PSMA PET/CT in Castration-Resistant Prostate Cancer: Myth or Reality?

BACKGROUND: prostate-specific membrane antigen (PSMA) ligand PET has been recently incorporated into international guidelines for several different indications in prostate cancer (PCa) patients. However, there are still some open questions regarding the role of PSMA ligand PET in castration-resistant prostate cancer (CRPC). The aim of this work is to assess the clinical value of PSMA ligand PET/CT in patients with CRPC. RESULTS: PSMA ligand PET has demonstrated higher detection rates in comparison to conventional imaging and allows for a significant reduction in the number of M0 CRPC patients. However, its real impact on patients' prognosis is still an open question. Moreover, in CRPC patients, PSMA ligand PET presents some sensitivity and specificity limitations. Due to its heterogeneity, CRPC may present a mosaic of neoplastic clones, some of which could be PSMA-/FDG+, or vice versa. Likewise, unspecific bone uptake (UBU) and second primary neoplasms (SNPs) overexpressing PSMA in the neoangiogenic vessels represent potential specificity issues. Integrated multi-tracer imaging (PSMA ligand and [18F]FDG PET) together with a multidisciplinary discussion could allow for reaching the most accurate evaluation of each patient from a precision medicine point of view.

Molecular imaging of PARP in cancer: state-of-the-art.

INTRODUCTION: Poly-ADP-ribose-polymerase inhibitors (PARPi), which exploit the processes of so-called 'synthetic lethality,' have been successfully implemented in oncological practice. However, not all patients respond to PARPi, and there is an unmet need for noninvasive biomarkers suitable for patient selection and monitoring during PARPi therapy. AREAS COVERED: The first clinical applications of molecular imaging with positron emission tomography/computed tomography (PET/CT) with [18F]-FluorThanatrace ([18F]-FTT) and [18F]-PARPi, highly effective PARP-ligands, in patients with several malignancies (head and neck, ovarian, prostate, and breast cancer) are covered, with a particular focus on its potential for pre-treatment selection and follow-up. EXPERT OPINION: By a search made on the most common database, such as PubMed and Google Scholar in a period from January 2010 and 2023, first clinical evidence suggests that PET/CT with [18F]-FTT and [18F]-PARPi might represent a reliable tool for in vivo imaging and quantification of PARP-1 expression in ovarian, prostate, breast, head, and neck cancer, supporting their potential usefulness for patient selection before PARPi-therapies. In addition, a reduction in [18F]-FTT uptake has been registered after therapy initiation and seems to be correlated with patient outcome after PARPi-based regimens. Further studies are needed to better address the value of PARPI-radiolabeled PET imaging in these clinical settings, especially as it concerns technical features such as optimal scan modality (dynamic vs. static) and timing.

Comparison of MRI vs. [18F]FDG PET/CT for Treatment Response Evaluation of Primary Breast Cancer after Neoadjuvant Chemotherapy: Literature Review and Future Perspectives.

The purpose of this systematic review was to investigate the diagnostic accuracy of [18F]FDG PET/CT and breast MRI for primary breast cancer (BC) response assessment after neoadjuvant chemotherapy (NAC) and to evaluate future perspectives in this setting. We performed a critical review using three bibliographic databases (i.e., PubMed, Scopus, and Web of Science) for articles published up to the 6 June 2023, starting from 2012. The Quality Assessment of Diagnosis Accuracy Study (QUADAS-2) tool was adopted to evaluate the risk of bias. A total of 76 studies were identified and screened, while 14 articles were included in our systematic review after a full-text assessment. The total number of patients included was 842. Eight out of fourteen studies (57.1%) were prospective, while all except one study were conducted in a single center. In the majority of the included studies (71.4%), 3.0 Tesla (T) MRI scans were adopted. Three out of fourteen studies (21.4%) used both 1.5 and 3.0 T MRI and only two used 1.5 T. [18F]FDG was the radiotracer used in every study included. All patients accepted surgical treatment after NAC and each study used pathological complete response (pCR) as the reference standard. Some of the studies have demonstrated the superiority of [18F]FDG PET/CT, while others proved that MRI was superior to PET/CT. Recent studies indicate that PET/CT has a better specificity, while MRI has a superior sensitivity for assessing pCR in BC patients after NAC. The complementary value of the combined use of these modalities represents probably the most important tool to improve diagnostic performance in this setting. Overall, larger prospective studies, possibly randomized, are needed, hopefully evaluating PET/MR and allowing for new tools, such as radiomic parameters, to find a proper place in the setting of BC patients undergoing NAC.

