Safety and Efficacy of Extended Therapy with [177Lu]Lu-PSMA: A German Multicenter Study.

Prospective results have demonstrated favorable safety and efficacy of [177Lu]Lu-PSMA radiopharmaceutical therapy for up to 6 cycles in men with metastatic castration-resistant prostate cancer. However, no systematic data are available outlining the feasibility of extended therapy beyond 6 cycles. We aim to evaluate the safety and efficacy of extended [177Lu]Lu-PSMA radiopharmaceutical therapy in patients who have received more than 6 cycles. Methods: In total, 111 patients were included in this multicenter retrospective analysis. Based on individual decisions, patients underwent uninterrupted continuation of therapy (continuous treatment) or reexposure after a therapy break (rechallenge treatment) between 2014 and 2023. Overall survival, 50% prostate-specific antigen (PSA) decline (measured 8-12 wk after treatment initiation or rechallenge), PSMA PET response, and grades per Common Terminology Criteria for Adverse Events were assessed. χ2 tests, multivariable Cox regression analysis, and log-rank tests were applied for statistical analyses. Results: Patients received extended treatment with [177Lu]Lu-PSMA, either as a continuous treatment (43/111, 38.7%) or as a rechallenge (68/111, 61.3%) treatment, with median cumulative doses of 57.4 or 60.8 GBq, respectively. Overall survival from the initiation of [177Lu]Lu-PSMA was 31.3, 23.2, and 40.2 mo for the entire cohort, the continuous treatment group, and the rechallenge treatment group, respectively. The initial 50% PSA decline was significantly higher in the retreated group than in the continuous group (57/63 [90.4%] vs. 26/42 [61.9%]; P = 0.006). A 50% PSA decline was observed in 23 of 62 patients (37.1%) after the first rechallenge. The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments (anemia, 7/43 [16.3%] vs. 13/68 [19.1%)], P = 0.6; leukocytopenia, 1/43 [2.3%] vs. 2/67 [3.0%], P = 0.3; thrombocytopenia, 3/43 [7.0%] vs. 3/68 [4.4%], P = 0.3; renal, 2/43 [4.7%] vs. 5/68 [7.4%], P = 0.2). Conclusion: Extended therapy with [177Lu]Lu-PSMA is safe and has not been associated with increased grades 3-4 toxicity. Patient candidates for extended treatment experienced a favorable median survival of 31.3 mo from the first administration. Response under [177Lu]Lu-PSMA rechallenge demonstrated preserved efficacy of [177Lu]Lu-PSMA after a treatment break.

Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

Imaging of Cardiac Fibrosis: How Far Have We Moved From Extracellular to Cellular?

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Myocardial fibrosis plays an important role in adverse outcomes such as heart failure and arrhythmias. As the pathological response and degree of scarring, and therefore clinical presentation varies from patient to patient, early detection of fibrosis is crucial for identifying the appropriate treatment approach and forecasting the progression of a disease along with the likelihood of disease-related mortality. Current imaging modalities provides information about either decreased function or extracellular signs of fibrosis. Targeting activated fibroblasts represents a burgeoning approach that could offer insights prior to observable functional alterations, presenting a promising focus for potential anti-fibrotic therapeutic interventions at cellular level. In this article, we provide an overview of imaging cardiac fibrosis and discuss the role of different advanced imaging modalities with the focus on novel non-invasive imaging of activated fibroblasts.

What Role Does PET/MRI Play in Musculoskeletal Disorders?

Musculoskeletal disorders of nononcological origin are one of the most frequent reasons for consultation. Patients suffering from musculoskeletal disorders also consult more than once for the same reason. This results in multiple clinical follow-ups after several radiological and serum examinations, the main ones including X-rays targeting the painful anatomical region and inflammatory serum parameters. As part of their work up, patients suffering from musculoskeletal disorders often require multisequence, multi-parameter MRI. PET/MRI is a promising imaging modality for their diagnosis, with the added advantage of being able to be performed in a single visit. PET/MRI is particularly useful for diagnosing osteomyelitis, spondylodiscitis, arthritis, many pediatric pathologies, and a wide range of other musculoskeletal pathologies. PET/MRI is already used to diagnose malignant bone tumors such as osteosarcoma. However, current knowledge of the indications for PET/MRI in nononcological musculoskeletal disorders is based on studies involving only a few patients. This review focuses on the usefulness of PET/MRI for diagnosing nononcological musculoskeletal disorders.

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy.

RATIONALE: 177Lu-PSMA ([177Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant 177Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and 177Lu-PSMA therapy efficacy is poorly understood. METHODS: Between March 2018 and December 2021, a total of 168 patients were referred to 177Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication. RESULTS: In the subset of patients who received 177Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=-0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01). CONCLUSION: Higher PD-L2 signature might be associated with a better response to 177Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.

