Gynura segetum induces hepatic sinusoidal obstruction syndrome in a child: A case report.

RATIONALE: Hepatic sinusoidal obstruction syndrome (HSOS), which includes hepatic stasis and portal hypertension, is a rare vascular disorder of the liver. It is often associated with hematopoietic stem cell transplantation. It is also possible to treat this disease using Chinese herbal medicines that contain pyrrolizidine alkaloids (PAs). This disease is extremely rare in children and poses a serious threat to their health. To our knowledge, this is the first case of HSOS in a child with PAs. PATIENT CONCERNS: We report a 4-year-old boy suffering from abdominal pain, hepatomegaly, massive ascites, elevated liver enzyme level, and severe portal hypertension as a result of the consumption of Gynura segetum (also known as Tusanqi in Chinese, a traditional herbal medicine containing PAs). DIAGNOSES: The child was finally diagnosed with PA-HSOS based on pathological diagnosis and imaging examination. INTERVENTION: With active symptomatic and supportive care and sequential anticoagulation therapy, the abdominal distension and liver function improved in the patient. OUTCOMES: The patient was eventually recovered. The levels of liver enzymes, hemoglobin, and bilirubin were normal, and the international normalized ratio fluctuated between 2.0 and 3.0 during 1-year follow-up after discharge. LESSONS: This case report emphasizes the prevention of Chinese herb-induced liver injury in children and the importance of active long-term sequential anticoagulant therapy to reduce the progressive damage of PA-HSOS in the liver.

Anticoagulant therapy likely increases risk of bleeding in Gynura segetum-induced hepatic sinus obstruction syndrome.

This study aimed to analyze the clinical characteristics of Gynura segetum (Tusanqi)-induced hepatic sinusoidal obstruction syndrome (HSOS) and the benefits and risks of anticoagulant therapy for Tusanqi-induced HSOS. This was a retrospective analysis of 49 patients with Tusanqi-induced HSOS who were treated with anticoagulation or standard therapy between July 2006 and December 2022. Clinical manifestations included abdominal pain (n = 47) and peritoneal or pleural effusion (n = 46); 2 patients died. Nineteen patients requested standard medical treatment, while 30 were treated with anticoagulants. HSOS resolved within 6 months in 22 patients but did not resolve in 27 patients. The resolution rate was higher in the anticoagulant than standard treatment group (P = .037). Logistic regression analysis revealed that a history of chronic liver disease or treatment increased the risk of poor outcomes. Bleeding complications occurred in 6 patients in the anticoagulant treatment group. Early diagnosis and anticoagulant treatment are beneficial for rapid recovery after Tusanqi-induced HSOS. However, anticoagulant treatment is associated with the risk of multisite bleeding.

Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission.

ABSTRACT: The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome-positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10-3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061.

Prospective Assessment of Treatment-Induced Liver Injury as a Cause of Diffuse Pathologic Hepatic Enhancement in Contrast-Enhanced Ultrasound.

OBJECTIVE: A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. METHODS: To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n = 20) or acute leukemia patients prior to IT (n = 20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. RESULTS: The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. CONCLUSION: Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE.

Assaying ADAMTS13 Activity as a Potential Prognostic Biomarker for Sinusoidal Obstruction Syndrome in Mice.

Sinusoidal obstruction syndrome (SOS) is a serious liver disorder that occurs after liver transplantation, hematopoietic stem cell transplantation, and the administration of anticancer drugs. Since SOS is a life-threatening condition that can progress to liver failure, early detection and prompt treatment are required for the survival of patients with this condition. In this study, female CD1 mice were divided into treatment and control groups after the induction of an SOS model using monocrotaline (MCT, 270 mg/kg body weight intraperitoneally). The mice were analyzed at 0, 12, 24, and 48 h after MCT administration, and blood and liver samples were collected for assays and histopathology tests. SOS was observed in the livers 12 h after MCT injection. In addition, immunohistochemical findings demonstrated CD42b-positive platelet aggregations, positive signals for von Willebrand factor (VWF), and a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) in the MCT-exposed liver sinusoid. Although ADAMTS13's plasma concentrations peaked at 12 h, its enzyme activity continuously decreased by 75% at 48 h and, inversely and proportionally, concentrations in the VWF-A2 domain, in which the cleavage site of ADAMTS13 is located, increased after MCT injection. These findings suggest that the plasma concentration and activity of ADAMTS13 could be useful biomarkers for early detection and therapeutic intervention in patients with SOS.

