Benefit of including CT urography in [68Ga]PSMA-11 PET/CT with low-dose CT: first results from a larger prostate cancer cohort analysis.

BACKGROUND: Accuracy of [68Ga]PSMA-11 PET/CT may be hampered by ureter accumulation, mimicking lymph node metastases depending on localization and configuration. The benefit of CT urography for differentiation of lymph node metastasis from urinary tract activity was evaluated in a "PET/CT with low-dose CT" setting. METHODS: Retrospective analysis of PET/CT for primary staging, biochemical recurrence or local treatment planning in patients with prostate cancer. For CT urography (CTU), iodinated contrast agent was administered 10 minutes prior to image acquisition. All potential pathologic (peri)ureteral tracer uptake was assigned to excretory ureteral accumulation or pathological lesion. To assess additional provided benefit of CTU all foci were rated with an introduced scoring system (ranging from 0 pts: CTU not needed; up to 3 pts: no differentiation possible without CTU). Success of ureter contrasting was assessed by measurement of Hounsfield units. Besides benefit for reading urography-enhanced PET/CT, the possible impact on subsequent patient treatment was evaluated. RESULTS: A number of N.=247 patients were included in this study. By CT urography, it was possible to identify each ureter on low-dose CT, with its major part contrasted. In 120/247 (48.6%) patients, urography increased the diagnostic confidence while providing substantial support for interpretation in 60 (24.3%) cases. In 42 (17.0%) patients, urography was clinically relevant (up-/downstaging) with potential impact on subsequent patient care. In 30 of these 42 cases (12.1% of all), discrepant treatment would have resulted from a misdiagnosed tracer accumulation without urography. CONCLUSIONS: CT urography benefits the interpretation of [68Ga]-PSMA-11 PET/CT with low-dose CT and leads to discrepant patient treatment in a small but significant subset of patients (12% in our cohort). The implementation of CT urography into standard protocols of [68Ga]PSMA-11 PET/CT with low-dose CT is recommended.

Response and outcome of liver metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing 177Lu-PSMA-617 radioligand therapy.

PURPOSE: Little is known about the efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) against liver metastases of metastatic castration-resistant prostate cancer (mCRPC). We retrospectively analyzed efficacy-related outcomes of 177Lu-PSMA-617 RLT in this setting and potential predictors of those outcomes. METHODS: Twenty-eight consecutive mCRPC patients with liver metastases given 177Lu-PSMA-617 RLT were analyzed retrospectively. Their planned regimen was 4-6 cycles at 6 ± 2-week intervals; the mean activity/cycle was 6.5 ± 0.5 GBq. Hepatic response was determined by modified positron emission tomography response criteria in solid tumors; association of such response with overall survival (OS) was tested, as were relationships of the selected patient, disease, and treatment characteristics with hepatic progression-free survival (PFShep) and OS. Survival analyses used Kaplan-Meier curves, log-rank test at p < 0.05 significance, and Cox proportional-hazards modeling. RESULTS: Median (minimum-maximum) follow-up was 37.5 (2.3-50.6) months. In liver metastases, complete or partial response was observed in 6 patients (21%) each, and stable disease in 1 (4%), for hepatic disease control in 46%. Overall, median (95% confidence interval) PFShep was 5.7 (2.2-9.2) months, and OS, 11.7 (3.0-20.4) months. Patients with hepatic disease control did not reach the median OS, while those with hepatic progressive disease had median OS (95% confidence interval) of 6.4 (1.6-11.1) months. In multivariate analysis, hepatic disease control by 177Lu-PSMA-617 RLT was significantly independently associated with OS, as was a prostate-specific antigen decline of ≥ 50% after 2 RLT cycles, and good baseline performance status (Eastern Cooperative Oncology Group 0-1). Hepatic tumor burden (≤ 25% vs. > 25% of liver volume) had no apparent relationship with hepatic tumor response, PFShep, or OS. CONCLUSION: 177Lu-PSMA-617 RLT frequently controlled liver metastases, resulting in long PFShep and significantly improved OS. Hepatic tumor burden appeared to lack any relationship with treatment efficacy, supporting 177Lu-PSMA-617 RLT of late-stage/end-stage mCRPC with liver metastases.