Prognostic Implications of PET-Derived Tumor Volume and Uptake in Patients with Neuroendocrine Tumors.

Historically, molecular imaging of somatostatin receptor (SSTR) expression in patients with neuroendocrine tumors (NET) was performed using SSTR scintigraphy (SRS). Sustained advances in medical imaging have led to its gradual replacement with SSTR positron-emission tomography (SSTR-PET). The higher sensitivity in comparison to SRS on the one hand and conventional cross-sectional imaging, on the other hand, enables more accurate staging and allows for image quantification. In addition, in recent years, a growing body of evidence has assessed the prognostic implications of SSTR-PET-derived prognostic biomarkers for NET patients, with the aim of risk stratification, outcome prognostication, and prediction of response to peptide receptor radionuclide therapy. In this narrative review, we give an overview of studies examining the prognostic value of advanced SSTR-PET-derived (semi-)quantitative metrics like tumor volume, uptake, and composite metrics. Complementing this analysis, a discussion of the current trends, clinical implications, and future directions is provided.

Prognostic factors of overall and prostate-specific antigen-progression-free survival in metastatic castration-resistant prostate cancer patients treated with 177 Lu-PSMA-617. A single-center prospective observational study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is characterized by heterogeneity among patients as well as therapy responses due to diverse genetic, epigenetic differences, and resistance mechanisms. At this stage of the disease, therapy modalities should be individualized in light of the patients' clinical state, symptoms, and genetic characteristics. In this prospective study, we aimed to evaluate the outcome of patients with mCRPC treated with 177 Lutetium labeled PSMA-617 therapy (PSMA-RLT), as well as baseline and therapy-related parameters associated with survival. METHODS: This prospective study included 52 patients who received two to six cycles of PSMA-RLT. Primary endpoints were overall survival (OS) and prostate-specific antigen (PSA)-progression-free survival (PFS). 18 F-Fluorodeoxyglucose (FDG) and 68 Ga-PSMA (PSMA) Positron Emission Tomography/Computer Tomography (PET/CT) scans were performed for a comprehensive assessment of tumor burden and heterogeneity. Biochemical, imaging, clinical, and therapy-related parameters were analyzed with the Kaplan-Meier, log-rank, and Cox regression analyses to predict OS and PFS. RESULTS: Median OS and PSA-PFS were 17.7 (95% confidence interval [CI]: 15.2-20.2) and 6.6 months (95% CI: 4.5-8.8), respectively. Primary resistance to PSMA-RLT (hazard ratio [HR]: 12.57, 95% CI: 2.4-65.2, p: 0.003), <30% PSA response rate after first cycle of PSMA-RLT (HR: 1.016, 95% CI: 1.006-1.03, p: 0.003), FDG > PSMA disease (HR: 4.9, 95% CI: 1.19-20.62, p: 0.03), PSA doubling time (PSA DT) of ≤2.4 months (HR: 15.7, 95% CI: 3.7-66.4, p: <0.0001), and low hemoglobin levels (HR: 0.59, 95% CI: 0.41-0.83, p: 0.003) were correlated with poor OS in the multivariate analysis. Bone scintigraphy > PSMA disease (HR: 5.6; 95% CI: 1.8-17, p: 0.002) and high C-reactive protein (HR: 1.4, 95% CI: 1.1-1.7, p: 0.001) were significant predictive biomarkers for PFS in the multivariate analysis. CONCLUSION: PSA response rate and pattern to PSMA-RLT are the most important predictors of survival in patients receiving PSMA-RLT. Being a strong predictive biomarker, combined FDG and PSMA PET can be helpful for the decision of PSMA-RLT eligibility.

Unspecific 18F-PSMA-1007 Bone Uptake Evaluated Through PSMA-11 PET, Bone Scanning, and MRI Triple Validation in Patients with Biochemical Recurrence of Prostate Cancer.

