In vitro 2-deoxy-2-[18F]fluoro-D-glucose uptake: practical considerations

In oncology 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]-FDG), a glucose analogue, is the most used positron emission tomography (PET) tracer. There are however some limitations due to low metabolic activity or high surrounding physiological uptake in several tumors or regions. Investigating new tracers or methods is expensive and elaborative when animal experiments or phase I clinical trials are used. In vitro experiments can overcome these limitations. We analyzed the influence of incubation time, cell medium conditions, administered activity, and cell density on [F-18]-FDG uptake in six different cell cultures. Glucose transporter 1 (GLUT1)- and hexokinase 2 (HK2)-expression at high and low cell density was analyzed using immunocytochemistry. FDG-uptake increases over time and absence of glucose in the incubation medium increases uptake. By increasing the administered activity, uptake per protein also increases and tracer uptake per protein is lower at higher cell densities. Immunocytochemical analysis reveals a lower expression of both GLUT1 and HK2 at higher cell concentrations. All investigated parameters influenced FDG uptake and therefore we can conclude it is of utmost importance to keep administered activity, incubation medium, and time constant and to correct uptake when cell density changes due to environmental conditions, such as therapy

Quantitative pretreatment VOI analysis of liver metastases 99mTc-MAA SPECT/CT and FDG PET/CT in relation with treatment response to SIRT

Using quantitive VOI analysis, the percentage Tc-99m-MAA uptake and SUVmax and mean values of liver metastases obtained prior to SIRT were related to treatment response using both a lesion-based and clinical dichotomous approach. Based on the VOI % of Tc-99m-MAA activity, the estimated Y-90-microspheres activity/cc (MBq/cc) was calculated from the effective dose injected. Baseline VOI FDG PET SUVmean and max values and estimated MBq/cc values were related to treatment response using a lesion-based approach (% change in SUVmean >= 50%) and a clinical dichotomous approach. Fifteen treatment sessions were analyzed (13 patients). Using the lesion-based approach (12 treatment sessions) 40 lesions responded and 37 did not. SUVmax and mean values proved significantly different between non-responding and responding lesions; 18:6 (SD 10.8) versus 13.5 (SD 8.4) for SUVmax (p = 0.02) and 11.4 (SD 3.8) versus 6.3 (SD 4.5) for SUVmean (p = 0.002). Using the clinical dichotomous approach (15 treatment sessions / 11 responding), 91 lesions were analyzed; 57 responded. VOI volumes and estimated Y-90-loaded glass microspheres activity (MBq/cc) did not differ between responders and non responders; 24 cc (SD 27) versus 21 cc (SD 21 cc) (p = 0.4) and 1.95 MBq/cc (SD 1.1 MBq/cc) versus 1.90 MB/cc (SD 2.7 MBq/cc) (p = 0.92). On the contrary, SUVmax and mean values proved significantly different between responders and non-responders; 23.7 (SD 9.8) versus 9.4 (SD 3.8) for SUVmax (p = 0.0001) and 13.1 (SD 8.1) versus 4.9 (SD 1.4) for SUVmean. Conclusion: These findings suggest that in patients presenting with high baseline SUVmax and mean values, the administration of higher activities or alternatively, other potentially more useful treatment options might be considered

Navigating the Future V: Marine Science for a Sustainable Future

Navigating the Future is a publication series produced by the European Marine Board providing future perspectives on marine science and technology in Europe. Navigating the Future V (NFV) highlights new knowledge obtained since Navigating the Future IV1 (2013). It is set within the framework of the 2015 Paris Agreement2 and builds on the scientific basis and recommendations of the IPCC reports3. NFV gives recommendations on the science required during the next decade to deliver the ocean we need to support a sustainable future. This will be important for the United Nations Decade of Ocean Science for Sustainable Development4 (2021 – 2030), the implementation of the UN Sustainable Development Goals5 and the European Commission’s next framework programme, Horizon Europe6 (2021 - 2027). There is a growing need to strengthen the links between marine science, society and policy since we cannot properly manage what we do not know. In recent years, the ocean and seas have received new prominence in international agendas. To secure a safe planet a priority is the management of the ocean as a “common good for humanity”, which requires smarter observations to assess of the state of the ocean and predictions about how it may change in the future. The ocean is a three-dimensional space that needs to be managed over time (thus four-dimensional), and there is a need for management and conservation practices that integrate the structure and function of marine ecosystems into these four dimensions (Chapter 2). This includes understanding the dynamic spatial and temporal interplay between ocean physics, chemistry and biology. Multiple stressors including climate change, pollution and over-fishing affect the ocean and we need to better understand and predict their interactions and identify tipping points to decide on management priorities (Chapter 3). This should integrate our understanding of land-ocean-atmosphere processes and approaches to reducing impacts. An improved science base is also needed to help predict and minimize the impact of extreme events such as storm surges, heat waves, dynamic sea-floor processes and tsunamis (Chapter 4). New technologies, data handling and modelling approaches will help us to observe, understand and manage our use of the fourdimensional ocean and the effect of multiple stressors (Chapter 5). Addressing these issues requires a strategic, collective and holistic approach and we need to build a community of sustainability scientists that are able to provide evidence-based support to policy makers within the context of major societal challenges (Chapter 6). We outline new frontiers, knowledge gaps and recommendations needed to manage the ocean as a common good and to develop solutions for a sustainable future (Chapter 7). The governance of sustainability should be at the core of the marine research agenda through co-production and collaboration with stakeholders to identify priorities. There is need for a fully integrated scientific assessment of resilience strategies, associated trade-offs and underlying ethical concepts for the ocean, which should be incorporated into decision support frameworks that involve stakeholders from the outset. To allow the collection, processing and access to all data, a key priority is the development of a business model that ensures the long-term economic sustainability of ocean observations

