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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. (C) 2021 The Authors. Published by Elsevier Ltd.

The design of three novel fatty nitrogen mustard-based anticancer agents with fluorophores incorporated into the alkene structure (CXL 118, CXL121, and CXL122) is described in this report. The results indicated that these compounds are selectively located in lysosomes and exhibit effective antitumour activity. Notably, these compounds can directly serve as both reporting and imaging agents in vitro and in vivo without the need to add other fluorescent tagging agents.

Since the discovery of cell-penetrating peptides (CPP) in the 1980s, they have played a unique role in various fields owing to their excellent and unique cell membrane penetration function. In particular, in the treatment of tumours, CPPS have been used to deliver several types of 'cargos' to cancer cells. To address the insufficient targeting ability, non-selectivity, and blood instability, activatable cell-penetrating peptides, which can achieve targeted drug delivery in tumour treatment, enhance curative effects, and reduce toxicity have been developed. This study reviews the application of different cell-penetrating peptides in tumour-targeted delivery, overcoming multidrug resistance, organelle targeting, tumour imaging, and diagnosis, and summarises the different mechanisms of activatable cell-penetrating peptides in detail.

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.

System xc- (Sxc -) has emerged as a new biological target for PET studies to detect oxidative and excitotoxic stress. Notably, applications have, thus far, been limited to tumour imaging although Sxc- ) may play a major role in neurodegeneration. The synthesis procedures of tosylate precursor and its translation to Sxc - PET tracer 5[18F]fluoro-L-amino suberate by manual and automated radiosyntheses are described. A brain-PET study has been conducted to evaluate the tracer uptake into brain in healthy mice.

We report the novel chemical design of fluorescent activatable chemokines as highly specific functional probes for imaging subpopulations of immune cells in live tumours. Activatable chemokines behave as AND‐gates since they emit only after receptor binding and intracellular activation, showing enhanced selectivity over existing agents. We have applied this strategy to produce mCCL2‐MAF as the first probe for in vivo detection of metastasis‐associated macrophages in a preclinical model of lung metastasis. This strategy will accelerate the preparation of new chemokine‐based probes for imaging immune cell function in tumours., Live show: Fluorescent activatable chemokines have been designed as the first chemical probes for in vivo detection of tumour‐associated macrophages in lung metastasis. Activatable chemokines behave as AND gates since they emit only after receptor binding and intracellular activation, thereby showing enhanced selectivity over existing agents.

The heterogeneity of brain tumours at the molecular, metabolic and structural levels poses significant challenge for accurate tissue characterisation. Artificial intelligence and radiomics have emerged as valuable tools to analyse quantitative features extracted from medical images which capture the complex microenvironment of brain tumours. In particular, a number of computational tools including machine learning algorithms have been proposed for image preprocessing, tumour segmentation, feature extraction, classification, and prognostic stratifications as well. In this chapter, we explore the fundamentals of multiparametric brain tumour characterisation, as an understanding of the strengths, limitations and applications of these tools allows clinicians to better develop and evaluate models with improved diagnostic and prognostic value in brain tumour patients.

A small, stable complex of 99mTc js currently required to replace 67Ga citrate as a general tumour imaging agent. Previous work had indicated that small 99mTc-complexes containing an aromatic sidechain may be preferentially taken up by tumour tissue. In this project, five complexes of 99mTc, all containing an aromatic side-chain, were synthesized and tested for tumour uptake in a Balb-C/EMT-6 mouse tumour model. The EMT-6 is a transplantable mouse sarcoma derived from mammary tissue. Three of the ligands synthesized were derivatives of EDTA and one was a substituted diaminedithiol (DADT) compound. Complexation was achieved by stannous chloride reduction of pertechnetate in the presence of the ligand. The labelling yield of all the synthesized complexes was 90% or greater. Tumour uptake of all the synthesized complexes was disappointingly low especially when compared with the relatively high uptake of pertechnetate in the control mice. All the complexes displayed apparently very high in vivo stability however. It was hypothesized that tumour uptake of the previously synthesized, relatively unstable 99mTc-complexes may have been due to tumour uptake of pertechnetate, released in vivo after complex breakdown. Due to the high uptake of pertechnetate by the tumours in the control mice and the rapid growth character of the EMT-6 tumour (which made it difficult to maintain a uniform tumour size over all the experiments), it was concluded that the EMT-6/Balb-C mouse tumour model was inadequate for testing complexes of 99mTc as potential tumour imaging radiopharmaceuticals.

