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Objective: Sentinel Lymph Node Biopsy (SLNB) is an important management tool for early-stage melanoma. Different radiopharmaceuticals are used internationally to localise the sentinel node using lymphoscintigraphy (LSG) before surgery. Recent reports have suggested that a delayed interval between LSG and SLNB using 99m Tc-labelled nanocolloid tracer has an adverse survival impact, but not with 99m Tc-labelled antimony sulphide colloid. This study aims to analyse survival outcome in a prospective cohort of melanoma patients undergoing same day or next day SLNB after LSG using 99m Tc-labelled nanocolloid., Methods: Outcome data were reviewed for patients undergoing SLNB, stratified by time interval between LSG and SLNB at a single UK academic centre. Kaplan-Meier survival analysis was used to assess overall survival (OS), melanoma-specific survival (MSS) and progression-free survival (PFS). Cox multivariable regression analysis identified independent risk factors., Results: 925 patients had LSG using the 99m Tc-nanocolloid tracer between 2009 and 2019, with a median follow-up of 6.36 years. No difference was seen on univariate analysis in OS, MSS, PFS, or nodal recurrence between patients undergoing same day or next day SLNB (Log-rank P = 0.437, 0.293, 0.587, 0.342 respectively). In addition, nodal recurrence as first site or anytime site of recurrence in SLNB negative patients was similar between the groups (Log-rank P = 0.093 and 0.457 respectively). Stratified analysis of time did not demonstrate an outcome difference (MSS Log-rank P = 0.938). Cox multivariable regression did not show time interval to independently influence OS, MSS or PFS., Conclusions: We do not find a significant effect on long-term outcomes when SLNB is performed the day after LSG with 99m Tc-labelled nanocolloid tracer. We infer that tracer migration is not clinically significant within 24 h of injection based on long term clinical outcome data., (© 2024. The Author(s).)

There is an expanding body of evidence showing that synthetic peptides in combination with radioactive isotopes can be utilized for medical purposes. This area is of particular interest in oncology where applications in diagnosis and therapy are at different stages of development. We review the contributions in this area by the group originally founded by Carlo Pedone in Naples many years ago. We highlight the work of this group in the context of other developments in this area, focusing on three biologically relevant receptor systems: somatostatin, gastrin-releasing peptide, and cholecystokinin-2/gastrin receptors. We focus on key milestones, state of the art, and challenges in this area of research as well as the current and future outlook for expanding clinical applications., (© 2024 European Peptide Society and John Wiley & Sons Ltd.)

Background: Dosimetry after [ 177 Lu]Lu-DOTA-TATE therapy can be demanding for both patients and the clinical service due to the need for imaging at several time points. In this work we compare three methods of single time point (STP) kidney dosimetry after [ 177 Lu]Lu-DOTA-TATE therapy with a multiple time point (MTP) dosimetry method., Method: Method 1 (MTP): Kidney doses were calculated from 31 patients including 107 therapy cycles. Post-therapy SPECT images were acquired on day 0, 4 and 7 along with a CT scan on day 4. A mono-exponential fit was used to calculate kidney doses using cycle specific data. Method 2 (Consistent effective half-life): The effective half-life [Formula: see text] calculated in cycle 1 was assumed consistent for subsequent cycles of therapy and the activity scaled using a single day 3-5 SPECT/CT. Methods 3 and 4 (Hänscheid and Madsen approximations): The Hänscheid approximation and Madsen approximation were both evaluated using a single SPECT/CT acquired on day 0, 4 and 7. All STP methods were compared to the MTP method for accuracy., Results: Using the MTP method, mean right and left kidney doses were calculated to be 2.9 ± 1.1 Gy and 2.8 ± 0.9 Gy respectively and the population [Formula: see text] was 56 ± 13 h. For the consistent [Formula: see text], Hänscheid and Madsen methods, the percentage of results within ± 20% of MTP method were 96% (n = 70), 95% (n = 80) and 94% (n = 80) respectively., Conclusion: All three single time point methods had > 94% of results within ± 20% of the MTP method, however the consistent [Formula: see text] method resulted in the highest alignment with the MTP method and is the only method which allows for calculation of the patient-specific [Formula: see text]. If only a single scan can be performed, day 4 is optimal for kidney dosimetry where the Hänscheid or Madsen approximation can be implemented with good accuracy., (© 2024. The Author(s).)

Radiomics analysis of [ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG) PET images could be leveraged for personalised cancer medicine. However, the inherent sensitivity of radiomic features to intensity discretisation and voxel interpolation complicates its clinical translation. In this work, we evaluated the robustness of tumour [ 18 F]-FDG-PET radiomic features to 174 different variations in intensity resolution or voxel size, and determined whether implementing parameter range conditions or dependency corrections could improve their robustness. Using 485 patient images spanning three cancer types: non-small cell lung cancer (NSCLC), melanoma, and lymphoma, we observed features were more sensitive to intensity discretisation than voxel interpolation, especially texture features. In most of our investigations, the majority of non-robust features could be made robust by applying parameter range conditions. Correctable features, which were generally fewer than conditionally robust, showed systematic dependence on bin configuration or voxel size that could be minimised by applying corrections based on simple mathematical equations. Melanoma images exhibited limited robustness and correctability relative to NSCLC and lymphoma. Our study provides an in-depth characterisation of the sensitivity of [ 18 F]-FDG-PET features to image processing variations and reinforces the need for careful selection of imaging biomarkers prior to any clinical application., (© 2024. The Author(s).)

Objective: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45)., Design: Retrospective single-center cohort study., Patients and Measurements: The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery., Results: In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas., Conclusions: This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Tumors of the pituitary gland, although mostly benign adenomas, are a cause of significant morbidity and even excess mortality due to local compressive effects (eg visual loss, hypopituitarism) and unregulated hormone secretion (eg acromegaly or Cushing Disease). Surgery, radiotherapy, and medical management (sometimes in combination) may be needed to mitigate the effects of tumor expansion and endocrine dysfunction. Magnetic resonance imaging (MRI) plays a central role in treatment planning for most patients. However, it does not always reliably identify the site(s) of primary or recurrent disease, especially where post-treatment remodeling results in indeterminate anatomical appearances. In these contexts, molecular imaging is a potential game-changer, allowing precise localization of sites of active disease and enabling safe and effective targeted intervention when patients would otherwise be consigned to expensive life-long medication. For pituitary and parasellar imaging, PET is the preferred modality due to its superior spatial resolution and sensitivity compared with SPECT, and an array of PET radioligands have been studied in different pituitary adenoma (PA) subtypes. While 18 F-fluorodeoxyglucose ( 18 F-FDG) is widely available, significant heterogeneity in tumoral uptake has limited its use. Instead, ligands targeting specific molecular pathways relevant to PA biology (eg somatostatin or dopamine receptor expression, amino acid uptake) are increasingly preferred and are beginning to find application in routine clinical practice. In addition, novel approaches to distinguish adenomatous tissue from normal gland (eg through comparison of images obtained with different radiotracers) and increase confidence that a suspected abnormal focus is indeed pathological (eg through subtraction imaging) have been proposed. It is likely therefore that molecular imaging will continue to find increasing application in the management of pituitary tumors just as it already does in other endocrine disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Image optimization is a key step in clinical nuclear medicine, and phantoms play an essential role in this process. However, most phantoms do not accurately reflect the complexity of human anatomy, and this presents a particular challenge when imaging endocrine glands to detect small (often subcentimeter) tumors. To address this, we developed a novel phantom for optimization of positron emission tomography (PET) imaging of the human pituitary gland. Using radioactive 3D printing, phantoms were created which mimicked the distribution of 11 C-methionine in normal pituitary tissue and in a small tumor embedded in the gland (i.e., with no inactive boundary, thereby reproducing the in vivo situation). In addition, an anatomical phantom, replicating key surrounding structures [based on computed tomography (CT) images from an actual patient], was created using material extrusion 3D printing with specialized filaments that approximated the attenuation properties of bone and soft tissue., Results: The phantom enabled us to replicate pituitary glands harboring tumors of varying sizes (2, 4 and 6 mm diameters) and differing radioactive concentrations (2 ×, 5 × and 8 × the normal gland). The anatomical phantom successfully approximated the attenuation properties of surrounding bone and soft tissue. Two iterative reconstruction algorithms [ordered subset expectation maximization (OSEM); Bayesian penalized likelihood (BPL)] with a range of reconstruction parameters (e.g., 3, 5, 7 and 9 OSEM iterations with 24 subsets; BPL regularization parameter (β) from 50 to 1000) were tested. Images were analyzed quantitatively and qualitatively by eight expert readers. Quantitatively, signal was the highest using BPL with β = 50; noise was the lowest using BPL with β = 1000; contrast was the highest using BPL with β = 100. The qualitative review found that accuracy and confidence were the highest when using BPL with β = 400., Conclusions: The development of a bespoke phantom has allowed the identification of optimal parameters for molecular pituitary imaging: BPL reconstruction with TOF, PSF correction and a β value of 400; in addition, for small (< 4 mm) tumors with low contrast (2:1 or 5:1), sensitivity may be improved using a β value of 100. Together, these findings should increase tumor detection and confidence in reporting scans., (© 2023. The Author(s).)

