Prostate-Specific Membrane Antigen-Targeted Therapy in Prostate Cancer: History, Combination Therapies, Trials, and Future Perspective.

In the last decades, the development of PET/CT radiopharmaceuticals, targeting the Prostate-Specific Membrane Antigen (PSMA), changed the management of prostate cancer (PCa) patients thanks to its higher diagnostic accuracy in comparison with conventional imaging both in staging and in recurrence. Alongside molecular imaging, PSMA was studied as a therapeutic agent targeted with various isotopes. In 2021, results from the VISION trial led to the Food and Drug Administration (FDA) approval of [177Lu]Lu-PSMA-617 as a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) and set the basis for a radical change in the future perspectives of PCa treatment and the history of Nuclear Medicine. Despite these promising results, primary resistance in patients treated with single-agent [177Lu]Lu-PSMA-617 remains a real issue. Emerging trials are investigating the use of [177Lu]Lu-PSMA-617 in combination with other PCa therapies in order to cover the multiple oncologic resistance pathways and to overcome tumor heterogeneity. In this review, our aim is to retrace the history of PSMA-targeted therapy from the first preclinical studies to its future applications in PCa.

Hypofractionated proton therapy for benign tumors of the central nervous system: A systematic review of the literature.

AIMS: Aim of the present analysis was to report results of a systematic review of the literature in the setting of patients treated with hypoF PT for benign lesions of the central nervous system (CNS). METHODS: The methodology complied with the PRISMA recommendations. PubMed, EMBASE and Scopus databases were interrogated in September 2022. RESULTS: Twelve papers have been selected including patients treated for base of the skull meningiomas (6 papers), vestibular schwannoma (3 papers) and pituitary adenomas (3 papers). Clinical outcomes were evaluated with both radiologic images and clinical parameters. Long-term toxicity was reported in all but one series with an incidence ranging from 2 % to 7 % in patients treated for base of skull meningioma and 1-9 % for schwannoma. CONCLUSIONS: HypoF PT is a safe and effective treatment in selected benign tumors of the CNS. Further dosimetric and clinical comparisons are required to better refine the patients' selection criteria.

A Retrospective Analysis of the Correlation between Functional Imaging and Clinical Outcomes in Grade 3 Neuroendocrine Tumors (NETs G3).

Grade 3 (G3) neuroendocrine tumors (NETs) are a novel category among digestive neuroendocrine neoplasms, characterized by Ki-67 >20% and a well-differentiated morphology, presenting high intra-tumor heterogeneity. We aimed to explore the role of dual-tracer PET imaging (68Gallium (Ga)-DOTATOC and 18Fluorodeoxyglucose (FDG)) as overall survival (OS) predictor in NET G3 patients. We performed a retrospective analysis in NET G3 patients treated at our institution between 2003 and 2021. Accordingly, 30 NET G3 patients were analyzed. 68Ga-DOTA-TOC and 18F-FDG uptake were assessed by tumor/non-tumor (T-nonT) ratio. We reported a slightly better OS for patients with ≥75% concordance between 68Ga-DOTA-TOC and 18F-FDG PET/CT (p = 0.42). Among patients with discordant functional imaging, we reported a better 5-y OS rate for patients with a prevalent 68Ga-DOTATOC vs. 18F-FDG PET/CT (p = 0.016). In positive 18F-FDG PET/CT cases, we reported a better OS for <4 vs. ≥4 T/non-T ratio (p = 0.021). Among upfront-NET G3 patients with concordant exams, 5-y OS rate was 83.3% (95% CI: 27.3-97.5). Among patients with discordant exams, 5-y OS rate was 81.3% (52.5-93.5), 100% for those with prevalent receptor expression, and 50% (11.1-80.4) for those with prevalent 18F-FDG uptake. Our findings suggest that dual-tracer PET/CT can be considered as a predictor of patient outcome, able to stratify NET G3 patients with poorer prognosis.

First Ex Vivo Results of ß--Radioguided Surgery in Small Intestine Neuroendocrine Tumors with 90Y-DOTATOC.

