Giulia Santo

Purpose: PSMA PET/CT has transformed the detection of nodal recurrence after radical prostatectomy, yet real-world evidence on long-term outcomes of PSMA PET/CT-guided salvage elective nodal radiotherapy (ENRT) remains limited. This study evaluated oncological outcomes of PSMA PET/CT-guided salvage ENRT in a bi-institutional cohort with extended follow-up. Methods: We retrospectively analysed 179 patients who received PSMA PET/CT-based ENRT for nodal recurrence after radical prostatectomy at two tertiary centres between 2014 and 2024. Patients with pelvic and/or paraaortic lymph node metastases were included. The primary endpoint was metastasis-free survival (MFS); secondary endpoints included biochemical progression-free survival (BPFS) and overall survival (OS). Survival outcomes were estimated using the Kaplan–Meier method, and prognostic factors were assessed using Cox regression analysis. Results: Of the 179 patients, 104 (58.1%) had true biochemical recurrence after radical prostatectomy, whereas 75 (41.9%) had PSA persistence. After a median follow-up of 60.3 months, 5-year MFS and BPFS rates were 74.3% and 62.3%, respectively, in patients with true biochemical recurrence, compared with 61.2% and 56.4% in the overall cohort. In multivariable analyses of the entire cohort, concomitant ADT was associated with improved MFS (HR 0.36, p < 0.001) and BPFS (HR 0.26, p < 0.001), compared with no ADT. PSA persistence after surgery was associated with worse outcomes (MFS: HR 2.72, p < 0.001; BPFS: HR 2.09, p = 0.005). Conclusion: PSMA PET/CT-guided salvage ENRT predominantly combined with ADT provides durable long-term disease control in patients with nodal recurrence in routine clinical practice. In patients with true recurrence after radical prostatectomy, the 5-year MFS rate was 74.3%, approaching outcomes reported in prospective trials. However, the absence of systematically collected clinician-assessed toxicity and patient-reported outcomes precludes a reliable assessment of treatment tolerability.

Suspicion remains high despite inconclusive PET findings, a comprehensive multimodal diagnostic approach including clinical evaluation, laboratory biomarkers, flow cytometry, and careful biopsy site selection remains essential to establish the correct diagnosis.The usefulness of [ 18 F]FDG PET/CT also extends to colorectal cancer. In a retrospective study including patients with colorectal carcinoma and colorectal adenoma, Li et al. (4) showed that volumetric metabolic parameters, particularly metabolic tumor volume (MTV) and total lesion glycolysis (TLG), outperform conventional SUV-based metrics in distinguishing malignant from benign colorectal lesions. These findings reinforce the growing importance of volumetric PET metrics, which may contribute to more accurate lesion characterization. The diagnostic value of [ 18 F]FDG PET/CT in colorectal cancer was further explored by Gong et al. (5), who compared PET/CT with whole-body bone scintigraphy using SPECT for the detection of bone metastases. Their results clearly demonstrated the superior diagnostic performance of PET/CT, which achieved substantially higher sensitivity, specificity, and overall diagnostic accuracy. The relevance of [ 18 F]FDG PET/CT is also reflected in the diagnosis of other tumor entities. Namely, the case reported by Yang et al. (6) highlights the pivotal contribution of PET/CT in the evaluation of oral mucosal melanoma. By accurately defining the extent of disease, PET/CT demonstrated its value as an essential component of multidisciplinary oncological management, even in rare clinical scenarios.While [ 18 F]FDG remains the reference standard for most oncological indications, the continuous development of novel radiopharmaceuticals is rapidly reshaping the landscape of molecular imaging. Among these, fibroblast activation protein inhibitor (FAPI)-based tracers have emerged as one of the most promising tracers of recent years. Two contributions included in this Research Topic further illustrate the expanding role of this imaging approach. In a retrospective single-center study, Liu and colleagues (7) evaluated the diagnostic performance of [ 18 F]AlF-NOTA-FAPI-04 PET/CT in 69 therapy-naïve patients with suspected breast cancer, comparing its performance with that of conventional multimodality imaging, including ultrasonography, mammography, breast magnetic resonance imaging, computed tomography, and bone scintigraphy. Although conventional imaging maintained excellent accuracy for the assessment of primary breast lesions, FAPI PET/CT demonstrated clear advantages in the evaluation of regional