Doxorubicin effect on myocardial metabolism: a translational 18F-FDG PET/CT approach

Systemic chemotherapy is the primary treatment for much diffuse solid neoplasms or hematological malignancies. One of its most significant drawbacks is the high incidence of side effects. Starting 30 years after treatment, the cumulative mortality from therapy-related medical illness exceeds the one from cancer recurrence. Besides secondary neoplasia, one of the most severe long-term complications is represented by cardiotoxicity that can significantly impact life expectancy, particularly in younger patients. One of the most acknowledged models of cardiotoxicity is represented by doxorubicin (DXR)-induced cardiomyopathy. Despite an extensive research effort, the mechanisms underlying this dose-dependent complication have not been fully elucidated, although a significant role has been proposed for oxidative stress. Together with the late onset of heart failure symptoms, this relative uncertainty prevents the availability of reliable methods to predict the risk of developing contractile dysfunction. In this line, several studies reported that myocardial uptake of the glucose analog 18F-fluorodeoxyglucose (FDG) increases during and after DXR administration. Similarly, GLUT-1 and GLUT-4 expression have been found to increase in a dose-dependent fashion, in neonatal rat ventricular cells exposed to DXR. Altogether, these observations seem to suggest that DXR might increase myocardial glucose consumption. However, an accelerated glycolytic flux in left ventricular myocardium has been usually reported during ischemia as a result of the impairment in oxidative phosphorylation and the consequent increase in the NADH cytosol level. By contrast, the increased expression of glucose carriers under DXR face a simultaneous evident oxidative damage to cardiomyocyte sarcolemma. On the other hand, we recently documented that FDG uptake in cancer cells is relatively independent of overall glucose consumption and selectively tracks the activity of a glucose-processing machine located within the endoplasmic reticulum and triggered by the autosomic enzyme hexose-6P-dehydrogenase (H6PD). The potential interest of this pathway is related to the observation that H6PD silencing, besides reducing FDG uptake, also caused a profound fall in the crucial cofactor for redox control NADPH. Whether confirmed to non-cancer cells, this finding might imply that FDG is a marker of cell\u2019s anti-oxidative stress competency. Based on these considerations, the present Ph.D. project aimed to: 1. Characterize the direct redox and metabolic effect of Doxorubicin in cardiomyocytes. 2. Characterize the DXR cardiotoxic effect in experimental animals. 3. Characterize the DXR cardiotoxic impact on cancer patients. Obtained results showed that FDG PET/CT might represent an early predictor of subsequent cardiotoxicity in cancer patients treated with DXR. Moreover, the application of PET/CT may also extend beyond the mere cardiotoxicity identification providing mechanistic insight on the cardiotoxic pathophysiology. Indeed, this tool further enriched the current knowledge on energy metabolism impairment in the DXR-induced cardiotoxic cascade

Is There a Role of Interim PSMA PET in Chemotherapy of Prostate Cancer?

While RECIST 1.1 is well established in radiological response assessment, it is of limited use in prostate cancer (PCa) considering that the disease is often seen only as sclerotic bone changes on conventional imaging. Therefore, a molecular imaging-based response assessment including bone scans has been proposed and used in clinical trials, however, due to the flare phenomenon on bone scans this assessment leads to substantial delays in the detection of progression. Indeed, a robust and reliable imaging tool to assess response to chemotherapy in PCa is still warranted. Whether Positron Emission Tomography (PET) targeting the Prostate-Specific Membrane Antigen (PSMA) could achieve this, is still controversial. In this review, we summarized the available data on cytotoxic agents and their impact on PSMA expression, as well as the available data on PSMA PET imaging for response assessment

Sex differences in neuroimaging biomarkers in healthy subjects and dementia

Several studies have investigated sex differences in morphological and functional neuroimaging in healthy conditions, but few data are available on the specific effect of sex on neuroimaging in dementia and related disorders. Sex is more often considered as a confounding variable than as a variable of interest. Furthermore, especially in the dementia field, the data are drawn from studies designed for other specific aims, and discrepant results are often found due to different equipment, studied cohorts, and analytical methods. Notably, investigating this aspect would be pivotal to better understand how age-related diseases, such as dementia, differentially impact on the main correlates of brain functions in males and females. We review some of the main findings of the literature, highlighting the need for a more systematic appraisal of sex and even gender differences in future neuroimaging studies

