The Prognostic Role of [18F]FDG PET/CT in Patients with Advanced Cutaneous Squamous Cell Carcinoma Submitted to Cemiplimab Immunotherapy: A Single-Center Retrospective Study.

Background: Baseline 2-deoxy-2[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET)-derived parameters and 12-week metabolic response were investigated as prognostic factors in advanced cutaneous squamous cell carcinoma (cSCC) submitted to cemiplimab immunotherapy. Materials and Methods: Clinical records of 25 cSCC patients receiving cemiplimab, submitted to [18F]FDG positron emission tomography/computed tomography (PET/CT) at baseline and after ∼12 weeks, were retrospectively reviewed. The Kaplan-Meier (KM) method was applied to analyze differences in event-free survival (EFS), and Cox regression analysis was employed to identify the prognostic factors. Results: At the 12-week PET/CT evaluation, 16 patients (64%) were classified as responders (complete or partial response) and 9 (36%) as nonresponders ("unconfirmed progressive metabolic disease") according to immune PET Response Criteria in Solid Tumors (iPERCIST). By KM analysis, baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) significantly correlated with the EFS (p < 0.05). Furthermore, the KM analysis showed that the lack of metabolic response at 12 weeks was associated with meaningfully shorter EFS (7.2 ± 1 months in nonresponders vs. 20.3 ± 2.3 months in responders). In Cox multivariate analysis, metabolic response at 12 weeks remained the only predictor of the EFS (p < 0.05). Conclusions: Baseline tumor load (i.e., MTV and TLG) and metabolic response at 12 weeks may have a prognostic impact in cSCC patients treated with cemiplimab.

Supraorbital Basosquamous Carcinoma Treated with Cemiplimab Followed by Sonidegib: A Case Report and Review of the Literature.

Basal cell carcinoma (BCC) is a skin cancer with low local aggressiveness and a low tendency to metastasize. Basosquamous Carcinoma (BSC) represents an aggressive histological subtype of BCC with intermediate features between Squamous Cell Carcinoma (SCC) and BCC. Cemiplimab is currently approved as first-line therapy in SCC and second-line therapy in BCC patients who have progressed on or are intolerant of a Hedgehog pathway Inhibitor (HHI). Our study describes the case of a 59-year-old man with BSC who was successfully treated with 5 cycles of Cemiplimab as first-line therapy and Sonidegib as second-line therapy. Currently, the efficacy of Cemiplimab against BSC and other histopathological subtypes of BCC has not been fully elucidated, as has the role of sequential or combination therapy with Cemiplimab and HHI in the management of BSC. The aim of this case report is to highlight the need to outline the use of checkpoint inhibitors in BCCs and focus attention on the synergistic role of Cemiplimab and HHIs in such a controversial entity as BSC.

The Importance of Uncertainty Analysis and Traceable Measurements in Routine Quantitative 90Y-PET Molecular Radiotherapy: A Multicenter Experience.

Molecular Radiation Therapy (MRT) is a valid therapeutic option for a wide range of malignancies, such as neuroendocrine tumors and liver cancers. In its practice, it is generally acknowledged that there is a need to evaluate the influence of different factors affecting the accuracy of dose estimates and to define the actions necessary to maintain treatment uncertainties at acceptable levels. The present study addresses the problem of uncertainty propagation in 90Y-PET quantification. We assessed the quantitative accuracy in reference conditions of three PET scanners (namely, Siemens Biograph mCT, Siemens Biograph mCT flow, and GE Discovery DST) available at three different Italian Nuclear Medicine centers. Specific aspects of uncertainty within the quantification chain have been addressed, including the uncertainty in the calibration procedure. A framework based on the Guide to the Expression of Uncertainty in Measurement (GUM) approach is proposed for modeling the uncertainty in the quantification processes, and ultimately, an estimation of the uncertainty achievable in clinical conditions is reported.