Importance: Although sentinel lymph node biopsy (SLNB) is a vital staging tool, its application in head and neck melanoma (HNM) is complicated by a higher false-negative rate (FNR) compared with other regions. This may be due to the complex lymphatic drainage in the head and neck., Objective: To compare the accuracy, prognostic value, and long-term outcomes of SLNB in HNM with melanoma from the trunk and limb, focusing on the lymphatic drainage pattern., Design, Setting, and Participants: This cohort observational study at a single UK University cancer center included all patients with primary cutaneous melanoma undergoing SLNB between 2010 to 2020. Data analysis was conducted during December 2022., Exposures: Primary cutaneous melanoma undergoing SLNB between 2010 to 2020., Main Outcomes and Measures: This cohort study compared the FNR (defined as the ratio between false-negative results and the sum of false-negative and true-positive results) and false omission rate (defined as the ratio between false-negative results and the sum of false-negative and true-negative results) for SLNB stratified by 3 body regions (HNM, limb, and trunk). Kaplan-Meier survival analysis was used to compare recurrence-free survival (RFS) and melanoma-specific survival (MSS). Comparative analysis of detected lymph nodes on lymphoscintigraphy (LSG) and SLNB was performed by quantifying lymphatic drainage patterns by number of nodes and lymph node basins. Multivariable Cox proportional hazards regression identified independent risk factors., Results: Overall, 1080 patients were included (552 [51.1%] men, 528 [48.9%] women; median age at diagnosis 59.8 years), with a median (IQR) follow-up 4.8 (IQR, 2.7-7.2) years. Head and neck melanoma had a higher median age at diagnosis (66.2 years) and higher Breslow thickness (2.2 mm). The FNR was highest in HNM (34.5% vs 14.8% trunk or 10.4% limb, respectively). Similarly, the false omission rate was 7.8% in HNM compared with 5.7% trunk or 3.0% limbs. The MSS was no different (HR, 0.81; 95% CI, 0.43-1.53), but RFS was lower in HNM (HR, 0.55; 95% CI, 0.36-0.85). On LSG, patients with HNM had the highest proportion of multiple hotspots (28.6% with ≥3 hotspots vs 23.2% trunk and 7.2% limbs). The RFS was lower for patients with HNM with 3 or more affected lymph nodes found on LSG than those with fewer than 3 affected lymph nodes (HR, 0.37; 95% CI, 0.18-0.77). Cox regression analysis showed head and neck location to be an independent risk factor for RFS (HR, 1.60; 95% CI, 1.01-2.50), but not for MSS (HR, 0.80; 95% CI, 0.35-1.71)., Conclusions and Relevance: This cohort study found higher rates of complex lymphatic drainage, FNR, and regional recurrence in HNM compared with other body sites on long-term follow-up. We advocate considering surveillance imaging for HNM for high-risk melanomas irrespective of sentinel lymph node status.

Background: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures., Objectives: We aimed to investigate somatostatin receptor 2 (SST 2 ) as a novel inflammation-specific molecular imaging target in LVV., Methods: In a prospective, observational cohort study, in vivo arterial SST 2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68 Ga-DOTATATE and 18 F-FET-βAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing., Results: Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST 2 maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST 2 signal was not elevated in any of the control subjects. SST 2 PET/MRI was generally consistent with 18 F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST 2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST 2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers., Conclusions: SST 2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA], NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE], NCT04073810)., Competing Interests: Funding Support and Author Disclosures This work was funded by grants to Dr Tarkin from the Wellcome Trust (Clinical Research Career Development Fellowship 211100/Z/18/Z), the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC); and the British Heart Foundation (BHF) (Clinical Research Training Fellowship for Dr Ćorović [FS/CRTF/20/24035]). This work was additionally supported by the Cambridge BHF Centre of Research Excellence (18/1/34212) and the Cancer Research UK Cambridge Centre (A25177). For the purpose of open access, the lead author has applied a CC BY public copyright license to any Author Accepted Manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Dr Nus; authors Imaz and Lambert; Dr Frontini (FS/18/53/33863); Dr Davenport (TG/18/4/33770); and Drs Huang, Mallat, Dweck, Newby, and Bennett are supported by the BHF. Author Zulcinski is supported by the European Union’s Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement no. 813545). Drs Jayne, Rassl, and Graves are supported by the NIHR Cambridge BRC. Dr Fayad is supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL135878). Dr Reynolds is supported by the Wellcome Trust. Dr Morgan is supported by the Medical Research Council (MRC) (MR/N011775/1), the NIHR Leeds BRC, the NIHR Leeds Medtech, and In Vitro Diagnostics Co-operative as well as an NIHR Senior Investigator award. Dr Aboagye acknowledges support from Imperial Experimental Cancer Research Centre and MRC (MR/J007986/1, MR/N020782/1); and is an inventor on the patent that developed the (18)F-FET-βAG-TOCA radiotracer. Dr Peters is supported by a UK Research and Innovation Fellowship at Health Data Research UK (MR/S004068/2). Dr Rudd is partly supported by the NIHR Cambridge BRC, the BHF, the Higher Education Funding Council for England, the Engineering and Physical Sciences Research Council, and the Wellcome Trust. Drs Gopalan, Maughan, Pericleous, Barwick, Aboagye, Peters, and Mason acknowledge support from the NIHR Imperial BRC. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The tumour immune microenvironment influences the efficacy of immune checkpoint inhibitors. Within this microenvironment are CD8-expressing tumour-infiltrating lymphocytes (CD8 + TILs), which are an important mediator and marker of anti-tumour response. In practice, the assessment of CD8 + TILs via tissue sampling involves logistical challenges. Radiomics, the high-throughput extraction of features from medical images, may offer a novel and non-invasive alternative. We performed a systematic review of the available literature reporting radiomic signatures associated with CD8 + TILs. We also aimed to evaluate the methodological quality of the identified studies using the Radiomics Quality Score (RQS) tool, and the risk of bias and applicability with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Articles were searched from inception until 31 December 2021, in three electronic databases, and screened against eligibility criteria. Twenty-seven articles were included. A wide variety of cancers have been studied. The reported radiomic signatures were heterogeneous, with very limited reproducibility between studies of the same cancer group. The overall quality of studies was found to be less than desirable (mean RQS = 33.3%), indicating a need for technical maturation. Some potential avenues for further investigation are also discussed.