Comparative diagnostic accuracy of 18F-FDG PET/CT for breast cancer recurrence

In the last decades, in addition to conventional imaging techniques and magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has been shown to be relevant in the detection and management of breast cancer recurrence in doubtful cases in selected groups of patients. While there are no conclusive data indicating that imaging tests, including FDG PET/CT, produce a survival benefit in asymptomatic patients, FDG PET/CT can be useful for identifying the site of relapse when traditional imaging methods are equivocal or conflicting and for identifying or confirming isolated loco-regional relapse or isolated metastatic lesions. The present narrative review deals with the potential role of FDG PET in these clinical settings by comparing its accuracy and impact with conventional imaging modalities such as CT, ultrasound, bone scan, 18F-sodium fluoride PET/CT (18F-NaF PET/CT) as well as MRI. Patient-focused perspectives in terms of patients\ue2\u80\u99 satisfaction and acceptability are also discussed

A Score-Based Approach to 18F-FDG PET Images as a Tool to Describe Metabolic Predictors of Myocardial Doxorubicin Susceptibility

Purpose: To verify the capability of 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to identify patients at higher risk of developing doxorubicin (DXR)-induced cardiotoxicity, using a score-based image approach. Methods: 36 patients underwent FDG-PET/CT. These patients had shown full remission after DXR-based chemotherapy for Hodgkin\u2019s disease (DXR dose: 40\u201350 mg/m2 per cycle), and were retrospectively enrolled. Inclusion criteria implied the presence of both pre- and post-chemotherapy clinical evaluation encompassing electrocardiogram (ECG) and echocardiography. Myocardial metabolism at pre-therapy PET was evaluated according to both standardized uptake value (SUV)- and score-based approaches. The capability of the score-based image assessment to predict the occurrence of cardiac toxicity with respect to SUV measurement was then evaluated. Results: In contrast to the SUV-based approach, the five-point scale method does not linearly stratify the risk of the subsequent development of cardiotoxicity. However, converting the five-points scale to a dichotomic evaluation (low vs. high myocardial metabolism), FDG-PET/CT showed high diagnostic accuracy in the prediction of cardiac toxicity (specificity = 100% and sensitivity = 83.3%). In patients showing high myocardial uptake at baseline, in which the score-based method is not able to definitively exclude the occurrence of cardiac toxicity, myocardial SUV mean quantification is able to further stratify the risk between low and intermediate risk classes. Conclusions: the score-based approach to FDG-PET/CT images is a feasible method for predicting DXR-induced cardiotoxicity. This method might improve the inter-reader and inter-scanner variability, thus allowing the evaluation of FDG-PET/CT images in a multicentral setting

Can We Predict Skeletal Lesion on Bone Scan Based on Quantitative PSMA PET/CT Features?

Objective: The increasing use of PSMA-PET/CT for restaging prostate cancer (PCa) leads to a patient shift from a non-metastatic situation based on conventional imaging (CI) to a metastatic situation. Since established therapeutic pathways have been designed according to CI, it is unclear how this should be translated to the PSMA-PET/CT results. This study aimed to investigate whether PSMA-PET/CT and clinical parameters could predict the visibility of PSMA-positive lesions on a bone scan (BS). Methods: In four different centers, all PCa patients with BS and PSMA-PET/CT within 6 months without any change in therapy or significant disease progression were retrospectively selected. Up to 10 non-confluent clear bone metastases were selected per PSMA-PET/CT and SUVmax, SUVmean, PSMAtot, PSMAvol, density, diameter on CT, and presence of cortical erosion were collected. Clinical variables (age, PSA, Gleason Score) were also considered. Two experienced double-board physicians decided whether a bone metastasis was visible on the BS, with a consensus readout for discordant findings. For predictive performance, a random forest was fit on all available predictors, and its accuracy was assessed using 10-fold cross-validation performed 10 times. Results: A total of 43 patients were identified with 222 bone lesions on PSMA-PET/CT. A total of 129 (58.1%) lesions were visible on the BS. In the univariate analysis, all PSMA-PET/CT parameters were significantly associated with the visibility on the BS (p < 0.001). The random forest reached a mean accuracy of 77.6% in a 10-fold cross-validation. Conclusions: These preliminary results indicate that there might be a way to predict the BS results based on PSMA-PET/CT, potentially improving the comparability between both examinations and supporting decisions for therapy selection

Assessment of skeletal tumor load in metastasized castration-resistant prostate cancer patients: A review of available methods and an overview on future perspectives