Rifaximin Prevents Intestinal Barrier Dysfunction and Alleviates Liver Injury in MCT-induced HSOS Mice.

OBJECTIVE: Rifaximin is an effective component of treatment strategies for liver and intestinal diseases. However, the efficacy of rifaximin in hepatic sinusoidal obstruction syndrome (HSOS) has not been explored. The present study aimed to investigate the efficacy and mechanism of rifaximin in HSOS. METHODS: An HSOS model was established in mice through the administration of monocrotaline (MCT, 800 mg/kg), and part of the HSOS mice were intragastrically administered with rifaximin. Then, the efficacy of rifaximin in HSOS was evaluated based on the liver pathological findings, liver proinflammatory cytokines, and alanine aminotransferase and aspartate aminotransferase levels. The Ussing chamber was used to evaluate the intestinal permeability, and tight junction (TJ) proteins were measured by Western blotting and real-time polymerase chain reaction to evaluate the intestinal barrier integrity. Then, the serum proinflammatory cytokine levels were evaluated by enzyme-linked immunosorbent assay. Afterwards, an in vitro experiment was performed to determine the relationship between rifaximin and TJ proteins. RESULTS: Rifaximin effectively alleviated the MCT-induced HSOS liver injury, suppressed the expression of liver proinflammatory cytokines, and reduced the serum levels of tumor necrosis factor-alpha and interleukin-6. Furthermore, rifaximin reduced the intestinal permeability, improved the intestinal barrier integrity, and promoted the expression of TJ proteins. CONCLUSION: The results revealed that the intestinal barrier integrity was destroyed in MCT-induced HSOS. The significant alleviation of MCT-induced HSOS induced by rifaximin might be correlated to the repairment of intestinal barrier integrity via the regulation of the TJ protein expression.

Andrographolide attenuated MCT-induced HSOS via regulating NRF2-initiated mitochondrial biogenesis and antioxidant response.

Hepatic sinusoidal obstruction syndrome (HSOS) is a death-dealing liver disease with a fatality rate of up to 67%. In the study present, we explored the efficacy of andrographolide (Andro), a diterpene lactone from Andrographis Herba, in ameliorating the monocrotaline (MCT)-induced HSOS and the underlying mechanism. The alleviation of Andro on MCT-induced rats HSOS was proved by biochemical index detection, electron microscope observation, and liver histological evaluation. Detection of hepatic ATP content, mitochondrial DNA (mtDNA) copy number, and protein expression of nuclear respiratory factor-1 (NRF1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) demonstrated that Andro strengthened mitochondrial biogenesis in livers from MCT-treated rats. Chromatin immunoprecipitation assay exhibited that Andro enhanced the occupation of nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) in the promoter regions of both PPARGC1A and NRF1. Andro also activated the NRF2-dependent anti-oxidative response and alleviated liver oxidative injury. In Nrf2 knock-out mice, MCT induced more severe liver damage, and Andro showed no alleviation in it. Furthermore, the Andro-activated mitochondrial biogenesis and anti-oxidative response were reduced in Nrf2 knock-out mice. Contrastingly, knocking out Kelch-like ECH-associated protein 1 (Keap1), a NRF2 repressor, reduced MCT-induced liver damage. Results from co-immunoprecipitation, molecular docking analysis, biotin-Andro pull-down, cellular thermal shift assay, and surface plasmon resonance assay showed that Andro hindered the NRF2-KEAP1 interaction via directly binding to KEAP1. In conclusion, our results revealed that NRF2-dependent liver mitochondrial biogenesis and anti-oxidative response were essential for the Andro-provided alleviation of the MCT-induced HSOS. Graphical Headlights: 1. Andro alleviated MCT-induced HSOS via activating antioxidative response and promoting mitochondrial biogenesis. 2. Andro-activated antioxidative response and mitochondrial biogenesis were NRF2-dependent. 3. Andro activated NRF2 via binding to KEAP1.