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still "Lutathera orphans", and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the "Response Assessment in Neuro-Oncology" (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone.

Radiomics and theranostics with molecular and metabolic probes in prostate cancer: toward a personalized approach.

INTRODUCTION: In the last decade, two new radionuclide-based therapies, 223Radichloride and radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA), have been approved by the regulatory authorities for the management of castrate-resistant prostate cancer (PCa). AREAS COVERED: The basic principles of PCa molecular imaging are illustrated, with a particular attention to the combined use of diagnosis and therapy in a unique approach (the so-called theranostics) for response prediction and assessment in patients submitted to 223Radichloride or PSMA targeted therapies. In this perspective, the potential of radiomics, an emerging discipline based on the extraction of quantitative features from medical images, is covered. EXPERT OPINION: Theranostic metabolic and molecular probes have been successfully applied to predict and monitor response to radionuclide-based therapies. In particular, both 99mTc-MDP and 18F-NaF resulted useful tools for personalized dosimetry and prognostic stratification before 223Ra-therapy, while PSMA-ligands, alone or in combination with 18F-FDG, provided valuable information to select patients who are more likely to benefit from RLT and getting information on PCa grade of differentiation and aggressiveness. In spite of its high potential, PET-radiomics for PCa is still at an embryonic phase and needs further validation.

Cavernous Hepatic Hemangioma at 18F-Choline Positron Emission Tomography-Computed Tomography: Be Aware of the Pitfall.

We report a case of a patient performing a positron emission tomography-computed tomography (PET-CT) scan with [18F]F-Choline for biochemical relapse (Prostate specific antigen (PSA) 1.2 ng/ml) of prostate cancer. Two large areas of focal uptake with a cold core within the liver were observed. A contrast-enhanced ultrasound scan performed after the PET scan characterized these lesions as cavernous hepatic hemangiomas, and therefore, a biopsy was not performed; 3 years of follow-up and PET and MRI finding stability confirmed the benignity of their nature.

Dosimetric optimization of nuclear medicine therapy based on the Council Directive 2013/59/EURATOM and the Italian law N. 101/2020. Position paper and recommendations by the Italian National Associations of Medical Physics (AIFM) and Nuclear Medicine (AIMN).

This recommendation by the Italian Associations of Nuclear Medicine (AIMN) and Medical Physics (AIFM) focuses on the dosimetric optimization of Nuclear Medicine Therapy (NMT) as clearly requested by the article 56 of the EURATOM Directive 2013/59 and its consequent implementation in article 158 in the Italian Law n. 101/2020. However, this statement must deal with scientific and methodological limits that still exist and, above all, with the currently available limited resources. This paper addresses these specific issues. It distinguishes among many possible kinds of NMT. For each type, dosimetric optimization is recommended or considered optional, according to the general criteria adopted in any human choice, i.e. a check of technical feasibility first, followed by a cost/benefit argument. The classification of therapies as standardized or non-standardized is presented. This is based on the complexity of the type of pathology, on the variability of the treatment outcome, and on the risks involved. According to the present document, which was officially delivered to Italian Health Ministry as necessary interpretation of the law, a therapeutic team can, in science and consciousness, overcome the indications of posology, to optimize and tailoring a treatment with dosimetry, on the basis of published national or international data or guidelines, without need of an Ethics Committee approval. Data collected in this way will provide additional evidence about optimal dosimetric reference values. As conclusion, a formal appeal is made to the European and National regulatory agencies for pharmaceuticals to obtain the official acknowledgment of this principle.

Reorganization of a Nuclear Medicine Department in Northern Italy During a 2-Month Lockdown for COVID-19 Pandemic.

