Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [⁶⁸Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2–6) RLT cycles. Maximum and mean standardized uptake values (SUV_max, SUV_mean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7–17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUV_max decline or falling below the blood pool uptake were considered responsive; ≥30% SUV_max increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUV_max, SUV_mean, and TLR values were associated with lesion response by a moderate but significant correlation (r_s = 0.33, p < 0.001, r_s = 0.32, p < 0.001, and r_s = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUV_max, SUV_mean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [⁶⁸Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [¹⁷⁷Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.

Bone-seeking ²²³Radium-dichloride (²²³Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with ¹⁷⁷Lutetium-PSMA-617 (¹⁷⁷Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of ¹⁷⁷Lu-PSMA-617 in patients with progressive bone involvement under treatment with ²²³Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started ¹⁷⁷Lu-PSMA-617 within 8 weeks after the last ²²³Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of ²²³Ra and a median of 4 (IQR 2–7) cycles ¹⁷⁷Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first ¹⁷⁷Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of ¹⁷⁷Lu-PSMA-617 after failing ²²³Ra is effective with an acceptable toxicity profile.

^99mTc-MIBI (MIBI) imaging is able to exclude malignancy of hypofunctioning thyroid nodules (TNs) with high probability but false positive results are frequent due to low specificity. Therefore, pre-test selection of appropriate TNs is crucial. For image evaluation visual and semiquantitative methods (Washout index, WOInd) are used. Aim of this study was to evaluate the diagnostic performance of MIBI imaging in hypofunctioning TNs with indeterminate fine-needle aspiration cytology results in a multicentric European setting. Patients with hypofunctioning TNs, EU-TIRADS 4 or 5, Bethesda III/IV and MIBI imaging were included. For visual evaluation the intensity of MIBI uptake in the TN was compared to normal thyroid tissue. 358 patients with 365 TNs (n = 68 malignant) were included. Planar imaging (SPECT) showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 96% (94%), 21% (22%), 22% (15%), 96% (96%), and 35% (32%). The WOInd (38.9% of all cases, optimal cutoff: −19%) showed a sens 100% (spec 89%, PPV 82%, NPV 100%, ACC 93%). For hypofunctioning TNs at intermediate or high risk with indeterminate cytology, a MIBI negative result on visual evaluation is an effective tool to rule-out thyroid malignancy. The semi-quantitative method could considerably improve overall diagnostic performance of MIBI imaging.

Advanced stage metastatic prostate cancer with extensive bone marrow involvement is associated with a high risk of therapy-induced myelotoxicity and unfavorable outcomes. The role of salvage radioligand therapy (RLT) with ¹⁷⁷Lu-PSMA-617 in this subset of patients remains to be further elucidated. Forty-five patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and diffuse bone marrow involvement were treated with repeated cycles of RLT after having exhausted standard treatment options. A mean treatment activity of 7.4 ± 1.4 GBq ¹⁷⁷Lu-PSMA-617 was administered in a median of four treatment cycles (IQR 2-6) and the mean cumulative activity was 32.6 ± 20.1 GBq. After two RLT cycles, ≥50% PSA decline was observed in 25/45 (56%) patients and imaging-based partial remission (PR) was observed in 18/45 (40%) patients. Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0–9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2–12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001). Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18–8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000–1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively. Cumulative treatment activity and absorbed whole-body dose were not correlated with new onset grade ≥ 3 hematotoxicity (p = 0.91, p = 0.69). No event of grade ≥ 3 chronic kidney disease was observed during RLT or the follow-up. Last line RLT with ¹⁷⁷Lu-PSMA-617 in mCRPC patients with diffuse bone marrow involvement may thus contribute to prolonged disease control at an acceptable safety profile.

This study aims to assess the change in uptake to reference organs, including the liver, parotid and salivary glands after radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-PSMA-617 in relation to pretreatment imaging metrics. Eighty-five patients with mCRPC underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging prior to (pre RLT PET) and after (post RLT PET) a median of 3 (IQR 2-6) RLT cycles with [¹⁷⁷Lu]Lu-PSMA-617. PSMA-positive tumor burden was stratified into 4 groups based on modified PROMISE criteria (oligofocal, multifocal, disseminated, diffuse). Uptake (SUV_mean, SUV_max) in liver tissue, parotid and submandibular glands was measured. A control group was established with 54 patients who had received two separate PET acquisitions following the same protocol (PET1, PET2) within 12 months for localized or oligofocal prostate cancer without RLT in the interim. Baseline uptake values (SUV_mean, SUV_max) in parotid (10.8 ± 3.2, 16.8 ± 5.4) and submandibular glands (11.3 ± 2.8, 18.1 ± 4.7) are 2-fold compared to liver uptake (4.9 ± 1.4, 7.7 ± 2.0), with no significant change between PET 1 and PET 2 in the control group. In the RLT group, increasing tumor burden class is significantly associated with decreasing uptake in the liver (p = 0.013), parotid (p < 0.001) and submandibular glands (p < 0.001); this tumor sink effect by respective tumor burden is widely maintained after RLT (p = 0.011, p < 0.001, p < 0.001). RLT has a significant impact on salivary gland uptake with decreasing values per patient in all groups of disease burden change (up to −30.4% in submandibular glands, p < 0.001), while liver tissue shows rising values in patients with declining tumor burden throughout RLT (+18.6%, p = 0.020). Uptake in liver tissue and salivary glands on [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging is inversely related to tumor burden prior to and following RLT with [¹⁷⁷Lu]Lu-PSMA-617. Per patient, salivary gland uptake is further reduced throughout RLT independently from tumor burden, while changes in liver uptake remain burden-dependent. Liver and salivary gland uptake-derived metrics and segmentation thresholds may thus be of limited value when used as reference for response assessment to RLT.

In the evolving landscape of precision oncology, this review delineates the role of radiopharmaceuticals targeting the norepinephrine transporter (NET), with a particular focus on the current clinical application of ¹²³I-MIBG diagnostic imaging and ¹³¹I-MIBG therapeutics, in particular for pheochromocytoma, neuroblastoma, or paraganglioma. We will also highlight recently introduced ¹⁸F-labeled NET targeting imaging radiotracers, which would offer unparalleled resolution, enhanced tumor localization, and staging properties. Complementing these novel second-generation PET agents in a theranostic approach, astatine-211 meta-astatobenzylguanidine (²¹¹At-MABG) would leverage the advantages of alpha-particles to selectively target and eradicate NET-expressing tumor cells with minimal off-target effects.