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Simple Summary: Immunotherapy or combined chemoimmunotherapy is currently first-line therapy for patients with metastatic NSCLC without a driver mutation. Despite immunotherapy contributing to improved survival outcomes, the estimated 5-year OS rate for metastatic NSCLC remains poor. The aim of our retrospective study was to assess how patients with different anatomical metastatic sites respond or develop resistance to immunotherapy, combination chemoimmunotherapy, or chemotherapy alone. We confirmed that patients with bone metastases have poorer survival outcomes compared to those without bone metastases. This highlights a group of patients that may benefit from a specific clinical trial evaluation to assess the benefit of additional novel therapeutics or upfront radiotherapy. Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether there are any changes in brain metastases or resection cavity volumes between planning magnetic resonance imaging (MRI) and radiosurgery (RS) treatment and whether these led to a change in management or alteration in the RS plan.Methods and Materials: Patients undergoing RS for brain metastasis or tumor resection cavities had a standardized planning MRI (MRI-1) performed and a repeat verification MRI (MRI-2) 24 hours before RS. Any change in management, including replanning based on MRI-2, was recorded.Results: Thirty-four patients with a total of 59 lesions (44 metastases and 15 tumor resection cavities) were assessed with a median time between MRI-1 and MRI-2 of 7 days. Seventeen patients (50%) required a change in management based on the changes seen on MRI-2. For patients with 7 days or less between scans, 41% (9 of 22) required a change in management; among patients with 8 days or more between scans, 78% (7 of 9) required a change in management. Per lesion, 32 out of 59 lesions required replanning, including 7 of 15 (47%) cavities and 25 of 44 (57%) metastases, with the most common reason (23 lesions) being an increase in gross target volume (tumor) or clinical target volume (tumor cavity).Conclusions: Measurable changes occur in brain metastasis over a short amount of time, with a change in management required in 41% of patients with 7 days between MRI-1 and MRI-2 and in 78% of patients when there is a delay longer than 7 days. We therefore recommend that the time between planning MRI and RS treatment be as short as possible. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is the most common and malignant primary brain tumor. In contrast to some other tumor types, aberrant glucose metabolism is an important component of GBM growth and chemoresistance. Recent studies of human orthotopic GBM in mice and in situ demonstrated GBM cells rely on both glycolysis and mitochondrial oxidation for glucose catabolism. These observations suggest that the homeostasis of energy metabolism of GBM cells might be further disturbed by dual-inhibition of glucose metabolism. The present study aimed to evaluate the efficacy and the mechanisms of dual-targeting therapy in GBM cells. Methods: Representative GBM cells (immortalized GBM cell lines and patient-derived GBM cells) and non-cancerous cells were treated with 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO), an in-house designed novel arsenic-based mitochondrial toxin, in combination with dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor. The efficacy of this combinatorial therapy was evaluated by MTS assay, clonogenic surviving assay and apoptotic assays. The underlying mechanisms of this dual-targeting treatment were unraveled by using mitochondrial membrane potential measurements, cytosol/mitochondrial ROS detection, western blotting, extracellular flux assay and mass spectrometry. Results: As monotherapies, both PENAO and DCA induced proliferation arrest in a panel of GBM cell lines and primary isolates. PENAO inhibited oxygen consumption, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis. By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells), impair the clonogenicity, and induce mitochondria-mediated apoptosis. An oxidative stress of mitochondrial origin takes a prominent place in the mechanism by which the combination of PENAO and DCA induces cell death. Additionally, PENAO-induced oxidative damage was enhanced by DCA through glycolytic inhibition which in turn diminished acid production induced by PENAO. Moreover, DCA treatment also led to an alteration in the multidrug resistance (MDR) phenotype of GBM cells, thereby leading to an increased cytosolic accumulation of PENAO. Conclusions: The findings of this study shed a new light with respect to the dual-targeting of glucose metabolism in GBM cells and the innovative combination of PENAO and DCA shows promise in expanding GBM therapies. [ABSTRACT FROM AUTHOR]

The correction does not have any effect on the results or conclusions of the paper. Reference 1 Mudassar F, Shen H, O'Neill G. Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. [Extracted from the article]

High-grade gliomas (HGGs), including glioblastoma and diffuse intrinsic pontine glioma, are amongst the most fatal brain tumors. These tumors are associated with a dismal prognosis with a median survival of less than 15 months. Radiotherapy has been the mainstay of treatment of HGGs for decades; however, pronounced radioresistance is the major obstacle towards the successful radiotherapy treatment. Herein, tumor hypoxia is identified as a significant contributor to the radioresistance of HGGs as oxygenation is critical for the effectiveness of radiotherapy. Hypoxia plays a fundamental role in the aggressive and resistant phenotype of all solid tumors, including HGGs, by upregulating hypoxia-inducible factors (HIFs) which stimulate vital enzymes responsible for cancer survival under hypoxic stress. Since current attempts to target tumor hypoxia focus on reducing oxygen demand of tumor cells by decreasing oxygen consumption rate (OCR), an attractive strategy to achieve this is by inhibiting mitochondrial oxidative phosphorylation, as it could decrease OCR, and increase oxygenation, and could therefore improve the radiation response in HGGs. This approach would also help in eradicating the radioresistant glioma stem cells (GSCs) as these predominantly rely on mitochondrial metabolism for survival. Here, we highlight the potential for repurposing anti-parasitic drugs to abolish tumor hypoxia and induce apoptosis of GSCs. Current literature provides compelling evidence that these drugs (atovaquone, ivermectin, proguanil, mefloquine, and quinacrine) could be effective against cancers by mechanisms including inhibition of mitochondrial metabolism and tumor hypoxia and inducing DNA damage. Therefore, combining these drugs with radiotherapy could potentially enhance the radiosensitivity of HGGs. The reported efficacy of these agents against glioblastomas and their ability to penetrate the blood-brain barrier provides further support towards promising results and clinical translation of these agents for HGGs treatment. [ABSTRACT FROM AUTHOR]