Molecular imaging of hypoxia with radiolabelled agents

Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia

Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19–9 (CA 19–9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC

Imaging of tumor vascularization and related hypoxia

Tumoren groeien soms zo snel dat de bloedtoevoer de groei niet meer “bijhoudt”. Zo ontstaan delen in de tumor waar de zuurstofconcentratie lager is. Deze zogenoemde ‘hypoxische’ delen van de tumor zijn moeilijker te bestrijden met chemotherapie of bestraling. UMCG-promovendus Gilles Mees onderzocht nieuwe mogelijkheden om tumordelen met verminderde zuurstofvoorziening (tumorale hypoxie) in kaart te brengen met behulp van PET-scans. Meerdere PET-tracervloeistoffen zijn speciaal ontwikkeld om tumorale hypoxie in kaart te brengen. Mees onderzocht of ook een algemeen toegepaste tracer voor de detectie van kankercellen gebruikt kan worden om tumorale hypoxie op te sporen. Deze tracer, [18F]FDG-PET, brengt de stofwisseling in tumorcellen in kaart. Mees stelt vast dat er een samenhang lijkt te bestaan tussen opname van [18F]FDG en hypoxie. De verkregen inzichten in deze samenhang kunnen beeldvorming met [18F]FDG-PET wellicht verbeteren. De tracer lijkt echter niet betrouwbaar genoeg om hypoxie mee in kaart te brengen. Ook evalueert Mees een nieuwe tracer, 99mTc-(CO)3 His-CNA35, die ontwikkeld is om bloedvatvorming in tumoren mee in kaart te brengen. Hij stelt vast dat deze tracer stabiel en functioneel is en een betrouwbare inschatting geeft van de bestaande tumorale vasculatuur. Met hulp van deze tracer kunnen tumoren wellicht effectiever bestreden worden en kan misschien ook het inzicht in tumorale hypoxie vergroot worden. Tumour hypoxia is a characteristic feature in solid tumours which is associated with a negative prognosis and impaired effectiveness of common anti-cancer therapies. Despite the existence of a number of specialized PET tracers for the detection of tumour hypoxia, the most widely used PET tracer for tumour detection, staging and evaluating therapy response is the glucose analogue [18F]FDG. As the proteins responsible for [18F]FDG-uptake are under control of HIF-1, the master transcription factor regulating the hypoxic response, the degree of [18F]FDG-uptake might indirectly reflect the level of tumour hypoxia and vice versa. Detection of tumour hypoxia under certain circumstances using [18F]FDG would obviate the need for more specialized hypoxia radiotracers and insight into the close relation between tumour hypoxia and tumour metabolism might provide opportunities to increase tumour [18F]FDG-uptake and thereby improve imaging. In the first part of this work, the effects of a modification of tumour oxygenation on tumour metabolism and its consequences and benefits for functional imaging were studied using [18F]FDG-PET. Although our results suggest that [18F]FDG-uptake might reflect tumour hypoxia, its use as a reliable non-invasive marker of tumour hypoxia seems questionable. Nevertheless, insights into the relationship between tumour hypoxia and tumour metabolism can create opportunities to increase tumour [18F]FDG-uptake in situations where diagnostic accuracy is suboptimal. In the second part of this work a new radiotracer was evaluated (99mTc-(CO)3 His-CNA35) that selectively binds tumour vasculature. Our results indicated the convenient preparation of a stable, functional and specific radiotracer that gives a reliable estimate of existing tumour vasculature through the binding of subendothelial collagen IV due to the characteristic leakiness and immatureness of tumour blood vessels. Non-invasive detection of tumour vasculature might (i) offer a tool to provide a reliable assessment of tumour vasculature and thus provide a means for the management and planning of anti-angiogenic therapy and (ii) might provide insights into tumour hypoxia.