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We propose a novel strategy for tailoring the structure of fluorescent molecules to achieve emission at the tail end of the NIR-II window. The favorable spectroscopic properties and low cytotoxicity of YNs make them powerful tools for bioimaging. Notably, YN-4 exhibits a brightness 2.5 times greater than YN-3, 6 times that of IR-783, and 5 times that of ICG. This enhanced brightness enabled high-resolution imaging of mouse thoracic and abdominal cavities, tumor vasculature, and real-time monitoring of gastrointestinal motility using YN-4. Furthermore, covalent grafting of glucose onto the YN-Glu scaffold significantly improved tumor-targeting capability and facilitated tracking of glucose metabolism. This work aims to extend the application of fluorescent molecule imaging beyond the NIR-IIa window., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We live in an unprecedented time in oncology. We have accumulated samples and cases in cohorts larger and more complex than ever before. New technologies are available for quantifying solid or liquid samples at the molecular level. At the same time, we are now equipped with the computational power necessary to handle this enormous amount of quantitative data. Computational models are widely used helping us to substantiate and interpret data. Under the label of systems and precision medicine, we are putting all these developments together to improve and personalize the therapy of cancer. In this review, we use melanoma as a paradigm to present the successful application of these technologies but also to discuss possible future developments in patient care linked to them. Melanoma is a paradigmatic case for disruptive improvements in therapies, with a considerable number of metastatic melanoma patients benefiting from novel therapies. Nevertheless, a large proportion of patients does not respond to therapy or suffers from adverse events. Melanoma is an ideal case study to deploy advanced technologies not only due to the medical need but also to some intrinsic features of melanoma as a disease and the skin as an organ. From the perspective of data acquisition, the skin is the ideal organ due to its accessibility and suitability for many kinds of advanced imaging techniques. We put special emphasis on the necessity of computational strategies to integrate multiple sources of quantitative data describing the tumour at different scales and levels., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Colorectal cancer is the fourth most diagnosed malignancy worldwide and surgery is one of the cornerstones of the treatment strategy. Near-infrared (NIR) fluorescence imaging is a new and upcoming technique, which uses an NIR fluorescent agent combined with a specialised camera that can detect light in the NIR range. It aims for more precise surgery with improved oncological outcomes and a reduction in complications by improving discrimination between different structures., Methods: A systematic search was conducted in the Embase, Medline and Cochrane databases with search terms corresponding to 'fluorescence-guided surgery', 'colorectal surgery', and 'colorectal cancer' to identify all relevant trials., Results: The following clinical applications of fluorescence guided surgery for colorectal cancer were identified and discussed: (1) tumour imaging, (2) sentinel lymph node imaging, (3) imaging of distant metastases, (4) imaging of vital structures, (5) imaging of perfusion. Both experimental and FDA/EMA approved fluorescent agents are debated. Furthermore, promising future modalities are discussed., Conclusion: Fluorescence-guided surgery for colorectal cancer is a rapidly evolving field. The first studies show additional value of this technique regarding change in surgical management. Future trials should focus on patient related outcomes such as complication rates, disease free survival, and overall survival., Competing Interests: Declaration of Competing Interest Alexander L Vahrmeijer and Cornelis Verhoef are local principal investigators of several industry driven studies initiated by Surgimab (Montpellier, France) using SGM-101 without any personal financial interests. Surgimab was not involved in the process of creating this manuscript. The other authors declare no competing interests. Study concepts: S.K., D.H. Study