277-019-03604-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 01/03/2019] [Indexed: 01/04/2023]
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Jain T, Kunze KL, Khetarpal BK, McCallen MR, Betcher JA, Ofori HT, Khera N, Slack JL, Leis JF, Sproat LZ, Noel P, Palmer J. Early fluctuations in busulfan levels with therapeutic dose monitoring during allogeneic stem cell transplantation: do they matter? Leuk Lymphoma 2019; 60:2034-2041. [PMID: 30626239 DOI: 10.1080/10428194.2018.1562183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Therapeutic dose monitoring is widely adopted for determination of busulfan (Bu) dose for use as a conditioning regimen. However, while dose adjustments are being incorporated, transient fluctuations of Bu levels may occur. We aim to understand if these fluctuations affect clinical outcomes of these patients. We compared outcomes in patients in whom the absolute dose changes and fluctuation of AUC were ≥ median% versus < median%. Rates of sinusoidal obstructive syndrome, grades 2-4/grades 3-4 acute and chronic graft versus host disease were not different between the two cohorts. The Kaplan-Meier curves for overall survival showed no significant differences. Six patients required >50% dose adjustment and four had a fluctuation in AUC of >50%. One of these patients died of sinusoidal obstruction syndrome and two died of infections. In our study, the transient fluctuations in Bu levels did not affect clinical outcomes; hence obviating the need for test dose strategy.
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Affiliation(s)
- Tania Jain
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
| | - Katie L Kunze
- b Division of Biostatistics , Mayo Clinic , Phoenix , AZ , USA
| | | | | | | | - Henry T Ofori
- d Division of Pharmacy , Mayo Clinic , Phoenix , AZ , USA
| | - Nandita Khera
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
| | - James L Slack
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
| | - Jose F Leis
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
| | - Lisa Z Sproat
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
| | - Pierre Noel
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
| | - Jeanne Palmer
- a Division of Hematology/Medical Oncology , Mayo Clinic , Phoenix , AZ , USA
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George AP, Tse WT. Acute Complications in Hematopoietic Stem Cell Transplantation and Cellular Immunotherapy. CLINICAL PEDIATRIC EMERGENCY MEDICINE 2018. [DOI: 10.1016/j.cpem.2018.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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14
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Cheuk DKL, Anand V, Chiang AKS, Ha SY, Chan GCF. Interventions for treatment of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation. Hippokratia 2016. [DOI: 10.1002/14651858.cd009312.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Daniel KL Cheuk
- The University of Hong Kong, Queen Mary Hospital; Department of Pediatrics and Adolescent Medicine; Pokfulam Road Hong Kong China
| | - Vidhu Anand
- University of Minnesota; Department of Medicine; 420 Delaware Street SE Mayo Mail Code 195 Minneapolis MN USA 55455
| | - Alan KS Chiang
- The University of Hong Kong, Queen Mary Hospital; Department of Pediatrics and Adolescent Medicine; 121 Pokfulam Road Hong Kong SAR China
| | - Shau Yin Ha
- The University of Hong Kong, Queen Mary Hospital; Department of Pediatrics and Adolescent Medicine; 121 Pokfulam Road Hong Kong SAR China
| | - Godfrey CF Chan
- The University of Hong Kong, Queen Mary Hospital; Department of Pediatrics and Adolescent Medicine; 121 Pokfulam Road Hong Kong SAR China
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15
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Nazemi KJ, Shen V, Finlay JL, Boyett J, Kocak M, Lafond D, Gardner SL, Packer RJ, Nicholson HS. High Incidence of Veno-Occlusive Disease With Myeloablative Chemotherapy Following Craniospinal Irradiation in Children With Newly Diagnosed High-Risk CNS Embryonal Tumors: A Report From the Children's Oncology Group (CCG-99702). Pediatr Blood Cancer 2016; 63:1563-70. [PMID: 27203542 PMCID: PMC4955719 DOI: 10.1002/pbc.26074] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/18/2016] [Accepted: 04/28/2016] [Indexed: 01/07/2023]
Abstract
BACKGROUND The outcomes with high-risk central nervous system (CNS) embryonal tumors remain relatively poor despite aggressive treatment. The purposes of this study using postirradiation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (ASCR) were to document feasibility and describe toxicities of the regimen, establish the appropriate dose of thiotepa, and estimate the overall survival (OS) and event-free survival (EFS). PROCEDURE The Children's Cancer Group conducted this pilot study in children and adolescents with CNS embryonal tumors. The treatment consisted of induction chemotherapy to mobilize hematopoietic stem cells, chemoradiotherapy, and myeloablative consolidation chemotherapy with ASCR. RESULTS The study accrued 25 subjects in 40 months and was closed early due to toxicity, namely, veno-occlusive disease (VOD) of the liver, more recently termed sinusoidal obstructive syndrome (SOS). Of 24 eligible subjects, three of 11 (27%) receiving thiotepa Dose Level 1 (150 mg/m(2) /day × 3 days) and three of 12 (25%) receiving de-escalated Dose Level 0 (100 mg/m(2) /day × 3 days) experienced VOD/SOS. One additional subject experienced toxic death attributed to septic shock; postmortem examination revealed clinically undiagnosed VOD/SOS. The 2-year EFS and OS were 54 ± 10% and 71 ± 9%, respectively. The 5-year EFS and OS were 46 ± 11% and 50 ± 11%. CONCLUSIONS The treatment regimen was deemed to have an unacceptable rate of VOD/SOS. There was complete recovery in all six cases. The overall therapeutic strategy using a regimen less likely to cause VOD/SOS may merit further evaluation for the highest risk patients.