Coronavirus disease (COVID-19) outbreak has profoundly changed the organization of hospital activities. We present our experience of reorganization of a nuclear medicine service settled in Northern Italy during the pandemic period of March and April 2020 characterized a government-mandated lockdown. Our service remained open during the whole period, performing approximately 80% of the routine practice, while maintaining it COVID-free despite the geographical context characterized by a high risk of infection. Reorganization involved all aspects of a nuclear medicine department, following local, national, and international guidelines for prioritizing patients, telephone and physical triages, deployment of appropriate personal protective equipment, social distancing, and logistic changes for scheduling examinations and disinfection procedures. All staff remained COVID-19-negative despite the unintentional admission of 4 patients who later turned out to be positive for the severe acute respiratory syndrome coronavirus 2. These adopted measures would serve as the basis for safe nuclear medicine services in the post-lockdown phase.

A new mobile self-dispensing and administering system for 18F-FDG: evaluation of operator dose reduction.

PURPOSE: Recently new mobile systems for dispensing positron emitters have been produced, designed to guarantee dispensing cycles in an aseptic environment. The aim of the present work was to assess the advantage of one of these systems in radiation protection of operators in clinical settings. METHODS: Recently, in our centre the new self-dispensing system named KARL100 by Tema Sinergie was adopted for 18F-FDG radiopharmaceuticals. The system is associated with an automatic Rad-inject infuser. The system that was previously used was a fixed isolator NMC DSI (Tema Sinergie), equipped with a µDDS-An activity fractioning system, together with a pneumatic post for the syringe delivery. The dosimetric evaluations on both systems were carried out through environmental measurements with an ionisation chamber and with the use of personal dosimeters. RESULTS: The operations of preparation and administration of 18F-FDG dose to the patient, with the use of Karl100 + RadInject, involve exposures much lower than those obtained by the fixed isolator. The average body exposure of the technician was reduced by 31%, and for the physician by 77%. On the extremities, the equivalent dose to the hands of the technician was reduced by 78%, and for the physician by 96%. Also the additional dosimeters worn by the technician confirmed the estimated environmental assessments. CONCLUSIONS: The exposures of the working personnel were significantly reduced with the introduction of the new KARL100 system.

How to harmonize SUVs obtained by hybrid PET/CT scanners with and without point spread function correction.

State of the art point-spread function (PSF) corrections implemented in positron emission tomography/computed tomography (PET/CT) reconstruction improved image quality and diagnostic performance but caused an increase in the standardized uptake value (SUV) compared to a conventional OSEM reconstruction system. The EANM suggested one produce two reconstructions, one optimised for maximum lesion detection and one for semi-quantitative analysis. In this work we investigated an alternative methodology, using a single reconstruction data set together with a post-reconstruction algorithm for SUV harmonization. Data acquisition was performed on a Siemens Biograph mCT system equipped with lutetium oxyorthosilicat crystals, PSF and time-of-flight algorithms and on a General Electric Discovery STE system equipped with BGO crystals. Both a EANM double reconstruction method and a dedicated post-reconstruction algorithm (marketed as EQ-filter) were tested to harmonize the quantitative values of the two PET/CT scanners. For phantom measurements we used a NEMA IQ phantom and a Jaszczak cylindrical phantom equipped with small spheres (lesion to background ratios of 8:1 and 4:1). Several different reconstruction settings were tested in order to provide a general methodology. Data obtained by phantom measurements were validated on seven oncologic patients who performed a one-bed extra acquisition on a different scanner. The evaluation regarded 39 small lesions (diameters: 0.3-2.6 cm) and was performed by two experienced nuclear medicine physicians. The SUV recoveries measured with the PSF reconstruction exceeded those obtained by the OSEM reconstruction with deviations ranging from 16% to 150%. These discrepancies resulted below 7% applying the optimized value of the EQ.filter or the double-reconstruction methods. For each reconstruction setting the optimal value of the EQ.filter was identified in order to minimize these discrepancies. Patient data, analyzed by Wilcoxon statistical test, confirmed and validated phantom measurements. EQ.filter can harmonize SUV values between different PET/CT scanners using a single reconstruction optimized to maximum lesion detectability. In this way, the second reconstruction proposed by EANM/EARL is avoided.