[18F]FDG PET/CT in a Case of Mycosis Fungoides Showing an Unusual Adverse Reaction to Mogamulizumab: Correlation Between Imaging and Histological Findings.

A 73-year-old female patient, affected by mycosis fungoides (MF), discontinued mogamulizumab, after initial clinical benefit, due to the onset of generalized erythema. Follow-up positron emission computed tomography (PET/CTs) carried out at 3 weeks and 6 months after therapy discontinuation showed, with respect to baseline PET/CT scan, a progressively increasing number of hypermetabolic enlarged lymph nodes suspected for a neoplastic involvement, but with histology indicative of an inflammatory reaction. After sequential therapy with corticosteroids and methotrexate, a complete remission was registered at 18F-fluorodeoxyglucose ([18F]FDG) PET/CT performed at 12 months after mogamulizumab interruption. The case we describe highlights the usefulness of serial examinations with [18F]FDG PET/CT in an MF patient presenting an unusual adverse reaction to mogamulizumab.

PET/CT with 18F-choline or 18F-FDG in Hepatocellular Carcinoma Submitted to 90Y-TARE: A Real-World Study.

Our aim was to assess the role of positron emission computed tomography (PET/CT) with 18F-choline (18F-FCH) or 18F-fluorodeoxyglucose (18F-FDG) in hepatocellular carcinoma (HCC) submitted to 90Y-radioembolization (90Y-TARE). We retrospectively analyzed clinical records of 21 HCC patients submitted to PET/CT with 18F-fluorocholine (18F-FCH) or 18F-fluodeoxyglucose (18F-FDG) before and 8 weeks after 90Y-TARE. On pre-treatment PET/CT, 13 subjects (61.9%) were 18F-FCH-positive, while 8 (38.1%) resulted 18F-FCH-negative and 18F-FDG-positive. At 8-weeks post 90Y-TARE PET/CT, 13 subjects showed partial metabolic response and 8 resulted non-responders, with a higher response rate among 18F-FCH-positive with respect to 18F-FDG-positive patients (i.e., 76.9% vs. 37.5%, p = 0.46). Post-treatment PET/CT influenced patients' clinical management in 10 cases (47.6%); in 8 subjects it provided indication for a second 90Y-TARE targeting metabolically active HCC remnant, while in 2 patients it led to a PET-guided radiotherapy on metastatic nodes. By Kaplan−Meier analysis, patients' age (≤69 y) and post 90Y-TARE PET/CT's impact on clinical management significantly correlated with overall survival (OS). In Cox multivariate analysis, PET/CT's impact on clinical management remained the only predictor of patients' OS (p < 0.001). In our real-world study, PET/CT with 18F-FCH or 18F-FDG influenced clinical management and affected the final outcome for HCC patients treated with 90Y-TARE.

Cerebellar Metastases from Prostate Cancer Detected by PET/CT with 18F-Choline.

A 76-year-old male, previously submitted enucleation renal-cell carcinoma (pT1) and prostatectomy for prostate cancer (Gleason score 3+5, pT3b pN0 pMx), was submitted to positron emission/computed tomography (PET/CT) with 18F-choline for restaging due to raised levels of prostate-specific antigen. PET/CT scan showed increased tracer incorporation corresponding to bone metastases in the left ischio-pubic ramus, also revealing 2 areas of increased tracer uptake in the cerebellum, subsequently confirmed by brain magnetic resonance imaging. The patient was urgently submitted to neurosurgery. Post-operative histology was positive for brain metastases from prostate cancer.

Imaging Findings of 18F-Choline and 18F-DOPA PET/MRI in a Case of Glioblastoma Multiforme Pseudoprogression: Correlation with Clinical Outcome.