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Affiliation(s)
- Kellie J. Nazemi
- Oregon Health & Science University, Doernbecher Children's Hospital, Department of Pediatrics, Division of Pediatric Hematology-Oncology, 3181 SW Sam Jackson Park Road, CDRC-P, Portland, Oregon 97239
| | - Violet Shen
- Children's Hospital of Orange County, Cancer Institute, 1201 West LaVeta, Orange, California 92868
| | | | - James Boyett
- Saint Jude Children's Research Hospital, Biostatistics, 262 Danny Thomas Place, MS763, Memphis, Tennessee 38105-3678
| | - Mehmet Kocak
- University of Tennessee Health Science Center, Department of Preventive Medicine, 66 N. Pauline Street, Suite 633, Memphis, Tennessee 38103
| | - Deborah Lafond
- Children's National Health System, Department of Hematology-Oncology, 111 Michigan Avenue NW, Washington, DC 20010-2970
| | - Sharon L. Gardner
- New York University Langone Medical Center, Hassenfeld Children's Center, 160 East 32 Street, 2 Floor, New York, NY 10016
| | - Roger J. Packer
- Children's National Health System, Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, 111 Michigan Avenue NW, Washington, DC 20010-2970
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16
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Botti S, Orlando L, Gargiulo G, Cecco VD, Banfi M, Duranti L, Samarani E, Netti MG, Deiana M, Galuppini V, Pignatelli AC, Ceresoli R, Vedovetto A, Rostagno E, Bambaci M, Dellaversana C, Luminari S, Bonifazi F. Veno-occlusive disease nurse management: development of a dynamic monitoring tool by the GITMO nursing group. Ecancermedicalscience 2016; 10:661. [PMID: 27594906 PMCID: PMC4990055 DOI: 10.3332/ecancer.2016.661] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Indexed: 01/17/2023] Open
Abstract
Veno-occlusive disease (VOD) is a complication arising from the toxicity of conditioning regimens that have a significant impact on the survival of patients who undergo stem cell transplantation. There are several known risk factors for developing VOD and their assessment before the start of conditioning regimens could improve the quality of care. Equally important are early identification of signs and symptoms ascribable to VOD, rapid diagnosis, and timely adjustment of support therapy and treatment. Nurses have a fundamental role at the stages of assessment and monitoring for signs and symptoms; therefore, they should have documented skills and training. The literature defines nurses’ areas of competence in managing VOD, but in the actual clinical practice, this is not so clear. Moreover, there is an intrinsic difficulty in managing VOD due to its rapid and often dramatic evolution, together with a lack of care tools to guide nurses. Through a complex evidence-based process, the Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO), cellule staminali emopoietiche e terapia cellulare nursing board has developed an operational flowchart and a dynamic monitoring tool applicable to haematopoietic stem cell transplantation patients, whether they develop this complication or not.
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Affiliation(s)
- Stefano Botti
- Haematology Unit, Arcispedale Santa Maria Nuova-IRCCS Reggio Emilia, Italy
| | - Laura Orlando
- Division of Clinical Haemato-Oncology, Istituto Europeo di Oncologia, Milan, Italy
| | | | - Valentina De Cecco
- Paediatric Haemato-Oncology Unit, Policlinico S Matteo Pavia, Viale Camillo Golgi, 19, 27100 Pavia PV, Italy
| | - Marina Banfi
- BMT Unit, Ospedale Maggiore IRCCS Milano, Milan, Italy
| | - Lorenzo Duranti
- Haematology and BMT Unit, Ospedale Silvestrini, Perugia, Italy
| | | | - Maria Giovanna Netti
- SODc Paediatric Tumours and BMT Unit, Ospedale Pediatrico Meyer Firenze, Florence, Italy
| | - Marco Deiana
- Paediatric Haematology/Oncology Department, IRCCS G Gaslini, Genova, Italy
| | | | | | | | - Alessio Vedovetto
- Paediatric Haemato-Oncology and BMT Unit, Azienda Ospedaliera di Padova, Via Nicolò Giustiniani, 2, 35128 Padova PD, Italy
| | - Elena Rostagno
- Paediatric Haematology/Oncology and BMT Department, Azienda Ospedaliero, Universitaria S Orsola Malpighi, Bologna, Italy
| | - Marilena Bambaci
- Paediatric Haemato-Oncology and BMT Unit , Ospedale Regina Margherita, Torino, Italy
| | | | - Stefano Luminari
- Haematology Unit, Arcispedale Santa Maria Nuova-IRCCS Reggio Emilia, Italy
| | - Francesca Bonifazi
- Haematology and BMT Unit, Azienda Ospedaliero, Universitaria S Orsola Malpighi, Bologna, Italy
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17
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Dalle JH, Giralt SA. Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment. Biol Blood Marrow Transplant 2015; 22:400-9. [PMID: 26431626 DOI: 10.1016/j.bbmt.2015.09.024] [Citation(s) in RCA: 201] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 09/24/2015] [Indexed: 12/13/2022]
Abstract
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), can develop in a subset of patients, primarily after myeloablative hematopoietic stem cell transplantation, but it also may occur after reduced-intensity conditioning. Severe VOD/SOS, typically characterized by multiorgan failure, has been associated with a mortality rate greater than 80%. Therefore, an accurate and prompt diagnosis of VOD/SOS is essential for early initiation of appropriate therapy to improve clinical outcomes. Moreover, some studies have support the use of prophylaxis for patients who are at high risk of developing VOD/SOS. This review summarizes risk factors associated with development of VOD/SOS, including pretransplantation patient characteristics and factors related to stem cell transplantation, that can facilitate patient stratification according to risk. The incidence of VOD/SOS, clinical features, and diagnostic criteria are reviewed. Data on emerging treatment strategies for patients with VOD/SOS are discussed in the context of recent treatment guidelines. Additionally, options for prophylaxis in individuals who are at increased risk are presented. Although historically only those patients with moderate to severe VOD/SOS have been treated, early therapy and prophylaxis may be appropriate for many patients and may have the potential to improve patients' outcomes and survival, including for those with nonsevere disease.
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Affiliation(s)
- Jean-Hugues Dalle
- Department of Paediatric Haematology, Paris Diderot University, Sorbonne Paris Cité, Hôpital Robert Debré, APHP, Paris, France
| | - Sergio A Giralt
- Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
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18
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Cheuk DKL, Chiang AKS, Ha SY, Chan GCF, Cochrane Haematological Malignancies Group. Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation. Cochrane Database Syst Rev 2015; 2015:CD009311. [PMID: 26017019 PMCID: PMC10891422 DOI: 10.1002/14651858.cd009311.pub2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy. OBJECTIVES We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT. SEARCH METHODS We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all-cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results. AUTHORS' CONCLUSIONS There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed.