design: H.G., R.M., S.K., D.H. Data acquisition: H.G., R.M. Quality control of data and algorithms: H.G., R.M. Data analysis and interpretation: na Statistical analysis: na Manuscript preparation: H.G., R.M., S.K., D.H. Manuscript editing: H.G., R.M., S.K., D.H. Manuscript review: L.L., C.V., J.B., A.V., M.H., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: In this study, a novel aluminium-[ 18 F]fluoride (Al 18 F)-labelled 1,4,7‑triazacyclononane-N,N',N″-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named Al 18 F-NOTA-FAPI, was developed for fibroblast activation protein (FAP)-targeted tumour imaging; it could deliver hundreds of millicuries of radioactivity using automated synthesis. The tumour detection efficacy of Al 18 F-NOTA-FAPI was further validated in both preclinical and clinical translational studies., Methods: The radiolabelling procedure of Al 18 F-NOTA-FAPI was optimized. Cell uptake and competitive binding assays were completed with the U87MG and A549 cell lines to evaluate the affinity and specificity of the Al 18 F-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the Al 18 F-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the Al 18 F-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients., Results: The radiolabelling yield of Al 18 F-NOTA-FAPI was 33.8 ± 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3-55.5 MBq/nmol. The whole body effective dose of Al 18 F-NOTA-FAPI was estimated to be 1.24E - 02 mSv/MBq, which was lower than several other FAPI probes ( 68 Ga-FAPI-04, 68 Ga-FAPI-46 and 68 Ga-FAPI-74). In U87MG tumour-bearing mice, Al 18 F-NOTA-FAPI showed good tumour detection efficacy based on the results of micro PET/CT imaging and biodistribution studies. In an organ biodistribution study of patients, Al 18 F-NOTA-FAPI showed a lower SUVmean than 2-[ 18 F]-fluoro-2-deoxy-D-glucose (2-[ 18 F]FDG) in most organs, especially in the liver (1.1 ± 0.2 vs. 2.0 ± 0.9), brain (0.1 ± 0.0 vs. 5.9 ± 1.3), and bone marrow (0.9 ± 0.1 vs. 1.7 ± 0.4). Meanwhile, Al 18 F-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[ 18 F]FDG in the PET/CT imaging of several patients., Conclusion: The Al 18 F-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein-targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour-bearing mice as well as in cancer patients., Trial Registration: Chinese Clinical Trial Registry ChiCTR2000038080. Registered 09 September 2020. http://www.chictr.org.cn/showproj.aspx?proj=61192., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Understanding the regional vascular delivery of particles to tumour sites is a prerequisite for developing new diagnostic and therapeutic composites for treatment of oncology patients. We describe a novel imageable 67 Ga-radiolabelled polymer composite that is biocompatible in an animal tumour model and can be used for preclinical imaging investigations of the transit of different sized particles through arterial networks of normal and tumour-bearing organs., Results: Radiolabelling of polymer microspheres with 67 Ga was achieved using a simple mix and wash method, with tannic acid as an immobilising agent. Final in vitro binding yields after autoclaving averaged 94.7%. In vivo stability of the composite was demonstrated in New Zealand white rabbits by intravenous administration, and intrahepatic artery instillations were made in normal and VX2 tumour implanted rabbit livers. Stability of radiolabel was sufficient for rabbit lung and liver imaging over at least 3 hours and 1 hour respectively, with lung retention of radiolabel over 91%, and retention in both normal and VX2 implanted livers of over 95%. SPECT-CT imaging of anaesthetised animals and planar imaging of excised livers showed visible accumulation of radiolabel in tumours. Importantly, microsphere administration and complete liver dispersal was more easily achieved with 8 μm diameter MS than with 30 μm MS, and the smaller microspheres provided more distinct and localised tumour imaging., Conclusion: This method of producing 67 Ga-radiolabelled polymer microspheres is suitable for SPECT-CT imaging of the regional vascular delivery of microspheres to tumour sites in animal models. Sharper distinction of model tumours from normal liver was obtained with smaller MS, and tumour resolution may be further improved by the use of 68 Ga instead of 67 Ga, to enable PET imaging.