Background: In neuroendocrine tumor (NET), complete surgery could better the prognosis. Radioguided surgery (RGS) with ß--radioisotopes is a novel approach focused on developing a new probe that, detecting electrons and operating with low background, provides a clearer delineation of the lesions with low radiation exposition for surgeons. As a first step to validate this procedure, ex vivo specimens of tumors expressing somatostatin receptors, as small intestine neuroendocrine tumor (SI-NET), were tested. Materials and Methods: SI-NET presents a high uptake of a beta-emitting radiotracer, 90Y-DOTATOC. Five SI-NET patients were enrolled after performing a 68Ga-DOTATOC positron emission tomography/computed tomography (CT) and a CT enterography; 24 h before surgery, they received 5 mCi of 90Y-DOTATOC. Results: Surgery was performed as routine. Tumors and surrounding tissue were sectioned in different samples and examined ex vivo with the beta-detecting probe. All the tumor samples showed high counts of radioactivity that was up to a factor of 18 times higher than the corresponding cutoff value, with a sensitivity of 96% and a specificity of 100%. Conclusions: These first ex vivo RGS tests showed that this probe can discriminate very effectively between tumor and healthy tissues by the administration of low activities of 90Y-DOTATOC, allowing more precise surgery.

18F-FDG PET/CT in asymptomatic patients with COVID-19: the submerged iceberg surfaces.

OBJECTIVE: The aim of this case series is to describe our experience in diagnosis and management of oncological asymptomatic patients with COVID-19 who underwent 18F-FDG PET/CT. METHODS: From March 9 to March 31, 2020, we identified 5 patients who had PET/CT findings suspicious for COVID-19, but no symptom of infection. RESULTS: The first three patients were administered an SARS-CoV-2 test in a COVID-dedicated center, while the fourth and fifth were tested in our institution, in accordance with a new internal procedure. The SARS-CoV-2 test yielded positive results in all five patients. CONCLUSION: In this COVID-19 emergency, our task as radiologists and nuclear medicine physicians is to be able to identify imaging findings suggestive of the disease and to manage patients without overloading the hospital system.

PET/CT with Fluorodeoxyglucose During Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

OBJECTIVE: The aim of the present study is to evaluate the accuracy of Positron Emission Tomography/Computed Tomography (PET/CT) with Fluorodeoxyglucose ([18F]FDG) to predict treatment response in patients with locally advanced rectal cancer (LARC) during neoadjuvant chemoradiotherapy. PATIENTS AND METHODS: Forty-one LARC patients performed [18F]FDG-PET/CT at baseline (PET0). All patients received continuous capecitabine concomitant to radiotherapy on the pelvis, followed by intermittent capecitabine until two weeks before curative surgery. [18F]FDG-PET/CT was also carried out at 40 Gy-time (PET1) and at the end of neoadjuvant therapy (PET2). PET imaging was analysed semi-quantitatively through the measurement of maximal standardised uptake value (SUVmax) and the tumour volume (TV). Histology was expressed through pTNM and Dworak tumor regression grading. Patients were categorised into responder (downstaging or downsizing) and non-responder (stable or progressive disease by comparison pretreatment parameters with clinical/pathological characteristics posttreatment/after surgery). Logistic regression was used to evaluate SUVmax and TV absolute and percent reduction as predictors of response rate using gender, age, and CEA as covariates. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Survivals were compared by the Log-Rank test. RESULTS: Twenty-three responders (9 ypCR, 14 with downstaged disease) and 18 non-responders showed differences in terms of both early and posttreatment SUVmax percent reduction (median comparison: responder = 63.2%, non-responder = 44.2%, p = 0.04 and responder = 76.9%, non-responder = 61.6%, p = 0.06 respectively). The best predictive cut-offs of treatment response for early and posttreatment SUVmax percent reduction were ≥57% and ≥66% from baseline (p = 0.02 and p = 0.01 respectively). CONCLUSIONS: [18F]FDG-PET/CT is a reliable technique for evaluating therapy response during neoadjuvant treatment in LARC, through a categorical classification of the SUV max reduction during treatment.

Long-term results of PRRT in advanced bronchopulmonary carcinoid.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumours (NET) has been explored for almost two decades, but there are still few trials that have exclusively investigated well-differentiated and moderately differentiated NET arising from the respiratory tree. Thus, the aim of this study was to explore the outcome in patients affected by bronchopulmonary carcinoid (BPC) following PRRT. METHODS: We retrospectively analysed 114 patients with advanced stage BPC consecutively treated with PRRT at the European Institute of Oncology, Milan, from 1997 to 2012 and followed until October 2014. The objective responses, overall survival (OS) and progression-free survival (PFS) were rated, and three different PRRT protocols ((90)Y-DOTATOC vs. (177)Lu-DOTATATE vs. (90)Y-DOTATOC + (177)Lu-DOTATATE) were compared with regard to their efficacy and tolerability. RESULTS: The median OS (evaluated in 94 of the 114 patients) was 58.8 months. The median PFS was 28.0 months. The (177)Lu-DOTATATE protocol resulted in the highest 5-year OS (61.4%). Morphological responses (partial responses + minor responses) were obtained in 26.5% of the cohort and were associated with longer OS and PFS. The (90)Y-DOTATOC + (177)Lu-DOTATATE protocol provided the highest response rate (38.1%). Adverse events were mild in the majority of patients. However, haematological toxicity negatively affected survival. No severe (grade 3/4) serum creatinine increase was observed. Patients treated with (90)Y-DOTATOC alone more frequently showed a mild/moderate decrease in renal function. In patients treated with chemotherapy before PRRT had a shorter OS and PFS, and a higher risk of developing nephrotoxicity. CONCLUSION: In a large cohort of patients with advanced BPC treated in a "real-world" scenario and followed up for a median of 45.1 months (range 2-191 months), PRRT proved to be promising in prolonging survival and delaying disease progression. Despite the potential selection biases, considering the risk-benefit ratio, (177)Lu-DOTATATE monotherapy seems the best option for PRRT. Our results indicate that the use of PRRT in earlier stages of the disease could provide a more favorable outcome.

Comparison of whole-body diffusion-weighted magnetic resonance and FDG-PET/CT in the assessment of Hodgkin's lymphoma for staging and treatment response.

Computed tomography (CT), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and hybrid FDG-PET/CT are the most commonly used diagnostic tools for the initial staging and treatment response assessment of lymphomas [1]. The aim of this report is to compare the correlations between functional imaging markers derived from FDG-PET/CT and whole-body, diffusion-weighted magnetic resonance imaging (DW-MRI) in a young patient affected by Hodgkin's lymphoma (HL).

Atypical primary pulmonary meningioma: a report of a case suspected of being a lung metastasis.

Primary extracranial and extraspinal meningiomas are very rare tumours, and primary pulmonary ones are even more uncommon. They present as a solitary pulmonary nodule, and most of them are benign, except for three cases. We describe a primitive atypical pulmonary meningioma first suspected of being a metastasis in a patient during follow-up ten years after therapy for breast cancer.

Ipilimumab-induced immunomediated adverse events: possible pitfalls in (18)F-FDG PET/CT interpretation.

A 42-year-old woman underwent resection of a high-risk melanoma of the right thigh. Adjuvant treatment with ipilimumab was then started within a phase III randomised, double-blind clinical trial. F-FDG PET/CT scan showed intense uptake in mediastinal hilar lymph nodes, bilaterally, and in rectus abdominis muscle. Biopsy at the abdominal wall revealed a chronic granulomatous inflammation. After oral steroid treatment, all the areas of abnormal tracer uptake disappeared. Ipilimumab can induce inflammatory immunomediated reactions that should be taken into account to avoid misinterpretation.

Intramedullary spinal cord metastases from breast cancer: detection with (18)F-FDG PET/CT.

A 35-year-old woman, already treated with surgery, chemotherapy, and radiotherapy for a ductal carcinoma of the left breast, underwent an (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) scan for an increase of the serum markers carcinoembryonic antigen (CEA) and cancer antigen 15.3 (CA15.3). The scan showed multiple FDG-avid lesions in the liver and bone. The images also detected two areas of uptake in the dorsal and lumbar spinal cord, which were suspicious for metastases; magnetic resonance imaging (MRI) confirmed these lesions.

Autonomous functioning thyroid nodules and 131I in diagnosis and therapy after 50 years of experience: what is still open to debate?

PURPOSE OF THE REPORT: Autonomous functioning thyroid nodules (AFTN), defined as "hot nodules" at thyroid scan, are often cured by radioiodine treatment. The aim of our study was to investigate the long-term outcome in patients treated with an 131I calculated dose, to identify a possible "size-tailored" dose, and to simplify follow-up procedures. PATIENTS AND METHODS: Retrospective analysis was carried out on 1402 cases, covering a period of 50 years, of AFTN treated with an 131I calculated dose. Our study focused on nodular size and mean administered dose. Concordance between thyroid scan and serum TSH levels at 3-6 months from treatment was considered. RESULTS: A single 131I dose was effective for the vast majority of patients (93%). The outcome was influenced by nodular size. On the basis of the Italian dose limit for outpatient treatment, our population was divided into subgroups according to administered doses (more or less than 16 mCi) and nodular dimensions: no differences in outcome were observed for each class of nodule size. A dose ≤10 mCi was effective on the smaller nodules (50.1% of our population). The agreement between TSH and scan after treatment was 90.3% at 3 months and 94.5% at 6 months. CONCLUSIONS: 131I therapy with a calculated dose is an effective treatment of AFTN. If a fixed dose is chosen, 16 mCi is often resolutive and for nodules <3 cm a dose of 10 mCi can suffice. Nodules >5 cm are eligible for surgery. TSH is the only parameter required to evaluate the outcome.