Metastasized castration-resistant prostate cancer (mCRPC), is the most advanced form of prostate neoplasia, where massive spread to the skeletal tissue is frequent. Patients with this condition are benefiting from an increasing number of treatment options. However, assessing tumor response in patients with multiple localizations might be challenging. For this reason, many computational approaches have been developed in the last decades to quantify the skeletal tumor burden and treatment response. In this review, we analyzed the progressive development and diffusion of such approaches. A computerized literature search of the PubMed/Medline was conducted, including articles between January 2008 and March 2018. The search was expanded by manually reviewing the reference list of the chosen articles. Thirty-five studies were identified. The number of eligible studies greatly increased over time. Studies could be categorized in the following categories: automated analysis of 2D scans, SUV-based thresholding, hybrid CT-and SUV-based thresholding, and MRI-based thresholding. All methods are discussed in detail. Automated analysis of bone tumor burden in mCRPC is a growing field of research; when choosing the appropriate method of analysis, it is important to consider the possible advantages as well as the limitations thoroughly

Metabolic and densitometric correlation between atherosclerotic plaque and trabecular bone: an 18F-Natrium-Fluoride PET/CT study

Increasing evidence links atherosclerosis to a decreased bone thickness. This correlation could reflect a bone/plaque interaction. Hereby we analyzed Hounsfield density (HU) and mineral turnover in bone and in the arterial calcifications (AC), using a computational method applied to PET/CT data. 79 18F-NaF PET/CT from patients with AC were retrospectively analyzed. Mean AC density and background-corrected uptake (TBR) were estimated after semi-automatic isocontour segmentation. The same values were assessed in the trabecular bone, using an automatic adaptive thresholding method. Patients were then stratified into terciles, according to their mean HU plaque density ("light", "medium" or "heavy" calcifications"). 35 18F-NaF PET/CT from patients without AC served as controls. Vertebral density and TBR were lower in patients than in controls (137\ub125 vs. 160\ub114 HU, P&lt;0.001); (6.2\ub13.9 vs. 8.4\ub13.4, P&lt;0.05). Mean trabecular TBR values were 8.3\ub14, 4.5\ub12.1 and 3.5\ub11.8 in light, medium and heavy AC groups, respectively (P&lt;0.05 for light vs. medium and P&lt;0.01 for light vs. heavy). Similarly, mean trabecular HU was 143\ub119, 127\ub126 and 119\ub118 in the three groups, respectively (P&lt;0.01 for light vs. heavy). Mean AC density was inversely associated with the trabecular HU (R=-0.56, P&lt;0.01). Conversely, plaques' TBR directly correlated with the one in trabecular bone (R=0.63, P&lt;0.001). At multivariate analysis, the sole predictor of vertebral density was plaque HU (P&lt;0.05). Our data highlight a correlation between plaque and bone morpho-functional parameters and suggest that observing skeletal bone characteristics could represent a novel window on atherosclerosis pathophysiology

The role of PSMA-based radioligand therapy in hormone-sensitive prostate cancer

PURPOSE Conventional systemic therapies are valuable options in prostate cancer (PCa); however, such treatments can determine adverse events and toxicity. The observed improvement in overall survival, coupled with PSA reduction and a favorable safety profile in the post-taxane castration-resistant PCa (CRPC) setting has prompted the consideration of PSMA-based radioligand therapy (RLT) earlier in the treatment sequence. In this review, we will describe the literature and ongoing clinical trials regarding the use of PSMA-based RLT in hormone-sensitive PCa (HSPC) including the neoadjuvant, de-novo/synchronous metastatic, adjuvant, and early BCR settings. METHODS We performed a systematic literature search on the PubMed/MEDLINE/EMBASE and clinicaltrials.gov databases for studies and protocols assessing the role of PSMA-based RLT in HSPC. RESULTS The literature search yielded 140 results. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 25 papers showing the potentialities of earlier RLT in HSPC, with several ongoing trials. CONCLUSION Early use of PSMA-based RLT holds significant potential in HSPC patients from the neoadjuvant to the BCR setting. In these stages, the lower tumor burden, more frequent exclusive nodal involvement, and higher organ reserve may improve treatment efficacy and allow for treatment combinations while maintaining a less toxic profile

Personalised PET imaging in oncology:an umbrella review of meta-analyses to guide the appropriate radiopharmaceutical choice and indication

PurposeFor several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies.MethodsWe performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [18F]FDG, somatostatin- receptor-targeting 68Ga-DOTA-peptides, 18F-labelled dihydroxyphenylalanine ([18F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours.ResultsThe literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [18F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [68Ga]Ga- DOTA-TOC and -TATE) or [18F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers.ConclusionThe comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations