FDG-PET/CT is a powerful tool to predict and evaluate response to chimeric antigen receptor (CAR) T-cell therapy in Non-Hodgkin-Lymphoma (NHL).

Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment especially for Non-Hodgkin-Lymphoma (NHL). This study evaluates the role of fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) in NHL treated with CAR T-cell therapy concerning response assessment and prognosis.We evaluated 34 patients with NHL who received a CAR T-cell therapy between August 2019 and July 2022. All patients underwent a pre-therapeutic FDG-PET/CT (PET-0) 6 days prior and a post-therapeutic FDG-PET/CT (PET-1) 34 days after CAR T-cell therapy. Deauville score (DS) was used for evaluation of response to therapy and compared to a minimum follow-up of 5 months.19/34 (55.9%) patients achieved DS ≤ 3 on PET-1, the remaining 15 (44.1%) patients had DS > 3 on PET-1. 14/19 patients with DS ≤ 3 on PET-1 had no relapsed or refractory (r/r)-disease and were still alive at last follow-up. The other 5 patients had r/r-disease and 4 of these died. Except for two patients who had no r/r-disease, all other patients (13/15) with DS > 3 on PET-1 had r/r-disease and 12 of these subsequently died. Patients with DS ≤ 3 on PET-1 had significantly better progression free survival (PFS; HR: 5.7; p < 0.01) and overall survival (OS; HR: 5.0; p < 0.01) compared to patients with DS > 3 on PET-1. In addition, we demonstrated that patients with DS ≤ 4 on PET-0 tended to have longer PFS (HR: 3.6; p = 0.05).Early FDG-PET/CT using the established DS after CAR T-cell therapy is a powerful tool to evaluate response to therapy.

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Volumetric Parameters Derived from CXCR4-Directed PET/CT Predict Outcome in Patients with Gastrointestinal Neuroendocrine Carcinomas.

BACKGROUND: Gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs) are an aggressive subgroup of neuroendocrine neoplasms (NENs). In patients affected with NEN, there is a growing body of evidence that increased C-X-C motif chemokine receptor (CXCR4) expression is linked to decreasing overall survival (OS) in an ex-vivo setting. Thus, we aimed to determine whether the in-vivo-derived CXCR4-directed whole-body PET signal can also determine GEP-NEC patients with shorter OS. METHODS: We retrospectively included 16 patients with histologically proven GEP-NEC, who underwent CXCR4-directed PET/CT for staging and therapy planning. We assessed maximum, peak, and mean standardized uptake values as well as whole-body tumor volume (TV) and total-lesion uptake (TLU = SUVmean × TV) using a semi-automatic segmentation tool with a 50% threshold. Association of PET-based biomarkers and OS or radiographic progression-free survival (rPFS; according to RECIST 1.1 criteria) was analyzed using univariable and multivariable cox regression. RESULTS: Median OS and rPFS was 7.5 and 7 months, respectively. A significant correlation between TV and TLU was found for OS (TV: hazard ratio (HR) 1.007 95% confidence interval (CI) 1.000-1.014, p = 0.0309; TLU: HR 1.002 95% CI 1.000-1.003, p = 0.0350) and rPFS (TV: HR 1.010 95% CI 1.002-1.021; p = 0.0275; TLU: HR 1.002 95% CI 1.000-1.004, p = 0.0329), respectively. No significant correlation with OS or rPFS was found for non-volumetric parameters (p > 0.4). TV remained a significant predictive marker for OS and rPFS in multivariable analysis (OS: HR 1.012 95%, CI 1.003-1.022, p = 0.0084; rPFS: HR 1.009, 95% CI 0.9999-1.019, p = 0.0491), whereas TLU remained only prognostic for OS (HR 1.009, 95% CI 0.9999-1.019, p = 0.0194) but narrowly failed significance for rPFS (p = 0.0559). CONCLUSION: In-vivo assessment of CXCR4 PET-derived volumetric parameters is predictive for outcome of patients with GEP-NEC and could be used as a risk stratification tool, which detects patients prone to early progression.

Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy.

BACKGROUND: Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT. METHODS: Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [68Ga]Ga-PSMA I&T or [18F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria. RESULTS: 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION- compared to VISION+ (OS: VISION-: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.1, p < 0.01; PFS: VISION-: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0-7.8, p < 0.01). For patients rated TheraP-, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP-: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8-3.3, p = 0.2; PFS: TheraP-: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0-4.5, p < 0.01). CONCLUSION: Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients.