lymph node involvement. These findings suggest that FAPI PET/CT may complement rather than replace conventional breast imaging, providing additional information in those clinical scenarios where accurate staging is most likely to influence therapeutic decision-making. The complementary value of FAPI imaging is further highlighted by the case report presented by Cheng et al. (8). A patient with progressive gastric outlet obstruction, marked weight loss, and persistent clinical suspicion of gastric cancer repeatedly underwent endoscopic biopsies that revealed only chronic inflammatory changes. Whereas conventional [ 18 F]FDG PET/CT demonstrated only mild uptake, [ 68 Ga]Ga-FAPI-04 PET/CT identified intense tracer accumulation corresponding to the infiltrative gastric lesion, guiding definitive surgical management. Histopathological examination confirmed a poorly differentiated gastric adenocarcinoma with signet-ring cell features.However, the potential of PET/CT is not limited to cancer characterization. An example of this evolving perspective is provided by Liu et al. (9), who explored the feasibility of [ 18 F]NaF PET/CT as a comprehensive tool for opportunistic bone health assessment in patients with prostate cancer without skeletal metastases. By combining low-dose CT-derived trabecular attenuation with quantitative measurements of fluoride uptake, the authors demonstrated a strong correlation between structural bone density and bone metabolism while identifying metabolically discordant phenotypes that would not be evident using anatomical imaging alone. The study also suggests that the added clinical value of [ 18 F]NaF PET/CT may be greatest in patients with indeterminate structural findings, where metabolic information could refine risk stratification beyond conventional CT assessment.The expanding role of PET imaging is equally evident in the field of neuroimaging. In a longitudinal PET/MRI study, Shokri Varniab and colleagues (10) investigated cerebral metabolic changes following high-dose methotrexate treatment in pediatric and young adult patients with cancer. Their findings revealed a dynamic pattern of brain metabolism characterized by an early increase in cortical [ 18 F]FDG uptake shortly after treatment, followed by normalization or mild hypometabolism during later follow-up. Although none of the patients developed clinically evident neurological toxicity, these metabolic alterations likely reflect evolving biological processes occurring before the appearance of structural abnormalities or neurological symptoms. Thus, molecular imaging may provide sensitive biomarkers for monitoring treatment effects long before irreversible damage becomes clinically manifest.To sum up, the studies collected in this Research Topic highlight the significant advances in PET/CT imaging. The growing understanding of [ 18 F]FDG PET/CT, together with the progressive introduction of novel radiopharmaceuticals and advances in quantitative imaging and disease detection, represents a promising perspective for consolidating PET/CT as an essential tool across a wide range of clinical scenarios.

No specific statements regarding the use of 2-[ ¹⁸ F]fluoro-2-deoxy-D-glucose positron-emission tomography/computed tomography ([ ¹⁸ F]FDG PET) in the context of immunotherapy are made in current international oncological guidelines for the management of the two cancer types for which the largest body of evidence has been generated, such as melanoma and non-small cell lung cancer (NSCLC). However, practice guidelines released jointly by leading nuclear medicine societies recommended the use of [ ¹⁸ F]FDG PET alongside computed tomography (CT) before immunotherapy initiation, for early response assessment, and in patients considered for therapy discontinuation. In the present paper we critically reviewed the available literature on the comparison between [ ¹⁸ F]FDG PET and CT for response assessment in patients undergoing immunotherapy, with the aim to identify where metabolic imaging holds the most significant promise. In early response assessment, where an accurate discrimination between pseudoprogression and true tumor progression is necessary, [ ¹⁸ F]FDG PET is of limited value. In contrast, there are at least two clinical scenarios in which [ ¹⁸ F]FDG PET could outperform CT because of its high negative predictive value, that are the evaluation of response to neoadjuvant immunotherapy or before therapy discontinuation. We emphasized that the generation of robust evidence is necessary before clinical implementation, as it ensures the optimal allocation of resources and better patient care.