The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Our aim was to evaluate if a recently introduced TOF PET system with digital photon counting technology (Philips Healthcare), potentially providing an improved image quality over analogue systems, can fulfil EANM research Ltd (EARL) accreditation specifications for tumour imaging with FDG-PET/CT., Findings: We have performed a phantom study on a digital TOF PET system using a NEMA NU2-2001 image quality phantom with six fillable spheres. Phantom preparation and PET/CT acquisition were performed according to the European Association of Nuclear Medicine (EANM) guidelines. We made list-mode ordered-subsets expectation maximization (OSEM) TOF PET reconstructions, with default settings, three voxel sizes (4 × 4 × 4 mm 3 , 2 × 2 × 2 mm 3 and 1 × 1 × 1 mm 3 ) and with/without point spread function (PSF) modelling. On each PET dataset, mean and maximum activity concentration recovery coefficients (RC mean and RC max ) were calculated for all phantom spheres and compared to EARL accreditation specifications. The RCs of the 4 × 4 × 4 mm 3 voxel dataset without PSF modelling proved closest to EARL specifications. Next, we added a Gaussian post-smoothing filter with varying kernel widths of 1-7 mm. EARL specifications were fulfilled when using kernel widths of 2 to 4 mm., Conclusions: TOF PET using digital photon counting technology fulfils EARL accreditation specifications for FDG-PET/CT tumour imaging when using an OSEM reconstruction with 4 × 4 × 4 mm 3 voxels, no PSF modelling and including a Gaussian post-smoothing filter of 2 to 4 mm.

With the advent of next-generation sequencing technology, there is rapidly increasing interest in long noncoding RNAs (lncRNAs). The objectives of this study were to develop a novel lncRNA MALAT1 near-infrared optical probe, to evaluate the characteristics of this optical imaging probe in vitro and to determine whether it can be used for imaging MALAT1 expression in malignant tumours in vivo . Conjugation of Cy5.5 to MALAT1 ASO was accomplished using standard NHS (N-hydroxysuccinimide) ester procedures, and the labelled MALAT1 ASO was purified with a Glen-Pak DNA Purification Cartridge and reversed-phase high performance liquid chromatography (HPLC). The in vitro cellular uptake results showed that the percentage of cell binding increased with an increasing final concentration and increased with increasing incubation time for the MHCC-LM3 tumour cell flow cytometry analyses. in vivo optical imaging exhibited 5' (Cy5.5)-MALAT1 ASO uptake in the tumour with a maximum at 30 min p.i. that slowly washed out over time. High contrast to normal tissue was gradually observed from 4 h to 48 h p.i. Tumour-to-normal ratios of fluorescence intensities were plotted as a function of time. The in vivo competition assay showed little uptake of the probe into the tumours at any time point, indicating effective competition, selectivity of probe binding and retention by tumours in vivo . Our proposed Cy5.5 labelling of MALAT1 ASO can serve as a potent optical probe for in vivo imaging of tumour expressing MALAT1. Importantly, the successful development of optical probes provides a basis for specific molecular diagnoses in the field of lncRNAs., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts interest.

Background: For tumour imaging with PET, the literature proposes to administer a patient-specific FDG activity that depends quadratically on a patient's body weight. However, a practical approach on how to implement such a protocol in clinical practice is currently lacking. We aimed to provide a practical method to determine a FDG activity formula for whole-body PET examinations that satisfies both the EANM guidelines and this quadratic relation., Results: We have developed a methodology that results in a formula describing the patient-specific FDG activity to administer. A PET study using the NEMA NU-2001 image quality phantom forms the basis of our method. This phantom needs to be filled with 2.0 and 20.0 kBq FDG/mL in the background and spheres, respectively. After a PET acquisition of 10 min, a reconstruction has to be performed that results in sphere recovery coefficients (RCs) that are within the specifications as defined by the EANM Research Ltd (EARL). By performing reconstructions based on shorter scan durations, the minimal scan time per bed position (T min) needs to be extracted using an image coefficient of variation (COV) of 15 %. At T min, the RCs should be within EARL specifications as well. Finally, the FDG activity (in MBq) to administer can be described by [Formula: see text] with c a constant that is typically 0.0533 (MBq/kg(2)), w the patient's body weight (in kg), and t the scan time per bed position that is chosen in a clinical setting (in seconds). We successfully demonstrated this methodology using a state-of-the-art PET/CT scanner., Conclusions: We provide a practical method that results in a formula describing the FDG activity to administer to individual patients for whole-body PET examinations, taking into account both the EANM guidelines and a quadratic relation between FDG activity and patient's body weight. This formula is generally applicable to any PET system, using a specified image reconstruction and scan time per bed position.