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Affiliation(s)
- Daniel KL Cheuk
- The University of Hong Kong, Queen Mary HospitalDepartment of Pediatrics and Adolescent MedicinePokfulam RoadHong Kong SARChina
| | - Alan KS Chiang
- The University of Hong Kong, Queen Mary HospitalDepartment of Pediatrics and Adolescent MedicinePokfulam RoadHong Kong SARChina
| | - Shau Yin Ha
- The University of Hong Kong, Queen Mary HospitalDepartment of Pediatrics and Adolescent MedicinePokfulam RoadHong Kong SARChina
| | - Godfrey CF Chan
- The University of Hong Kong, Queen Mary HospitalDepartment of Pediatrics and Adolescent MedicinePokfulam RoadHong Kong SARChina
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19
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Seifert C, Wittig S, Arndt C, Gruhn B. Heparanase polymorphisms: influence on incidence of hepatic sinusoidal obstruction syndrome in children undergoing allogeneic hematopoietic stem cell transplantation. J Cancer Res Clin Oncol 2015; 141:877-85. [PMID: 25335953 DOI: 10.1007/s00432-014-1857-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 10/11/2014] [Indexed: 12/29/2022]
Abstract
PURPOSE Sinusoidal obstruction syndrome (SOS) is a life-threatening early complication after hematopoietic stem cell transplantation (HSCT), and until now, examinations about the influence of genetic risk factors are extremely rare. The purpose of this study was to identify an association between heparanase (HPSE) single nucleotide polymorphisms (SNPs) and SOS in children undergoing allogeneic HSCT. METHODS We retrospectively analyzed the distribution of the both HPSE SNPs rs4693608 and rs4364254 and the occurrence of SOS after allogeneic HSCT in 160 children with malignant and non-malignant diseases. RESULTS Patients with HPSE genotypes GG or AG of rs4693608 (G>A) had a significantly reduced incidence of SOS on day 100 after HSCT compared to patients with genotype AA (4.7 vs. 14.3 %, P = 0.038). In addition, incidence of SOS in patients with genotype CC or CT of rs4364254 (C>T) was significantly decreased in comparison with patients with genotype TT (2.3 vs. 14.7 %, P = 0.004). Interestingly, no patient with genotype CC developed SOS. Because both SNPs co-occur in vivo, we generated subsets: AA-TT, GG-CC, and a group with remaining SNP combinations. We found significant differences between all three patient groups (P = 0.035). Patients with AA-TT showed the highest incidence of SOS (16.7 %), while SOS did not appear in patients with GG-CC (0 %) and residual combinations were numerically in-between (4.9 %). An impact caused by main patient and donor characteristics, established risk factors for SOS, and conditioning regimen could be excluded in multivariate analyses. CONCLUSIONS HPSE polymorphisms turned out to be significant independent risk factors (P = 0.030) for development of SOS and should be evaluated in further trials.
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Affiliation(s)
- Claudia Seifert
- Section for Hematology and Oncology, Department of Pediatrics, Jena University Hospital, Kochstraße 2, 07740, Jena, Germany
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20
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Norvell JP. Liver disease after hematopoietic cell transplantation in adults. Transplant Rev (Orlando) 2014; 29:8-15. [PMID: 25315987 DOI: 10.1016/j.trre.2014.08.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 08/10/2014] [Accepted: 08/22/2014] [Indexed: 01/22/2023]
Abstract
Liver-related complications constitute a large component of the overall morbidity and mortality associated with hematopoietic cell transplantation. Affecting up to 80% of allogeneic HCT recipients, prompt recognition and treatment are essential. The differential diagnosis is broad and is best categorized by time of onset after transplantation. Early complications include drug-induced liver injury, sinusoidal obstruction syndrome, and graft-versus-host disease. Late complications include infectious sequelae, cirrhosis, and hepatic malignancies. Patients being considered for hematopoietic cell transplantation should be screened and evaluated for liver-related complications to help improve outcomes.
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Affiliation(s)
- J P Norvell
- Department of Medicine, Division of Digestive Diseases, Emory Transplant Center, Emory University, Atlanta, GA, USA.
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21
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Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant. Int J Hematol 2014; 99:766-72. [DOI: 10.1007/s12185-014-1578-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/31/2014] [Accepted: 03/31/2014] [Indexed: 01/07/2023]
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22
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Abstract
Children with cancer undergo a host of surgeries and procedures that require anesthesia during the various phases of the disease. A safe anesthetic plan includes consideration of the direct effects of tumor, toxic effects of chemotherapy and radiation therapy, the specifics of the surgical procedure, drug-drug interactions with chemotherapy agents, pain syndromes, and psychological status of the child. This article provides a comprehensive overview of the anesthetic management of the child with cancer, focuses on a systems-based approach to the impact from both tumor and its treatment in children, and presents a discussion of the relevant anesthetic considerations.
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Affiliation(s)
- Gregory J Latham
- Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way Northeast, MB.11.500.3, Seattle, WA 98105, USA.
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23
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Nagler A, Labopin M, Berger R, Bunjes D, Campos A, Socié G, Kröger N, Goker H, Yakoub-Agha I, Shimoni A, Mohty M, Rocha V. Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome. Bone Marrow Transplant 2014; 49:628-33. [PMID: 24535127 DOI: 10.1038/bmt.2014.7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 09/26/2013] [Accepted: 09/26/2013] [Indexed: 11/09/2022]
Abstract
I.v. BU is frequently used in the conditioning regimen prior to allogeneic hematopoietic SCT (allo-HSCT); however, overall outcomes, incidence of hepatic sinusoidal obstructive syndrome (SOS) and its risk factors are not well known. With this aim, we performed a study on 257 AML adult recipients. Seattle Criteria were used for diagnosis and classification of SOS. The median age was 44 years. Donors were HLA-identical siblings in 60%, HLA-matched unrelated in 29% and HLA mismatched in 11%. Conditioning regimen was myeloablative in 84% (i.v. BU with CY was the most frequently used regimen) and it was reduced intensity in 16% (i.v. BU associated with fludarabine). Acute and chronic GVHD was observed in 28% and 44%, respectively. Two-year incidence of non-relapse mortality was 16±2% and 2-year leukemia-free survival for patients in CR1, CR2 and non remission at HSCT were 55±4%, 58±7%, and 20±5%, respectively. At 6 months, incidence of SOS was 7.8±2%; and it was severe in eight patients (3%). Factors associated with the occurrence of SOS were: HLA-mismatched donor HSCT (P=0.002) and patients transplanted in non-remission (P=0.002). In conclusion, outcomes of HSCT using i.v. BU are encouraging in this setting, SOS incidence is low and it is influenced by the type of donor and disease status at the time of transplant.