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia driven by excess parathyroid hormone (PTH) secretion. PHPT is a common endocrine condition with a prevalence of 1 to 7 cases per 1000 adults. PHPT typically presents in the fifth or sixth decade and shows significant female preponderance. Solitary hyperfunctioning parathyroid adenomas account for 85% to 90% of PHPT cases. The remaining 10% to 15% include cases of multiglandular disease (multiple adenomas or hyperplasia) and, rarely, parathyroid carcinoma (1%). Ectopic parathyroid adenomas may arise due to abnormal embryological migration of the parathyroid glands and can be difficult to localize preoperatively, making surgical cure challenging on the first attempt. The potential existence of multiglandular disease should be considered in all patients in whom preoperative localization fails to identify a target adenoma or following unsuccessful parathyroidectomy. Risk factors for multiglandular disease include underlying genetic syndromes (eg, MEN1/2A), lithium therapy, or previous radiotherapy. In addition to multifocal disease, the possibility of an ectopic parathyroid gland should also be considered in patients requiring repeat parathyroid surgery. In this article, we use illustrative clinical vignettes to discuss the approach to a patient with primary hyperparathyroidism (PHPT) and a suspected ectopic parathyroid adenoma., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Pituitary adenomas (PA) affect ~ 1:1200 of the population and can cause a wide range of symptoms due to hormone over-secretion, loss of normal pituitary gland function and/or compression of visual pathways, resulting in significantly impaired quality of life. Surgery is potentially curative if the location of the adenoma can be determined. However, standard structural (anatomical) imaging, in the form of MRI, is unable to locate all tumors, especially microadenomas (< 1 cm diameter). In such cases, functional imaging [ 11 C-methionine PET/CT (Met-PET)] can facilitate tumor detection, although may be inconclusive when the adenoma is less metabolically active. We, therefore, explored whether subtraction imaging, comparing findings between two Met-PET scans with medical therapy-induced suppression of tumor activity in the intervening period, could increase confidence in adenoma localization. In addition, we assessed whether normalization to a reference region improved consistency of pituitary gland signal in healthy volunteers who underwent two Met-PET scans without medical suppression., Results: We found that the mean percentage differences in maximum pituitary uptake between two Met-PET scans in healthy volunteers were 2.4% for (SUVr) [cerebellum], 8.8% for SUVr [pons], 5.2% for SUVr [gray matter] and 23.1% for the SUVbw [no region]. Laterality, as measured by contrast-noise ratio (CNR), indicated the correct location of the adenoma in all three image types with mean CNR values of 6.2, 8.1 and 11.1 for SUVbw, SUVbwSub and SUVrSub [cerebellum], respectively. Subtraction imaging improved CNR in 60% and 100% of patients when using images generated from SUVbw [no region] and SUVr [cerebellum] scans compared to standard clinical SUVbw imaging., Conclusions: Met-PET scans should be normalized to the cerebellum to minimize the effects of physiological variation in pituitary gland uptake of 11C-methionine, especially when comparing serial imaging. Subtraction imaging following endocrine suppression of tumor function improved lateralization of PA when compared with single time point clinical Met-PET but, importantly, only if the images were normalized to the cerebellum prior to subtraction., (© 2022. The Author(s).)

Background: Immune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI., Methods: Fifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T 2 -weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year., Results: Differential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (D app ) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (K app ), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (K trans , v e , and v p ) detected after 12 weeks of immunotherapy (p<0.05)., Conclusions: Multiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma., Competing Interests: Competing interests: No conflict of interest to declare with respect to the content of this work. AL, MS, LB, and J-ML are employees of AstraZeneca UK., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Molecular imaging techniques have rapidly progressed over recent decades providing unprecedented in vivo characterization of metabolic pathways and molecular biomarkers. Many of these new techniques have been successfully applied in the field of neuro-oncological imaging to probe tumor biology. Targeting specific signaling or metabolic pathways could help to address several unmet clinical needs that hamper the management of patients with brain tumors. This review aims to provide an overview of the recent advances in brain tumor imaging using molecular targeting with positron emission tomography and magnetic resonance imaging, as well as the role in patient management and possible therapeutic implications., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell therapy is a rapidly evolving field involving a wide spectrum of therapeutic cells for personalised medicine in cancer. In vivo imaging and tracking of cells can provide useful information for improving the accuracy, efficacy, and safety of cell therapies. This review focuses on radiopharmaceuticals for the non-invasive detection and tracking of therapeutic cells using positron emission tomography (PET). A range of approaches for imaging therapeutic cells is discussed: Direct ex vivo labelling of cells, in vivo indirect labelling of cells by utilising gene reporters, and detection of specific antigens expressed on the target cells using antibody-based radiopharmaceuticals (immuno-PET). This review examines the evaluation of PET imaging methods for therapeutic cell tracking in preclinical cancer models, their role in the translation into patients, first-in-human studies, as well as the translational challenges involved and how they can be overcome.

Aims: To examine pericoronary adipose tissue (PCAT) and periaortic adipose tissue (PAAT) density on coronary computed tomography angiography for assessing arterial inflammation in Takayasu arteritis (TAK) and atherosclerosis., Methods and Results: PCAT and PAAT density was measured in coronary ( n = 1016) and aortic ( n = 108) segments from 108 subjects [TAK + coronary artery disease (CAD), n = 36; TAK, n = 18; atherosclerotic CAD, n = 32; matched controls, n = 22]. Median PCAT and PAAT densities varied between groups (mPCAT: P < 0.0001; PAAT: P = 0.0002). PCAT density was 7.01 ± standard error of the mean (SEM) 1.78 Hounsfield Unit (HU) higher in coronary segments from TAK + CAD patients than stable CAD patients ( P = 0.0002), and 8.20 ± SEM 2.04 HU higher in TAK patients without CAD than controls ( P = 0.0001). mPCAT density was correlated with Indian Takayasu Clinical Activity Score ( r = 0.43, P = 0.001) and C-reactive protein ( r = 0.41, P < 0.0001) and was higher in active vs. inactive TAK ( P = 0.002). mPCAT density above -74 HU had 100% sensitivity and 95% specificity for differentiating active TAK from controls [area under the curve = 0.99 (95% confidence interval 0.97-1)]. The association of PCAT density and coronary arterial inflammation measured by 68 Ga-DOTATATE positron emission tomography (PET) equated to an increase of 2.44 ± SEM 0.77 HU in PCAT density for each unit increase in 68 Ga-DOTATATE maximum tissue-to-blood ratio ( P = 0.002). These findings remained in multivariable sensitivity analyses adjusted for potential confounders., Conclusions: PCAT and PAAT density are higher in TAK than atherosclerotic CAD or controls and are associated with clinical, biochemical, and PET markers of inflammation. Owing to excellent diagnostic accuracy, PCAT density could be useful as a clinical adjunct for assessing disease activity in TAK., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited., Objective: To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis., Design, Setting, and Participants: This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line-treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020., Interventions: Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo-folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm)., Main Outcomes and Measures: The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL)., Results: Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm; P = .89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm; P = .15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99; P = .04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%]; P = .006) and nausea (2 [1.8%] vs 8 [7.0%]; P = .05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs -7.41 [2.95] at 24 weeks; P = .02), and constipation scores (mean [SD] change from baseline, -17.2 [3.73] vs -0.62 [4.44]; P = .003)., Conclusions and Relevance: In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives., Trial Registration: EudraCT Identifier: 2011-004997-27; ClinicalTrials.gov Identifier: NCT01718873.

