European Groundshot-addressing Europe's cancer research challenges: a Lancet Oncology Commission.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

Towards a cancer mission in Horizon Europe: recommendations.

A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research-care-prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.

Focused Ultrasound Hyperthermia Augments Release of Glioma-derived Extracellular Vesicles with Differential Immunomodulatory Capacity.

Background: Increasing evidence points to the critical role of extracellular vesicles (EVs) as molecular parcels that carry a diverse array of bioactive payloads for coordination of complex intracellular signaling. Focused ultrasound (FUS) hyperthermia is a technique for non-invasive, non-ionizing sublethal heating of cells in a near-instantaneous manner; while it has been shown to improve drug delivery and immunological recognition of tumors, its impact on EVs has not been explored to date. The goal of this study was to determine whether FUS impacts the release, proteomic profile, and immune-activating properties of tumor-derived EVs. Methods: Monolayered murine glioma cells were seeded within acoustically transparent cell culture chambers, and FUS hyperthermia was applied to achieve complete coverage of the chamber. Glioma-derived EVs (GEVs) were isolated for characterization by Nanoparticle Tracking Analysis, cryo-electron microscopy and mass spectrometry. An in vitro experimental setup was designed to further dissect the impact of GEVs on innate inflammation; immortalized murine dendritic cells (DCs) were pulsed with GEVs (either naïve or FUS hyperthermia-exposed) and assayed for production of IL-12p70, an important regulator of DC maturation and T helper cell polarization toward the interferon-γ-producing type 1 phenotype. Results: We confirmed that FUS hyperthermia significantly augments GEV release (by ~46%) as well as shifts the proteomic profile of these GEVs. Such shifts included enrichment of common EV-associated markers, downregulation of markers associated with cancer progression and resistance and modulation of inflammation-associated markers. When DCs were pulsed with GEVs, we noted that naïve GEVs suppressed IL-12p70 production by DCs in a GEV dose-dependent manner. In contrast, GEVs from cells exposed to FUS hyperthermia promoted a significant upregulation in IL-12p70 production by DCs, consistent with a pro-inflammatory stimulus. Conclusion: FUS hyperthermia triggers release of proteomically distinct GEVs that are capable of facilitating an important component of innate immune activation, lending both to a potential mechanism by which FUS interfaces with the tumor-immune landscape and to a role for GEV-associated biomarkers in monitoring response to FUS.

Towards an evidence-informed value scale for surgical and radiation oncology: a multi-stakeholder perspective.

Surgery and radiotherapy, two locoregional cancer treatments, are essential to help improve cancer outcomes, control, and palliation. The continued evolution in treatment processes, techniques, and technologies-often at substantially increased costs-demands for direction on outcomes that are most valued by patients, and the evidence that is required before clinical adoption of these practices. Three recently introduced frameworks-the European Society for Medical Oncology Magnitude of Clinical Benefit Scale, the American Society of Clinical Oncology Value Framework, and the National Comprehensive Cancer Network Blocks-which all help define the value of oncology treatments, were appraised with a focus on their methods and definition of patient benefit. In this Review, we investigate the applicability of these frameworks to surgical and radiotherapy innovations. Findings show that these frameworks are not immediately transferable to locoregional cancer treatments. Moreover, the lack of emphasis on patient perspective and the reliance on traditional, trial-based endpoints such as survival, disease-free survival, and safety, calls for a new framework that includes real-world evidence with focus on the whole spectrum of patient-centred endpoints. Such an evidence-informed value scale would safeguard against the proliferation of low-value innovation while simultaneously increasing access to treatments that show significant improvements in the outcomes of cancer care.

Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound.

OBJECTIVE Ultrasound can be precisely focused through the intact human skull to target deep regions of the brain for stereotactic ablations. Acoustic energy at much lower intensities is capable of both exciting and inhibiting neural tissues without causing tissue heating or damage. The objective of this study was to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and selective mapping in the thalamus of a large-brain animal. METHODS Ten Yorkshire swine ( Sus scrofa domesticus) were used in this study. In the first neuromodulation experiment, the lemniscal sensory thalamus was stereotactically targeted with LIFU, and somatosensory evoked potentials (SSEPs) were monitored. In a second mapping experiment, the ventromedial and ventroposterolateral sensory thalamic nuclei were alternately targeted with LIFU, while both trigeminal and tibial evoked SSEPs were recorded. Temperature at the acoustic focus was assessed using MR thermography. At the end of the experiments, all tissues were assessed histologically for damage. RESULTS LIFU targeted to the ventroposterolateral thalamic nucleus suppressed SSEP amplitude to 71.6% ± 11.4% (mean ± SD) compared with baseline recordings. Second, we found a similar degree of inhibition with a high spatial resolution (∼ 2 mm) since adjacent thalamic nuclei could be selectively inhibited. The ventromedial thalamic nucleus could be inhibited without affecting the ventrolateral nucleus. During MR thermography imaging, there was no observed tissue heating during LIFU sonications and no histological evidence of tissue damage. CONCLUSIONS These results suggest that LIFU can be safely used to modulate neuronal circuits in the central nervous system and that noninvasive brain mapping with focused ultrasound may be feasible in humans.