Background: Little is known about predictors of response to radionuclide therapy with PSMA-ligands in patients with [ ¹⁸ F]FDG-positive metastatic castration-resistant prostate cancer (mCRPC). We assessed the correlation between baseline characteristics, including dual tracer PET parameters, and response to [ ¹⁷⁷ Lu]Lu-PSMA-I&T in a cohort of patients with [ ¹⁸ F]FDG-positive mCRPC. Prognostic factors related to progression-free survival (PFS) and overall survival (OS) were also investigated. Methods: mCRPC patients who underwent [ ⁶⁸ Ga]Ga-PSMA-11 and [ ¹⁸ F]FDG PET/CT prior to [ ¹⁷⁷ Lu]Lu-PSMA-I&T were retrospectively evaluated. Only [ ¹⁸ F]FDG-positive patients were included in the analysis. A semi-automatic segmentation tool was applied to measure the whole-body maximum standardized uptake value (SUV _max ), mean standardized uptake value (SUV _mean ), metabolic tumor volume (MTV), and total lesion uptake (TLU) on both PET/CTs. PSA response was defined as ≥ 30% and ≥ 50% decline. Imaging response, assessed two months after the last cycle, was defined according to RECIST 1.1 and/or PSMA PET progression (PPP) criteria. Clinical, biochemical, and imaging-based factors were correlated to response to treatment, PFS, and OS. Results: Twenty-five [ ¹⁸ F]FDG-positive patients who received [ ¹⁷⁷ Lu]Lu-PSMA-I&T were included. PSA30 and PSA50 responses were achieved in 11/25 (44%) and in 9/25 (36%) patients, respectively. In the univariate analysis [ ⁶⁸ Ga]Ga-PSMA-11 SUV _mean ( p = 0.022) and [ ⁶⁸ Ga]Ga-PSMA/[ ¹⁸ F]FDG SUV _mean ratio ( p = 0.021) were significantly associated with PSA30 response. [ ⁶⁸ Ga]Ga-PSMA-11 SUV _mean was also significant in the multivariate model. ROC analysis indicated an optimal [ ⁶⁸ Ga]Ga-PSMA-11 SUV _mean cutoff value of 10.23 (AUC = 0.741), and a best discriminating [ ⁶⁸ Ga]Ga-PSMA/[ ¹⁸ F]FDG SUV _mean cutoff ratio of 2.08 (AUC = 0.727). In the univariate analysis for radiological PFS (rPFS), high ALP ( p = 0.023), [ ⁶⁸ Ga]Ga-PSMA-11 MTV ( p = 0.011), [ ⁶⁸ Ga]Ga-PSMA-11 TLU ( p = 0.015), and [ ¹⁸ F]FDG MTV ( p = 0.013) were significantly associated with shorter rPFS. [ ⁶⁸ Ga]Ga-PSMA-11 MTV showed a borderline association with rPFS in the multivariate model ( p = 0.061). Hemoglobin levels ( p = 0.008), ALP ( p = 0.018) and PSA ( p = 0.023) values before treatment were associated with OS, as well as [ ⁶⁸ Ga]Ga-PSMA-11 MTV ( p = 0.003), [ ⁶⁸ Ga]Ga-PSMA-11 TLU ( p = 0.025), and [ ¹⁸ F]FDG MTV ( p = 0.024). However, no independent predictors of OS were identified in the multivariate analysis. Conclusions: Our preliminary results suggest that a whole-body [ ⁶⁸ Ga]Ga-PSMA-11 SUV _mean higher than 10 and a [ ⁶⁸ Ga]Ga-PSMA-11/[ ¹⁸ F]FDG SUV _mean ratio > 2 may serve as useful predictors for identifying patients likely to achieve at least a 30% reduction in PSA levels, even among [ ¹⁸ F]FDG-positive mCRPC patients. Furthermore, our findings support the prognostic significance of tumor burden either calculated by imaging-based volumetric parameters or by known biochemical markers of disease.