Purpose: Phantoms are routinely used in molecular imaging to assess scanner performance. However, traditional phantoms with fillable shapes do not replicate human anatomy. 3D-printed phantoms have overcome this by creating phantoms which replicate human anatomy which can be filled with radioactive material. The problem with these is that small objects suffer to a greater extent than larger objects from the effects of inactive walls, and therefore, phantoms without these are desirable. The purpose of this study was to explore the feasibility of creating resin-based 3D-printed phantoms using 18 F., Methods: Radioactive resin was created using an emulsion of printer resin and 18 F-FDG. A series of test objects were printed including twenty identical cylinders, ten spheres with increasing diameters (2 to 20 mm), and a double helix. Radioactive concentration uniformity, printing accuracy and the amount of leaching were assessed., Results: Creating radioactive resin was simple and effective. The radioactive concentration was uniform among identical objects; the CoV of the signal was 0.7% using a gamma counter. The printed cylinders and spheres were found to be within 4% of the model dimensions. A double helix was successfully printed as a test for the printer and appeared as expected on the PET scanner. The amount of radioactivity leached into the water was measurable (0.72%) but not visible above background on the imaging., Conclusions: Creating an 18 F radioactive resin emulsion is a simple and effective way to create accurate and complex phantoms without inactive walls. This technique could be used to print clinically realistic phantoms. However, they are single use and cannot be made hollow without an exit hole. Also, there is a small amount of leaching of the radioactivity to take into consideration.

Background: [ 68  Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [ 177 Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [ 68  Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called 'wild-type' GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST., Aims: To investigate (i) the diagnostic role of [ 68  Ga]Ga-DOTATATE PET/CT; and, (ii) to investigate the potential of this imaging modality to guide treatment with [ 177 Lu]Lu-DOTATATE in patients with wtGIST., Methods: [ 68  Ga]Ga-DOTATATE PET/CT was performed on 11 patients with confirmed or metastatic wtGIST and one patient with a history of wtGIST and a mediastinal mass suspicious for metastatic wtGIST, who was subsequently diagnosed with a metachronous mediastinal paraganglioma. Tumour expression of somatostatin receptor subtype 2 (SSTR2) using immunohistochemistry was performed on 54 tumour samples including samples from 8/12 (66.6%) patients who took part in the imaging study and 46 tumour samples from individuals not included in the imaging study., Results: [ 68  Ga]Ga-DOTATATE PET/CT imaging was negative, demonstrating that liver metastases had lower uptake than background liver for nine cases (9/12 cases, 75%) and heterogeneous uptake of somatostatin tracer was noted for two cases (16.6%) of wtGIST. However, [ 68  Ga]Ga-DOTATATE PET/CT demonstrated intense tracer uptake in a synchronous paraganglioma in one case and a metachronous paraganglioma in another case with wtGIST., Conclusions: Our data suggest that SSTR2 is not a diagnostic or therapeutic target in wtGIST. [ 68  Ga]Ga-DOTATATE PET/CT may have specific diagnostic utility in differentiating wtGIST from other primary tumours such as paraganglioma in patients with sporadic and hereditary forms of wtGIST.

Targeting specific cell membrane markers for both diagnostic imaging and radionuclide therapy is a rapidly evolving field in cancer research. Some of these applications have now found a role in routine clinical practice and have been shown to have a significant impact on patient management. Several molecular targets are being investigated in ongoing clinical trials and show promise for future implementation. Advancements in molecular biology have facilitated the identification of new cancer-specific targets for radiopharmaceutical development., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

A retrospective analysis was performed of epidemiological data assessing the survival of patients who had received radium-223 for castrate-resistant metastatic prostate cancer treated at a regional tertiary referral center over a 5-year period. The patients' age, date of first treatment, and the number of cycles of radium-223 given were obtained from the patients' electronic patient record (EPR). Data on the date of death were provided by national death registrations which update the EPR via a unique national health service number. A total of 187 patients (mean age on the date of first treatment: 73 years; range: 56-93) were treated from April 1, 2014, to June 30, 2019. The median overall survival of the 119 patients (71%) who had died by December 31, 2019, was 15 months. There was no significant age difference between those who had died and survivors (72 vs. 74 years). On a further analysis, it was found that the median overall survival of the 107 patients who had received all the six cycles of radium-223 was 31 months, significantly longer than the median overall survival of only 6 months for those eighty patients who had received less than the full course of six cycles of radium-223 ( P = 0.001). Of those who received all the six cycles of treatment, 58 patients had died (58%) and the 1-year survival was 87%. This was compared to the group of patients receiving <6 cycles of radium-223 where 61 patients (76%) had died and the 1-year survival was 30%. Therefore, the hazard ratio of dying before 1 year if the patient did not receive all the six cycles of treatment was 2.9. Where the reason for stopping treatment was recorded on the EPR the most common cause for the cessation of treatment was because of the side effects caused by the treatment itself. Other causes were hospitalization with comorbidities, disease progression, or patient choice. Given the survival advantage of receiving the full course of all the six cycles of treatment, this should be administered if possible and the patients should be managed in such a way as to allow the complete treatment course to be given., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 World Journal of Nuclear Medicine.)

Efficient T-cell targeting, infiltration and activation within tumors is crucial for successful adoptive T-cell therapy. Intravital microscopy is a powerful tool for the visualization of T-cell behavior within tumors, as well as spatial and temporal heterogeneity in response to immunotherapy. Here we describe an experimental approach for intravital imaging of adoptive T-cell morphology, mobility and trafficking in a skin-flap tumor model, following immune modulation with immune checkpoint inhibitors (ICIs) targeting PD-L1 and CTLA-4. A syngeneic model of ovalbumin and mCherry-expressing amelanotic mouse melanoma was used in conjunction with adoptively transferred OT-1 + cytotoxic T-cells expressing GFP to image antigen-specific live T-cell behavior within the tumor microenvironment. Dynamic image analysis of T-cell motility showed distinct CD8 + T-cell migration patterns and morpho-dynamics within different tumor compartments in response to ICIs: this approach was used to cluster T-cell behavior into four groups based on velocity and meandering index. The results showed that most T-cells within the tumor periphery demonstrated Lévy-like trajectories, consistent with tumor cell searching strategies. T-cells adjacent to tumor cells had reduced velocity and appeared to probe the local environment, consistent with cell-cell interactions. An increased number of T-cells were detected following treatment, traveling at lower mean velocities than controls, and demonstrating reduced displacement consistent with target engagement. Histogram-based analysis of immunofluorescent images from harvested tumors showed that in the ICI-treated mice there was a higher density of CD31 + vessels compared to untreated controls and a greater infiltration of T-cells towards the tumor core, consistent with increased cellular trafficking post-treatment., (Copyright © 2020 Lau, Garçon, Chandra, Lechermann, Aloj, Chilvers, Corrie, Okkenhaug and Gallagher.)

Purpose: Tracking cells in vivo using imaging can provide non-invasive information to understand the pharmacology, efficacy, and safety of novel cell therapies. Zirconium-89 (t 1/2 = 78.4 h) has recently been used to synthesize [ 89 Zr]Zr(oxinate) 4 for cell tracking using positron emission tomography (PET). This work presents an in vitro approach to estimate the detection limit for in vivo PET imaging of Jurkat T cells directly labeled with [ 89 Zr]Zr(oxinate) 4 utilizing clinical PET/CT and PET/MRI., Methods: Jurkat T cells were labeled with varying concentrations of [ 89 Zr]Zr(oxinate) 4 to generate different cell-specific activities (0.43-31.91 kBq/10 6 cells). Different concentrations of labeled cell suspensions (10 4 , 10 5 , and 10 6 cells) were seeded on 6-well plates and into a 3 × 3 cubic-well plate with 1 cm 3 cubic wells as a gel matrix. Plates were imaged on clinical PET/CT and PET/MRI scanners for 30 min. The total activity in each well was determined by drawing volumes of interest over each well on PET images. The total cell-associated activity was measured using a well counter and correlated with imaging data. Simulations for non-specific signal were performed to model the effect of non-specific radioactivity on detection., Results: Using this in vitro model, the lowest cell number that could be visualized on 6-well plate images was 6.8 × 10 4 , when the specific activity was 27.8 kBq/10 6 cells. For the 3 × 3 cubic-well, a plate of 3.3 × 10 4 cells could be detected on images with a specific activity of 15.4 kBq/10 6 cells., Conclusion: The results show the feasibility of detecting [ 89 Zr]Zr(oxinate) 4 -labeled Jurkat T cells on clinical PET systems. The results provide a best-case scenario, as in vivo detection using PET/CT or PET/MRI will be affected by cell number, specific activity per cell, the density of cells within the target volume, and non-specific signal. This work has important implications for cell labeling studies in patients, particularly when using radiosensitive cells (e.g., T cells), which require detection of low cell numbers while minimizing radiation dose per cell.