PSMA PET/CT for Response Assessment of 177Lu-PSMA Therapy.

Prostate-specific membrane antigen (PSMA) PET/CT has been widely integrated into the management of prostate cancer (PCa) patients with biochemical recurrence, is increasingly used for initial staging in high-risk patients prior to surgery or to identify candidates for PSMA-targeted radioligand therapy (RLT). To date, monitoring response in PCa patients in prospective studies remains the domain of conventional imaging, such as magnetic resonance/CT or bone scintigraphy. With the increasing use of PSMA-targeted PET/CT in PCa, however, varying criteria based on molecular imaging have been established to define progressive disease, including "PSMA PET Progression Criteria," "Response evaluation criteria in PSMA PET/CT (RECIP 1.0)" or consensus statements of respective societies. In the present review, we will discuss the current status of PSMA PET/CT for response monitoring, focusing on PSMA RLT with [177Lu]Lu-labeled PSMA ligands, along with a head-to-head comparison of recently published response criteria.

SUVmean on baseline [18F]PSMA-1007 PET and clinical parameters are associated with survival in prostate cancer patients scheduled for [177Lu]Lu-PSMA I&T.

BACKGROUND: Quantification of [68 Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [18F]-labeled radiotracers, we aimed to determine whether the uptake derived from [18F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters. METHODS: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [177Lu]Lu-PSMA I&T. We calculated SUVmean, SUVmax, PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUVmean) on pre-therapeutic [18F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification. RESULTS: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUVmean, CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUVmean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUVmean below or above a median SUVmean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001). CONCLUSION: A lower SUVmean derived from [18F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification.

PET/CT reading for relapse in non-small cell lung cancer after chemoradiotherapy in the PET-Plan trial cohort.

BACKGROUND: Current studies indicate that fluorine-18-fluorodeoxyglucose positron emission tomography/ computed tomography ([18F]FDG PET/CT) is the most accurate imaging modality for the detection of relapsed locally advanced non-small cell lung cancer (NSCLC) after curatively intended chemoradiotherapy. To this day, there is no objective and reproducible definition for the diagnosis of disease recurrence in PET/CT, the reading of which is relevantly influenced by post radiation inflammatory processes. The aim of this study was to evaluate and compare visual and threshold-based semi-automated evaluation criteria for the assessment of suspected tumor recurrence in a well-defined study population investigated during the randomized clinical PET-Plan trial. METHODS: This retrospective analysis comprises 114 PET/CT data sets of 82 patients from the PET-Plan multi-center study cohort who underwent [18F]FDG PET/CT imaging at different timepoints for relapse, as suspected by CT. Scans were first analyzed visually by four blinded readers using a binary scoring system for each possible localization and the associated reader certainty of the evaluation. Visual evaluations were conducted repeatedly without and with additional knowledge of the initial staging PET and radiotherapy delineation volumes. In a second step, uptake was measured quantitatively using maximum standardized uptake value (SUVmax), peak standardized uptake value corrected for lean body mass (SULpeak), and a liver threshold-based quantitative assessment model. Resulting sensitivity and specificity for relapse detection were compared to the findings in the visual assessment. The gold standard of recurrence was independently defined by prospective study routine including external reviewers using CT, PET, biopsies and clinical course of the disease. RESULTS: Overall interobserver agreement (IOA) of the visual assessment was moderate with a high difference between secure (ĸ = 0.66) and insecure (ĸ = 0.24) evaluations. Additional knowledge of the initial staging PET and radiotherapy delineation volumes improved the sensitivity (0.85 vs 0.92) but did not show significant impact on the specificity (0.86 vs 0.89). PET parameters SUVmax and SULpeak showed lower accuracy compared to the visual assessment, whereas threshold-based reading showed similar sensitivity (0.86) and higher specificity (0.97). CONCLUSION: Visual assessment especially if associated with high reader certainty shows very high interobserver agreement and high accuracy that can be further increased by baseline PET/CT information. The implementation of a patient individual liver threshold value definition, similar to the threshold definition in PERCIST, offers a more standardized method matching the accuracy of experienced readers albeit not providing further improvement of accuracy.

