Novel approaches to managing gestational trophoblastic tumors in the age of immunotherapy.

The discovery that anti-programmed death-1 antibody (anti-PD-1) immunotherapy can cure patients with multidrug-resistant gestational trophoblastic neoplasia provides a new powerful and low toxicity treatment. This heralds an era within which the majority of patients, including those with previously difficult to treat disease, can expect to achieve long-term remission. This development should prompt a rethink of how patients with this rare disease are managed, focusing on maximizing cure rate with minimal exposure to toxic chemotherapy.

The potential role of HIF on tumour progression and dissemination.

Cancer is the second cause of mortality worldwide, primarily owing to failure to cure metastatic disease. The need to target the metastatic process to reduce mortality is clear and research over the past decade has shown hypoxia-inducible factor-1 (HIF-1) to be one of the promising targets. In order for metastatic disease to be established, multiple steps need to be taken whereby the tumour cells escape into the bloodstream and survive, disseminate and then establish at a premetastatic niche. HIF-1 mediates hypoxia-induced proangiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which promote extravasation and chemotaxis. The migration of tumour cells is mediated by loss of E-cadherin, which results in a more invasive phenotype; dissemination of the tumour cells by increased vascular permeability and survival in the bloodstream through resistance to apoptosis as well as adhesion at the premetastatic niche are all controlled by factors under the influence of HIF-1. The overexpression of HIF in many aggressive cancer types as well as its role in the establishment of metastatic disease and treatment resistance demonstrate its potential target in therapeutics. Taken together, the role of HIF-1 in cancer and metastatic disease is clear and the need for better treatment targeting metastases is paramount; more aggressive phenotypes with less response to treatment are associated with HIF-1 expression. Our research has shown promise but many questions still remain to be answered.

Regional traumatic limb hypothermia attenuates distant hepatic and renal injury following blast limb trauma in rats.

BACKGROUND: Blast limb injury was reported to result in distant organ injury including the lungs, which can be attenuated with transient regional hypothermia (RH) to the injured limb. We aimed to further study hepatic and renal injuries following blast limb trauma and also to evaluate the protective effects of regional traumatic limb hypothermia on such injuries in rats. METHODS: Blast limb trauma (BLT) was created using chartaceous electricity detonators in anesthetized male Sprague-Dawley rats. The BLT rats were randomly allocated to undergo regional traumatic limb hypothermic treatment (RH) for 30 minutes, 60 minutes, or 6 hours immediately after the onset of blast or without RH (n = 8 per group). The severity of hepatic and renal injury was assessed through histologic examination and water content (wet/dry weight) in all animals 6 hours later. The level of plasma tumor necrosis factor α (TNF-α), interleukin 6, hydrogen sulfide (H2S), and myeloperoxidase (MPO) together with hepatic and renal MPO, malondialdehyde (MDA), superoxide dismutase, and total antioxidant capacity were measured 6 hours after the blast injury. RESULTS: Following BLT, hepatic injury was evidenced by histopathologic changes, increased water content, as well as plasma alanine aminotransferase and aspartate aminotransferase. Renal histopathologic but not functional changes were also found. RH treatment for all durations attenuated this distant renal injury, but only RH treatment for 60 minutes and 6 hours attenuated distant hepatic injury following BLT. RH treatment for all durations decreased plasma TNF-α and interleukin 6, reduced liver and kidney MPO activity and kidney MDA, and elevated superoxide dismutase and total antioxidant capacity in both liver and kidneys. RH treatment for 60 minutes is the most effective duration to reduce hepatic MPO activity, plasma TNF-α, and kidney MDA. CONCLUSION: This study indicates that BLT-induced distant renal and hepatic injury could be attenuated by RH treatment through reduction of cytokine release and inhibition of neutrophil accumulation and oxidative stress.