Busulfan-induced hepatic sinusoidal endothelial cell injury: Modulatory role of pirfenidone for therapeutic purposes.

Transplantation conditioning using Busulfan has been known to cause hepatotoxicity, which has great individual differences. Some have mild symptoms like the increase of hepatic drug-metabolizing enzyme, while others may have very serious ones, like hepatic sinusoidal obstruction syndrome. However, simply controlling the exposure of Busulfan may not effectively prevent or reduce the occurrence of hepatic sinusoidal obstruction syndrome. The occurrence of hepatic sinusoid obstruction syndrome is closely related to hepatic sinusoidal endothelial cells (HSECs). The objective of this study is to investigate the potential protective effect of Pirfenidone against Busulfan-induced damage to hepatic sinusoidal endothelial cells and to preliminarily explore the mechanisms underlying this protective effect. Our results indicate that Pirfenidone has a great protective effect on the injury induced by Busulfan. In addition, Busulfan increased the relative mRNA expression of transforming growth factor-ß1 (TGF-ß1), collagen and tissue inhibitor of metalloproteinase-1 in HSECs. After pretreatment with Pirfenidone, the expression level of TGF-ß1 was down-regulated. Mechanically, Pirfenidone primarily improves liver fibrosis by inhibiting collagen formation and hepatic stellate cell activation, thereby providing a protective effect on HSECs damaged by Busulfan. Therefore, Pirfenidone may reduce the hepatotoxicity caused by transplantation conditioning regimens based on Busulfan.

Prognostic risk factors for patients with hepatic sinusoidal obstruction syndrome caused by pyrrolizidine alkaloids.

Pyrrolizidine alkaloids induced hepatic sinusoidal obstruction syndrome (PA-HSOS) often occurs after consuming herbs or a dietary supplement containing the plant Tu-San-Qi. Limited data exists to identify patients with fatal outcomes for early interventions. We aimed to analyze the predictors for 3-month survival. We retrospectively enrolled PA-HSOS patients in 5 hospitals and extracted data from the onset of PA-HSOS to 36 months. Outcome measurements were 3-month and 36-month survival rates, baseline prognostic predictors for survival, and the effects of anticoagulant therapy. Among 49 enrollees, the median age was 60 and 49% male. At the onset of PA-HSOS, patients with Child-Turcotte-Pugh (CTP) class of A, B, or C were 8.2% (4/49), 42.8% (21/49) and 49.0% (24/49), respectively. None of them received a transjugular intrahepatic portosystemic shunt or a liver transplant. The 3-month and 36-month survival rates were 86% and 76%, respectively. Compared to the CTP class A or B, class C at baseline independently predicted lower survival rates at both 3 and 36 months. However, anticoagulation therapy treatment within the first 3 months independently predicted significantly higher survival rates at both time points. CTP class C and anticoagulant therapy were the independent predictors for short-term and long-term survival. Anticoagulant therapy could decrease mortality rate of CTP class C patients. The greatest benefit of anticoagulant evaluated by 3-month survival rate was in patients with CTP class C compared with those without treatment (93% vs 40%, P = .009). There were no bleeding complications reported in patients treated with the anticoagulant.

Transjugular intrahepatic portosystemic shunt for pyrrolidine alkaloids-induced hepatic sinusoidal obstruction syndrome: a retrospective cohort study.