This review investigated the relative performance of digital breast tomosynthesis (DBT) (alone or with full field digital mammography (FFDM) or synthetic digital mammography) compared with FFDM alone for detecting breast cancer lesions in asymptomatic women. A systematic review was carried out according to systematic reviewing principles provided in the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. A protocol was developed a priori. The review was registered with PROSPERO (number CRD42014013949). Searches were undertaken in October 2014. Following selection, five studies were eligible. Higher cancer detection rates were observed when comparing DBT + FFDM with FFDM in two European studies: the summary difference per 1000 screens was 2.43 (95% CI: 1.8 to 3.1). Both European studies found lower false positive rates for individual readers. One found a lower recall rate based on conditional recall. The second study was not designed to compare post-arbitration recall rates between FFDM and DBT + FFDM. One European study presented data on interval cancer rates; sensitivity and specificity for DBT + FFDM were both higher compared to FFDM. One large multicentre US study showed a higher cancer detection rate for DBT + FFDM, while two smaller US studies did not find statistically significant differences. Reductions in recall and false positive rates were observed in the US studies in favour of DBT + FFDM. In comparison to FFDM, DBT, as an adjunct to FFDM, has a higher cancer detection rate, increasing the effectiveness of breast cancer screening. Additional benefits of DBT may also include reduced recalls and, consequently, reduced costs and distress caused to women who would have been recalled., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Point-spread function (PSF) or PSF + time-of-flight (TOF) reconstruction may improve lesion detection in oncologic PET, but can alter quantitation resulting in variable standardized uptake values (SUVs) between different PET systems. This study aims to validate a proprietary software tool (EQ.PET) to harmonize SUVs across different PET systems independent of the reconstruction algorithm used., Methods: NEMA NU2 phantom data were used to calculate the appropriate filter for each PSF or PSF+TOF reconstruction from three different PET systems, in order to obtain EANM compliant recovery coefficients. PET data from 517 oncology patients were reconstructed with a PSF or PSF+TOF reconstruction for optimal tumour detection and an ordered subset expectation maximization (OSEM3D) reconstruction known to fulfil EANM guidelines. Post-reconstruction, the proprietary filter was applied to the PSF or PSF+TOF data (PSFEQ or PSF+TOFEQ). SUVs for PSF or PSF+TOF and PSFEQ or PSF+TOFEQ were compared to SUVs for the OSEM3D reconstruction. The impact of potential confounders on the EQ.PET methodology including lesion and patient characteristics was studied, as was the adherence to imaging guidelines., Results: For the 1380 tumour lesions studied, Bland-Altman analysis showed a mean ratio between PSF or PSF+TOF and OSEM3D of 1.46 (95%CI: 0.86-2.06) and 1.23 (95%CI: 0.95-1.51) for SUVmax and SUVpeak, respectively. Application of the proprietary filter improved these ratios to 1.02 (95%CI: 0.88-1.16) and 1.04 (95%CI: 0.92-1.17) for SUVmax and SUVpeak, respectively. The influence of the different confounding factors studied (lesion size, location, radial offset and patient's BMI) was less than 5%. Adherence to the European Association of Nuclear Medicine (EANM) guidelines for tumour imaging was good., Conclusion: These data indicate that it is not necessary to sacrifice the superior lesion detection and image quality achieved by newer reconstruction techniques in the quest for harmonizing quantitative comparability between PET systems.

Recently, a new class of in vitro and ex vivo radiotracers/radioprotectors, the nitroxyl-labelled agent 1-ethyl-1-nitroso-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-urea (SLENU), has been discovered. Our previous investigations demonstrated that SLENU is a low-molecular-weight stable free radical which is freely membrane permeable, easily crosses the blood brain barrier and exhibited in/ex vivo the lowest general toxicity and higher anticancer activity against some experimental tumour models. Further investigation was aimed to develop a 99m Tc-labelled SLENU (97%) as a chelator and evaluate its labelling efficiency and potential use as a tumour seeking agent and for early diagnosis. Tissue biodistribution of 99m Tc-SLENU was determined in normal mice at 1, 2 and 24 h ( n = 4/time interval, route of administration i.v.). The distribution data were compared using male albino non-inbred mice and electron paramagnetic resonance investigation. The imaging characteristics of 99m Tc-SLENU conjugate examined in BALB/c mice grafted with Ehrlich Ascitis tumour in the thigh of hind leg demonstrated major accumulation of the radiotracer in the organs and tumour. Planar images and auto-radiograms confirmed that the tumours could be visualized clearly with 99m Tc-SLENU. Blood kinetic study of radio-conjugate showed a bi-exponential pattern, as well as quick reduced duration in the blood circulation. This study establishes nitroxyls as a general class of new spin-labelled diagnostic markers that reduce the negative lateral effects of radiotherapy and drug damages, and are appropriate for tumour-localization.