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Affiliation(s)
- A Nagler
- Hematology Division and Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - M Labopin
- EBMT Acute Leukemia Working Party and Registry, Hospital Saint-Antoine, Paris University, Paris, France
| | - R Berger
- Hematology Division and Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - D Bunjes
- Klinik fuer Innere Medzin III, Universitätsklinikum, Ulm, Germany
| | - A Campos
- Instituto Portugues de Oncologia do Porto, BMT Unit, Porto, Portugal
| | - G Socié
- Hopital St Louis, Department of Hematology-BMT, Paris, France
| | - N Kröger
- Bone Marrow Transplantation Centre, University Hospital Eppendorf, Hamburg, Germany
| | - H Goker
- Department of Hematology, BMT Unit, Hacettepe University, Ankara, Turkey
| | - I Yakoub-Agha
- Bone Marrow Transplant Unit, Hôpital Huriez, Lille, France
| | - A Shimoni
- Hematology Division and Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - M Mohty
- EBMT Acute Leukemia Working Party and Registry, Hospital Saint-Antoine, Paris University, Paris, France
| | - V Rocha
- Haematology Department, Bone Marrow Transplant Unit, Churchill Hospital, Oxford University Hopitals, Oxford, UK
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24
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Averbuch D, Cordonnier C, Livermore DM, Mikulska M, Orasch C, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M. Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011). Haematologica 2013; 98:1836-47. [PMID: 24323984 PMCID: PMC3856958 DOI: 10.3324/haematol.2013.091330] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 10/14/2013] [Indexed: 01/19/2023] Open
Abstract
The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists.
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25
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Abstract
Hemostatic changes and thrombotic events are frequent in patients undergoing stem cell transplantation. Arterial and venous thromboses are major causes of morbidity and mortality. Thrombotic complications can be classified into four groups including: catheter-related thrombosis, venous thromboembolic (VTE) events, sinusoidal obstructive syndrome (SOS)/veno-occlusive disease, and transplant-associated thrombotic microangiopathy (TAM). The incidence of catheter-related thrombosis is 8-20% in patients undergoing autologous hematopoietic stem cell transplantation (HSCT), and the incidence is low in syngeneic and allogeneic transplant patients. Venous duplex Doppler ultrasound, venogram, and computed tomography scan are required to visualize the venous thrombus. The treatment should be aimed at the prevention of pulmonary embolism, the avoidance of thrombus extension, and the preservation of catheter patency. Patients undergoing HSCT may have risk factors for VTE including underlying malignancy, traumatic brain injury, prolonged hospitalization, administration of conditioning regimens, and central venous catheters. Important risk factors are presence of history of VTE and graft-versus-host disease. One-year incidence of symptomatic VTE is 3.7%. SOS, also known as veno-occlusive disease, is a serious liver disease, seen in approximately 50-60% of HSCT patients. The mortality rate from the severe form of SOS is 84.3% and majority of the patients have multi-organ failure. The frequency is quite low after autologous transplantation. Risk factors for SOS include pre-existing hepatic damage, previous high-dose chemotherapy and abdominal irradiation, female gender and donor-recipient human leukocyte antigen disparity. Cyclophosphamide and busulphan are the most common agents with the highest incidence and fatal SOS. Histopathologic features of SOS include dilatation of sinusoids, necrosis of perivenular hepatocytes, and obstruction of small intrahepatic central venules by microthrombi and fibrin deposition. Signs of SOS usually occur within first 30 days after HSCT including hyperbilirubinemia, hepatomegaly, ascites, and weight gain. Symptoms of liver failure, including encephalopathy, coagulopathy, and renal failure will appear in severe form. A hepatic venous pressure gradient above 10 mmHg is highly specific for SOS. Early use of defibrotide has been shown to be effective in the treatment of high-risk SOS. TAM is a distinct, infrequent, and significant life-threatening complication of HSCT. TAM is seen in the range of 0·5-76% and was reported to be 10-25% in patients undergoing allogeneic HSCT with a mortality rate around 50%. It can also be seen after autologous HSCT and mainly affects the glomerular capillaries. There has been no standard therapy for TAM. Few case series reported good response to rituximab and high-dose corticosteroids were used with limited success. Trials with complement inhibitors such as eculizumab are currently underway.
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Affiliation(s)
- Emin Kansu
- Hacettepe University Institute of Oncology, Hematopoietic Stem Cell Transplantation Unit, Ankara, Turkey.
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26
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Hepatic veno-occlusive disease with immunodeficiency (VODI): first reported case in the U.S. and identification of a unique mutation in Sp110. Clin Immunol 2012; 145:102-7. [PMID: 22982295 DOI: 10.1016/j.clim.2012.07.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 07/26/2012] [Accepted: 07/28/2012] [Indexed: 11/21/2022]
Abstract
Familial hepatic veno-occlusive disease with immunodeficiency (VODI, OMIM: 235550), a rare form of severe combined immune deficiency, was first described in Australian Lebanese patients as being associated with homozygous mutations in SP110, a gene encoding a PML nuclear body-associated protein. We present the first case of confirmed VODI in the United States, and identify the first novel missense mutation in SP110. The 3-year-old daughter of Hispanic parents without known consanguinity presented at age 5 months with fever, hepatomegaly, and pancytopenia. Her brother died at age 3 months from hepatic failure of undetermined etiology. Initial T- and B-cell counts were low, but eventually normalized. Serum IgG and IgM levels were low for age. Lymphoproliferation to mitogens and allogenic B-cells was normal, but absent to tetanus and candida antigens. Serum antibody levels against pneumococcal, Hib and tetanus antigens were low. Liver biopsies at ages 5 and 9 months were consistent with hepatic veno-occlusive disease or hVOD (also known as sinusoidal obstruction syndrome or SOS) and broncho-alveolar lavage detected Pneumocystis jiroveci. The patient recovered from her acute disease and has been clinically stable on immunoglobulin replacement therapy and trimethoprim-sulfamethoxazole prophylaxis. T-Cell receptor excision circle (TREC) analysis suggests that VODI will not be detected by newborn screening for severe combined immunodeficiency that relies on this assay. DNA was obtained from the patient, 4 siblings, and both parents, and SP110 was sequenced. The first missense mutation, a homozygous deletion/insertion variation in exon 2 (NM_080424.2 (SP110):c.78_79delinsAT) was detected in the patient. This novel mutation segregated in the heterozygous state in other living unaffected family members. The mechanism by which this SP110 mutation associates with VODI is consistent with the normal length mutated SP110 protein being subject to enhanced proteosome degradation resulting in marked reductions in SP110 protein.