BACKGROUND: This study aimed to investigate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of patients with pyrrolidine alkaloids-induced hepatic sinusoidal obstruction syndrome (PA-HSOS). METHODS: Patients diagnosed with PA-HSOS and treated in Ningbo No.2 Hospital between November 2017 and October 2022 were enlisted in this retrospective cohort study. RESULTS: This cohort comprised a total of 22 patients with PA-HSOS, of which 12 patients received TIPS treatment and 10 patients experienced conservative treatment. The median follow-up duration was 10.5 months. Baseline characteristics existed with no significant difference between the two groups. No operation failures or any TIPS-associated intraoperative complications were observed after TIPS. In the TIPS group, the portal venous pressure was substantially decreased from 25.3 ±â€…6.3 mmHg to 14.4 ±â€…3.5 mmHg after TIPS ( P  = 0.002). Compared with preoperative, the ascites after TIPS were significantly subsided ( P  = 0.001) and there existed a considerable decrease in Child-Pugh score. At the end of follow-up, 5 patients died, involving 1 in the TIPS group and 4 in the conservative treatment group. The median survival time was 13 (3-28) months in the TIPS group and 6.5 (1-49) months in the conservative treatment group, respectively. The survival analysis demonstrated that the total survival time of TIPS group was longer than that of the conservative treatment group, no statistical significance was observed ( P  = 0.08). CONCLUSION: TIPS may be a secure and effective therapeutic strategy for PA-HSOS patients who do not respond to conservative treatment.

Melatonin attenuates monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats via activation of Sirtuin-3.

Melatonin possesses potent hepatoprotective properties, but it remains to be elucidated whether melatonin has a therapeutic effect on monocrotaline (MCT)-induced hepatic sinusoidal obstruction syndrome (HSOS). In this study, male Sprague Dawley rats were intraperitoneally injected with melatonin or the same volume of vehicle at 0 and 24 h after MCT intragastric administration. Next, hematoxylin-eosin staining and electron microscopy were performed to evaluate the hepatic sinusoidal injury of rats. Endothelial cell marker RECA-1 was observed by immunohistochemistry. Hepatic oxidative stress was analyzed by detecting malondialdehyde, glutathione S-transferase, and reactive oxygen species. Assessment of liver function was carried out by analysis of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels. Real-time polymerase chain reaction and Western blot analysis were used to identify liver Sirtuin-3 (SIRT3) and active matrix metallopeptidase 9 (MMP-9) expression. Besides, liver sinusoidal endothelial cells (LSECs) were used for the in vitro functional verification experiment. Specifically, liver histology of the melatonin-treated groups showed that the pathological damages caused by MCT were significantly attenuated, total HSOS scores were decreased, and the elevation of serum hyaluronic acid observed in the model group was also reduced. Moreover, melatonin treatment also improved the survival of rats after partial hepatectomy. Administration of melatonin ameliorated MCT-induced LSECs injury, hepatic oxidative stress, and hepatic dysfunction. Furthermore, melatonin treatment increased SIRT3 expression while attenuating MMP-9 activity in liver tissues. Cell experiment also demonstrated that SIRT3 might mediate the protective effect of melatonin on LSECs. Collectively, our study provided the potential rationale for the application of melatonin for the prevention of MCT-induced HSOS.

Mid- to long-term outcomes of initial transjugular intrahepatic portosystemic shunt versus anticoagulation for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

BACKGROUND: Anticoagulation therapy (AT) is often used as the initial treatment for pyrrolizidine alkaloid (PA)-induced hepatic sinusoidal obstruction syndrome (HSOS). However, transjugular intrahepatic portosystemic shunt (TIPS) is an alternative treatment. This study aimed to determine the mid- to long-term outcomes of TIPS versus AT as the initial treatment for PA-induced HSOS. METHODS: We retrospectively analyzed the clinical data of 61 patients with PA-induced HSOS that were collected between November 2015 and July 2021. The patients were allocated to the TIPS group ( n = 20) or the AT group ( n = 41). These two groups were divided into subgroups according to the severity grading. The clinical data of the patients in both groups were analyzed. Cumulative survival rates were calculated and compared between the two groups and among the subgroups. RESULTS: The clinical symptoms and signs improved or stabilized in 100% of the patients following TIPS and in 85% of the patients following AT at discharge ( P = 0.166). The mortality rate was 0.0% in the TIPS group and 34.1% in the AT group ( P = 0.005). The patients were followed up for 2-69 months (mean, 26.3 ± 20.5 months). In the mild- and moderate-grade subgroups, there was no difference in the cumulative survival rate between the TIPS and AT groups ( P = 0.589 and P = 0.364, respectively). In the severe and very severe-grade subgroups, the cumulative survival rate was higher in the TIPS group than in the AT group ( P = 0.018 and P = 0.025, respectively). CONCLUSION: AT is a suitable initial treatment for mild or moderate PA-induced HSOS, whereas TIPS should be considered the appropriate initial treatment for severe or very severe PA-induced HSOS.