Khellin was successfully extracted from Ammi visnaga fruits with a recovery percent of 96.15%. Next radio-iodination of Khellin was successfully achieved with a high yield. The biodistribution study of [131I]iodo-khellin in tumour bearing mice revealed that khellin preferentially localization at tumour tissue. Target prediction study for [131I]iodo-khellin revealed that PI3K and VEGFR are potential targets for iodo-khellin with good affinity. The results of this study potentiate [131I]iodo-khellin as a good theranostic agent for tumour imaging and therapy.

BackgroundFibroblast activation protein (FAP) is commonly expressed in activated stromal fibroblasts in various epithelial tumours. Recently, 68Ga-FAPI-04 has been used for tumour imaging in positron emission tomography/computed tomography (PET/CT). This study aimed to compare the diagnostic performances of 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in hepatocellular carcinoma (HCC), and to assess factors associated with 68Ga-FAPI-04 uptake in HCC.Materials and MethodsTwenty-nine patients with suspiciously HCC who received both 18F-FDG and 68Ga-FAPI-04 PET/CT were included in this retrospective study. The results were interpreted by two experienced nuclear medicine physicians independently. The maximum and mean standardized uptake values (SUVmax and SUVmean) were measured in the lesions and liver background, respectively. The tumour-to-background ratio (TBR) was then calculated as lesion’s SUVmax divided by background SUVmean.ResultsA total of 35 intrahepatic lesions in 25 patients with HCC were finally involved in the statistical analysis. 68Ga-FAPI-04 PET/CT showed a higher sensitivity than 18F-FDG PET/CT in detecting intrahepatic HCC lesions (85.7% vs. 57.1%, P = 0.002), including in small (≤ 2 cm in diameter; 68.8% vs. 18.8%, P = 0.008) and well- or moderately-differentiated (83.3% vs. 33.3%, P = 0.031) tumors. SUVmax was comparable between 68Ga-FAPI-04 and 18F-FDG (6.96 ± 5.01 vs. 5.89 ± 3.38, P > 0.05), but the TBR was significantly higher in the 68Ga-FAPI-04 group compared with the 18F-FDG group (11.90 ± 8.35 vs. 3.14 ± 1.59, P < 0.001). SUVmax and the TBR in 68Ga-FAPI-04 positive lesions were associated with tumour size (both P < 0.05), but not the remaining clinical and pathological features (all P > 0.05).Conclusions68Ga-FAPI-04 PET/CT is more sensitive than 18F-FDG PET/CT in detecting HCC lesions, and 68Ga-FAPI-04 uptake is correlated mainly with tumour size.

Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood-brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.

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 67Ga-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 67Ga 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 67Ga-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 68Ga instead of 67Ga, to enable PET imaging.

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with advanced cancers, and results in increasing numbers of long-term survivors. For registration studies, progression-free survival and disease-free survival often serve as primary endpoints. This requires repeated computed tomography (CT) scans for tumour imaging which might lead to major radiation exposure. To determine this, all immune checkpoint inhibitors trials that led to FDA approval were retrieved up to July 29, 2019. From the available protocols, imaging modalities and schedules used in each trial were identified. The anticipated cumulative number of scans made after 1, 3, 5, and 10 years study participation were calculated. The percentage of lifetime attributable cancer risk was calculated using the Biological Effects of Ionizing Radiation VII report. Fifty-one trials were identified, from which 39 protocols were retrieved. Four were adjuvant trials. All protocols required repeated chest-abdomen imaging and specified CT scans as preferred imaging modality. Median calculated cumulative numbers of chest-abdomen CT scans after 1, 3, 5, and 10 years study participation were 7, 16, 24 and 46, respectively. For ages 20-70 years at study entry, the average lifetime attributable cancer risk after 1 year of study participation ranged from 1.11 to 0.40% for men and from 1.87 to 0.46% for women. At 10 years study participation, this risk increased to a range of 5.91 to 1.96% for men and 9.64 to 2.32% for women. Given high imaging radiation exposure for long-term survivors in current ICI trials an adaptive imaging interval and imaging termination rules should be considered for long-term survivors.