The Prognostic Value of 18F-FDG PET/CT in Monitoring Chemotherapy in Ovarian Cancer Both at Initial Diagnosis and at Recurrent Disease.

Published experiences related to the prognostic relevance of negative or positive FDG PET/CT in patients treated for ovarian cancer for progression-free survival and overall survival are typically heterogeneous retrospective analyses. Several points have been well defined, these are as follows: (a) there is a correlation between FDG tumor uptake and prognosis; (b) ovarian cancer patients treated by neoadjuvant or adjuvant chemotherapy can be divided into responders with reduction in tumor FDG uptake during and after treatment and nonresponders where tumor FDG uptake remains stable or increases after treatment;

Fludeoxyglucose F 18 PET/CT Assessment of Ovarian Cancer.

Ovarian cancer is one of the most common gynecologic cancers and one of the leading causes of cancer death in women. It is often asymptomatic in early stages, and thus most patients are diagnosed when it is of advanced stage. For these reasons, the role of biomarkers and tomographic imaging is crucial. Fludeoxyglucose F 18 PET/CT is a useful imaging modality in different clinical settings of the disease, overcoming some limits of conventional imaging and influencing prognosis and therapeutic approaches. PET/MR imaging is an emerging modality, and its potential role remains to be explored.

18F-FDG PET/CT of Generalized Arteritis.

A 75-year-old man presented with significant weight loss, persistent cough, single episode of frontotemporal pulsatile headache, and leg weakness. A paraneoplastic syndrome was suspected, and F-FDG PET/CT was performed. Diffuse, moderate-to-intense tracer symmetrical uptake of many large and medium arteries was unexpectedly noted. The peculiarity of this case is the extensive involvement of both large and medium head and neck and extremity vessels, whereas the aorta was relatively spared.

18F-FDG PET/CT of Brown Adipose Tissue Hyperactivation Associated With Pregnancy and Paraganglioma.

This 32-year-old woman presented with pregnancy-related arterial hypertension unresponsive to antihypertensive therapy. During cesarean delivery, a lobulated retroperitoneal mass was discovered. F-FDG PET/CT performed 18 days postpartum demonstrated the hyperactive retroperitoneal mass and extensive hyperactivated brown adipose tissue. The mass was surgically removed, revealing a para-aortic multicentric paraganglioma. After surgery, blood pressure normalized, and serum chromogranin A and urinary metanephrines normalized. Brown adipose tissue hypermetabolism disappeared on follow-up FDG PET. Her initial FDG PET demonstrated brown adipose tissue hyperactivation, which may have been caused by the combination of hormonal changes in pregnancy and the paraganglioma.

FDG PET/CT in Aortic Valve Bioprosthesis Infection.

A 62-year-old man presented with persistent fever, weakness, and retrosternal pain 3 years after aortic valve bioprosthesis (AVR). His white blood cell count was 11,000/µL and C-reactive protein was 13.6 mg/dL. Consecutive blood cultures isolated Staphylococcus epidermidis and capitis. Transesophageal echocardiography demonstrated small aortic valve prosthesis vegetation. F-FDG PET/CT revealed prominent AVR activity, SUVmax = 12.2. He was treated with daptomycin, meropenem, and gentamicin for 1 month and followed by daptomycin and carbapenem for 3 months. Follow-up F-FDG PET/CT at 6 months demonstrated complete clearing of AVR activity associated with full asymptomatic recovery.

pH-Sensitive, Long-Circulating Liposomes as an Alternative Tool to Deliver Doxorubicin into Tumors: a Feasibility Animal Study.