Pharmacokinetics of L-arginine in adults with moderately severe malaria.

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g,L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K(m) of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.

Hyalomatrix: a temporary epidermal barrier, hyaluronan delivery, and neodermis induction system for keratinocyte stem cell therapy.

Keratinocyte stem cell technology provides at least an adjuvant therapy to clinically close large cutaneous wounds (e.g., burn wounds). Here, the performance of keratinocyte cultures depends primarily on the quality of the bed to which they are applied. Clinical take rates for cultured keratinocyte grafts are optimal when applied to a vascularized dermal bed with minimal bacterial colonization. In the absence of autologous dermis, staged reconstruction with a dermal equivalent or dermal regeneration template is required. A novel product, Hyalomatrix, is a bilayer of an esterified hyaluronan scaffold beneath a silicone membrane. The scaffold delivers hyaluronan to the wound bed, and the silicone membrane acts as a temporary epidermal barrier. The product has been investigated in a controlled, porcine, acute full-thickness excisional wound model. Cultured autologous keratinocytes (CAKs) were delivered on Laserskin to acute full-thickness wounds treated with Hyalomatrix within chambers, and graft take rates were assessed longitudinally using image analysis. In the absence of chambers, wound contraction was assessed. Clinical CAK take rates fall sequentially with delay in application post-Hyalomatrix pre-treatment, but repeated pre-treatment removed this, with maximal take of 57.2% at 5 weeks post-wounding. In the absence of chambers, more-complete wound closure resulted from edge re-epithelialization and contraction, by a factor of 5 at 1 month, and was achieved at least 2 weeks sooner in the gold standard controls of split-thickness autograft to an acute or pre-treated wound bed. Wound contraction and late neodermal morphology (1 year) were similar in pre-treated CAKs and split-thickness autograft wounds. In this model, the Hyalomatrix wound bed pre-treatment increase in CAK take appeared to be dose dependent. The product appeared to act as a hyaluronan delivery system rather than a dermal regeneration template. The silicone membrane may limit wound bed colonization, and the combination of this temporary barrier with hyaluronan delivery and neodermis induction has been termed a barrier-delivery-induction system. The development of similar systems for serial application offers an alternative to a dermal regeneration template when CAKs are engrafted in the hostile, colonized environment of large burn wounds.

CSF quinolinic acid levels are determined by local HIV infection: cross-sectional analysis and modelling of dynamics following antiretroviral therapy.

Quinolinic acid (QUIN) is a product of tryptophan metabolism that can act as an endogenous brain excitotoxin when released by activated macrophages. Previous studies have shown correlations between increased CSF QUIN levels and the presence of the AIDS dementia complex (ADC), a neurodegenerative condition complicating late-stage human immunodeficiency virus type 1 (HIV) infection in some patients. CSF QUIN is putatively one of the important molecular mediators of the brain injury in this clinical setting and, more generally, serves as a marker of local macrophage activation. This study was undertaken to examine the relationship of CSF QUIN concentrations to local HIV infection and to define the effects of antiretroviral drug treatment on CSF QUIN using two complementary approaches. The first was an exploratory cross-sectional analysis of a clinically heterogeneous sample of 62 HIV-infected subjects, examining correlations of CSF QUIN levels with CSF and plasma HIV RNA levels and other salient parameters of infection. The second involved longitudinal observations of a subset of 20 of these subjects who initiated new antiretroviral therapy regimens. In addition to descriptive analysis, we used kinetic modelling of QUIN decay in relation to that of HIV RNA to assess further the relationship between CSF QUIN and infection in the dynamic setting of treatment. The cross-sectional studies showed strong correlations of CSF QUIN with both CSF HIV RNA and blood QUIN levels, as well as with elevations in CSF white blood cells, CSF total protein and CSF:blood albumin ratio. In this group of subjects with a low incidence of active, untreated ADC, CSF QUIN did not correlate with ADC stage or measures of quantitative neurological performance. Antiviral treatment reduced the CSF QUIN levels in all the longitudinally followed, treated subjects. Kinetic modelling of CSF QUIN decay indicated that CSF QUIN levels were driven primarily by CSF HIV infection with a lesser contribution from blood QUIN levels. In three subjects with new-onset, untreated ADC, CSF QUIN decay paralleled both CSF HIV decrement and improvement in neurological performance. These studies show that CSF QUIN concentrations relate primarily to active CSF HIV infection and to a lesser extent to plasma QUIN. CSF QUIN serves as a marker of local infection with a wide dynamic range. The time course of therapy-induced changes links CSF QUIN to local infection and supports the action of antiviral therapy in ameliorating immunopathological brain injury and ADC.