There is an unmet need for predictive biomarkers of the clinical benefit of antiangiogenic drugs. The aim of the present study was to prospectively evaluate the value of 18 F-FDG PET/CT performed during and after preoperative chemoradiotherapy with bevacizumab for the prediction of complete pathologic tumor regression and survival in patients with MRI-defined high-risk locally advanced rectal cancer. Methods: Sixty-one patients treated in a nonrandomized phase II study (BRANCH) with concomitant or sequential (4 d before chemoradiotherapy) administration of bevacizumab with preoperative chemoradiotherapy were included. 18 F-FDG PET/CT was performed at baseline, 11 d after the beginning of chemoradiotherapy (early), and before surgery (late). Metabolic changes were compared with pathologic complete tumor regression (TRG1) versus incomplete tumor regression (TRG2-TRG5), progression-free survival, cancer-specific survival, and overall survival. Receiver-operating-characteristic curves were calculated for those 18 F-FDG PET/CT parameters that significantly correlated with TRG1. Results: Early total-lesion glycolysis and its percentage change compared with baseline (ΔTLG-early) could discriminate TRG1 from TRG2-TRG5. Only receiver-operating-characteristic analysis of ΔTLG-early showed an area under the curve greater than 0.7 (0.76), with an optimal cutoff at 59.5% (80% sensitivity, 71.4% specificity), for identifying TRG1. Late metabolic assessment could not discriminate between the 2 groups. After a median follow-up of 98 mo (range, 77-132 mo), metabolic responders (ΔTLG-early ≥ 59.5%) demonstrated a significantly higher 10-y progression-free survival (89.3% vs. 63.6%, P = 0.02) and cancer-specific survival (92.9% vs. 72.6%, P = 0.04) than incomplete metabolic responders. Conclusion: Our results suggest that early metabolic response can act as a surrogate marker of the benefit of antiangiogenic therapy. The findings provide further support for the use of early 18 F-FDG PET/CT evaluation to predict pathologic response and survival in the preoperative treatment of patients with locally advanced rectal cancer. ΔTLG-early showed the best accuracy in predicting tumor regression and may be particularly useful in guiding treatment-modifying decisions during preoperative chemoradiotherapy based on expected response., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To investigate dynamic contrast enhanced-MRI (DCE-MRI) in the preoperative chemo-radiotherapy (CRT) assessment for locally advanced rectal cancer (LARC) compared to18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)., Methods: 75 consecutive patients with LARC were enrolled in a prospective study. DCE-MRI analysis was performed measuring SIS: linear combination of percentage change (Δ) of maximum signal difference (MSD) and wash-out slope (WOS). 18F-FDG PET/CT analysis was performed using SUV maximum (SUVmax). Tumor regression grade (TRG) were estimated after surgery. Non-parametric tests, receiver operating characteristic were evaluated., Results: 55 patients (TRG1-2) were classified as responders while 20 subjects as non responders. ΔSIS reached sensitivity of 93%, specificity of 80% and accuracy of 89% (cut-off 6%) to differentiate responders by non responders, sensitivity of 93%, specificity of 69% and accuracy of 79% (cut-off 30%) to identify pathological complete response (pCR). Therapy assessment via ΔSUVmax reached sensitivity of 67%, specificity of 75% and accuracy of 70% (cut-off 60%) to differentiate responders by non responders and sensitivity of 80%, specificity of 31% and accuracy of 51% (cut-off 44%) to identify pCR., Conclusions: CRT response assessment by DCE-MRI analysis shows a higher predictive ability than 18F-FDG PET/CT in LARC patients allowing to better discriminate significant and pCR.

Previous studies indicate that FDG PET/CT may predict pathological response in patients undergoing neoadjuvant chemo-radiotherapy for locally advanced rectal cancer (LARC). Aim of the current study is evaluate if pathological response can be similarly predicted in LARC patients after short course radiation therapy alone., Methods: Thirty-three patients with cT2-3, N0-2, M0 rectal adenocarcinoma treated with hypo fractionated short course neoadjuvant RT (5x5 Gy) with delayed surgery (SCRTDS) were prospectively studied. All patients underwent 3 PET/CT studies at baseline, 10 days from RT end (early), and 53 days from RT end (delayed). Maximal standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) of the primary tumor were measured and recorded at each PET/CT study. We use logistic regression analysis to aggregate different measures of metabolic response to predict the pathological response in the course of SCRTDS., Results: We provide straightforward formulas to classify response and estimate the probability of being a major responder (TRG1-2) or a complete responder (TRG1) for each individual. The formulas are based on the level of TLG at the early PET and on the overall proportional reduction of TLG between baseline and delayed PET studies., Conclusions: This study demonstrates that in the course of SCRTDS it is possible to estimate the probabilities of pathological tumor responses on the basis of PET/CT with FDG. Our formulas make it possible to assess the risks associated to LARC borne by a patient in the course of SCRTDS. These risk assessments can be balanced against other health risks associated with further treatments and can therefore be used to make informed therapy adjustments during SCRTDS., Competing Interests: The authors have declared that no competing interests exist.

Background: Overexpression of the gastrin-releasing peptide receptor (GRP-R) has been documented in several human neoplasms such as breast, prostate, and ovarian cancer. There is growing interest in developing radiolabeled peptide-based ligands toward these receptors for the purpose of in vivo imaging and radionuclide therapy of GRP-R-overexpressing tumors. A number of different peptide sequences, isotopes, and labeling methods have been proposed for this purpose. The aim of this work is to perform a direct side-by-side comparison of different GRP-R binding peptides utilizing a single labeling strategy to identify the most suitable peptide sequence., Methods: Solid-phase synthesis of eight derivatives (BN1-8) designed based on literature analysis was carried out. Peptides were coupled to the DOTA chelator through a PEG4 spacer at the N-terminus. Derivatives were characterized for serum stability, binding affinity on PC-3 human prostate cancer cells, biodistribution in tumor-bearing mice, and gamma camera imaging at 1, 6, and 24 h after injection., Results: Serum stability was quite variable among the different compounds with half-lives ranging from 16 to 400 min at 37 °C. All compounds tested showed K d values in the nanomolar range with the exception of BN3 that showed no binding. Biodistribution and imaging studies carried out for compounds BN1, BN4, BN7, and BN8 showed targeting of the GRP-R-positive tumors and the pancreas. The BN8 compound (DOTA-PEG-DPhe-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2) showed high affinity, the longest serum stability, and the highest target-to-background ratios in biodistribution and imaging experiments among the compounds tested., Conclusions: Our results indicate that the NMeGly for Gly substitution and the Sta-Leu substitution at the C-terminus confer high serum stability while maintaining high receptor affinity, resulting in biodistribution properties that outperform those of the other peptides.