We describe the case of 74-year-old-male, previously treated with fronto-parietal craniotomy due to primary glioblastoma multiforme (GBM), followed by concurrent radiation therapy (RT) and temozolomide (TMZ) chemotherapy. Magnetic resonance imaging (MRI) of the brain, at 1 month after completing RT + TMZ, depicted partial response. Three months later, the patient was submitted to a further brain MRI, that resulted doubtful for therapy induced changes (i.e., pseudoprogression). The patient, who had been previously treated with prostatectomy for prostate cancer (PC), underwent a positron emission tomography/computed tomography (PET/CT) scan with 18F-choline for PC biochemical recurrence. 18F-choline whole body PET/CT resulted negative for PC relapse, while segmental brain PET, co-registered with MRI, demonstrated increased tracer uptake corresponding to tumor boundaries. In order to solve differential diagnosis between pseudoprogression and GBM recurrence, brain PET/CT with 18F-L-dihydroxy-phenil-alanine (18F-DOPA) was subsequently performed: fused axial PET/MRI images showed increased 18F-DOPA incorporation in the peri-tumoral edema, but not in tumor boundaries, consistent with the suspicion of GBM pseudoprogression, as then confirmed by clinical and radiological follow-up.

Surgical Resection Is Superior to TACE in the Treatment of HCC in a Well Selected Cohort of BCLC-B Elderly Patients-A Retrospective Observational Study.

Hepatocellular carcinoma (HCC) usually develops in cirrhotic liver, with high recurrence rates. However, considering its increasing detection in non-cirrhotic liver, the choice of treatment assumes particular relevance. This study aimed to investigate outcomes of patients among BCLC stages and enrolled for surgical resection (SR) according to a more complex evaluation, to establish its safety and efficacy. A total of 186 selected HCC patients (median age 73.2 yrs), submitted to SR between January 2005 and January 2021, were retrospectively analyzed. Of which, 166 were staged 0, A, B according to the BCLC system, while 20 with a single large tumor (>5 cm) were classified as stage AB. No perioperative mortality was recorded; complications occurred in 48 (25.80%) patients, and all but two were Clavien−Dindo grade I−II. Median follow-up was 9.2 years. Subsequently, 162 recurrent patients (87,1%) were selected for new treatments. Comparable overall survival rates (OS) were observed at 1, 3, 5, and 10 years in 0, A, B and AB stages (p = 0.2). Eventually, the BCLC-B group was matched to 40 BCLC-B patients treated (2015-2021) with TACE. Significant differences in baseline characteristics (p <0.0001) and in OS were observed at 1 and 3 years (p <0.0001); a significant difference was also observed in oncological outcomes, in terms of the absence, residual, or relapse of disease (p <0.05). Surgery might be a valid treatment in HCC for patients affected by chronic liver disease in a condition of compensation, up to BCLC-B stage. Surgical indication for liver resection in case of HCC should be extensively revised.

Digital PET/CT with 18F-FACBC in early castration-resistant prostate cancer: our preliminary results.

BACKGROUND: We assessed the role of digital PET/CT (dPET/CT) with 18F-FACBC in patients affected by castration-resistant prostate cancer with PSA levels ≤ 3 ng/mL (early CRPC), no lesions detectable at cross-sectional imaging (CIM) and bone scan (BS). METHODS: Clinical data of patients submitted to 18F-FACBC dPET/CT were retrospectively reviewed. PET/CT results were analyzed: lesions' number, location, and, in case of positive lymph nodes, largest node's short axis (i.e. SA) were annotated. According to PET/CT's results, patients with 18F-FACBC-avid lesions were further stratified into 1) unifocal; 2) oligometastatic (≤ 5 lesions); 3) disseminated (> 6 lesions). RESULTS: Twenty-four patients were enrolled. 18F-FACBC dPET/CT was positive in 21 out of 24 patients (87.5%). Thirteen patients (54.1%) showed recurrence in pelvic region, seven of whom with pelvic nodes' involvement, while eight cases (33.3%) presented 18F-FACBC-avid metastases to extra-pelvic nodes or bone. Average SA of PET-positive nodes resulted in 8.9 ± 3 mm. Patients were categorized as unifocal in four cases (26.6%), oligometastatic in 10 subjects (66.6%) and disseminated in 1 case (0.6%). PET/CT impacted on clinical management in 14 cases (58.3%). CONCLUSIONS: 18F-FACBC dPET/CT detected M1 status in 33.3% of early CRPC patients, significantly impacting on clinical management.

