Search

The combination of high and low LET radionuclides has been tested in several patient studies to improve treatment response. Radionuclide mixtures can also be released in nuclear power plant accidents or nuclear bomb deployment. This study investigated the DNA damage response and DNA double-strand break (DSB) repair in peripheral blood mononuclear cells (PBMCs) after internal exposure of blood samples of 10 healthy volunteers to either no radiation (baseline) or different radionuclide mixtures of the α- and β-emitters [ 223 Ra]RaCl 2 and [ 177 Lu]LuCl 3 , i.e., 25 mGy/75 mGy, 50 mGy/50 mGy and 75 mGy/25 mGy, respectively. DSB foci and γ-H2AX α-track enumeration directly after 1 h of exposure or after 4 h or 24 h of repair revealed that radiation-induced foci (RIF) and α-track induction in 100 cells was similar for mixed α/β and pure internal α- or β-irradiation, as were the repair rates for all radiation qualities. In contrast, the fraction of unrepaired RIF (Q β ) in PBMCs after mixed α/β-irradiation (50% 223 Ra & 50% 177 Lu: Q β = 0.23 ± 0.10) was significantly elevated relative to pure β-irradiation (50 mGy: Q β, pure = 0.06 ± 0.02), with a similar trend being noted for all mixtures. This α-dose-dependent increase in persistent foci likely relates to the formation of complex DNA damage that remains difficult to repair.

This work reports on a model that describes patient-specific absorbed dose-dependent DNA damage response in peripheral blood mononuclear cells of thyroid cancer patients during radioiodine therapy and compares the results with the ex vivo DNA damage response in these patients. Blood samples of 18 patients (nine time points up to 168 h post-administration) were analyzed for radiation-induced γ-H2AX + 53BP1 DNA double-strand break foci (RIF). A linear one-compartment model described the absorbed dose-dependent time course of RIF (Parameters: c characterizes DSB damage induction; k 1 and k 2 are rate constants describing fast and slow repair). The rate constants were compared to ex vivo repair rates. A total of 14 patient datasets could be analyzed; c ranged from 0.012 to 0.109 mGy -1 , k 2 from 0 to 0.04 h -1 . On average, 96% of the damage is repaired quickly with k 1 (range: 0.19-3.03 h -1 ). Two patient subgroups were distinguished by k 1 -values ( n = 6, k 1 > 1.1 h -1 ; n = 8, k 1 < 0.6 h -1 ). A weak correlation with patient age was observed. While induction of RIF was similar among ex vivo and in vivo, the respective repair rates failed to correlate. The lack of correlation between in vivo and ex vivo repair rates and the applicability of the model to other therapies will be addressed in further studies.

Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [ 68 Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [ 68 Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [ 68 Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [ 68 Ga]KISS1-54 was obtained in a 77 ± 7% radiochemical yield and at a >99% purity. The [ 68 Ga]KISS1-54 cell uptake amounted to 0.6-4.4% per 100,000 cells. Moreover, the accumulation of [ 68 Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [ 68 Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [ 68 Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.

Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [ 123/131 I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.

Background: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT)., Methods: A total of 67 patients (26 females; age, 41-80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUV max ) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded., Results: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUV max was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUV max vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = -0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively., Conclusions: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patients.

Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence., Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3-72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0)., Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1-97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2-100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred., Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.

(1) Background: We aimed to quantitatively investigate [ 68 Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [ 68 Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV mean ) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV max ), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV mean ). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV mean values were 2.15 in the pancreas (range, 1.05-9.91), 1.42 in the right (range, 0.57-3.06) and 1.41 in the left kidney (range, 0.73-2.97), 1.2 in the heart (range, 0.46-2.59), 0.86 in the spleen (range, 0.55-1.58), 0.65 in the liver (range, 0.31-2.11), and 0.57 in the bone marrow (range, 0.26-0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV max (ρ = 0.29, p = 0.07) and TV (ρ = -0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV max (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV max (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [ 68 Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs.