Purpose: Neoadjuvant therapy is able to reduce local recurrence in rectal cancer. Immediate surgery after short course radiotherapy allows only for minimal downstaging. We investigated the effect of delayed surgery after short-course radiotherapy at different time intervals before surgery, in patients affected by rectal cancer., Methods: From January 2003 to December 2013 sixty-seven patients with the following characteristics have been selected: clinical (c) stage T3N0 ≤ 12 cm from the anal verge and with circumferential resection margin > 5 mm (by magnetic resonance imaging); cT2, any N, < 5 cm from anal verge; and patients facing tumors with enlarged nodes and/or CRM+ve who resulted unfit for chemo-radiation, were also included. Patients underwent preoperative short-course radiotherapy with different interval to surgery were divided in three groups: A (within 6 weeks), B (between 6 and 8 weeks) and C (after more than 8 weeks). Hystopatolgical response to radiotherapy was measured by Mandard's modified tumor regression grade (TRG)., Results: All patients completed the scheduled treatment. Sixty-six patients underwent surgery. Fifty-three of which (80.3%) received a sphincter saving procedure. Downstaging occurred in 41 cases (62.1%). The analysis of subgroups showed an increasing prevalence of TRG 1-2 prolonging the interval to surgery (group A-16.7%, group B-36.8% and 54.3% in group C; p value 0.023)., Conclusions: Preoperative short-course radiotherapy is able to downstage rectal cancer if surgery is delayed. A higher rate of TRG 1-2 can be obtained if interval to surgery is prolonged to more than 8 weeks., Competing Interests: The authors have declared that no competing interests exist.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome predisposing to many endocrine and neuroendocrine tumors (NET). Conventional imaging (CI) cannot provide satisfactory results for all the different types of MEN1-related tumors. Objective of this prospective observational study was to evaluate the role of (68)Ga-DOTATATE PET/CT in MEN1 compared to CI. Diagnostic performance of (68)Ga-DOTATATE PET/CT for the detection of NET was evaluated as well as the prognostic role of SUVmax. Eighteen patients with genetically confirmed MEN1 were evaluated by (68)Ga-DOTATATE PET/CT, endoscopic ultrasounds, multidetector-row computed tomography, magnetic resonance imaging, and hormone/markers serum measurements. Four MEN1-related tumor sites (pancreas, pituitary, parathyroids, adrenals) were considered. Sensitivity and specificity of (68)Ga-DOTATATE PET/CT for the detection of NET were calculated. There was (68)Ga-DOTATATE PET/CT uptake in 11/11 patients with pancreatic lesions, in 9/12 with pituitary adenoma, in 5/15 with parathyroid enlargements, and in 5/7 with adrenal lesions. (68)Ga-DOTATATE PET/CT showed sensitivity and specificity of 100 and 100 % in pancreas, 75 and 83 % in pituitary, 28 and 100 % in parathyroids, and 62.5 and 100 % in adrenals, respectively. Compared with CI, no significant difference in sensitivity for pancreas, pituitary, and adrenals was found, while CI had a better sensitivity for parathyroids (p = 0.002). On the ROC analysis, progression of pancreatic lesions was significantly associated to SUVmax <12.3 (p < 0.05). (68)Ga-DOTATATE PET/CT is greatly helpful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. There is also a prognostic role of (68)Ga-PET in patients with MEN1-pancreatic lesions.

Background: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy., Methods/design: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project., Discussion: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Background: 6-[Bis(carboxymethyl)amino]-1,4-bis(carboxymethyl)-6-methyl-1,4-diazepane (AAZTA ) is a promising chelator with potential advantages over 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radiopharmaceutical applications. Its mesocyclic structure enables fast radiolabelling under mild conditions with trivalent metals including not only (68)Ga for positron emission tomography (PET) but also (177)Lu and (111)In for single-photon emission computed tomography (SPECT) and radionuclide therapy. Here, we describe the evaluation of a bifunctional AAZTA derivative conjugated to a model minigastrin derivative as a potential theranostic agent., Methods: An AAZTA derivative with an aliphatic C9 chain as linker was coupled to a minigastrin, namely [AAZTA(0), D-Glu(1), desGlu(2-6)]-minigastrin (AAZTA-MG), and labelled with (68)Ga, (177)Lu and (111)In. The characterisation in vitro included stability studies in different media and determination of logD (octanol/PBS). Affinity determination (IC50) and cell uptake studies were performed in A431-CCK2R cells expressing the human CCK2 receptor. μPET/CT and ex vivo biodistribution studies were performed in CCK2 tumour xenograft-bearing nude mice and normal mice., Results: AAZTA-MG showed high radiochemical yields for (68)Ga (>95 %), (177)Lu (>98 %) and (111)In (>98 %). The logD value of -3.7 for both [(68)Ga]- and [(177)Lu]-AAZTA-MG indicates a highly hydrophilic character. Stability tests showed overall high stability in solution with some degradation in human plasma for [(68)Ga]- and transchelation towards DTPA for and [(177)Lu]-AAZTA-MG. An IC50 value of 10.0 nM was determined, which indicates a high affinity for the CCK2 receptor. Specific cell uptake after 60 min was >7.5 % for [(68)Ga]-AAZTA-MG and >9.5 % for [(177)Lu]-AAZTA-MG, comparable to other DOTA-MG-analogues. μPET/CT studies in CCK2 receptor tumour xenografted mice not only revealed high selective accumulation in A431-CCK2R positive tumours of (68)Ga-labelled AAZTA-MG (1.5 % ID/g in 1 h post injection) but also higher blood levels as corresponding DOTA-analogues. The (111)In-labelled peptide had a tumour uptake of 1.7 % ID/g. Biodistribution in normal mice with the [(177)Lu]-AAZTA-MG showed a considerable uptake in intestine (7.3 % ID/g) and liver (1.5 % ID/g)., Conclusion: Overall, AAZTA showed interesting properties as bifunctional chelator for peptides providing mild radiolabelling conditions for both (68)Ga and trivalent metals having advantages over the currently used chelator DOTA. Studies are ongoing to further investigate in vivo targeting properties and stability issues and the influence of spacer length on biodistribution of AAZTA.

Background: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy., Patients and Methods: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate., Results: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule., Conclusions: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.

The introduction of total mesorectal excision (TME) and preoperative multimodality treatment have substantially improved the management of rectal cancer reducing local recurrence and increasing sphincter-saving surgery; distant metastases however remain a clinical challenge. Besides, although surgery remains the mainstay for cure of rectal cancer with the multimodality approach (chemotherapy, radiotherapy and surgery) being the standard of care for the majority of rectal cancer patients, there is a need of individualized risk-adapted treatment schemes based on clinico-pathological features because of treatment-induced morbidity and quality of life deterioration. This short viewpoint describes the emerging strategies addressing all these issues., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target., Methods/design: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT., Discussion: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28., Trial Registration: ClinicalTrials.gov number, NCT01898104.

We explored activity and safety of a dose-dense/dose-intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI ) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two-stage Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without consolidation radiotherapy. Cycles were supported with granulocyte colony-stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co-primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event-free (EFS) and disease-free survival (DFS). All patients received the four doxorubicin-intensified courses and 96% concluded all six cycles (82.3% within the intended 18 weeks). This translated into a 66.9% increase of received dose-intensity for doxorubicin and 31.8% for the other agents over standard ABVD. The CR rate was 95.1% (78/82) and 87.8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14.6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-year EFS and DFS was 88.3% and 93.7%, respectively. ABVDDD-DI regimen was well-tolerated and ensured substantial CR and EFS rates without radiotherapy., (© 2014 John Wiley & Sons Ltd.)