18F-PSMA-1007 PET is used in the management of patients with prostate cancer. However, recent reports indicate a high rate of unspecific bone uptake (UBU) with 18F-PSMA-1007, which may lead to a false-positive diagnosis. UBU has not been evaluated thoroughly. Here, we evaluate the frequency of UBU and bone metastases separately for 18F-PSMA-1007 and 68Ga-PSMA-11 in biochemical recurrence (interindividual comparison). Additionally, we investigate UBU seen in 18F-PSMA-1007 through follow-up examinations (intraindividual comparison) using 68Ga-PSMA-11 PET, bone scintigraphy, and MRI. Methods: First, all patients (n = 383) who underwent 68Ga-PSMA-11 PET between January 2020 and December 2020 and all patients (n = 409) who underwent 18F-PSMA-1007 PET between January 2020 and November 2021 due to biochemical recurrence were included for an interindividual comparison of bone metastases and UBU rate. In a second approach, we regarded all patients with UBU in 18F-PSMA-1007, characterized by focal bone uptake with an SUVmax > 4 and prostate-specific antigen (PSA) ≤ 5 ng/mL, who underwent additional 68Ga-PSMA-11 PET (n = 17) (interindividual comparison). Of these, 12 patients also had bone scintigraphy and whole-body MRI within a 1- to 5-wk interval. Bone uptake seen on 18F-PSMA-1007 but not on any of the other 4 modalities (CT, MRI [n = 1], bone scanning, and 68Ga-PSMA-11 PET) was recorded as false-positive. Results: Patients scanned with 18F-PSMA-1007 PET had a significantly higher rate of UBU than those scanned with 68Ga-PSMA-11 (140 vs. 64; P < 0.001); however, the rate of bone metastases was not significantly different (72 vs. 64; P = 0.7). In the intraindividual comparison group, workup by CT, MRI, bone scanning, and 68Ga-PSMA-11 PET resulted in a positive predictive value for 18F-PSMA-1007 focal bone uptake (mean SUVmax, 6.1 ± 2.9) per patient and per lesion of 8.3% and 3.6%, respectively. Conclusion: In patients with PSA ≤ 5 ng/mL and SUV > 4 at biochemical recurrence, most 18F-PSMA-1007 focal bone uptake is likely to be false-positive and therefore due to UBU. In the case of low clinical likelihood of metastatic disease, 18F-PSMA-1007 bone uptake without morphologic surrogate should be assessed carefully with regard to localization and clinical context. However, the rate of bone metastases was not higher with 18F-PSMA-1007 in the clinical routine, indicating that experienced reporting physicians adjust for UBU findings.

Is 18F-FDG PET Needed to Assess 177Lu-PSMA Therapy Eligibility? A VISION-like, Single-Center Analysis.

18F-FDG and prostate-specific membrane antigen (PSMA) PET have been used to assess eligibility for PSMA-targeted therapy by some centers. However, it remains unclear whether both examinations are needed as a part of workup in the clinical practice or whether PSMA PET alone, as was done in the positive phase 3 VISION trial, is sufficient to identify suitable candidates. The aim was to reanalyze all patients who underwent both 18F-FDG and PSMA PET for PSMA-targeted therapy eligibility assessment using the VISION trial criteria. Methods: Eighty-nine men with metastatic castration-resistant prostate cancer referred to 177Lu-PSMA therapy from June 2019 to October 2021 who underwent both 18F-FDG and PSMA PET (using either 68Ga-PSMA-11 or 18F-PSMA-1007) examinations within 2 wk were included in this analysis. Eligibility status was determined in accordance with either knowledge of both 18F-FDG and PSMA PET (clinical routine) or VISION criteria with PSMA PET-only (study reassessment, done twice with liver only for PSMA-11 and liver/spleen as reference for PSMA-1007). A metastasis seen on 18F-FDG PET or CT but not on PSMA PET was denoted as a mismatch finding and led to exclusion from 177Lu-PSMA therapy. On the basis of clinical assessment, 52 patients received 177Lu-PSMA therapy, and 37 did not; all patients were reassessed. Results: Patients treated with 177Lu-PSMA therapy had significantly longer overall survival than those not treated (12.4 vs. 6.8 mo, P < 0.01). PSMA-only analysis (spleen/liver reference) and 18F-FDG/PSMA mismatch reads had substantial agreement (Cohen κ = 0.73). Eighteen percent (n = 16/89) of patients had a mismatch finding based on 18F-FDG/PSMA PET. With the liver/spleen reference, a minor fraction of patients who had no mismatch finding (and were therefore treated) would have been withheld from therapy by PSMA-only analysis (3%). Three percent (n = 3) of all patients had an 18F-FDG/PSMA mismatch finding not detected by PSMA PET-only (VISION-like) analysis. For patients not receiving PSMA therapy, the overall survival was not statistically significantly different comparing 18F-FDG/PSMA mismatch versus nonmismatch (P = 0.61) patients. Conclusion: 18F-FDG and PSMA PET provide complementary information, yet less than 5% of patients had mismatch findings not detected using PSMA PET-only. Based on our data, 18F-FDG/PSMA mismatch examination and PSMA-only analysis have a substantial level of agreement.

Predictive factors of tumor sink effect: Insights from 177Lu-Prostate-specific membrane antigen therapy.