(1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV max were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUV maxall , ΔSUV max10 , ΔSUV max5 , ΔPSMA-TV all , ΔPSMA-TV 10 , ΔPSMA-TV 5 , ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUV max10 /ΔSUV max5 or ΔPSMA-TV 10 /ΔPSMA-TV 5 compared to ΔSUV maxall and ΔPSMA-TV all . For patients treated with taxanes, up to 6/21 (28.6%) showed clinically relevant deviations between ΔSUV maxall and ΔSUV max10 or ΔSUV max5 , but only up to 2/21 (9.5%) patients showed clinically relevant deviations between ΔPSMA-TV all and ΔPSMA-TV 10 or ΔPSMA-TV 5 . For patients treated with radioligand therapy (RLT), up to 5/28 (17.9%) showed clinically relevant deviations between ΔSUV maxall and ΔSUV max10 or ΔSUV max5 , but only 1/28 (3.6%) patients showed clinically relevant deviations between ΔPSMA-TV all and ΔPSMA-TV 10 or ΔPSMA-TV 5 . The highest correlations with ΔPSA were found for ΔPSMA-TV all (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV 10 (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV 5 (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUV maxall (r = 0.60, p = 0.02) and with ΔSUV max10 (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUV maxall (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT.

(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [ 177 Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [ 177 Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [ 99m Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = -0.40, p = 0.005) and the eGFR change with Gleason score (r = -0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [ 177 Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.

Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with 18 F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUV max , SUV peak , SUV mean ) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUV max was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories ( p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUV max and SUV peak compared to the entire PSMA-RADS-4 or -5 cohort ( p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort ( p < 0.0001), but not to the PSMA-RADS-4 cohort (SUV max , p = 0.07; SUV peak , p = 0.08). SUV mean ( p = 0.30) and TL-PSMA ( p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT ( p = 0.0066), which was driven by lymph nodes ( p = 0.0239), but not bone lesions ( p = 0.15). SUV max was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in 18 F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUV mean and TL-PSMA in contrast to PSMA-TV.

Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate-specific membrane antigen (PSMA) is crucial for the assessment of adequate PSMA expression in patients with metastatic castration-resistant prostate cancer (mCRPC) prior to PSMA radioligand therapy (PSMA RLT). Moreover, initial dual tracer staging using combined PSMA and [ 18 F]fluorodeoxyglucose (FDG) PET/CT provides relevant information, since discordant FDG-positive but PSMA-negative (FDG+/PSMA-) lesions constitute a negative prognostic marker of overall survival (OS) after PSMA RLT. However, little is known about the prognostic implications of dual tracer imaging for restaging at follow-up. The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA- lesions during or after PSMA RLT., Methods: This bicentric analysis included 32 patients with mCRPC who underwent both FDG and PSMA PET/CT imaging after two or four cycles of PSMA RLT. Patients with FDG+/PSMA- lesions prior to PSMA RLT were not considered. The presence of FDG+/PSMA- lesions was assessed with follow-up dual tracer imaging of patients after two or four cycles of PSMA RLT. Patients with at least one new FDG+/PSMA- lesion were compared to patients without any FDG+/PSMA- lesions at the respective time points. A log-rank analysis was used to assess the difference in OS between subgroups., Results: After two cycles of PSMA RLT, four of 32 patients (13%) had FDG+/PSMA- metastases. No significant difference in OS was observed ( p = 0.807), as compared to patients without FDG+/PSMA- lesions. Follow-up dual tracer imaging after the 4th cycle of PSMA RLT was available in 18 patients. Of these, four patients presented with FDG+/PSMA- findings ( n = 2 already after two cycles). After the fourth cycle of PSMA RLT, no significant difference in OS was observed between patients with and without FDG+/PSMA- lesions ( p = 0.442)., Conclusion: This study shows that FDG+/PSMA- lesions develop in a limited number of patients undergoing PSMA RLT. Further studies are needed to establish the clinical relevance of such lesions.

Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1-10) lines of therapy. Six (25%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUV max ) in patients harboring del(17p) compared with those without del(17p) ( p = 0.025). Moreover, a high SUV max of >15 indicated significantly shortened progression-free survival (PFS) ( p = 0.01) and overall survival (OS) ( p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUV max of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/ TP53 alteration and high SUV max on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point.

This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV mean ) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans ( r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans ( r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV mean of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans ( r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR mean ) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT ( r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT ( r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR mean in 18F-FDG PET/CT ( r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR max of lumbar vertebrae L2-L4 ( r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.

11 C-methionine ( 11 C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than 18 F-fluorodeoxyglucose ( 18 F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of 11 C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to 18 F-FDG. Twenty-two patients with newly diagnosed, treatment-naïve symptomatic MM who had undergone 11 C-MET and 18 F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion 11 C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), 11 C-MET detected more focal lesions (FL) than FDG ( p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in 11 C-MET than in 18 F-FDG ( p < 0.05, respectively). 11 C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that 11 C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than 18 F-FDG. Its implications for prognosis evaluation need further investigation.