We report the pharmaceutical stability of trastuzumab stored for a short time (12 h) at room temperature (RT; 20–25 °C) compared to trastuzumab stored at 2–8 °C. The physicochemical properties were evaluated by UV–visible and FTIR spectroscopy, SDS-PAGE and size-exclusion HPLC (SE-HPLC). Trastuzumab was reacted with benzylisothiocyanate diethylenetriaminepentaacetic acid (BzDTPA) to complex 111In. The HER2-binding affinity of 111In-BzDTPA-trastuzumab synthesised from trastuzumab stored at RT or at 2–8 °C was measured using HER2-positive SK-Br-3 human breast cancer (BC) cells. The tumour and normal tissue uptake of 111In-BzDTPA-trastuzumab was studied by microSPECT/CT imaging and biodistribution studies in CD1 athymic mice with s.c. HER2-positive SK-Ov-3 human ovarian cancer xenografts. There were no differences in λmax or molar absorptivity (e) values in the UV–visible spectra of trastuzumab stored at RT or at 2–8 °C. FTIR spectroscopy suggested no differences in secondary structure. SDS-PAGE revealed protein bands corresponding to the expected molecular weights. SE-HPLC showed identical properties for trastuzumab stored at RT or at 2–8 °C. The dissociation constant (Kd) for binding of 111In-BzDTPA-trastuzumab to HER2 on SK-Br-3 cells (2.2–4.4 nM) was not significantly different when the radioimmunoconjugates were synthesised from trastuzumab stored at RT or at 2–8 °C. MicroSPECT/CT demonstrated high uptake in SK-Ov-3 tumours in mice that was not significantly different using trastuzumab stored at RT or at 2–8 °C (33.7 ± 8.8% vs. 22.2 ± 8.1% i.d./g, respectively; P = 0.36). There were no significant differences in normal tissue uptake or in tumour/normal tissue (T/NT) ratios. We conclude that short-term storage of trastuzumab at RT for 12 h did not affect the physicochemical or biological properties of the drug.

This chapter gives an overview of emerging MRI techniques, which show promise in the application of brain tumour imaging, but are not yet used routinely in the clinic. For each method, the basic principles are reviewed, and potential applications and advantages/disadvantages for widespread clinical use discussed.

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.

An easily accessible fluorescent dye, FEB, which has a high fluorescence quantum yield and is suitable for in vivo tumour imaging is reported., A fluorescent dye, FEB, with high fluorescence quantum yield for tumour imaging is reported. FEB dyes can be efficiently synthesized in three steps and then easily modified with either PEG or PEG-iRGD to yield FEB-2000 or FEB-2000-iRGD, respectively. Both modified dyes showed negligible toxicity and were thus able to be adopted for in vivo tumour imaging. PEG modification endowed the dye FEB-2000 with both long circulating times and good tumour targeting properties in a MDA-MB-231 xenograft model. Further conjugation with iRGD to generate FEB-2000-iRGD showed minimal targeting enhancement. These results provide a template for the efficient preparation of FEB dyes for use in tumour imaging, thus providing a foundation for future modifications.

Standard whole-body clinical fluoro-deoxyglucose (FDG)-PET scans typically involve imaging for around 15 minutes about 60 minutes after tracer injection. The scan duration is often the critical constraint limiting patient through-put. Scans taken long after tracer injection restrict the ability to assess vascular and perfusion information that might be revealed by the early pattern of tracer uptake. On the other hand, early scanning may compromise the recovery of the late time uptake (SUV) which in many contexts has well established prognostic value. In this study, we explore the potential for short-duration dynamic scans, acquired immediately after tracer injection, to recover information that can predict late-stage uptake of FDG. The work involves re-analysis of existing series of dynamic brain and breast tumour imaging data to simulate the type of information that would arise from early and late scanning. Using a collection of machine learning techniques (including random forests, neural networks, gradient boosting), we find that short-duration clinical protocols, soon after the tracer injection, show significant potential to recover the late stage FDG flux information.