Peptide receptor radionuclide therapy (PRRT) has established itself as a pivotal component in the management of advanced, somatostatin receptor (SSTR)-positive neuroendocrine tumours (NETs). The NETTER-1 phase III trial demonstrated that [ ¹⁷⁷ Lu]Lu-DOTATATE significantly prolongs progression-free survival (PFS) and improves quality of life in patients with midgut NETs refractory to somatostatin analogues, leading to regulatory approval by both EMA (2017) and FDA (2018). The recent NETTER-2 phase III trial further extended these findings by supporting the first-line use of PRRT in Grade 2 and 3 gastroentero-pancreatic (GEP)-NETs (Ki-67 ≥ 10 ≤ 55%). Beyond standard β-emitting therapy, several developments are reshaping the field: the clinical adoption of SSTR antagonists such as radiolabelled JR-11 and LM3, targeted α-particle–emitting therapies ( ²²⁵ Ac, ²¹² Pb, ²¹³ Bi) for resistant disease, and rational combination strategies with chemotherapy, DNA-repair inhibitors, and immunotherapy. Parallel innovation in radiopharmaceutical chemistry has yielded new peptide ligands, including cholecystokinin-2 receptor (CCK2R)–targeted compounds such as DOTA-MGS5, which show promise for rare NETs such as medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). This review summarises clinical evidence, translational advances, and future perspectives for PRRT as a cornerstone of precision nuclear oncology. Emphasis is placed on expanding indications, integrating α-emitters, improving safety and dosimetry, and developing novel theragnostic ligands that enable personalised treatment strategies for NETs patients.

Background/Objectives: Peptide receptor radionuclide therapy (PRRT) is an established treatment for neuroendocrine tumors (NETs), enabling targeted radiation delivery via radiolabeled peptides. Small cell lung cancer (SCLC) remains a major therapeutic challenge due to its aggressive nature and poor prognosis. Despite advances, relapse rates are high and effective therapies are limited. We previously demonstrated the diagnostic potential of the cholecystokinin-2 receptor (CCK2R)-targeting minigastrin analog [⁶⁸Ga]Ga-DOTA-MGS5 in PET/CT imaging of different NETs. Building on this, we developed and evaluated [¹⁷⁷Lu]Lu-DOTA-MGS5 as a therapeutic PRRT agent. Methods: Preclinical studies investigating the receptor-mediated cellular internalization and intracellular distribution over time in A431 cells with and without CCK2R expression were performed using the fluorescent tracer ATTO-488-MGS5. Short- and long-term cytotoxic effects of [¹⁷⁷Lu]Lu-DOTA-MGS5 were evaluated on the same cell line using trypan blue exclusion and clonogenic survival assays. CCK2R expression was assessed by immunohistochemistry in 42 SCLC tissue specimens. In addition, the first PRRT with [¹⁷⁷Lu]Lu-DOTA-MGS5 was conducted in a patient with extensive disease SCLC (ED-SCLC) after confirming CCK2R-positive uptake in [⁶⁸Ga]Ga-DOTA-MGS5 PET/CT. Results: Rapid binding and internalization into A431-CCK2R cells, with progressive accumulation in intracellular compartments, was observed for ATTO-488-MGS5. Short-term irradiation effects of [¹⁷⁷Lu]Lu-DOTA-MGS5 were comparable for 4 h and 24 h incubation and were between the effects obtained with 2 and 4 Gy of external beam radiotherapy (EBRT). Clonogenic survival of A431-CCK2R cells incubated with increasing activity of [¹⁷⁷Lu]Lu-DOTA-MGS5 decreased in a dose-dependent manner. Immunohistochemistry on SCLC specimens confirmed moderate to high CCK2R expression in 16 out of 42 SCLC samples. In the first patient with SCLC treated with four cycles of [¹⁷⁷Lu]Lu-DOTA-MGS5 with a total activity of 17.2 GBq, an improvement in clinical symptoms was observed. Conclusions: The preclinical and clinical results confirm the feasibility of [¹⁷⁷Lu]Lu-DOTA-MGS5 PRRT in patients with SCLC and support further clinical studies investigating the therapeutic value and clinical applicability of this new CCK2R-targeted theranostic approach in larger patient cohorts.