Purpose: The extra-domain A1 of tenascin-C (TC-A1) is highly expressed in the extracellular matrix of tumours and on newly formed blood vessels and is thus a valuable target for radionuclide therapy. Tenarad is a fully human miniantibody or small immunoprotein (SIP, molecular weight 80 kDa) labelled with (131)I that is derived from a TC-A1-binding antibody. Previous phase I/II studies with a similar compound ((131)I-L19SIP) used for radioimmunotherapy (RIT) have shown preliminary efficacy in a variety of cancer types. In this ongoing phase I/II trial, Tenarad was administered to patients with recurrent Hodgkin's lymphoma (HL) refractory to conventional treatments., Methods: Eight patients (four men, four women; age range 19 - 41) were enrolled between April 2010 and March 2011. All patients had received a median of three previous lines of chemotherapy (range three to six) and seven had also undergone autologous stem cell transplantation (ASCT) or bone marrow transplantation. In addition, seven patients received external beam radiation. All patients had nodal disease, constitutional B symptoms and some showed extranodal disease in skeletal bone (four patients), lung (three), liver (two) and spleen (one). Baseline assessments included whole-body FDG PET with contrast-enhanced CT and diagnostic Tenarad planar and SPECT studies. Patients were considered eligible to receive a therapeutic dose of Tenarad (2.05 GBq/m(2)) if tumour uptake was more than four times higher than that of muscle., Results: All patients were eligible and received the therapeutic dose of Tenarad. Only one patient developed grade 4 thrombocytopenia and leucocytopenia, requiring hospitalization and therapeutic intervention. All other patients had haematological toxicity of grade 3 or lower, which resolved spontaneously. At the first response assessment (4 - 6 weeks after therapy), one patient showed a complete response, one showed a partial response (PR) and five had disease stabilization (SD). Five patients were given up to three repeated Tenarad treatments. One patient showed SD which then improved to a PR, three showed clinical benefit while maintaining SD and one patient showed disease progression., Conclusion: Tenarad RIT is effective in chemorefractory HL and resulted in objective responses or clinical benefit in the majority of patients. Toxicity was acceptable despite the high load of prior treatments, previous ASCT and multiple Tenarad administrations. Further studies are planned to define the most effective schedule for this type of RIT in HL patients.

Active targeting by means of drug encapsulated nanoparticles decorated with targeting bioactive moieties represents the next frontier in drug delivery; it reduces drug side effects and increases the therapeutic index. Peptides, based on their chemical and biological properties, could have a prevalent role to direct drug encapsulated nanoparticles, such as liposomes, micelles, or hard nanoparticles, toward the tumor tissues. A considerable number of molecular targets for peptides are either exclusively expressed or overexpressed on both cancer vasculature and cancer cells. They can be classified into three wide categories: integrins; growth factor receptors (GFRs); and G-protein coupled receptors (GPCRs). Therapeutic agents based on nanovectors decorated with peptides targeting membrane receptors belonging to the GPCR family overexpressed by cancer cells are reviewed in this article. The most studied targeting membrane receptors are considered: somatostatin receptors; cholecystokinin receptors; receptors associated with the Bombesin like peptides family; luteinizing hormone-releasing hormone receptors; and neurotensin receptors. Nanovectors of different sizes and shapes (micelles, liposomes, or hard nanoparticles) loaded with doxorubicin or other cytotoxic drugs and externally functionalized with natural or synthetic peptides are able to target the overexpressed receptors and are described based on their formulation and in vitro and in vivo behaviors.

Purpose: To assess the incidence of nonmajor lymphatic basin sentinel nodes in patients with cutaneous melanoma in order to propose a correct nomenclature and inform appropriate surgical management., Methods: This was a retrospective review of 1,045 consecutive patients with cutaneous melanoma who underwent sentinel lymph node biopsy and dynamic lymphoscintigraphy to identify sentinel node site. Nonmajor drainage sites were classified as uncommon (located in a minor lymphatic basin along the lymphatic drainage to a major classical nodal basin) or interval (located anywhere along the lymphatics between the primary tumor site and the nearest lymphatic basin) sentinel nodes., Results: Nonclassical sentinel nodes were identified in 32 patients (3.0 %). Uncommon sentinel nodes were identified in 3.2 % (n = 17) of trunk melanoma primary disease and in 1.5 % (n = 7) of upper and lower extremity sites. Interval sentinel nodes were identified in 1.3 % (n = 7) of trunk primary lesions, with none from upper and lower extremities melanomas. The incidence of tumor-positive sentinel nodes was 24.1 % (245 of 1,013) in classical sites and 12.5 % (4 of 32) in uncommon/interval sites., Conclusions: The definition of uncommon and interval sentinel nodes allows the identification of different lymphatic pathways and inform appropriate surgical treatment. Wider experience with uncommon/interval sentinel nodes will better clarify the clinical implications and surgical management to be adopted in the management of uncommon and interval sentinel node sites.

Unlabelled: Markers predictive of treatment effect might be useful to improve the treatment of patients with metastatic solid tumors. Particularly, early changes in tumor metabolism measured by PET/CT with (18)F-FDG could predict the efficacy of treatment better than standard dimensional Response Evaluation Criteria In Solid Tumors (RECIST) response., Methods: We performed PET/CT evaluation before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase 2 trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum standardized uptake value (SUV) and the total lesion glycolysis (TLG) were determined. On the basis of previous studies, a ≤ -50% change from baseline was used as a threshold for significant metabolic response for maximum SUV and, exploratively, for TLG. Standard RECIST response was assessed with CT after 3 mo of treatment. Pathologic response was assessed in patients undergoing resection. The association between metabolic and CT/RECIST and pathologic response was tested with the McNemar test; the ability to predict progression-free survival (PFS) and overall survival (OS) was tested with the Log-rank test and a multivariable Cox model., Results: Thirty-three patients were analyzed. After treatment, there was a notable decrease of all the parameters measured by PET/CT. Early metabolic PET/CT response (either SUV- or TLG-based) had a stronger, independent and statistically significant predictive value for PFS and OS than both CT/RECIST and pathologic response at multivariate analysis, although with different degrees of statistical significance. The predictive value of CT/RECIST response was not significant at multivariate analysis., Conclusion: PET/CT response was significantly predictive of long-term outcomes during preoperative treatment of patients with liver metastases from colorectal cancer, and its predictive ability was higher than that of CT/RECIST response after 3 mo of treatment. Such findings need to be confirmed by larger prospective trials.

In humans, glucocorticoid excess may cause neuropsychiatric symptoms, including psychosis and cognitive impairment, and glucocorticoid signaling hyperactivation may sensitize to substance of abuse. The aim of this work was to evaluate whether exposure to glucocorticoid excess triggers molecular changes in dopaminergic and opioidergic systems within relevant forebrain areas. We acutely exposed Sprague-Dawley rats to dexamethasone, a glucocorticoid analog, or vehicle and evaluated the mRNA expression of dopamine D1 and D2 receptors and enkephalin within the cortex, the striatum, and the midbrain. Dexamethasone reduced mRNA expression of D1 receptor and enkephalin in the cortex. In the striatum, dexamethasone reduced the expression of D1 receptor mRNA, but not that of D2 receptor and enkephalin. No significant changes in D2 receptor mRNA expression were observed in the midbrain. Basal distribution of D1 and D2 receptor mRNA showed a clear-cut striatal/cortical gradient, while this distribution was less obvious for enkephalin mRNA. Dexamethasone increased the cortico-striatal separation in terms of D1 and D2 receptor mRNA expression. These molecular changes may represent adaptive mechanisms to dexamethasone-induced potentiation of dopaminergic and opioidergic transmission, mostly in cortical areas.

With optimized local treatment, achieved in the last years by TME surgery and the shift from a postoperative to a preoperative treatment approach, distant metastases have become the predominant mode of failure in rectal cancer. Therefore, the intensification of chemotherapy seems essential to improve distant control and survival in rectal cancer. The integration of newer generation chemotherapeutics and target agents into fluoropyrimidines-based chemoradiotherapy (CRT) has been the more actively pursued intensification strategy. However, early results from randomized phase III trials, evaluating the addition of oxaliplatin to preoperative fluoropyrimidines-based CRT, did not show a significant impact on early pathological response with the addition of oxaliplatin, with the exception of the German CAO/ARO/AIO-04 study. Moreover, the integration of target agents into preoperative CRT, although attractive in principle, has yielded low rates of pathologic complete responses when combined with cetuximab and some concerns on surgical morbidity following preoperative treatment with bevacizumab have been raised. Several novel strategies with different sequence of multimodal treatment components have been developed. However, the evidence that rectal cancers are a widely heterogeneous group of tumors with different prognostic implications, has indicated that the careful assessment of the risk of recurrence is a critical issue. In the era of the preoperative approach, staging with MRI, for its ability to predict the involvement of the mesorectal fascia, should be mandatory for all patients with rectal cancer, to refine the selection of patients for different treatment strategies. Moreover, considering that response to preoperative treatment is not uniformly obtained in all patients and post-operative chemotherapy is generally met with poor adherence, a risk-adapted strategy should be pursued in the postoperative setting as well. The selection of patients for different multidisciplinary treatment strategies based on clinico-pathological features, rather than the current "one size fits all" approach, will allow minimizing therapy and maximizing outcome for rectal cancer patients.