An aggregation-induced emission (AIE) dye-powered afterglow luminogen has been designed for in vivo tumor imaging. The underlying afterglow mechanism can be described as a closed-loop of “photon–1O2–SP intermediates–photon”., Semiconducting polymer (SP)-based afterglow luminogens are showing increasing potential for in vivo imaging because of their long-life luminescence and the associated benefits (e.g., zero-autofluorescence background and high signal-to-noise ratio). However, such organic afterglow luminescence agents are still rare and their application is usually limited by their relatively low afterglow intensity and short afterglow duration. Herein, we report an aggregation-induced emission (AIE) dye-powered SP afterglow luminogen by leveraging on the unique characteristics of an AIE dye to circumvent the concentration-quenching effect, enhance afterglow intensity and prolong afterglow duration. The underlying working mechanism is investigated by a series of experiments and it is found that the AIE dye provides sufficient 1O2 to excite SPs and form massive amounts of high-energy intermediates, and then the SP intermediates emit photons that can activate the AIE dye to generate 1O2 and simultaneously trigger the energy transfer process between the SPs and AIE dye, resulting in a deep-red emission. It is this closed-loop of “photon–1O2–SP intermediates–photon” that provides the afterglow emission even after the cessation of the excitation light. The as-prepared luminogen shows good performance in in vivo tumour imaging. This study demonstrates the advantages of AIE-facilitated afterglow luminescence and discloses its mechanism, and hopefully it could inspire the development of other innovative designs for cancer theranostics.

In the last decade, many tracers have been introduced to overcome some limitations of 18F-FDG in brain imaging including large neutral amino acid tracers 11C-methionine [11C-MET], 18F-fluoroethyl-tyrosine [18F-FET], 18F-fluorodopa [18F-DOPA] and 18F-choline [18FCH] and hypoxia tracers as 18F-fluoromisonidazole [18F-MISO] and 18F-Fluoroazomycin arabinofuranoside [18F-FAZA]. Most of these tracers have been specifically developed for brain tumour imaging and will be better described in the dedicated tumour section. In the present review, we will provide a brief introduction of some clinical data on their main advantages and limitations.

(1) Background: Standard magnetic resonance imaging (MRI) remains the gold standard for brain tumour imaging in paediatric and teenage and young adult (TYA) patients. Combining positron emission tomography (PET) with MRI offers an opportunity to improve diagnostic accuracy. (2) Method: Our single-centre experience of 18F-fluorocholine (FCho) and 18fluoro-L-phenylalanine (FDOPA) PET&ndash, MRI in paediatric/TYA neuro-oncology patients is presented. (3) Results: Hybrid PET&ndash, MRI shows promise in the evaluation of gliomas and germ cell tumours in (i) assessing early treatment response and (ii) discriminating tumour from treatment-related changes. (4) Conclusions: Combined PET&ndash, MRI shows promise for improved diagnostic and therapeutic assessment in paediatric and TYA brain tumours.

Breast tomosynthesis (pseudo-3D mammography) improves breast cancer detection when added to 2D mammography. In this study, we examined whether integrating 3D mammography with either standard 2D mammography acquisitions or with synthetic 2D images (reconstructed from 3D mammography) would detect more cases of breast cancer than 2D mammography alone, to potentially reduce the radiation burden from the combination of 2D plus 3D acquisitions.The Screening with Tomosynthesis Or standard Mammography-2 (STORM-2) study was a prospective population-based screening study comparing integrated 3D mammography (dual-acquisition 2D-3D mammography or 2D synthetic-3D mammography) with 2D mammography alone. Asymptomatic women aged 49 years or older who attended population-based screening in Trento, Italy were recruited for the study. All participants underwent digital mammography with 2D and 3D mammography acquisitions, with the use of software that allowed synthetic 2D mammographic images to be reconstructed from 3D acquisitions. Mammography screen-reading was done in two parallel double-readings conducted sequentially for 2D acquisitions followed by integrated acquisitions. Recall based on a positive mammography result was defined as recall at any screen read. Primary outcome measures were a comparison between integrated (2D-3D or 2D synthetic-3D) mammography and 2D mammography alone of the number of cases of screen-detected breast cancer, the cancer detection rate per 1000 screens, the incremental cancer detection rate, and the number and percentage of false-positive recalls.Between May 31, 2013, and May 29, 2015, 10 255 women were invited to participate, of whom 9672 agreed to participate and were screened. In these 9672 participants (median age 58 years [IQR 53-63]), screening detected 90 cases of breast cancer, including 74 invasive breast cancers, in 85 women (five women had bilateral breast cancer). To account for these bilateral cancers in cancer detection rate estimates, the number of screens used for analysis was 9677. Both 2D-3D mammography (cancer detection rate 8·5 per 1000 screens [82 cancers detected in 9677 screens]; 95% CI 6·7-10·5) and 2D synthetic-3D mammography (8·8 per 1000 [85 in 9677]; 7·0-10·8) had significantly higher rates of breast cancer detection than 2D mammography alone (6·3 per 1000 [61 in 9677], 4·8-8·1; p0·0001 for both comparisons). The cancer detection rate did not differ significantly between 2D-3D mammography and 2D synthetic-3D mammography (p=0·58). Compared with 2D mammography alone, the incremental cancer detection rate from 2D-3D mammography was 2·2 per 1000 screens (95% CI 1·2-3·3) and that from 2D synthetic-3D mammography was 2·5 per 1000 (1·4-3·8). Compared with the proportion of false-positive recalls from 2D mammography alone (328 of 9587 participants not found to have cancer at assessment) [3·42%; 95% CI 3·07-3·80]), false-positive recall was significantly higher for 2D-3D mammography (381 of 9587 [3·97%; 3·59-4·38], p=0·00063) and for 2D synthetic-3D mammography (427 of 9587 [4·45%; 4·05-4·89], p0·0001).Integration of 3D mammography (2D-3D or 2D synthetic-3D) detected more cases of breast cancer than 2D mammography alone, but increased the percentage of false-positive recalls in sequential screen-reading. These results should be considered in the context of the trade-off between benefits and harms inherent in population breast cancer screening, including that significantly increased breast cancer detection from integrating 3D mammography into screening has the potential to augment screening benefit and also possibly contribute to overdiagnosis.None.

Radiomics describes the use radiological data in a quantitative manner to establish correlations in between imaging biomarkers and clinical outcomes to improve disease diagnosis, treatment monitoring and prediction of therapy responses. In this study, we evaluated whether a radiomic analysis on contrast-enhanced ultrasound (CEUS) data allows to automatically differentiate three xenograft mouse tumour models. Next to conventional imaging biomarker classes, i.e. intensity-based, textural, and wavelet-based features, we included biomarkers describing morphological and functional characteristics of the tumour vasculature. In total, 235 imaging biomarkers were extracted and evaluated. Dedicated feature selection allowed us to identify user-independent and stable imaging biomarkers for each imaging biomarker class. The selected radiomic signature, composed of median image intensity, energy of grey-level co-occurrence matrix, vessel network length, and run length nonuniformity of the grey-level run length matrix from the diagonal details, was used to train a linear support vector machine (SVM) to classify tumour phenotypes. The model was trained by using a four-fold cross-validation scheme and achieved 82.1% (95% CI [0.64 0.92]) correct classifications. In conclusion, our results show that a radiomic analysis can be successfully performed on CEUS data and may help to render ultrasound-based tumour imaging more accurate, reproducible and reliable.

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. Electronic supplementary material The online version of this article (doi:10.1007/s00259-015-3128-0) contains supplementary material, which is available to authorized users.

Background Positron emission tomography (PET) is an instrumental diagnostic modality developed around the positron-emitting radioisotopes of biologically important elements such as carbon, oxygen and nitrogen (11C, 15O, 13N). Among longer-lived PET radionuclides, 18F is by far the most commonly used radiotracer, extensively used for tumour imaging with FDG ([18F]-fluorodeoxyglucose) and also frequently investigated in the development of novel radiopharmaceuticals. Many other positron- emitting radionuclides with higher atomic numbers and longer half-lives have been investigated for both imaging and therapeutic purposes, including the halogens (124I, 120I, 76Br) and a number of metal radionuclides. The radio-copper has attracted considerable attention, because they include isotopes which, due to their emission properties, offer themselves as agents of both diagnostic imaging (60Cu, 61Cu, 62Cu, 64Cu) and in vivo targeted radiation therapy (64Cu and 67Cu). Objectives Although the use of this radionuclide has grown exponentially over the last decade, academic institutions have largely been responsible for its production and for the development of the vast majority of radiopharmaceutical based on these nuclides. A number of compounds labelled with Cuisotopes have been proposed, not only for imaging purposes but also for therapy. The aim of the present paper is to provide an overview on the clinical results obtained in human beings with copper radionuclides. Conclusion Several preliminary studies and clinical trials evaluated the potential clinical role of copper radioisotopes for diagnostic and therapeutic purposes. 64Cu seems to be the most suitable radioisotope for future clinical applications due to its longer half-life (12.7 h) and its commercial availability. Future clinical applications of copper radioisotopes could be enhanced by the possibility of radioligand therapy with the beta-emitting 67Cu, creating a new "theranostics pair".

A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. We found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial we found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

International audience; Quantum dots (QDs) are increasingly widely used in clinical medicine. Their most promising potential applications are cancer diagnosis, including in vivo tumour imaging and targeted drug delivery. In this connection, the main questions are whether or not QDs are toxic for humans and, if they are, what concentration is relatively harmless. We have carried out in vivo experiments with CdSe/ZnS fluorescent semiconductor core/shell QDs, which are currently the most widely used in research.

Breast cancer is a leading cause of death for woman in the world. Cancer has the potential to spread to different organs around the body, and form metastases that can even develop after surgical removal of the primary tumour. Nanotechnology offers new promising strategies for the treatment of breast cancer, and has emerged as a powerful tool for fighting cancer. Nanoparticles can be fabricated to perform more than one task simultaneously, and can have a number of roles, such as acting as a therapeutic agent, drug delivery vehicle and/or tumour imaging agent. This review will focus on various forms of nanoparticles serving as potential agents for cancer therapeutics, illustrating their use in breast cancer therapies. This article also highlights the properties, current progress in the design and engineering of nanoparticles.

OBJECTIVES O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) is an established tracer for brain tumour imaging. (18)F-FET kinetics in gliomas appear to have potential for tumour grading, but the mechanisms remain unclear. The aim of this study was to explore the relationship between regional cerebral blood flow (rCBF) as measured by arterial spin labelling MRI and the kinetic behaviour of (18)F-FET PET in cerebral gliomas. MATERIALS AND METHODS Twenty patients with cerebral gliomas were investigated using arterial spin labelling MRI and dynamic (18)F-FET PET. Time-activity curves (TACs) of (18)F-FET uptake were analysed in 33 different tumour regions. The slopes of TAC during the early (0-5 min; slopeup) and late phases of tracer uptake (17-50 min; slopedown) were fitted using linear regression lines. In addition, TACs of each lesion were assigned to different curve patterns. Furthermore, we calculated tumour-to-brain ratios of (18)F-FET uptake. The relationship between (18)F-FET parameters and rCBF was determined. RESULTS (18)F-FET uptake in the early phase (slopeup) showed a significant correlation with rCBF (r=0.4; P=0.02). In contrast, both slopedown and TAC patterns showed no significant correlation with rCBF. Furthermore, a significant correlation was found between rCBF and tumour-to-brain ratio (r=0.53; P=0.002). CONCLUSION There is a relationship between rCBF and (18)F-FET uptake in cerebral gliomas in the initial uptake phase, but the kinetic behaviour of (18)F-FET uptake in the late phase is not significantly influenced by rCBF. Thus, the differential kinetic pattern of (18)F-FET uptake in high-grade and low-grade gliomas appears to be determined by factors other than rCBF.

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 (Tmin) needs to be extracted using an image coefficient of variation (COV) of 15 %. At Tmin, the RCs should be within EARL specifications as well. Finally, the FDG activity (in MBq) to administer can be described by \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ A=c \cdot {w}^2\cdot \frac{T_{\min }}{t} $$\end{document}A=c⋅w2⋅Tmint with c a constant that is typically 0.0533 (MBq/kg2), 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.

The objective of this study was to prepare the complexes of 5-aminolevulinic acid (5-ALA) and iron oxide nanoparticles with different surface potentials and evaluate the imaging efficiency for mouse melanoma cells (B16 cells). The ferric and ferrous ions were co-precipitated in the presence of pullulan or the cationised and anionised derivatives to prepare iron oxide-pullulan nanoparticles (IOPNs). The surface potential of IOPN was changed by altering the mixing percentage of pullulan derivatives. The 5-ALA was mixed with the IOPN of different surface potentials to obtain IOPN?5-ALA complexes. When incubated with IOPN?5-ALA complexes, B16 cells exhibited the fluorescence of protoporphyrin IX (PpIX) bio-synthesised from 5-ALA internalised. The time profile of PpIX fluorescence percentage was greatly influenced by the surface potential of IOPN. This finding indicates that IOPN is a promising carrier for 5-ALA-based imaging of tumour cells.

SummaryFor the primary diagnosis of brain tumours, morphological imaging by means of magnetic resonance imaging (MRI) is the current method of choice. The complementary use of functional imaging by positron emitting tomography (PET) and single photon emitting computerized tomography (SPECT) with labelled amino acids can provide significant information on some clinically relevant questions, which are beyond the capacity of MRI. These diagnostic issues affect in particular the improvement of biopsy targeting and tumour delineation for surgery and radiotherapy planning. In addition, amino acid labelled PET and SPECT tracers are helpful for the differentiation between tumour recurrence and non-specific post-therapeutic tissue changes, in predicting prognosis of low grade gliomas, and for metabolic monitoring of treatment response. The application of dynamic PET examination protocols for the assessment of amino acid kinetics has been shown to enable an improved non-invasive tumour grading.The purpose of this guideline is to provide practical assistance for indication, examination procedure and image analysis of brain PET/ SPECT with labelled amino acids in order to allow for a high quality standard of the method. After a short introduction on pathobiochemistry and radiopharmacy of amino acid labelled tracers, concrete and detailed information is given on the several indications, patient preparation and examination protocols as well as on data reconstruction, visual and quantitative image analysis and interpretation. In addition, possible pitfalls are described, and the relevant original publications are listed for further information.

For effective tumour imaging by magnetic resonance imaging (MRI) there is a clear need to develop organ, tissue and cell specific contrast agents that can selectively bind to tumour biomarkers. The versatility of a range of bioconjugation techniques and facile coupling chemistries has facilitated the synthesis of MRI contrast agents bearing tumour targeting moieties that comprise small molecule affinity ligands, peptides, antibodies and even proteins. The aim of this review is to describe the development and implementation of tumour targeted T(1) MRI contrast agents, with an emphasis on the chemistry used to modify pre-existing clinical MRI contrast agents for targeted tumour imaging.

The aim of this document is to provide general information about mIBG scintigraphy in cancer patients. The guidelines describe the mIBG scintigraphy protocol currently used in clinical routine, but do not include all existing procedures for neuroendocrine tumours. The guidelines should therefore not be taken as exclusive of other nuclear medicine modalities that can be used to obtain comparable results. It is important to remember that the resources and facilities available for patient care may vary from one country to another and from one medical institution to another. The present guidelines have been prepared for nuclear medicine physicians and intend to offer assistance in optimizing the diagnostic information that can currently be obtained from mIBG scintigraphy. The corresponding guidelines of the Society of Nuclear Medicine (SNM) and the Dosimetry, Therapy and Paediatric Committee of the EANM have been taken into consideration, and partially integrated into this text. The same has been done with the most relevant literature on this topic, and the final result has been discussed within a group of distinguished experts.

The purpose of this study was to determine the benefit of high-resolution susceptibility-weighted imaging and the apparent diffusion coefficient for brain tumour imaging, and to assess the clinical feasibility of using a non-contrast MR protocol at 3 T. 73 patients with intra-axial tumours were enrolled into the study. Two experienced neuroradiologists reviewed three MRI sessions: (i) a non-contrast protocol including high-resolution susceptibility-weighted images and apparent diffusion coefficient; (ii) a contrast protocol including MR perfusion images; and (iii) combined contrast and non-contrast protocols. The two observers categorised tumours as glial or non-glial tumours, and then subcategorised the gliomas into low-grade or high-grade tumours. For semi-quantitative analysis, a scoring system based on the degree of intra-tumoral susceptibility signals and the visual apparent diffusion coefficient was used. The two observers diagnosed accurate tumour pathology in 52 (71%) of 73 tumours in the first review, 55 (75%) of 73 tumours in the second review and 61 (84%) of 73 tumours in the third review. The addition of the non-contrast protocol to the contrast protocol significantly differentiated glioblastoma multiforme and metastatic tumours, which was not possible with the contrast protocol alone. The sensitivity, specificity, positive predictive value and negative predictive value for glioma grading with the non-contrast protocol were 83.2%, 100%, 100% and 79.3%, respectively. The addition of both high-resolution susceptibility-weighted imaging and the apparent diffusion coefficient improved the diagnostic performance of the contrast MR protocol for brain tumour imaging and could be feasible in selected patients who cannot tolerate a contrast agent.

Background: The type I insulin-like growth factor receptor (IGF1R) is a transmembrane tyrosine kinase involved in cancer proliferation, survival, and metastasis. Methods: In this study, we used two different fluorescent technologies (small-molecule fluorophores and quantum dot (QD) nanoparticles) to detect receptor expression and its downregulation by antibodies in vivo. Results: After conjugation with AVE-1642, a humanised anti-IGF1R monoclonal antibody, both QDs (705 nm) or Alexa 680 (small-molecule fluorophore) detected expression and downregulation of IGF1R in vitro. To examine their utility in vivo, either AVE-1642 conjugates were intravenously delivered to mice bearing xenograft tumours of mouse embryo fibroblasts expressing human IGF1R or MCF-7 human breast cancer cells. Quantum dot fluorescence was mainly localised to the reticuloendothelial system in several organs and engulfed by macrophages, with only very small amount of QDs detected in the xenograft tumours. Depletion of macrophages by clodronate liposomes did not alter the nonspecific uptake of QDs. In contrast, AVE-1642-conjugated Alexa 680 solely targeted to xenograft tumour and was able to detect IGF1R downregulation, with little nonspecific targeting to other tissues or organs in mice. Conclusion: Taken together, our data suggest that small-molecule fluorophores, not QDs, are suitable to detect the expression and downregulation of IGF1R in vivo.

