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Oxaliplatin is a platinum-based antineoplastic agent used in cancer chemotherapy. Oxaliplatin-induced hepatic sinusoidal obstruction syndrome (HSOS) has been reported in the context of chemotherapy for liver metastasis of colorectal cancer. However, to the best of our knowledge, there is no report of oxaliplatin-associated HSOS in patients with gastric cancer. The present study reported a patient with gastric cancer who received proximal gastrectomy and oxaliplatin-containing chemotherapy. Contrast-enhanced computed tomography revealed that liver parenchyma appeared heterogeneous and demonstrated hypoattenuation in the portal phase. In dynamic contrast-enhanced magnetic resonance imaging, hypointense heterogeneity was demonstrated in the portal-venous phase. Pathological examination indicated distinctive multifocal sinusoidal dilatation. In conclusion, the present report indicated a case of oxaliplatin-induced HSOS in a patient with gastric cancer who received oxaliplatin-contained chemotherapy.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.

Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely have been linked to liver toxicities that impair liver function and regeneration. Recognition of chemotherapy-related liver toxicity emphasizes the importance of multidisciplinary planning to optimize care. This review aims to summarize current data on multimodal treatment concepts for CRC, provide an overview of liver damage caused by commonly administered chemotherapeutic agents, and evaluate currently suggested protective agents.

Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.

Herbs and dietary supplement-induced liver injury (HILI) is the leading cause of drug-induced liver injury in China. Among different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-producing herb Gynura japonica contributes significantly to HILI by inducing hepatic sinusoidal obstruction syndrome (HSOS), a liver disorder characterized by hepatomegaly, hyperbilirubinemia, and ascites. In China, G. japonica has been used as one of the plant species for Tu-San-Qi and is often misused with non-PA-producing Tu-San-Qi ( Sedum aizoon ) or even San-Qi ( Panax notoginseng ) for self-medication. It has been reported that over 50% of HSOS cases are caused by the intake of PA-producing G. japonica . In this review, we provide comprehensive information to distinguish these Tu-San-Qi-related herbal plant species in terms of plant/medicinal part morphologies, medicinal indications, and chemical profiles. Approximately 2156 Tu-San-Qi-associated HSOS cases reported in China from 1980 to 2019 are systematically reviewed in terms of their clinical manifestation, diagnostic workups, therapeutic interventions, and outcomes. In addition, based on the application of our developed mechanism-based biomarker of PA exposure, our clinical findings on the definitive diagnosis of 58 PA-producing Tu-San-Qi-induced HSOS patients are also elaborated. Therefore, this review article provides the first comprehensive report on 2214 PA-producing Tu-San-Qi ( G. japonica )-induced HSOS cases in China, and the information presented will improve public awareness of the significant incidence of PA-producing Tu-San-Qi ( G. japonica )-induced HSOS and facilitate future prevention and better clinical management of this severe HILI.

Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N -oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N -oxides remains unclear. The current study unequivocally identified PA N -oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N -oxides were recorded to induce HSOS in human. PA N -oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 μmol PA N -oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N -oxide (55 μmol/kg) on rats revealed the toxic mechanism that PA N -oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N -oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N -oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N -oxides present in herbs and foods should be regulated and controlled in use.

Background Hepatic veno-occlusive disease or sinusoidal obstruction syndrome is a potentially life-threatening complication of hematopoietic stem cell transplantation. Objective To assess the usefulness of point shear-wave elastography (pSWE) for the early diagnosis of sinusoidal obstruction syndrome (SOS) in children. Materials and methods A retrospective study was carried out in 43 patients with suspected SOS assessed between March 2018 and November 2021. Diagnosis of SOS was confirmed in 28 patients based on the European Society for Blood and Marrow Transplantation diagnostic criteria. Abdominal ultrasound and pSWE of the liver were performed before and after hematopoietic stem cell transplantation on first suspicion of SOS. Results Liver stiffness on initial suspicion was higher in patients diagnosed with SOS and these values increased compared to the pre-transplantation values. A cutoff value of 1.37 m/s was found for the diagnosis of SOS, with an area under the curve of 0.779 (95% CI 0.61–0.93). Conclusion Point shear wave elastography of the liver is a promising technique for the early diagnosis of pediatric SOS. Graphical abstract

Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes.

Background: Adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have dismal prognoses, underscoring the need for effective salvage therapies. Inotuzumab ozogamicin (INO) and blinatumomab (BLIN) have demonstrated efficacy in achieving complete remission (CR) and measurable residual disease (MRD) response. Objectives: We tried to evaluate the clinical outcomes and toxicities of INO in adults with R/R BCP-ALL. Design: Prospective observational multicenter study. Methods: A total of 100 patients (25 Ph-positive, 75 Ph-negative) received INO (0.8 mg/m2 on week 1; 0.5 mg/m2 on weeks 2–3) for the initial cycle, followed by 0.5 mg/m2 dosing in subsequent cycles. Allogeneic hematopoietic cell transplantation (allo-HCT) was planned after remission. Results: Among the cohort, 7 patients were primary refractory (4 post-BLIN), 36 relapsed after chemotherapy (23 post-BLIN), and 57 relapsed after allo-HCT (23 post-BLIN). Extramedullary relapse occurred in 39% of patients. After the first cycle, 60% achieved CR or CR with incomplete hematologic recovery; the overall best response rate after two cycles was 67%, with MRD negativity achieved in 63.1%. Thirty-nine patients (58.2%) underwent allo-HCT. Early mortality occurred in 12%, and hepatic veno-occlusive disease/sinusoidal obstruction syndrome was observed in 10%. With a median follow-up of 31.5 months, the 3-year overall survival was 21.3% in the entire cohort and 37.6% among transplanted patients. Conclusion: INO represents a potent salvage option for R/R BCP-ALL. However, substantial toxicities highlight the critical need for careful patient selection and dose optimization strategies to maximize its therapeutic benefit. Trial registration: This study was registered in Clinical Research Information Service (CRIS #KCT0010009) which is connected to WHO ICTRP (Operated by Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare, Republic of Korea).

Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a humanized monoclonal antibody targeting the cell surface receptor CD22 coupled to a cytotoxic calicheamicin payload via an acid labile linker. InO has shown significant activity in relapsed and refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in both single agent and combination chemotherapy regimens in adult and pediatric trials. Its use in newly diagnosed elderly patients has also been established while clinical trials investigating its use in newly diagnosed pediatric patients and fit adults are ongoing. Notable toxicities include sinusoidal obstruction syndrome (SOS), particularly in patients who undergo hematopoietic stem cell transplantation (HSCT) after InO as well as myelosuppression and B-cell aplasia which confer increased infection risk, particularly in combination with cytotoxic chemotherapy. In the relapsed/refractory (R/R) setting, the planned subsequent curative therapy modality must be considered when using InO to mitigate SOS risk if proceeding to HSCT and account for potential B-cell aplasia if proceeding to chimeric antigen receptor CAR-T therapy. Studies exploring mechanisms of resistance or failure of InO are ongoing but modulation or loss CD22 expression, alternative CD22 splicing, and high Bcl-2 expression have been implicated. In this review, we will summarize the currently available data on InO, with an emphasis on pediatric trials, and explore future directions including combinatorial therapy.