Oxaliplatin-Induced Sinusoidal Obstruction Syndrome Masquerading as Colorectal Liver Metastasis: A Case Report.

INTRODUCTION: Oxaliplatin-based chemotherapy is commonly used in adjuvant treatment of colon cancer as well as in neoadjuvant setting in patients with liver metastases. However oxaliplatin can cause damage to non-tumor bearing liver which presents as sinusoidal obstructive syndrome (SOS). These changes are difficult to differentiate from metastasis clinic-radiologically and manifests as sinusoidal dilatation, peliosis and nodular regenerative hyperplasia. CASE: The present study reports the case of a patient with oxaliplatin-induced SOS which mimicked colo-rectal liver metastasis on follow up imaging studies after receiving neoadjuvant oxaliplatin based chemotherapy. After multidisciplinary discussion, patient was planned for simultaneous resection of rectal primary and right hepatectomy for metastasis. Final histopathology revealed no tumour in liver but the liver lesions seen radiologically were actually changes of oxaliplatin induced focal SOS and mimicked metastatic nodules. CONCLUSION: In patients with colo-rectal cancer having received oxaliplatin-based chemotherapy, SOS may be considered as one of the causes of newly developed liver lesions, and should be subjected to additional radio-pathologic evaluation to prevent overtreatment and avoiding potentially morbid surgeries.

Predictive factors of collateral vessel development induced by oxaliplatin-based chemotherapy.

BACKGROUND AND AIM: Oxaliplatin can lead to hepatic sinusoidal injury, called hepatic sinusoidal obstruction syndrome (SOS), resulting in portal hypertension-related complications. This could worsen the clinical course of the patients treated with oxaliplatin. Early diagnosis is challenging. We explored predictive markers of oxaliplatin-induced collateral vessels. METHODS: Patients who received oxaliplatin-based chemotherapy were retrospectively screened. We evaluated their laboratory findings and spleen size on computed tomography immediately before oxaliplatin-based chemotherapy and after 6 months of treatment. The primary outcome was collateral vessel development, as a surrogate marker for oxaliplatin-induced SOS in patients who underwent oxaliplatin-based chemotherapy. The secondary outcome was the identification of factors that predicted the development of collateral vessels. RESULTS: We enrolled 161 patients who received oxaliplatin-based chemotherapy. They had a median age of 69 years, and 63.3% were men. Collateral vessels developed in nine (5.6%) patients during the study period. After oxaliplatin-based chemotherapy, the spleen size increased in 104 patients (64.6%), with a ≥ 30% increase in 19.4% of the patients. Univariate analysis showed that the Fibrosis-4 (FIB-4) index (≥ 1.76; OR 9.17), aspartate aminotransferase:platelet ratio index (APRI) (≥ 0.193; OR 9.62), cumulative dose of oxaliplatin (≥ 1000 mg; OR 8.43), and increase in spleen size (≥ 30%; OR 6.01) were significant risk factors for collateral vessel development. Multivariate analysis after stepwise selection revealed that the FIB-4 index and spleen size were significant independent predictive factors. CONCLUSION: A ≥ 1.76 increase in the FIB-4 index and a ≥ 30% increase in spleen size after 6 months of oxaliplatin-based chemotherapy were significant predictive markers for collateral vessel development.

Enoxaparin attenuates pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome by inhibiting oncostatin M expression.