Introduction: Early detection of pancreatic cancer could save many thousands of lives. Non-invasive diagnostic imaging, including PET with [(18)F]FDG, has inadequate resolution for detection of small (2-3 mm) pancreatic tumours. We demonstrated the efficacy of PET imaging with an (18)F-labelled lactose derivative, [(18)F]FEDL, that targets HIP/PAP, a biomarker that is overexpressed in the peritumoural pancreas. We developed another analogue, 1-[(18)F]fluoroethyl lactose ([(18)F]FEL), which is simpler to synthesise, for the same application. We conducted a preliminary evaluation of the new probe and its efficacy in detecting orthotopic pancreatic carcinoma xenografts in mice., Methods: Xenografts were developed in nude mice by injecting L3.6 pl/GL(+) pancreatic carcinoma cells into the pancreas of each mouse. Tumour growth was monitored by bioluminescence imaging (BLI); accuracy of BLI tumour size estimates was verified by MRI in two representative mice. When the tumour size reached approximately 2-3mm, the animals were injected with [(18)F]FEL (3.7 MBq) and underwent static PET/CT scans. Blood samples were collected at 2, 5, 10, 20 and 60 min after [(18)F]FEL injection to track blood clearance. Following imaging, animals were sacrificed and their organs and tumours/pancreatic tissue were collected and counted on a gamma counter. Pancreas, including tumour, was frozen, sliced and used for autoradiography and immunohistochemical analysis of HIP/PAP expression., Results: Tumour growth was rapid, as observed by BLI and MRI. Blood clearance of [(18)F]FEL was bi-exponential, with half-lives of approximately 3.5 min and 40 min. Mean accumulation of [(18)F]FEL in the peritumoural pancreatic tissue was 1.29±0.295 %ID/g, and that in the normal pancreas of control animals was 0.090±0.101 %ID/g. [(18)F]FEL was cleared predominantly by the kidneys. Comparative analysis of autoradiographic images and immunostaining results demonstrated a correlation between [(18)F]FEL binding and HIP/PAP expression., Conclusion: [(18)F]FEL may be useful for non-invasive imaging of early-stage pancreatic tumours by PET. The results warrant further studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The redox-active transition metal copper is an essential trace element for growth and development and serves as a structural or catalytic cofactor for many enzymes in a range of physiological processes. Mammalian copper homeostasis is tightly regulated, and an imbalance in copper metabolism is implicated in various pathological disorders. Radioactive copper isotopes, in particular (64) Cu (t1/2  = 12.7 h) and (67) Cu (t1/2  = 62.01 h), have made important contributions to the understanding of copper metabolism in health and disease. This review gives a brief account of how radiolabelled copper(II) salts and bioreductive copper complexes have been used to trace copper uptake, transport and efflux in vitro and in vivo. Recently, positron emission tomography (PET) has emerged as a noninvasive tool to image copper metabolism in living subjects and (64) Cu-PET is investigated for the study of copper-related neurological disorders, genetic diseases and cancer., (Copyright © 2014 John Wiley & Sons, Ltd.)

In this review we discuss the development of paramagnetic liposomes incorporating MRI contrast agents and show how these are utilized in cellular imaging in vitro. Bi-functional, bi-modal imaging paramagnetic liposome systems are also described. Next we discuss the upgrading of paramagnetic liposomes into bi-modal imaging neutral nanoparticles for in vivo imaging applications. We discuss the development of such systems and show how paramagnetic liposomes and imaging nanoparticles could be developed as platforms for future multi-functional, multi-modal imaging theranostic nanodevices tailor-made for the combined imaging of early stage disease pathology and functional drug delivery.