Objectives: The identification of metastatic disease in patients with biochemical failure of prostate cancer (PCa) after radical prostatectomy (RP) determines subsequent treatment management. Our objectives were (i) to assess the prevalence of metastatic PCa in patients with biochemical failure following RP and PSA levels ≤ 1 ng/mL, as detected by ¹⁸ F-PSMA-1007 PET/CT (PSMA-PET), and (ii) to identify predictors of metastatic disease. Methods: Fifty-five patients with biochemical recurrence (BCR, n = 47) or persistent disease ( n = 8) following RP as their primary and only prior treatment were retrospectively included if presenting with PSA levels ≤ 1 ng/mL. Patients who received any other anticancer treatment were excluded. PSMA-PET findings were categorized as either local recurrence (i.e., prostatic fossa and seminal vesicles) or metastases. Predictors of PSMA-PET positivity were assessed with univariate and multivariate regression analyses both in the whole sample and in two subgroups defined according to PSA levels (Group A = PSA < 0.5 ng/mL; Group B = PSA between 0.5 and 1 ng/mL). Results: Median PSA at the time of PET/CT was 0.37 ng/mL (range: 0.13–1.0). PSMA-PET was positive in 22/55 (40%) patients, 14/55 (25%) patients had metastatic disease. Overall, 31 PSMA-positive lesions were identified: 12/31 (39%) and 19/31 (61%) were local recurrences and metastases, respectively. In the whole cohort, ISUP grade > 3 ( p = 0.003), pN1 status after surgery ( p = 0.011), time to BCR ≤ 26 months ( p = 0.03), and persistent disease ( p = 0.003) were significantly associated with a higher rate of PSMA-positive metastases. At multivariate analysis, ISUP grade > 3 ( p = 0.016) was the only independent predictor of metastases. Metastatic disease was detected in 8/38 (21%) patients in Group A and in 6/17 (35%) patients in Group B, respectively. In Group A, pN1 ( p = 0.043) and persistent disease ( p = 0.040) were significant predictors of metastases. In Group B, ISUP grade > 3 was the only predictor ( p = 0.028). Conclusions: ISUP grade > 3, time to BCR ≤ 26 months, pN1 status, and persistent disease after surgery indicated a higher likelihood of PSMA-positive metastatic disease in a homogeneous cohort of patients with biochemical failure and low PSA values. pN1 status and persistent disease were significant predictors of metastatic disease also in patients with PSA levels < 0.5 ng/mL.

Background: Recent data demonstrate that one possibility for increasing Peptide Receptor Radionuclide Therapy (PRRT) results lies in the combination of PRRT with chemotherapy. This study aimed to evaluate response and outcome in [ ¹⁸ F]FDG-positive metastatic neuroendocrine tumor (mNET) patients treated with PRRT alone or in combination with temozolomide (TEM) plus/minus capecitabine (CAP). Methods: All mNET patients presented with [ ¹⁸ F]FDG-positive disease prior to treatment (or retreatment) with PRRT alone or in combination with chemotherapy were retrospectively included in this single-center study. Patients received [ ¹⁷⁷ Lu]Lu-DOTATATE with an activity of 7.4 GBq alone or combined with TEM (200 mg/kg/5d) plus/minus CAP (1500 mg/kg/14d). Contrast-enhancement CT (ceCT), [ ⁶⁸ Ga]Ga-DOTATOC and [ ¹⁸ F]FDG PET/CT studies were performed at baseline, after treatment, and every 6 months thereafter. Overall response rate (ORR) and disease control rate (DCR) were calculated for each group. Survival analysis was performed using the Kaplan-Meier method. Adverse events were collected and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: A total of 24 patients were included in the final analysis. Group 1 received PRRT with [ ¹⁷⁷ Lu]Lu-DOTATATE alone ( n = 10), group 2 received [ ¹⁷⁷ Lu]Lu-DOTATATE plus TEM ( n = 7), and group 3 received [ ¹⁷⁷ Lu]Lu-DOTATATE plus CAPTEM ( n = 7). There were no differences between groups in terms of clinicopathological features before treatment. The pancreas was the primary tumor site in 58%, and 92% of patients had more than three liver metastases. Based on [ ⁶⁸ Ga]Ga-DOTATOC PET/CT and ceCT, in group 1 the ORR and DCR were 10% and 50%, respectively. [ ¹⁸ F]FDG PET/CT showed 2 responders (1 CR, 1 PR). In group 2, the ORR and DCR were 14% and 43%, respectively. [ ¹⁸ F]FDG PET/CT showed 2 responders (1 CR, 1 PR). In group 3, the ORR and DCR were 71%, respectively. [ ¹⁸ F]FDG PET/CT showed 5 responders (3 CR, 2 PR). In the latter group, 4/7 patients had not progressed and 5/7 were still alive at the time of analysis after a median follow-up of 31 months. Conclusion: Our results show PRRT combined with CAPTEM as the most promising regimen, achieving higher response rates in [¹⁸F]FDG-positive mNETs compared with PRRT alone or PRRT plus TEM. Further studies are required to confirm its added value in terms of survival outcomes. No increased toxicity seems to be associated with combination therapy compared to PRRT alone.