BACKGROUND AND AIMS: The definitive treatment for pyrrolizidine alkaloids (PAs)-induced hepatic sinusoidal obstruction syndrome (HSOS) is not available. The effectiveness of anticoagulation therapy remains controversial. The efficacy of low molecular weight heparin (LMWH) should be investigated in patients and animal models, and the underlying mechanism should be explored. METHODS: The prognosis of patients with PAs-HSOS who received anticoagulation therapy was retrospectively analysed. The effect of enoxaparin on the liver injury was determined in animal models of monocrotaline (MCT)-induced HSOS was determined, and the underlying mechanism was investigated using a murine model. RESULTS: The cumulative survival rate of patients with PAs-induced HSOS was 60.00% and 90.90% in the non-anticoagulation group and anticoagulation group. Enoxaparin attenuated liver injury effectively in a rat model of MCT-induced HSOS. Additionally, the improvement of severe liver injury was observed in MCT-treated mice after the administration of enoxaparin (40 mg/kg). The alleviation of liver injury was observed in mice with hepatocyte-specific deletion of oncostatin M (Osm△Hep ). In MCT-treated mice administrated with enoxaparin, no significant differences in liver injury were observed between Osm△Hep mice and Osmflox/flox mice. Additionally, adenovirus-mediated overexpression of Osm resulted in severe liver injury in MCT-induced mice after the administration of enoxaparin. CONCLUSIONS: LMWH attenuated severe liver injury in patients with PAs-Induced HSOS and animal models of MCT-induced HSOS, which provides a rationale for the application of anticoagulation therapy.

Defibrotide improved the outcome of monocrotaline induced rat hepatic sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Pyrrolizidine alkaloids (PA) induced hepatic sinusoidal obstruction syndrome (HSOS) occurred worldwide and the mortality rate remained high because there were no specific therapies. Defibrotide was effective for HSOS following hematopoietic stem cell transplantation. But the pathogenesis of the two types of HSOS were not equivalent. The purpose of this study was to see if defibrotide was also effective in PA induced rat HSOS. METHODS: First we improved rat HSOS model by using higher dose (230 mg/kg) of monocrotaline (a kind of PA) as the dose of median lethal dose. So drug effectiveness could be assessed by survival time. Next, male SD rats were divided into 5 groups. They were control group, model group, low dose low molecular weight heparin (LMWH) treatment group, high dose LMWH treatment group and defibrotide treatment group. Rats' survival time, liver function, white blood cell count and cytokines were compared among the groups. The DeLeve score was used to assess the severity of liver pathology. RESULTS: The model group exhibited typical liver pathology of HSOS, such as hepatic sinus dilation, congestion, endothelial injury of central lobular vein, coagulative necrosis of hepatocytes and fibrin deposition in the subendothelial. The pathologic characteristics indicated that the model was built up successfully. The survival rate was significantly higher in defibrotide group (81.8%) than model group (43.7%), while the survival rates were similar in the two LMWH groups (62.5% and 75%) and model group. The survival time only be prolonged by defibrotide (P=0.028) but not LMWH (P>0.05). DeLeve score was improved most in the defibrotide group than the two LMWH groups (both P<0.01). Changes in DeLeve score, liver function, plasma level of tumor necrosis factor α and plasminogen activator inhibitor-1 exhibited the same trends. CONCLUSION: Defibrotide could improve the outcome of monocrotaline-induced rat HSOS indicating that defibrotide might be a better choice than LMWH in clinical practice.

Effects of bicyclol on hepatic sinusoidal obstruction syndrome induced by Gynura segetum.

BACKGROUND: The intake of Gynura segetum, a traditional Chinese medicine, may be induce hepatic sinusoidal obstruction syndrome (HSOS). It has a high mortality rate based on the severity of the disease and the absence of therapeutic effectiveness. Therefore, the current study was designed to investigate the effects of bicyclol on HSOS induced by Gynura segetum and the potential molecular mechanisms. METHODS: Gynura segetum (30 g/kg) was administered for 4 weeks in the model group, while the bicyclol pretreatment group received bicyclol (200 mg/kg) administration. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol (CHO), triglyceride (TG), and liver histological assays were detected to assess HSOS. The gene expressions of cytochrome P450 (CYP450) isozymes were quantified by real-time PCR. Moreover, hepatocellular apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, then apoptosis and autophagy-related markers were determined using Western blot. RESULTS: As a result, bicyclol pretreatment is notably protected against Gynura segetum-induced HSOS, as observed by reducing serum ALT levels, inhibiting the reduction in CHO and TG levels, and alleviating the histopathological changes. Bicyclol pretreatment inhibited the changes in mRNA levels of CYP450 isozymes (including the increase in CYP2a5 and decrease in CYP2b10, 2c29, 2c37, 3a11, and 7b1). In addition, the upregulation of Bcl-2 and the downregulation of LC3-II/LC3-I proteins expression in HSOS were inhibited with bicyclol pretreatment. CONCLUSION: Bicyclol exerted a protective effect against HSOS induced by Gynura segetum, which could be attributed to the regulated expressions of CYP450 isozymes and alleviated the downregulation of autophagy.