Molecular imaging of arterial fibroblast activation protein: association with calcified plaque burden and cardiovascular risk factors.

PURPOSE: We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden. METHODS: We analyzed 69 oncologic patients who underwent [68 Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma). RESULTS: High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P < 0.01; TBR: r = - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r = - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: r = - 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 - 1.12, P < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13). CONCLUSION: [68 Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise.

Prognostic Value of Tumor Volume Assessment on PSMA PET After 177Lu-PSMA Radioligand Therapy Evaluated by PSMA PET/CT Consensus Statement and RECIP 1.0.

Quantitative evaluation of prostate-specific membrane antigen (PSMA)-targeting PET/CT remains challenging but is urgently needed for the use of standardized PET-based response criteria, such as the PSMA PET/CT consensus statement or Response Evaluation Criteria in PSMA PET/CT (RECIP 1.0). A recent study evaluated the prognostic value of whole-body tumor volume using a semiautomatic method relying on a 50% threshold of lesion SUVmax (PSMATV50). In the present study, we analyzed the suitability of this approach comparing 18F-PSMA-1007 with 68Ga-PSMA-11 PET/CT scans and the potential of PSMATV50 for the prediction of overall survival (OS) in patients before 177Lu-PSMA radioligand therapy (RLT). Moreover, PSMATV50 was integrated into the PSMA PET/CT consensus statement as well as RECIP 1.0, and the prognostic value of these response classification systems was compared. Methods: This retrospective study included 70 patients with metastatic castration-resistant prostate cancer undergoing PSMA RLT. Thirty-three patients were monitored by 68Ga-PSMA-11 PET/CT, and 37 patients by 18F-PSMA-1007 PET/CT. PET/CT scans before (baseline) and at the end of PSMA RLT after 2-4 cycles (follow-up) were separately analyzed by 2 readers. PSMATV50 at baseline and its change at the time of follow-up (ΔPSMATV50, expressed as a ratio) were correlated with OS using Cox proportional-hazards regression. The results of both subgroups were compared. The integration of ΔPSMATV50 in existing response classification systems was evaluated. To assess and compare the discriminatory strength of these classification systems, Gönen and Heller concordance probability estimates were calculated. Results: PSMATV50 determination was technically feasible in all examinations. A higher PSMATV50 at baseline and a higher ΔPSMATV50 were strongly associated with a shorter OS for both 68Ga-PSMA-11 (PSMATV50: hazard ratio [HR] of 1.29 [95% CI, 1.05-1.55], P = 0.009; ΔPSMATV50: HR of 1.83 [95% CI, 1.08-3.09], P = 0.024) and 18F-PSMA-1007 (PSMATV50: HR of 1.84 [95% CI, 1.13-2.99], P = 0.014; ΔPSMATV50: HR of 1.23 [95% CI, 1.04-1.51], P = 0.03). Response assessment provided high discriminatory power for OS for the PSMA PET/CT consensus statement (concordance probability estimate, 0.73) as well as RECIP 1.0 (concordance probability estimate, 0.74). Conclusion: PSMATV50 and ΔPSMATV50 proved to be predictive of OS not only for 68Ga-PSMA-11 but also for 18F-PSMA-1007 PET/CT scans. Subsequent integration of ΔPSMATV50 into the PSMA PET/CT consensus statement and RECIP 1.0 provided equally high prognostic value for both classification systems.

Impact of 68 Ga-FAPI-04 PET/CT on Staging and Therapeutic Management in Patients With Digestive System Tumors.

PURPOSE: We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)-directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI). PATIENTS AND METHODS: Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and 68 Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and 68 Ga-FAPI-04 PET/CT. RESULTS: Compared with GCI, 68 Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%). CONCLUSIONS: In patients affected with digestive system tumors, 68 Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types.

Radiopharmaceuticals for Treatment of Adrenocortical Carcinoma.

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 [123/131I]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.

Diffuse Bone Marrow Involvement of Multiple Myeloma on [ 18 F]PSMA-1007 PET/CT : Is There a Theranostic Potential?