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Yamada N, Urahashi T, Ihara Y, Sanada Y, Wakiya T, Okada N, Mizuta K. Veno-occlusive disease/sinusoidal obstruction syndrome associated with potential antibody-mediated rejection after pediatric living donor liver transplantation: a case report. Transplant Proc 2012; 44:810-3. [PMID: 22483502 DOI: 10.1016/j.transproceed.2012.01.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A 9-month-old girl with biliary atresia underwent successful living donor liver transplantation from her 42-year-old ABO blood-type incompatible mother. The postoperative course was uneventful until postoperative day (POD) 13 when the recipient displayed an increased volume of drained ascites and decreased her platelet count showing low-velocity portal venous inflow without hepatic venous outflow obstruction. We suspected potential veno-occlusive disease/sinusoidal obstruction syndrome (vod/sos) due to an acute cellular rejection (ACR) episode and performed a liver biopsy (LB). We diagnosed severe episode (Rejection Activity Index Score; P3V3B1 = 7) and started steroid pulse therapy. We performed a second LB on POD 27 because the patient showed weight gain and tender hepatomegaly, diagnosing moderate ACR (P1V3B1 = 5). We started a second course of steroid pulse therapy, but the patient's clinical findings did not improve. On POD 43, her third LB finding showed P1V1B1 with improved processes from ACR, but still displaying severe congestion and fibrotic obliteration of small hepatic veins. We suspected that her immunologic responses were associated with antibody-mediated rejection (AMR) because her anti-HLA class I and class II antibodies were positive by flow panel-reactive antibody method and donor-specific antigen class II and C4d staining were also positive. We added mycophenolate mofetil and administered high-dose intravenous immunoglobulin to control the AMR, and anticoagulant therapy for the VOD/SOS. Her clinical findings and graft venous abnormalities finally improved; she was eventually discharged without sequelae on POD 72.
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Affiliation(s)
- N Yamada
- Department of Transplant Surgery, Jichi, Medical University, Szhimotsuke-shi, Tochigi, Japan.
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Cheuk DK. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies. World J Transplant 2012; 2:27-34. [PMID: 24175193 PMCID: PMC3782230 DOI: 10.5500/wjt.v2.i2.27] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 10/18/2011] [Accepted: 03/20/2012] [Indexed: 02/05/2023] Open
Abstract
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a major complication of hematopoietic stem cell transplantation and it carries a high mortality. Prophylaxis for hepatic VOD is commonly given to transplant recipients from the start of conditioning through the early weeks of transplant. However, high quality evidence from randomized controlled trials is scarce with small sample sizes and the trials yielded conflicting results. Although various treatment options for hepatic VOD are available, most have not undergone stringent evaluation with randomized controlled trial and therefore it remains uncertain which treatment offers real benefit. It remains controversial whether VOD prophylaxis should be given, which prophylactic therapy should be given, who should receive prophylaxis, and what treatment should be offered once VOD is established.
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Affiliation(s)
- Daniel Kl Cheuk
- Daniel KL Cheuk, Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
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Michel G, Valteau-Couanet D, Gentet JC, Esperou H, Socié G, Méchinaud F, Doz F, Neven B, Bertrand Y, Galambrun C, Demeocq F, Yakouben K, Bordigoni P, Frappaz D, Nguyen L, Vassal G. Weight-based strategy of dose administration in children using intravenous busulfan: clinical and pharmacokinetic results. Pediatr Blood Cancer 2012; 58:90-7. [PMID: 21254374 DOI: 10.1002/pbc.22959] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Accepted: 11/11/2010] [Indexed: 11/08/2022]
Abstract
BACKGROUND A prospective clinical trial was performed in order to validate the pharmacokinetic (PK) and clinical benefits of a new dosing schedule of intravenous busulfan (IV Bu) in children. PROCEDURE IV Bu was administered as a 2-hr infusion every 6 hr for 4 days. Five dose levels were given according to body-weight strata. RESULTS The 67 children aged from 4 months to 17.2 years were followed up over 50 months after autologous or allogeneic stem-cell transplantation. Reduced PK variability was seen after IV Bu administration enabling efficient targeting with 78% of patients within the 900-1,500 µM · min therapeutic window and reproducible exposures across administrations. No neurological complications occurred. The low incidence of hepatic veno-occlusive disease (VOD) recorded was not correlated with high area under the curve (AUC). Only stomatitis was correlated with high AUC in the autologous group. The 4-year overall survival was 59% in the autologous group and 82% in the allogeneic group. CONCLUSION The new dosing schedule using IV Bu provides adequate therapeutic targeting from the first administration, with low toxicity and good disease control in high-risk children. The choice of this formulation of Bu should be considered because of its low morbidity and good outcome.
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Affiliation(s)
- Gérard Michel
- Pediatric Hematology, Hopital Enfants Timone, Marseille, France
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Cheuk DKL, Chiang AKS, Ha SY, Chan GCF. Interventions for prophylaxis of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2011. [DOI: 10.1002/14651858.cd009311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Munchel A, Chen A, Symons H. Emergent Complications in the Pediatric Hematopoietic Stem Cell Transplant Patient. CLINICAL PEDIATRIC EMERGENCY MEDICINE 2011; 12:233-244. [PMID: 25411564 PMCID: PMC4234095 DOI: 10.1016/j.cpem.2011.07.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hematopoietic cell transplantation is the only potentially curative option for a variety of pediatric malignant and nonmalignant disorders. Despite advances in transplantation biology and immunology as well as in posttransplant management that have contributed to improved survival and decreased transplant-related mortality, hematopoietic cell transplantation does not come without significant risk of complications. When patients who have undergone hematopoietic cell transplantation present to the emergency department, it is important to consider a variety of therapy-related complications to optimize management and outcome. In this article, we use clinical cases to highlight some of the more common emergent complications after hematopoietic cell transplantation.