The relationship between 24 h/4 h radioiodine-131 uptake ratio and outcome after radioiodine therapy in 1402 patients with solitary autonomously functioning thyroid nodules.

OBJECTIVE: To evaluate the role of 24 h/4 h uptake ratio (UR) in response to radioiodine-131 ((131)I) therapy in patients with autonomously functioning thyroid nodules (AFTN). METHODS: A total of 1402 consecutive hyperthyroid patients were treated with (131)I, between 1958 and 2005. Therapeutic doses (D) were calculated according to the formula: D = weight of nodule x dose per gram of nodular tissue (q)/24 h (131)I uptake. The ratios of the 24 and 4 h uptake were retrospectively calculated and the patients were grouped according to outcome and q into three groups of UR (< or =1.25; 1.26-1.68; > or =1.69) by means of terziles. RESULTS: Of the 1402 patients, 95 did not respond to (131)I treatment while 93/1307 developed hypothyroidism. Most non-responders (55.8%) had UR < or =1.25, while many hypothyroid patients (66.7%) had UR > or =1.69 (chi (2): P < 0.001). As q increased, the proportion of successfully treated patients increased (level of significance) only in the group with UR < or =1.25; while in the other two terziles, with increasing dose per gram of nodular tissue, the number of successfully treated patients did not increase (level of significance). The cumulative incidence of hypothyroidism was 2.2% at the 1st year after (131)I treatment, increasing to 13.9% at 5 years and 26.2% at 10 years. CONCLUSIONS: The (131)I UR can predict the outcome of (131)I treatment in AFTN and may have utility in modifying treatment in some patients to limit post-radioiodine induced hypothyroidism and treatment failures in order to achieve euthyroidism.

Age influences TSH serum levels after withdrawal of l-thyroxine or rhTSH stimulation in patients affected by differentiated thyroid cancer.

Recombinant human TSH (rhTSH) has been recently suggested for radioiodine ablation in patients with differentiated thyroid cancer (DTC). To date, studies are still not available about the effectiveness of rhTSH stimulation depending on the age, since serum TSH clearance may be different in younger and in older patients. The aim of this study was to investigate the influence of age to serum TSH levels after rhTSH stimulation and thyroid hormone withdrawal (THW). We retrospectively evaluated two groups of consecutive DTC patients: group 1 (311 patients, age 49.0+/-13.6 years, ranging 15-86) underwent rhTSH stimulation 6-12 months after thyroid ablation (rhTSH-group); group 2 (84 patients, age 46.9+/-13.5 years, ranging 20-77) was followed by THW (THW-group). The influence of age, gender, body mass index and body surface area to serum TSH levels were evaluated in both groups. RhTSH-group: on day 5 (d5), TSH levels were 32.7+/-21.4 microU/ml (range 0.8-136.6). By univariate analysis, d5-TSH was positively related to age (r=0.27, p=0.0001) and no correlations were found with the other parameters. At multivariate analysis, both age and gender (female) were independently associated with d5-TSH levels. THW-group: after thyroid hormone withdrawal, TSH levels were 71.1+/-36.4 microU/ml (range 8.5-200). At univariate analysis, only age was significantly and negatively related to serum TSH levels (r=-0.31, p=0.004). Our data indicate that age and gender seem to positively influence serum TSH levels after rhTSH stimulation. An opposite effect of age on serum TSH levels has been observed after THW. Therapeutic implications ((131)I-treatment) of these findings have to be better investigated in prospective studies.

Radioiodine uptake in non-lactating mammary glands: evidence for a causative role of hyperprolactinemia.

CONTEXT: Radioiodine uptake is rarely observed in normal non-lactating breast tissue. Investigation of the in vivo regulation of iodide uptake in breast tissue may be useful for the induction of radioiodine uptake in breast cancer tissue for diagnostic and therapeutic purposes. CASE REPORTS: We report the cases of two post-menopausal women who underwent radioiodine therapy for papillary thyroid carcinoma and in whom breast uptake of radioiodine on post-therapy whole body scan (WBS) was observed. METHODS AND RESULTS: In both patients, elevated serum prolactin levels (123 ng/mL in patient 1 and 48 ng/mL in patient 2) were documented at the time when radioiodine uptake in the breast was observed. The hyperprolactinemia was due to prolonged treatment with the anti-dopaminergic neuroleptic risperidone in Case 1, and chronic renal failure in Case 2. When prolactin levels were normalized (by withdrawal of risperidone in Case 1 and with cabergoline in Case 2), breast tissue uptake was no longer evident on WBS. CONCLUSION: These cases provide the first documented correlation between serum levels of endogenous prolactin and radioiodine uptake by involuted breast tissue in humans.