Somatostatin Receptor Targeted PET-Imaging for Diagnosis, Radiotherapy Planning and Theranostics of Meningiomas: A Systematic Review of the Literature.

The aims of the present systematic review are to: (1) assess the diagnostic performance of somatostatin receptor (SSR)targeted positron emission tomography (PET) with different tracers and devices in patients affected by meningiomas; and (2) to evaluate the theranostic applications of peptide receptor radionuclide therapy (PRRT) in meningiomas. A systematic literature search according to PRISMA criteria was made by using two main databases. Only studies published from 2011 up to March 2022 in the English language with ≥10 enrolled patients were selected. Following our research strategy, 17 studies were included for the assessment. Fourteen studies encompassed 534 patients, harboring 733 meningiomas, submitted to SSR-targeted PET/CT (n = 10) or PET/MRI (n = 4) for de novo diagnosis, recurrence detection, or radiation therapy (RT) planning (endpoint 1), while 3 studies included 69 patients with therapy-refractory meningiomas submitted to PRRT (endpoint 2). A relevant variation in methodology was registered among diagnostic studies, since only a minority of them reported histopathology as a reference standard. PET, especially when performed through PET/MRI, resulted particularly useful for the detection of meningiomas located in the skull base (SB) or next to the falx cerebri, significantly influencing RT planning. As far as it concerns PRRT studies, stable disease was obtained in the 66.6% of the treated patients, being grade 1-2 hematological toxicity the most common side effect. Of note, the wide range of the administered activities, the various utilized radiopharmaceuticals (90Y-DOTATOC and/or 177Lu-DOTATATE), the lack of dosimetric studies hamper a clear definition of PRRT potential on meningiomas' management.

Management of a Patient With Metastatic Gastrointestinal Neuroendocrine Tumor and Meningioma Submitted to Peptide Receptor Radionuclide Therapy With 177 Lu-DOTATATE.

ABSTRACT: A 76-year-old woman affected by pancreatic neuroendocrine tumor previously subjected to surgery with progressive liver disease and a concomitant mild symptomatic meningioma of the left pontocerebellar angle underwent 4 cycles of peptide receptor radionuclide therapy with 177 Lu-DOTATATE. A prophylactic therapy with corticosteroids was carried out before each treatment cycle, and the neurosurgery unit was alerted in case of cerebral edema and related neurologic symptoms. A 68 Ga-DOTATOC PET/CT scan performed after the completion of the 4 cycles' treatment documented a hepatic partial response and a substantial stability of the brain mass. No neurological complications occurred during treatment and follow-up.

Cutaneous Squamous Cell Carcinoma Subjected to Anti PD-1 Immunotherapy: Monitoring Response Through Serial PET/CT Scans with 18F-FDG.

Background: The effectiveness of 18F-fluorodeoxyglucose (18F-FDG) positron emission computed tomography (PET/CT) for monitoring response to immunotherapy (IT) with cemiplimab in patients affected by cutaneous squamocellular carcinoma (cSCC) was investigated. Materials and Methods: Thirteen cSCC patients performed PET/CT at baseline (PET-1) and 3 months after IT (PET-2). According to immune PET Response Criteria in Solid Tumors (iPERCIST), patients showing progressive disease at PET-2 were classified as having "unconfirmed progressive metabolic disease" (uPMD) and were scheduled to perform a further PET/CT (PET-3) after 4 weeks. PET/CT's results were correlated with best clinical response (BCR) categorized, within 6 months from the start of IT, as clinical benefit (CB) or no clinical benefit (NCB) according to clinical follow-up. Results: At PET-2, 9 subjects (69.2%) showed metabolic response, whereas four (30.8%) were classified as uPMD. After 4 weeks, three uPMD patients were subjected to PET-3, which confirmed progressive disease in all cases, whereas 1 patient with uPMD did not undergo PET-3 due to clinical deterioration. All subjects with metabolic response at PET-2 were classified as having CB and continued IT in 8 out of 9 cases, whereas all patients with uPMD were categorized as NCB and discontinued IT. Conclusions: PET/CT, performed in cSCC patients after 3 months of cemiplimab, resulted capable to identify responders from nonresponders.