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Affiliation(s)
- Ashley Munchel
- Pediatric Hematology/Oncology, The Johns Hopkins Hospital, Baltimore, MD
- Pediatric Oncology Branch at the National Institutes of Health, Bethesda, MD
| | - Allen Chen
- Division of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD
- Division of Pediatrics, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD
| | - Heather Symons
- Division of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD
- Division of Pediatrics, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD
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32
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Peng C, Doan J, Monagle P, Newall F. Compliance of antithrombotic management at a tertiary paediatric hospital with international guidelines: A 100-Day audit. Thromb Res 2011; 128:135-40. [DOI: 10.1016/j.thromres.2011.03.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Revised: 03/18/2011] [Accepted: 03/20/2011] [Indexed: 11/27/2022]
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Robinson S, Manas D, Pedley I, Mann D, White S. Systemic chemotherapy and its implications for resection of colorectal liver metastasis. Surg Oncol 2011; 20:57-72. [DOI: 10.1016/j.suronc.2009.10.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2009] [Revised: 10/07/2009] [Accepted: 10/26/2009] [Indexed: 12/29/2022]
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Sakaguchi H, Watanabe N, Muramatsu H, Doisaki S, Yoshida N, Matsumoto K, Kato K. Danaparoid as the prophylaxis for hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation in childhood hematological malignancy. Pediatr Blood Cancer 2010; 55:1118-25. [PMID: 20589662 DOI: 10.1002/pbc.22645] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Veno-occlusive disease (VOD) is a regimen-related toxicity that occurs in the early phase of hematopoietic stem cell transplantation (HSCT). Therapeutic modalities for established VOD are limited, and severe VOD characterized by multiple organ failure is associated with a fatal prognosis despite intensive supportive care. PROCEDURE We analyzed the data of 95 consecutive allogeneic HSCT for childhood hematological malignancies, and assessed the efficacy of our VOD prophylaxis regimen based on danaparoid (n = 48), comparing with historical control regimen based on dalteparin (n = 47). RESULTS Eight patients (danaparoid cohort in one; dalteparin cohort in seven) developed VOD on day +30 (median onset, day +22; range, day +11 to day +28) after HSCT. The probability of developing VOD for the danaparoid cohort was 2% (95% CI, 0-6%) and that of the dalteparin cohort was 15% (95% CI, 5-26%). In the Cox hazard proportional model, the danaparoid cohort had a significant advantage over the dalteparin cohort for the prophylaxis of VOD (hazard ratio (HR), 0.0; 95% CI, 0.0-0.3; P < 0.01) without increasing hemorrhagic events. CONCLUSIONS Our findings suggest that danaparoid may have promise for the prophylaxis of VOD after allogeneic HSCT and further randomized studies are warranted.
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Affiliation(s)
- Hirotoshi Sakaguchi
- Division of Haematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
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Cefalo MG, Maurizi P, Arlotta A, Scalzone M, Attinà G, Ruggiero A, Riccardi R. Hepatic veno-occlusive disease: a chemotherapy-related toxicity in children with malignancies. Paediatr Drugs 2010; 12:277-284. [PMID: 20799757 DOI: 10.2165/11531840-000000000-00000] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.
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Pullarkat V. Iron overload in patients undergoing hematopoietic stem cell transplantation. Adv Hematol 2010; 2010:345756. [PMID: 20871852 PMCID: PMC2943091 DOI: 10.1155/2010/345756] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 07/01/2010] [Indexed: 01/19/2023] Open
Abstract
Recipients of hematopoietic stem cell transplantation (HSCT) frequently have iron overload resulting from chronic transfusion therapy for anemia. In some cases, for example, in patients with myelodysplastic syndromes and thalassemia, this can be further exacerbated by increased absorption of iron from the gut as a result of ineffective erythropoiesis. Accumulating evidence has established the negative impact of elevated pretransplantation serum ferritin, a surrogate marker of iron overload, on overall survival and nonrelapse mortality after HSCT. Complications of HSCT associated with iron overload include increased bacterial and fungal infections as well as sinusoidal obstruction syndrome and possibly other regimen-related toxicities. Based on current evidence, particular attention should be paid to prevention and management of iron overload in allogeneic HSCT candidates, especially in patients with thalassemia and myelodysplastic syndromes. The pathophysiology of iron overload in the HSCT patient and optimum strategies to deal with iron overload during and after HSCT require further study.
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Affiliation(s)
- Vinod Pullarkat
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, 150 East Duarte Road, Duarte, CA 91010, USA
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37
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Lakshminarayanan S, Sahdev I, Goyal M, Vlachos A, Atlas M, Lipton JM. Low incidence of hepatic veno-occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation attributed to a combination of intravenous heparin, oral glutamine, and ursodiol at a single transplant institution. Pediatr Transplant 2010; 14:618-21. [PMID: 20051023 DOI: 10.1111/j.1399-3046.2009.01285.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
We report the low incidence of hepatic VOD in pediatric patients with various diagnoses including hematologic malignancies and non-malignant conditions transplanted at our institution. Retrospective review of 188 patients who underwent HSCT and received a combined prophylactic regimen of intravenous heparin, oral glutamine, and ursodiol was undertaken. Analysis of the outcome of VOD revealed only one clinical case with acute myeloid leukemia; the patient developed hepatic VOD 10 days after receiving myeloablative chemotherapy with busulfan and CTX followed by HLA-matched related peripheral blood stem cell transplantation. The low incidence of hepatic VOD in an otherwise high-risk pediatric transplant population is an important observation, which may be partly attributed to this prophylactic regimen, and warrants further randomized clinical trials for confirmation.