PURPOSE: Therapeutic agents used in chemotherapy have low specificity leading to undesired severe side effects. Hence, the development of drug delivery systems that improve drug specificity, such as liposome moieties, is an alternative to overcome chemotherapy limitations and increase antitumor efficacy. In this study, the biodistribution profile evaluation of pH-sensitive long-circulating liposomes (SpHL) containing [99mTc]DOX in 4T1 tumor-bearing BALB/c mice is described. PROCEDURES: [99mTc]DOX was radiolabeled by direct method. Liposomes were prepared and characterized. [99mTc]DOX was encapsulated into liposomes by freezing and thawing. Circulation time for SpHL-[99mTc]DOX was determined by measuring the blood activity from healthy animals. Biodistribution studies were carried out in tumor-bearing mice at 1, 4, and 24 h after injection. RESULTS: Blood levels of the SpHL-[99mTc]DOX declined in a biphasic manner, with an α half-life of 14.1 min and ß half-life of 129.0 min. High uptake was achieved in the liver and spleen, due to the macrophages captured. Moreover, tumor uptake was higher than control tissue, resulting in high tumor-to-muscle ratios, indicating higher specificity for the tumor area. CONCLUSION: [99mTc]DOX was successfully encapsulated in liposomes. Biodistribution indicated high tumor-to-muscle ratios in breast tumor-bearing BALB/c mice. In summary, these results showed the higher accumulation of SpHL-[99mTc]DOX in the tumor area, suggesting selective delivery of doxorubicin into tumor.

Sentinel Lymph Node Biopsy in Breast Cancer: Indications, Contraindications, and Controversies.

Axillary lymph node status, a major prognostic factor in early-stage breast cancer, provides information important for individualized surgical treatment. Because imaging techniques have limited sensitivity to detect metastasis in axillary lymph nodes, the axilla must be explored surgically. The histology of all resected nodes at the time of axillary lymph node dissection (ALND) has traditionally been regarded as the most accurate method for assessing metastatic spread of disease to the locoregional lymph nodes. However, ALND may result in lymphedema, nerve injury, shoulder dysfunction, and other short-term and long-term complications limiting functionality and reducing quality of life. Sentinel lymph node biopsy (SLNB) is a less invasive method of assessing nodal involvement. The concept of SLNB is based on the notion that tumors drain in an orderly manner through the lymphatic system. Therefore, the SLN is the first to be affected by metastasis if the tumor has spread, and a tumor-free SLN makes it highly unlikely for other nodes to be affected. Sentinel lymph node biopsy has become the standard of care for primary treatment of early breast cancer and has replaced ALND to stage clinically node-negative patients, thus reducing ALND-associated morbidity. More than 20 years after its introduction, there are still aspects concerning SLNB and ALND that are currently debated. Moreover, SLNB remains an unstandardized procedure surrounded by many unresolved controversies concerning the technique itself. In this article, we review the main indications, contraindications, and controversies of SLNB in breast cancer in the light of the most recent publications.

Value of (18)F-FDG PET for Predicting Response to Neoadjuvant Therapy in Rectal Cancer: Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to assess the predictive value of (18)F-FDG PET/ CT for pathologic response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. MATERIALS AND METHODS: A systematic search was performed (PubMed and Cochrane databases) for potentially relevant studies up to January 2014. Pooled sensitivity and specificity were calculated. The AUCs of the global cohort and for "major response," "complete response," "only PET after chemoradiotherapy," "ad interim PET," "major response excluding ad interim studies," "complete response excluding ad interim studies," "response index (RI)," "posttreatment maximum standardized uptake value (SUV(max) post)," "visual response analysis (VRA)," "percentage reduction of the total lesion glycolysis (ΔTLG)," and "percentage reduction of the metabolic tumor volume (ΔMTV)" were analyzed. Heterogeneity was explored for multiple variables. Pooled prevalence and 95% CI were calculated. RESULTS: Thirty-four of 131 (26%) initial articles met the inclusion criteria. Those articles included 1526 patients. PET/CT showed good pooled accuracy both in the global cohort (pooled sensitivity, 73%; pooled specificity, 77%; pooled AUC, 0.83) and for subgroups. Pooled accuracy was similar for early PET restaging and at 1 and 2 weeks after beginning chemoradiotherapy (pooled sensitivity, 84%; pooled specificity, 81%; pooled AUC, 0.89). The major response group showed similar sensitivity to the complete response group (74% and 71%, respectively). RI, SUV(max), and VRA were the most frequent parameters used. Pooled RI and SUV(max) postcutoff values were 63% and 4.4. Pooled time to PET during and after chemoradiotherapy was 1.5 and 6.5 weeks, respectively. CONCLUSION: This meta-analysis supports the use of FDG PET for restaging locally advanced rectal cancer.