European Journal of Nuclear Medicine and Molecular Imaging, 36 (1), ISSN:1619-7070, ISSN:1619-7089

This is a report on the clinical use of sonographic imaging. Experimental studies have shown that parallel sonographic sections are available only in vitro, which means no in-vivo three-dimensional reconstruction is possible as it is with magnetic resonance and computed tomography. The idea that a coordinated sequence of sections can be obtained by spatial rotation of the plane of sound so that the individual sections differ from one another by defined angular distances, enables three-dimensional reconstruction of sonographic in-vivo sections. A transducer was constructed that enables the production of sonographic sections rotating around a fixed center of rotation. Its clinical usefulness was tried and confirmed in the imaging of early pregnancies, benign and malignant carcinomas of the breast, and in imaging a gallbladder with a solitary gallstone. Three-dimensional imaging can be achieved either as a ring-shaped structure or with a continuous surface. This points to the possibility of diagnosing malformations early in pregnancy if the number of sections is sufficiently high. In tumour imaging the malignant tumour seems to be clearly distinguishable from the benign one; three-dimensional diagnosis is likely to furnish important additional criteria in diagnosis. Further clinical studies will have to verify this.

Nanotechnology is increasingly finding use in the management of cancer. Nanoscale devices have impacted cancer biology at three levels: early detection using, for example, nanocantilevers or nanoparticles; tumour imaging using radiocontrast nanoparticles or quantum dots; and drug delivery using nanovectors and hybrid nanoparticles. This review addresses some of the major milestones in the integration of nanotechnology and cancer biology, and the future of nanoscale approaches for cancer management.

As MRI threatens the use of bone scintigraphy for skeletal metastases and 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) emerges as the main focus in nuclear oncology, the future role of the gamma camera in cancer imaging appears unclear. However, there is a range of pre-existing conventional gamma camera techniques that have incremental benefit over CT and other structural imaging techniques, but are yet to be fully exploited in the care of cancer patients. This article reviews some of the more advanced conventional nuclear medicine techniques for cancer imaging. Often gamma camera techniques perform close to 18FDG - PET or provide complementary information.Where 18FDG - PET is diagnostically superior, the incremental cost-effectiveness gain of 18FDG - PET over conventional gamma camera techniques has not always been fully evaluated.

3-O-Methyl-6-[(18)F]fluoro-L-DOPA (OMFD) is a major metabolite of 6-[(18)F]fluoro-L-DOPA. Although synthesis of OFMD was primarily established to study the dopaminergic system, as it is an amino acid analogue, uptake in experimental tumours has been found. The aim of this study was to evaluate the applicability of OMFD for brain tumour imaging and to obtain initial estimates of whole-body biodistribution and radiation dosimetry in humans. Nineteen patients with suspected or confirmed brain tumours were investigated with OMFD and dynamic brain PET, complemented by whole-body PET in seven patients. Tracer kinetics were compared for normal brain and intracerebral lesions. Tissue accumulation was quantified with standardised uptake values (SUVs). Whole-body distribution in combination with tracer kinetics from animal experiments was used for the calculation of radiation dosimetry data. On the basis of OMFD PET, viable brain tumour was suspected in 16 patients with SUVs of 3.0+/-0.8 and a tumour to non-tumour ratio of 1.9+/-0.5. Highest tumour and normal brain uptake occurred between 15 and 30 min, with a subsequent slow decrease. Late whole-body tracer distribution was uniform without specific organ accumulation. Elimination occurred via urine. The mean radiation dose to the whole body was estimated at 0.016 mSv/MBq, with the kidneys as dose-critical organ (0.033 mGy/MBq). In conclusion, OMFD enables the visualisation of brain tumours with SUVs similar to other fluorinated amino acids. The whole-body radiation exposure from OMFD is comparable to that from FDG imaging.