ABSTRACT

Hepatoblastoma (HB) is the main paediatric liver cancer, but it is a very rare disease. Despite significant improvements in the treatment of children diagnosed with HB, limited treatment options exist for patients with advanced tumours. Besides, survivors generally have long-term adverse effects derived from treatment such as ototoxicity, cardiotoxicity, delayed growth, and secondary tumours. Accordingly, there is an urgent need to define new and efficient therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumour's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in paediatric cancers are lacking because of paucity of data. In this study, we computationally screened the efficacy of drugs in HB patients with the aggressive C2 subtype and poor clinical outcome starting from their transcriptome. Our method utilized publicly available collections of pan-cancer transcriptional profiles and drug responses across 36 tumour types and 495 compounds. The drugs predicted to be most effective were experimentally validated using patient-derived xenograft (PDX) models of HB grown in vitro and in vivo. We thus identified two CDK9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high CDK9 tumour expression was significantly associated with poor prognosis. Our work proves the usefulness of computational methods trained on pan-cancer datasets to reposition drugs in rare paediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.

PMID:37729391 | DOI:10.1097/HEP.0000000000000601

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PubMed articles on: Cancer & VTE/PE

Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial

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PubMed articles on: Cardio-Oncology

SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury

Elife. 2023 Sep 20;12:e85571. doi: 10.7554/eLife.85571. Online ahead of print.

ABSTRACT

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

PMID:37728319 | DOI:10.7554/eLife.85571

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PubMed articles on: Cancer & VTE/PE

The risk of recurrent venous thromboembolism after discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis: a systematic review and meta-analysis

EClinicalMedicine. 2023 Sep 8;64:102194. doi: 10.1016/j.eclinm.2023.102194. eCollection 2023 Oct.

ABSTRACT

BACKGROUND: The optimal duration of anticoagulation in patients with active cancer and venous thromboembolism (VTE) is unknown. Current clinical guidelines advocate anticoagulant therapy for 3-6 months and to continue anticoagulant therapy for as long as the cancer is active. However, an adequate systematic review on the rate of recurrent VTE after discontinuation of anticoagulant therapy has not been performed.

METHODS: For this systemic review and meta-analysis, we searched Embase.com, Medline (Ovid), Web of Science, Cochrane Library, and Google Scholar, from database inception to February 16, 2023, for studies on anticoagulant therapy in patients with cancer and the recurrence of venous thromboembolism after discontinuation of this therapy. We included randomised controlled trials and cohort studies published in English that reported on patients who met the following: cancer and a first VTE, completed at least 3 months of anticoagulant therapy, were followed after discontinuation of anticoagulant therapy, and with symptomatic recurrent VTE as an outcome during follow-up. Study-level data were requested from study authors. The primary outcome was the rate of recurrent VTE after discontinuation of anticoagulant therapy. A Bayesian random-effects meta-analysis was used to estimate the rate of recurrent VTE per 100 person-years for the pooled studies at different time intervals after discontinuation of anticoagulation therapy. We also calculated the cumulative VTE recurrence rate at different time intervals. Forest plots were mapped and the results were summarized by the median and 95% credible interval (CIs). This study was registered with PROSPERO, CRD42021249060.

FINDINGS: Of 3856 studies identified in our search, 33 studies were identified for inclusion. After requesting study-level data, 14 studies involving 1922 patients with cancer-associated thrombosis were included. The pooled rate of recurrent VTE per 100 person-years after discontinuation of anticoagulant therapy was 14.6 events (95% credible interval 6.5-22.8) in the first three months, decreasing to 1.1 events (95% CI 0.3-2.1) in year 2-3, and 2.2 events (95% CI 0.0-4.4) in year 3-5 after discontinuation of anticoagulant therapy. The cumulative VTE recurrence rate was 28.3% (95% CI 15.6-39.6%) at 1 year; 31.1% (95% CI 16.5-43.8%) at 2 years; 31.9% (95% CI 16.8-45.0%) at 3 years; and 35.0% (95% CI 16.8-47.4%) at 5 years after discontinuation of anticoagulant therapy.

INTERPRETATION: This meta-analysis demonstrates a high rate of recurrent VTE over time after discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis. Our results support the current clinical guidelines to continue anticoagulant therapy in patients with active cancer.

FUNDING: Erasmus MC.

PMID:37731937 | PMC:PMC10507196 | DOI:10.1016/j.eclinm.2023.102194

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PubMed articles on: Cancer & VTE/PE

Incidence and risk factors of deep vein thrombosis and pulmonary thromboembolism after spinal cord disease at a rehabilitation unit: a retrospective study

J Yeungnam Med Sci. 2023 Sep 20. doi: 10.12701/jyms.2023.00689. Online ahead of print.

ABSTRACT

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) are major complications of spinal cord disease. However, studies of their incidence in Korean patients are limited. Thus, this study investigated the incidence and risk factors of DVT and PTE in Korean patients with spinal cord disease.

METHODS: We retrospectively analyzed the medical records of 271 patients with spinal cord disease who were admitted to a rehabilitation unit within 3 months of disease onset at a tertiary hospital. The presence of DVT and PTE was mainly determined using Doppler ultrasonography and chest embolism computed tomography. Risk factor analysis included variables such as sex, age, obesity, completeness of motor paralysis, neurological level of injury, cause of injury, lower extremity fracture, active cancer, and functional ambulation category (FAC) score.

RESULTS: The incidences of DVT and PTE in the patients with spinal cord disease were both 6.3%. Risk factor analysis revealed that age of ≥65 years (p=0.031) and FAC score of ≤1 (p=0.023) were significantly associated with DVT development. Traumatic cause of injury (p=0.028) and DVT (p<0.001)

CONCLUSION: Patients with spinal cord disease developed DVT and PTE within 3 months of disease onset with incidence rates of 6.3% and 6.3%, respectively. Age of ≥65 years and an FAC of score ≤1 were risk factors for DVT. Traumatic cause of injury and DVT were risk factors for PTE. However, given the inconsistent results of previous studies, the risk factors for DVT and PTE remain inconclusive. Therefore, early screening for DVT and PTE should be performed in patients with acute-to-subacute spinal cord disease regardless of the presence or absence of these risk factors.

PMID:37726959 | DOI:10.12701/jyms.2023.00689

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PubMed articles on: Cancer & VTE/PE

Impact of pegaspargase dose capping on incidence of pegaspargase-related adverse events in adults

J Oncol Pharm Pract. 2023 Sep 20:10781552231202217. doi: 10.1177/10781552231202217. Online ahead of print.