Model establishment and microarray analysis of mice with oxaliplatin­induced hepatic sinusoidal obstruction syndrome.

Hepatic sinusoidal obstruction syndrome (HSOS) is a serious side effect of oxaliplatin (OXA) treatment. The present study aimed to establish a reproducible mouse model of OXA­induced HSOS and to preliminarily explore the underlying molecular mechanisms using mRNA microarray analysis. A total of 45 C57BL/6 male mice were randomly divided into five groups: Control, 5 mg/kg OXA, 10 mg/kg OXA, 15 mg/kg OXA and 20 mg/kg OXA. The mice were respectively injected intraperitoneally with 5% glucose solution, or 5, 10, 15 or 20 mg/kg OXA solution once a week for 6 consecutive weeks. The body weight of the mice was recorded every day. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Hematoxylin and eosin staining, Sirius red staining and scanning electron microscopy were used to identify pathological changes. mRNA microarray was used to analyze changes in the gene expression profiles mainly from the functional aspects of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The oxidation mechanism was verified by measuring oxidative stress­related markers and reactive oxygen species with dihydroethidium probe technology, according to the microarray results. Among all of the OXA groups, 10 mg/kg OXA resulted in an acceptable survival rate of 78%. The mice showed obvious splenomegaly, increases in serum levels of ALT and AST, aggravation of liver pathological injuries and hepatic sinusoidal injuries. The microarray results suggested that mRNA expression changes after OXA treatment were associated with 'oxidative stress', 'coagulation function', 'steroid anabolism' and 'pro­inflammatory responses'. The results confirmed that OXA aggravated oxidative damage in the livers of the mice. The present study successfully established a mouse model of OXA­induced HSOS and preliminarily analyzed the underlying molecular mechanisms involved, thus laying a foundation for a subsequent in­depth study.

Usefulness of ultrasonography and elastography in diagnosing oxaliplatin-induced sinusoidal obstruction syndrome.

BACKGROUND: Sinusoidal obstruction syndrome (SOS) refers to liver injury caused by hematopoietic stem cell transplantation (HSCT) and anticancer drugs including oxaliplatin. Increased splenic volume (SV) on computed tomography (CT) indicates oxaliplatin-induced SOS. Similarly, ultrasonography and liver stiffness measurement (LSM) by shear-wave elastography (SWE) can help diagnose SOS after HSCT; however, their usefulness for diagnosing oxaliplatin-induced SOS remains unclear. We investigated the usefulness of the Hokkaido ultrasonography-based scoring system with 10 ultrasonographic parameters (HokUS-10) and SWE in diagnosing oxaliplatin-induced SOS early. METHODS: In this prospective observational study, ultrasonography and SWE were performed before and at 2, 4, and 6 months after oxaliplatin-based chemotherapy. HokUS-10 was used for assessment. CT volumetry of the SV was performed in clinical practice, and an SV increase ≥ 30% was considered the diagnostic indicator of oxaliplatin-induced SOS. We assessed whether HokUS-10 and SWE can lead to an early detection of oxaliplatin-induced SOS before an increased SV on CT. RESULTS: Of the 30 enrolled patients with gastrointestinal cancers, 12 (40.0%) with an SV increase ≥ 30% on CT were diagnosed with SOS. The HokUS-10 score was not correlated with an SV increase ≥ 30% (r = 0.18). The change in rate of three HokUS-10 parameters were correlated with an SV increase ≥ 30% (r = 0.32-0.41). The change in rate of LSM by SWE was correlated with an SV increase ≥ 30% (r = 0.40). CONCLUSIONS: The usefulness of HokUS-10 score was not demonstrated; however, some HokUS-10 parameters and SWE could be useful for the early diagnosis of oxaliplatin-induced SOS.