ABSTRACT: A 71-year-old man presented with chronic anemia (hemoglobin 7.3 g/dL). Further serum analyses showed elevated prostate-specific antigen (13 ng/mL), suggestive of prostate cancer. However, ultrasound-guided transrectal sextant biopsy did not find any evidence of prostate cancer. In order to improve guidance of intended repeated biopsy, [ 18 F]prostate-specific membrane antigen (PSMA) 1007 PET/CT was performed, which showed a solitary lesion with strong PSMA expression in the left peripheral zone in the prostate gland. Surprisingly, also a diffuse bone marrow involvement with predominantly osteolytic lesions was observed. This massive osseous tumor burden was clearly discordant to the only relatively mild elevated prostate-specific antigen. The subsequent bone biopsy revealed multiple myeloma. This case does not only highlight a possible pitfall on PSMA PET/CT, but also raises the question on how far PSMA ligands may offer diagnostic and therapeutic potential in multiple myeloma.

Bone marrow impairment during early [177Lu]PSMA-617 radioligand therapy: Haematotoxicity or tumour progression?

BACKGROUND: The recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT. METHODS: In this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12-16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria. RESULTS: All grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079). CONCLUSION: During early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles. German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered ( www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665 ).

Expression of Prostate Specific Membrane Antigen (PSMA) in Breast Cancer.

Background Prostate specific membrane antigen (PSMA) is a promising protein for breast cancer patients. It has not only been detected in prostate cancer but is also expressed by tumor cells and the endothelial cells of tumor vessels in breast cancer patients. PSMA plays a role in tumor progression and tumor angiogenesis. For this reason, a number of diagnostic and therapeutic methods to target PSMA have been developed. Method This paper provides a general structured overview of PSMA and its oncogenic potential, with a special focus on its role in breast cancer. This narrative review is based on a selective literature search carried out in PubMed and the library of Freiburg University Clinical Center. The following key words were used for the search: "PSMA", "PSMA and breast cancer", "PSMA PET/CT", "PSMA tumor progression". Relevant articles were explicitly read through, processed, and summarized. Conclusion PSMA could be a new diagnostic and therapeutic alternative, particularly for triple-negative breast cancer. It appears to be a potential predictive and prognostic marker.

Gastrin-Releasing Peptide Receptor Antagonist [68Ga]RM2 PET/CT for Staging of Pre-Treated, Metastasized Breast Cancer.

BACKGROUND: Positron emission tomography (PET)/computed tomography (CT) using the gastrin-releasing peptide receptor antagonist [68Ga]RM2 has shown to be a promising imaging method for primary breast cancer (BC) with positive estrogen receptor (ER) status. This study assessed tumor visualization by [68Ga]RM2 PET/CT in patients with pre-treated ER-positive BC and suspected metastases. METHODS: This retrospective pilot study included eight female patients with initial ER-positive, pre-treated BC who underwent [68Ga]RM2 PET/CT. Most of these patients (seven out of eight; 88%) were still being treated with or had received endocrine therapy. [68Ga]RM2 PET/CTs were visually analyzed by two nuclear medicine specialists in consensus. Tumor manifestations were rated qualitatively (i.e., RM2-positive or RM2-negative) and quantitatively using the maximum standardized uptake value (SUVmax). SUVmax values were compared between the two subgroups (RM2-positive vs. RM2-negative). RESULTS: Strong RM2 binding was found in all metastatic lesions of six patients (75%), whereas tracer uptake in all metastases of two patients (25%) was rated negative. Mean SUVmax of RM2-positive metastases with the highest SUVmax per patient (in lymph node and bone metastases; 15.8 ± 15.1 range: 3.7-47.8) was higher than mean SUVmax of the RM2-negative metastases with the highest SUVmax per patient (in bone metastases; 1.6 ± 0.1, range 1.5-1.7). CONCLUSIONS: Our data suggest that RM2 binding is maintained in the majority of patients with advanced disease stage of pre-treated ER-positive BC. Thus, [68Ga]RM2 PET/CT could support treatment decision in these patients, radiotherapy planning in oligometastatic patients or selection of patients for RM2 radioligand therapy. Further studies with larger patient cohorts are warranted to confirm these findings.

Development of Discordant Hypermetabolic Prostate Cancer Lesions in the Course of [177Lu]PSMA Radioligand Therapy and Their Possible Influence on Patient Outcome.

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 [18F]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.

Assessing Response to [177Lu]PSMA Radioligand Therapy using modified PSMA PET Progression Criteria.

Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate specific membrane antigen (PSMA) plays a key role in staging of patients with prostate cancer (PCa). Moreover, it is not only used for the assessment of adequate PSMA expression of PCa cells before PSMA-targeting radioligand therapy (PSMA RLT) but also for re-staging during the course of therapy to evaluate response to treatment. Whereas no established criteria exist for systematic response evaluation so far, recently proposed PSMA PET Progression (PPP) criteria might fill this gap. The aim of this study was to assess the feasibility of PPP criteria in patients undergoing PSMA RLT and their prognostic implications. Methods: In this retrospective analysis, PSMA PET/CT scans of 46 patients acquired before and after completion of PSMA RLT were analyzed separately by two readers using modified PPP criteria. After interobserver agreement assessment, consensus results (progressive vs. non-progressive disease) were compared in a multivariate cox regression model (endpoint overall survival, OS). Results: Interobserver agreement on modified PPP criteria was substantial (Cohens κ = 0.73) with a concordance in 87% of patients. Median OS of all patients after PSMA RLT (n = 46) was 9.0 [95% confidence interval (CI) 7.8 - 10.2] months. Progression according to modified PPP criteria was found in 32 patients and was a significant (p ≤0.001) prognostic marker for OS with a hazard ratio of 15.5 [95% CI 3.4 - 70.2]. Conclusion: Response assessment in patients undergoing PSMA RLT using modified PPP criteria are reproducible and highly prognostic for OS. Modified PPP criteria should be validated in future prospective trials.

Prognostic implications of dual tracer PET/CT: PSMA ligand and [18F]FDG PET/CT in patients undergoing [177Lu]PSMA radioligand therapy.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [18F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT. MATERIALS AND METHODS: This bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA-) lesions were compared to patients without any FDG+/PSMA- lesions. A log-rank analysis was used to assess the difference in OS between subgroups. RESULTS: Median OS was 11 ± 1.8 months (95% CI 7.4-14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA- lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0-7.0 months). In comparison, patients without any FDG+/PSMA- lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2-20.8 months). CONCLUSION: FDG+/PSMA- lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA- lesions should be excluded from PSMA RLT.

Detection of Insulinomas Using Dual-Time-Point 68Ga-DOTA-Exendin 4 PET/CT.

PURPOSE: Insulinomas are predominantly benign neuroendocrine tumors originating from beta cells within the islets of Langerhans of the endocrine pancreas. Because surgical resection represents the only curative therapy option, exact tumor localization and discrimination of insulinomas from focal or diffuse manifestations of congenital hyperinsulinism are crucial for optimal treatment strategies. We investigated the diagnostic value of glucagon-like peptide 1 receptor PET/CT using Ga-DOTA-exendin 4 for detecting insulinomas and compared the diagnostic value of PET scans performed at 2 time points. METHODS: In 10 patients with clinically and biochemically suspected insulinoma, PET/CT was performed at 1 hour (PET1) and 2 hours (PET2) after injection of Ga-DOTA-exendin 4. In this retrospective analysis, tracer uptake was visually assessed in both scans by 2 independent readers. SUVmax and tumor-to-background ratio (TBR) of focal lesions were assessed. Imaging results were compared with histopathologic findings, if patients underwent resection. RESULTS: Increased focal Ga-DOTA-exendin 4 uptake was observed in 8 of 10 patients concordantly by both readers. Seven patients with focal uptake underwent surgery with tumor enucleation and histopathologic proof of insulinoma (7/8). Two of 10 patients without focal uptake were considered to suffer from diffuse form of congenital hyperinsulinism and consequently received medical treatment. A significant increase of tumoral SUVmax on PET2 (PET1: SUVmax 20.2 ± 8.2 g/mL; PET2: SUVmax 24.7 ± 7.9 g/mL; P = 0.0018) did not result in a significant improvement in TBR (PET1: TBR 4.9 ± 1.7; PET2: TBR 4.3 ± 1.2; P = 0.2892). CONCLUSIONS: Focal uptake of Ga-DOTA-exendin 4 reliably indicated insulinomas as histopathologically confirmed in all patients undergoing consecutive surgery. The diagnostic value of PET2 was not found to be superior to PET1, indicating that a single 1-hour Ga-DOTA-exendin 4 PET/CT scan is a sufficient and convenient approach for patient care.