Detection Rate and Clinical Impact of PET/CT with 18F-FACBC in Patients with Biochemical Recurrence of Prostate Cancer: A Retrospective Bicentric Study.

Our aim was to assess the detection rate (DR) of positron emission computed tomography (PET/CT) with anti-1-amino-3-[18F]-flurocyclobutane-1-carboxylic acid (18F-FACBC) in patients with biochemical recurrence (BCR) from prostate cancer (PC). As a secondary endpoint, we evaluated 18F-FACBC PET/CT's impact on patients management. Clinical records of 81 patients submitted to 18F-FACBC PET/CT due to PC BCR in two Italian Nuclear Medicine Units were retrospectively assessed. DR was gauged in the whole cohort and stratifying patients by discrete intervals of PSA levels. PET/CT's impact on clinical management was scored as (1) major if it entailed an intermodality change (e.g., from systemic to loco-regional therapy); (2) minor if it led to an intramodality change (e.g., modified radiotherapy field). PET/CT's DR resulted in 76.9% in the whole cohort, with a positive predictive value of 96.7%. Stratified by PSA quartile intervals, PET/CT's DR was 66.7%, 71.4%, 78.9% and 90% for PSA 0.2-0.57 ng/mL, 0.58-0.99 ng/mL, 1-1.5 ng/mL and >1.5 ng/mL without significant difference among groups (p = 0.81). The most common sites of relapse were prostate bed and pelvic lymph nodes (59.3%). PET/CT impacted on clinical management in 33/81 cases (40.7%), leading to a major change in 30 subjects (90.9%). 18F-FACBC PET/CT localized recurrence in patients with BCR, with meaningful DR also at low PSA levels and significantly impacted on clinical management.

Molecular and Metabolic Imaging of Castration-Resistant Prostate Cancer: State of Art and Future Prospects.

Prostate cancer (PCa) represents to be the most common tumor in male and one of the most relevant causes of death in the Western countries. Androgen deprivation therapy (ADT) constitutes a widely used approach in advanced PCa. When PCa progresses in spite of ADT and castrate levels of testosterone, the severe clinical condition termed as metastatic castration-resistant prostate cancer (mCRPC) takes place. The only approach to mCRPC has been represented by chemotherapy with taxanes for many years. Nevertheless, recently introduced treatments such as 2nd generation antiandrogens (i.e., enzalutamide and abiraterone), cell immunotherapy with sipuleucel-T or targeted alpha therapy with 223Ra-dichloride, have dramatically changed mCRPC prognosis. These novel therapies call for an unmet need for imaging biomarkers suitable for patients' pre-treatment stratification and response assessment. In this scenario, nuclear medicine can provide several metabolic and molecular probes for investigating pathological processes at a cellular and sub-cellular level. The aim of this paper is to review the most relevant findings of the literature published to date on this topic, giving particular emphasis on the pros and cons of each tracer and also covering future prospects for defining personalized therapeutic approaches.

DNA Damage Repair Defects and Targeted Radionuclide Therapies for Prostate Cancer: Does Mutation Really Matter? A Systematic Review.