Background: Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting., Methods: Patients aged 18-75 years, PS 0-1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg(-1) followed by irinotecan 180 mg m(-)(2), leucovorin 200 mg m(-)(2), 5-fluorouracil 400 mg m(-)(2) bolus and 5-fluorouracil 2400 mg m(-)(2) 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required., Results: From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8-80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6-76.6). Median PFS and OS were 14 (95% CI: 11-24) and 38 (95% CI: 28-NA) months, respectively., Conclusion: Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.

Purpose: This study addresses novel peptide modified liposomal doxorubicin to specifically target tissues overexpressing bombesin (BN) receptors., Methods: DOTA-(AEEA) 2 -peptides containing the [7-14]bombesin and the new BN-AA1 sequence have been synthesized to compare their binding properties and in serum stabilities. The amphiphilic peptide derivative (MonY-BN-AA1) containing BN-AA1, a hydrophobic moiety, polyethylenglycole (PEG), and diethylenetriaminepentaacetate (DTPA), has been synthesized. Liposomes have been obtained by mixing of MonY-BN-AA1 with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)., Results: Both 111 In labeled peptide derivatives present nanomolar Kd to PC-3 cells. 177 Lu labeled peptide DOTA-(AEEA) 2 -BN-AA1 is very stable (half-life 414.1 h), while DOTA-(AEEA) 2 -BN, shows a half-life of 15.5 h. In vivo studies on the therapeutic efficacy of DSPC/MonY-BN-AA1/Dox in comparison to DSPC/MonY-BN/Dox, were performed in PC-3 xenograft bearing mice. Both formulations showed similar tumor growth inhibition (TGI) compared to control animals treated with non-targeted DSPC/Dox liposomes or saline solution. For DSPC/MonY-BN-AA1/Dox the maximum effect was observed 19 days after treatment., Conclusions: DSPC/MonY-BN-AA1/Dox nanovectors confirm the ability to selectively target and provide therapeutic efficacy in mice. The lack of receptor activation and possible acute biological side effects provided by using the AA1 antagonist bombesin sequence should provide safe working conditions for further development of this class of drug delivery vehicles.

Purpose: The aim of the present study is to prospectively evaluate the prognostic value of previously defined [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) criteria of early metabolic response in patients with locally advanced rectal cancer (LARC) after long-term follow-up., Methods: Forty-two patients with poor prognosis LARC underwent three biweekly courses of chemotherapy with oxaliplatin, raltitrexed and 5-fluorouracil modulated by levofolinic acid during pelvic radiotherapy. FDG PET studies were performed before and 12 days after the beginning of the chemoradiotherapy (CRT) treatment. Total mesorectal excision (TME) was carried out 8 weeks after completion of CRT. A previously identified cutoff value of ≥52 % reduction of the baseline mean FDG standardized uptake value (SUV(mean)) was applied to differentiate metabolic responders from non-responders and correlated to tumour regression grade (TRG) and survival., Results: Twenty-two metabolic responders showed complete (TRG1) or subtotal tumour regression (TRG2) and demonstrated a statistically significantly higher 5-year relapse-free survival (RFS) compared with the 20 non-responders (86 vs 55 %, p = .014) who showed TRG3 and TRG4 pathologic responses. A multivariate analysis demonstrated that early ∆SUV(mean) was the only pre-surgical parameter correlated to the likelihood of recurrence (p = .05)., Conclusion: This study is the first prospective long-term evaluation demonstrating that FDG PET is not only an early predictor of pathologic response but is also a valuable prognostic tool. Our results indicate the potential of FDG PET for optimizing multidisciplinary management of patients with LARC.

Psychosis has been associated with glucose metabolism impairment. Here, we explored the gene expression of hexokinase 1 (Hk1) and glucose transporter 3 (GLUT3) after the administration of a subanesthetic or a subconvulsant dose of ketamine in rats, considered to provide an animal model of psychosis. Indeed, Hk1 and GLUT3 are crucially involved in the glucose utilization in brain tissues and have also been implicated in the pathophysiology of psychosis. Quantitative brain imaging of transcripts was used to evaluate Hk1 and GLUT3 mRNA in rat brain regions related to ketamine-induced behavioral abnormalities. Hk1 transcript was significantly increased by 50 mg/kg ketamine in cortical and subcortical areas, whereas 12 mg/kg ketamine affected Hk1 expression in the auditory cortex only. GLUT3 expression was increased by 12 mg/kg ketamine in the frontal cortex and decreased by 50 mg/kg ketamine in subcortical areas. The results show that Hk1 and GLUT3 are extensively and differentially affected by ketamine dose, supporting the view that glucose metabolism and psychosis may be causally related and suggesting that these molecules may play a role in the pathophysiology of ketamine-induced behavioral abnormalities., (Copyright © 2012 Wiley Periodicals, Inc.)

Prostate cancer is the most commonly diagnosed malignancy in men in developed countries. ErbB2, a tyrosine kinase receptor overexpressed in many human cancer types, contributes to prostate cancer progression by activating the androgen receptor in a steroid poor environment, thus promoting androgen-independent cell growth. The consequent development of hormone refractory tumors is a major obstacle in prostate cancer therapy. The inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable alternative strategy for cancer therapy. We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4. Thus, Erb-hcAb could be a promising candidate in the immunotherapy of prostate cancer for which no obvious treatment has been reported so far.

Background: Approximately 200,000 new cases of melanoma are diagnosed worldwide each year. Skin metastases are a frequent event, occurring in 18.2% of cases. This can be distressing for the patient, as the number and size of cutaneous lesions increases, often worsened by ulceration, bleeding and pain. Electrochemotherapy (ECT) is a local modality for the treatment of cutaneous or subcutaneous tumors that allows delivery of low- and non-permeant drugs into cells. ECT has been used in palliative management of metastatic melanoma to improve patients' quality of life. This is, to our knowledge, the first application of ECT as neoadjuvant treatment of metastatic subcutaneous melanoma., Methods and Results: A 44-year-old Caucasian woman underwent extensive surgical resection of a melanoma, with a Breslow thickness of 1.5 mm, located on the right side of her scalp. No further treatment was given and the woman remained well until she came to our attention with a large nodule in her right cheek. Whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed for staging and treatment monitoring. Baseline FDG PET/CT showed the lesion in the cheek to have a maximal standardized uptake value (SUVmax) of 19.5 with no evidence of further disease spread. Fine needle aspiration cytology confirmed the presence of metastatic melanoma. The patient underwent two sessions of ECT with intravenous injections of bleomycin using a CliniporatorTM as neoadjuvant treatment permitting conservative surgery three months later.Follow-up PET/CT three months after the first ECT treatment showed a marked decrease in SUVmax to 5. Further monitoring was performed through monthly PET/CT studies. Multiple cytology examinations showed necrotic tissue. Conservative surgery was carried out three months after the second ECT. Reconstruction was easily achieved through a rotation flap. Pathological examination of the specimen showed necrotic tissue without residual melanoma. One year after the last ECT treatment, the patient was disease-free as determined by contrast-enhanced CT and PET/-CT scans with a good functional and aesthetic result., Conclusions: ECT represents a safe and effective therapeutic approach that is associated with clear benefits in terms of quality of life (minimal discomfort, mild post-treatment pain and short duration of hospital stay) and may, in the neoadjuvant setting as reported here, offer the option of more conservative surgery and an improved cosmetic effect with complete local tumor control.