OBJECTIVE: Tumor sink effect (TSE) has been defined as; decreased uptake in healthy tissue with increased tumor sequestration of the radiopharmaceuticals. It enables us to give high tumoral radiation doses while resulting in lower absorbed radiation to critical organs. However, the factors which influence this effect are yet to be defined. In this study, we have investigated the predictive factors of the tumor sink effect in a group of patients who received 177Lu-Prostate-specific membrane antigen (PSMA) therapy due to progressive metastatic castration-resistant prostate cancer (mCRPC). METHODS: We have retrospectively analyzed the pre-therapy 68Ga-PSMA positron-emission tomography (PET)-computed tomography (CT) and post-therapy planar whole-body scans of 65 patients who received at least two cycles of 7.4 GBq of 177Lu-PSMA therapy. All patients with mCRPC were referred to our department after multiple treatment lines. Age, previous therapies, International Society of Urological Pathology (ISUP) score, and pre-therapy serum tumor marker levels were recorded. Post 177Lu-PSMA therapy images were analyzed for TSE. 68Ga-PSMA PET-CT images were used for the calculation of SUVmax in malignant and healthy tissues as well as metabolic tumor volume (MTV) and total lesion PSMA index (TLPI). RESULTS: Based on the post-therapy scans, TSE was seen in 17/65 (26.2%) patients. In univariate analysis, patients with TSE had higher pre-therapy PSA, PSA velocity, and ALP (p < 0.0001). In relation to PET parameters, patients with TSE had higher 68Ga-PSMA MTV, 68Ga-PSMA TLPI and lower pretherapy renal SUVmax (p < 0.0001)), pretherapy liver SUVmax (p:0.012), pretherapy parotid gland SUVmax (p:0.032), and pretherapy parotid gland SUVmean (p:0.038). In the multivariant analysis, 68Ga-PSMA TLPI, pre-therapy PSA, and PSA velocity were found to be statistically significant. When analyzed according to Youden index, pretherapy PSA level of 133 ng/ml (sensitivity 0.765 and 0.875), PSA velocity of 246 ng/ml/year (sensitivity 0.765 and 0.833), and 68Ga-PSMA TLPI of 2969 g (sensitivity 0.765 and 0.875) was found to be the best cut-off points to predict TSE. CONCLUSION: The tumor sink effect was seen in 26.2% of patients. 68Ga- PSMA TLPI, pre-therapy PSA, and PSA velocity was found to be the predictors of TSE. Accurate prediction of TSE may lead to increased tumoral doses while sparing healthy organs. Clinical trials that consider this effect as a part of a dose algorithm may further increase therapeutic efficacy.

Colonic Visualization of 99mTc-DMSA Due to Enterovesical Fistula.

A 60-year-old woman with recurrent urinary tract infection who had several operations for colorectal carcinoma underwent Tc-DMSA renal scintigraphy which showed an unexpected accumulation of radiotracer in the colon. When symptoms were reviewed, we noticed that she was suffering from pneumaturia and fecaluria which raised the suspicion of enterovesical fistula. Rectal contrast-enhanced computer tomography of pelvis demonstrated enterovesical and enterovaginal fistulas. Colonic radioactivity was considered to be related to retrograde peristalsis of Tc-DMSA from bladder activity via enterovesical fistula. In patients with pelvic surgeries and radiotherapy, radioactivity in the colon should raise the suspicion of enterovesical fistula.

Clinical Impact of PET Imaging in Patients With Metastatic Prostate Cancer.

Prostate cancer (Pca) is the most common cancer and the second leading cause of death among men. Although conventional bone scans and abdominal CT are preferred in most of the guidelines and clinical trials, PET/CT has already started to become the inevitable part of Pca management because of its higher sensitivity and specificity. Radiotracers used for PET imaging show different molecular aspects of the disease process. Although Ga-prostate-specific membrane antigen offers the highest sensitivity and specificity, other PET radiotracers such as F-FDG and Ga-DOTATATE still have a role in patients with prostate-specific membrane antigen-negative diseases such as Pca with neuroendocrine differentiation. In this pictorial essay, we have presented a series of patients with metastatic Pca who had PET images with different radiotracers and discussed the clinical role of this imaging modality in patient management.

The Complementary Role of 68Ga-DOTATATE PET/CT in Neuroblastoma.

A girl diagnosed with neuroblastoma at 33 months underwent I-MIBG scan after surgery and chemoradiotherapy. Although MIBG scan showed complete response, the bone marrow biopsy showed refractory disease. Therefore, she underwent Ga-DOTATATE PET/CT, which revealed bone marrow involvement and Ga-DOTATATE-avid brain metastasis. Rare physiological pineal gland uptake was also depicted. Ga-DOTATATE PET/CT showed active progressive disease earlier, before it was detectable with MIBG scan. For patients with MIBG-negative relapsed/refractory disease, Ga-DOTATATE may have an important role in restaging, detecting unsuspected metastasis, therapy planning.