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Affiliation(s)
- Sonali Lakshminarayanan
- Division of Pediatric Hematology/Oncology and Stem Cell Transplantation, Schneider Children's Hospital, North Shore-Long Island Jewish Health System, New Hyde Park, NY 11040, USA
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Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient--part 2: systems-based approach to anesthesia. Paediatr Anaesth 2010; 20:396-420. [PMID: 20199611 DOI: 10.1111/j.1460-9592.2010.03260.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
One of the prices paid for chemo- and radiotherapy of cancer in children is damage to the vulnerable and developing healthy tissues of the body. Such damage can exist clinically or subclinically and can become apparent during active antineoplastic treatment or during remission decades later. Furthermore, effects of the tumor itself can significantly impact the physiologic state of the child. The anesthesiologist who cares for children with cancer or for survivors of childhood cancer should understand what effects cancer and its therapy can have on various organ systems. In part two of this three-part review, we review the anesthetic issues associated with childhood cancer. Specifically, this review presents a systems-based approach to the impact from both tumor and its treatment in children, followed by a discussion of the relevant anesthetic considerations.
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Affiliation(s)
- Gregory J Latham
- Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way N.E., Seattle, WA 98105, USA.
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Takamoto T, Hashimoto T, Sano K, Maruyama Y, Inoue K, Ogata S, Takemura T, Kokudo N, Makuuchi M. Recovery of liver function after the cessation of preoperative chemotherapy for colorectal liver metastasis. Ann Surg Oncol 2010; 17:2747-55. [PMID: 20425145 DOI: 10.1245/s10434-010-1074-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Indexed: 12/22/2022]
Abstract
BACKGROUND Preoperative chemotherapy containing oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) causes histological liver injury and increases postoperative morbidity and mortality in patients with colorectal liver metastasis (CRLM). However, information on the aggravation of liver function and its reversibility is scarce. METHODS A total of 55 patients who underwent a hepatectomy after receiving FOLFOX and/or FOLFIRI were included in the present study. Indocyanine green tests were repeatedly performed before hepatectomy for monitoring the change of hepatic functional reserve. RESULTS A significant decrement in the ICG R15 value was observed at 2-4 weeks (12.9%, P = .04), 4-8 weeks (11.4%, P = .01), and 8 or more weeks (11.1%, P = .006) after the last chemotherapy, compared with results documented within 2 weeks (16.8%). However, no significant change was observed among the values obtained at 2-4 weeks, 4-8 weeks, and 8 or more weeks. The individual ICG R15 values at the beginning and end of the cessation period also improved from 17.7% to 11.6% (P = .001). Histological liver injury was associated with larger amounts of operative blood loss but not with morbidity. Neither liver failure nor mortality occurred in the present series. CONCLUSIONS The hepatic functional reserve, represented by the ICG R15 value, improves during the period after chemotherapy cessation. The present study suggests that chemotherapy cessation for at least 2-4 weeks enables an improvement in the hepatic functional reserve, especially among patients with an abnormal ICG R15 value (> 10%) who have received 6 or more cycles of FOLFOX and/or FOLFIRI.
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Affiliation(s)
- Takeshi Takamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Japanese Red Cross Medical Center, Tokyo, Japan.
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Iguchi A, Kobayashi R, Kaneda M, Kobayashi K. Plasma protein C is a useful clinical marker for hepatic veno-occlusive disease (VOD) in stem cell transplantation. Pediatr Blood Cancer 2010; 54:437-43. [PMID: 19911420 DOI: 10.1002/pbc.22314] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hepatic veno-occlusive disease (VOD) is one of the most serious complications in stem cell transplantation (SCT). Although plasma protein C activity decreases in VOD after SCT, the timeframe of plasma protein C activity decreases during SCT is not known. PROCEDURE We examined levels of plasma protein C serially during the course of SCT to determine the critical level and risk factors for VOD. RESULTS Of 151 children who received SCT, 12 of them (7.9%) developed VOD. The mean minimum protein C activity in patients with VOD was significantly lower compared to that in patients without VOD (P < 0.0001). Receiver operating characteristic curve analysis revealed that the critical plasma protein C activity (cut-off point) for VOD was identified to be 34.5% with high sensitivity (100%) and specificity (83.3%), and the reduction of plasma protein C below the cut-off level (day +6.50 +/- 2.43) was observed mostly prior to the onset of VOD (day +7.33 +/- 2.64). The patients receiving melphalan in conditioning were found to be at high risk for VOD (P = 0.003). Among the melphalan containing regimens, melphalan + carboplatin + etoposide was a significant risk factor for depression of plasma protein C (P = 0.037). CONCLUSION Plasma protein C level was a useful parameter of VOD after SCT, and activity below 34.5% was critical for VOD. The use of melphalan in conditioning causes a high risk for VOD.
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Affiliation(s)
- Akihiro Iguchi
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
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Snyder ML, Ritchie JC. Quantification of busulfan in plasma using liquid chromatography electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). Methods Mol Biol 2010; 603:129-136. [PMID: 20077065 DOI: 10.1007/978-1-60761-459-3_12] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Busulfan is a chemotherapy drug widely used as part of conditioning regimens for patients undergoing bone marrow transplantation (BMT). Challenges of busulfan treatment include a narrow therapeutic window and wide inter- and intra-patient variability. Inappropriately low drug levels lead to relapse and even graft rejection, while higher doses frequently have toxic and sometimes fatal consequences. Maintenance of plasma busulfan concentrations using repeated measurements and proper adjustment of dosage can reduce busulfan-related toxicity and improve treatment outcomes. We describe a rapid (2-minute total analysis time per sample) and simple method for accurate and precise busulfan concentration determination in plasma samples (100 microL) using high performance liquid chromatography combined with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Busulfan is isolated from plasma after internal standard (busulfan-D(8))-methanol extraction, dilution with mobile phase (ammonium acetate-formic acid-water), and centrifugation. The supernatant plasma is injected onto the HPLC-ESI-MS/MS and quantified using a six-point standard curve. The assay is linear from 0.025 microg/mL (approximately 0.1 micromol/L) to at least 6.2 microg/mL (approximately 25 micromol/L) with precisions of <5% over the entire range.