The aim of the present review was to assess the impact of DNA damage repair (DDR) mutations on response and outcome of patients (pts) affected by advanced prostate cancer (PCa) submitted to radionuclide therapies with [223Ra]RaCl2 (223Ra-therapy) or prostate specific membrane antigen (PSMA) ligands. A systematic literature search according to PRISMA criteria was made by using two main databases. Only studies published up until to October 2022 in the English language with ≥10 enrolled patients were selected. Seven studies including 326 pts, of whom 201 (61.6%) harboring DDR defects, were selected. The majority of selected papers were retrospective and four out of seven (57.1%) had small sample size (<50 pts). Three out of seven (42.8%) studies reported a more favorable outcome (overall or progression free survival) after therapy with alpha emitters (223Ra-therapy or [225Ac]Ac-PSMA-617) in subjects with DDR defects with respect to those without mutations. In two studies employing alpha or beta emitters ([177Lu]/[225Ac]-PMSA), no significant benefit was registered in pts harboring DDR defects. In all but one paper, no significant difference in response rate was reported among pts with or without DDR mutations. Although preliminary and biased by the retrospective design, preliminary data suggest a trend towards a longer survival in PCa pts harboring DDR defects submitted to radionuclide targeted therapy with alpha emitters.

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.

Long-Term Maintained Response to Selective Internal Radiation Therapy in an Oligometastatic Uveal Melanoma Patient Treated with Concomitant Anti-PD-1 Therapy.

Uveal melanoma (UM) is a primary neoplasm of the eye arising from the melanocytes residing in the iris, ciliary body or choroid. It is the most frequent intraocular malignancy and often determines metastases at distant sites, with a peculiar tropism for the liver. Metastatic UM has a poor prognosis, as any treatment affects the natural course of this fatal disease. Herein, we report a case of a UM metastatic to the liver in a 54 year-old female patient, initially treated with nivolumab without success. The patient was then scheduled for selective internal radiation therapy (SIRT) while continuing immunotherapy. This combination led to a complete and durable response and the patient is currently free of disease, two years after the diagnosis of the hepatic metastases. The association between SIRT and immunotherapy (IT) has very promising perspectives for metastatic UM, especially considering the disappointing or contradictory results of classic chemotherapies, IT alone and targeted therapies. Furthermore, this combination has been shown to have a good security profile. However, further studies are needed to confirm the efficacy of associating SIRT and IT and to clarify some unsolved problems, such as the timing of administration of these two therapies.

Usefulness of PET/CT with 18F-FDG in Patients with Differentiated Thyroid Carcinoma after Radioiodine Therapy: An Italian Multicenter Study.

BACKGROUND: our aim was to assess the diagnostic performance and clinical impact of 18F-FDG PET/CT in patients with differentiated thyroid carcinoma (DTC), previously treated with surgery and radioiodine therapy (RAI). METHODS: patients subjected to 18F-FDG PET/CT for suspected DTC recurrence in three Italian nuclear medicine units were evaluated. Two different clinical settings were identified: clinical setting 1 included patients (n = 40) that were enrolled according to the American Thyroid Association guidelines (i.e., negative 1311-WBS and Tg level > 10 ng/mL); and clinical setting 2, that encompassed subjects (n = 26) with serum Tg ≤ 10 ng/mL but morphological findings suspected of relapse. PET/CT's impact was scored as significant if it provided an indication for surgery, or led to a novel therapeutic decision. RESULTS: In total, 51/66 patients (77.3%) were 18F-FDG positive, while 15 (22.7%) were negative. PET/CT showed an overall sensitivity and specificity of 84.4% and 75%, respectively. Sensitivity was higher in clinical setting 1 (89.1%) as compared to clinical setting 2 (76.1%), although this difference was not statistically significant (p = 0.83). PET/CT influenced clinical management in 28 cases (42.4%), without a significant difference between the 2 groups of patients (p = 0.6). CONCLUSIONS: our preliminary data, although limited by the retrospective nature of the study and possible selection bias, suggest that 18F-FDG PET/CT may be utilized for the detection of DTC recurrence in different clinical settings, with a meaningful impact on clinical management.