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Affiliation(s)
- Marion L Snyder
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine and Emory Healthcare Systems, Atlanta, GA, USA
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Lee SH, Yoo KH, Sung KW, Koo HH, Kwon YJ, Kwon MM, Park HJ, Park BK, Kim YY, Park JA, Im HJ, Seo JJ, Kang HJ, Shin HY, Ahn HS. Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Bone Marrow Transplant 2009; 45:1287-93. [PMID: 20010866 DOI: 10.1038/bmt.2009.349] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Four hundred and sixty-seven hematopoietic stem cell transplantations (HSCTs) (217 autologous and 250 allogeneic HSCT) were performed in 374 children at four pediatric HSCT centers in Korea from January 2005 to December 2007. Among 467 transplants, veno-occlusive disease (VOD) developed in 72 transplants (15.4%) at a median of 10 days after HSCT. Multivariate analysis showed that BU or TBI-containing regimen (P=0.002), VOD prophylaxis without lipo-prostaglandin E1 (PGE1) (P=0.012), number of previous HSCT (P=0.014), and pretransplant serum ferritin (P=0.018) were independent risk factors for developing VOD. Mean serum ferritin levels were significantly higher in HSCT with VOD (2109.6+/-2842.5 ng/ml) than in HSCT without VOD (1315.9+/-1094.4 ng/ml) (P<0.001). The relative risk of death within 100 days of HSCT in transplants with VOD compared with transplants without VOD was 3.39 (confidence interval: 1.78-6.45). Our results suggest that lipo-PGE1 might have a protective effect against the development of VOD, and pretransplant serum ferritin could act as a risk factor for VOD. A larger prospective study is needed to confirm a possible role of lipo-PGE1 and iron chelation therapy in reducing the incidence of VOD.
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Affiliation(s)
- S H Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant 2009; 16:157-68. [PMID: 19766729 DOI: 10.1016/j.bbmt.2009.08.024] [Citation(s) in RCA: 425] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Accepted: 08/21/2009] [Indexed: 02/07/2023]
Abstract
The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI]=13.3%-14.1%). The mean incidence of VOD was significantly lower between 1979-1994 than between 1994-2007 (11.5% [95% CI, 10.9%-12.1%] vs 14.6% [95% CI, 14.0%-15.2%]; P <.05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%-88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome.
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Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation. Blood 2009; 114:1270-5. [DOI: 10.1182/blood-2009-03-212282] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication in hematopoietic stem cell transplant (HSCT) recipients. To determine the impact of pretransplantation hyperferritinemia on the risk of SOS after HSC transplantation, we retrospectively studied 427 HSCT recipients (179 autologous and 248 allogeneic). Serum ferritin levels were measured before transplantation. Patients with and without a diagnosis of SOS were compared regarding demographics; underlying disease; transplant characteristics; receipt of imatinib, busulfan, total body irradiation, gemtuzumab, vancomycin, acyclovir, or methotrexate; and baseline serum ferritin. Univariate and multivariate (stepwise logistic regression) analyses were performed. SOS was diagnosed in 88 patients (21%) at a median of 10 days (range, 2-29 days) after transplantation. By multivariate analysis, allogeneic HSC transplantation (odds ratio [OR] = 8.25; 95% confidence interval [95% CI], 3.31-20.57), receipt of imatinib (OR = 2.60; 95% CI, 1.16-5.84), receipt of busulfan (OR = 2.18; 95% CI, 1.25-3.80), and ferritin serum level higher than 1000 ng/dL (OR = 1.78; 95% CI, 1.02-3.08) were risk factors for SOS. A ferritin serum level higher than 1000 ng/dL in the pretransplantation period is an independent risk factor for SOS. The results suggest the need for prospective studies addressing the use of iron chelation in the pretransplantation period.
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Abstract
This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association.
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Affiliation(s)
- Laurie D DeLeve
- Division of Gastrointestinal and Liver Diseases and the Research Center for Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
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Faraci M, Dini G. Assessing the risk of transplant-related complications and individually tailoring the HSCT procedure in children and adolescents—is it possible? Bone Marrow Transplant 2008; 42 Suppl 2:S90-6. [DOI: 10.1038/bmt.2008.292] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Early complications following haematopoietic SCT in children. Bone Marrow Transplant 2008; 41 Suppl 2:S39-42. [DOI: 10.1038/bmt.2008.53] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 2007; 110:2761-7. [DOI: 10.1002/cncr.23099] [Citation(s) in RCA: 278] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Kitio B, Bertholle V, Galambrun C, Mialou V, Bertrand Y, Aulagner G, Bleyzac N. Risk-adjusted monitoring of veno-occlusive disease following Bayesian individualization of busulfan dosage for bone marrow transplantation in paediatrics. Pharmacoepidemiol Drug Saf 2007; 17:135-43. [DOI: 10.1002/pds.1504] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Cheuk DKL, Wang P, Lee TL, Chiang AKS, Ha SY, Lau YL, Chan GCF. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 2007; 40:935-44. [PMID: 17768390 DOI: 10.1038/sj.bmt.1705835] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
A cohort of 138 children with 144 hematopoietic stem cell transplantation (HSCT) performed in 1997-2006 were analyzed to evaluate risk factors and mortality predictors of hepatic veno-occlusive disease (VOD). Nineteen patients (13.2%) developed VOD (nine boys, median age 3.5 years) at 1-21 days after HSCT (median 13 days). Age < or =2 years at transplant (odds ratio (OR)=5.25, P=0.011), BU-CY conditioning (OR=5.16, P=0.001), thalassemia major (OR=3.97, P=0.015), platelet engraftment beyond day +21 (OR=8.67, P=0.025) were univariate risk factors for VOD. The first two remained significant in multivariate regression. Seven patients (36.8%) with VOD died, at a median of 44 days post transplant (range, 30-421 days). The 5-year survival was 62%. All surviving patients had normal liver function on follow-up at 0.5-9 years. Patients with VOD had higher 100-day mortality (16.3 vs 9.6%, P=0.024). Mortality predictors included donors other than autologous or matched sibling (hazard ratio (HR)=23.6, P=0.006), hepatic and cutaneous GVHD (HR=8.15, P=0.038), maximal weight gain >9% (HR=6.81, P=0.023), pleural effusion, intensive care unit admission, peak bilirubin >300 micromol l(-1) (HR=13.6, P=0.016), day +21 bilirubin >200 micromol l(-1) (HR=33.9, P=0.001), and rise of bilirubin >15 micromol l(-1) per day within the first week (HR=19.8, P=0.006). Mortality was substantially higher if >3 predictors were present (HR=33.9, P=0.001). Meticulous monitoring in high-risk patients and early treatment should be considered before VOD progresses beyond salvage.
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Affiliation(s)
- D K L Cheuk
- Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), Hong Kong, China.
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