New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide.

PURPOSE: There is preliminary evidence for prostate-specific membrane antigen (PSMA) upregulation effects of androgen receptor blockade in prostate cancer. In an attempt to find the best condition for PSMA radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC) patients, we evaluated the effect of oral enzalutamide in patients, predominantly having previously progressed on enzalutamide treatment. METHODS: Ten patients with advanced mCRPC scheduled for PSMA radioligand therapy were examined with 68Ga-PSMA-11 PET/CT before and after a mean of 11.8 days of enzalutamide 160 mg/day. Imaging results were compared using total PSMA tumor burden quantification. We assessed whole-body total lesion PSMA (TLP), defined as SUVmean × tumor volume and calculated TLP-to-liver ratio (TLP-LR), TLP-to-parotid gland ratio (TLP-PR), and TLP-to-kidney ratio (TLP-KR). RESULTS: The mean (median) increase of TLP-LR, TLP-PR, and TLP-KR in the cohort was 49.3% (38.8%), 45.1% (23.5%), and 54.9% (37.6%), respectively. These increases were statistically significant (p = 0.002, p = 0.014, and p = 0.014), while PSA values did not change significantly (p = 0.846). Seven of the 10 patients had previously undergone enzalutamide treatment with eventual progression, formally classified as treatment failure. No side effects were noted in the short term. CONCLUSIONS: Our results suggest that enzalutamide could be considered as a PSMA radioligand treatment enhancing primer medication, which may increase PSMA expression by a dimension of 50% in mCRPC. The effect was shown even in patients having previously failed enzalutamide treatment for arrest of progression in the mCRPC setting. Our observation deserves evaluation in a prospective setting.

225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience.

PURPOSE: Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to 177Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter 225Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients' quality-of-life. We hypothesized that when 177Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity 225Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity. METHODS: We retrospectively analyzed pilot experience with 1 course of 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to 177Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and 177Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%). RESULTS: Median (minimum-maximum) administered activities were 225Ac-PSMA-617, 5.3 (1.5-7.9) MBq, and 177Lu-PSMA-617, 6.9 (5.0-11.6) GBq. Significant responders to tandem therapy received 177Lu-PSMA-617 monotherapy as maintenance (median [minimum-maximum]: 1 [0-5] cycle). After a median (minimum-maximum) 22 (14-63) weeks' follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12-26) weeks, and overall survival was 48 (4-92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20. CONCLUSIONS: Our results suggest that a single course of tandem therapy with low-activity 225Ac-PSMA-617/full-activity 177Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.

Remember the Pitfall: Intrapancreatic Accessory Spleen Mimicking Neuroendocrine Neoplasm.

We report of a 71-year-old woman with a 2-cm somatostatin receptor-positive intrapancreatic lesion almost misdiagnosed as neuroendocrine neoplasm. By additional red blood cell scintigraphy with heat-damaged erythrocytes, the lesion was identified as an intrapancreatic accessory spleen, and unnecessary operation (which was already planned) could be avoided. This case report reminds colleagues to consider accessory spleen as differential diagnosis for somatostatin receptor-positive lesions even when located inside the pancreas. In doubtful cases, a scintigraphy with heat-damaged erythrocytes is a very useful and complementary imaging method and should be performed before any planning of surgery.

Determination of split renal function by PSMA imaging: comparison of 68Ga-PSMA-11 PET with 99mTc-MAG3 scintigraphy.

MAG3 scintigraphy with determination of split renal function (SRF) is a standard procedure in patients with metastasized castration-resistant prostate carcinoma (mCRPC) undergoing PSMA radioligand therapy (PSMA-RLT). These patients also receive frequent PSMA PET/CT scans for staging and follow up. PSMA is not only overexpressed in prostate cancer epithelial cells, but also physiologically overexpressed in the proximal tubular cells of the kidney. This study investigates the utility of PSMA-targeted imaging for determination of relative renal function. mCRPC patients (n = 97) having received 68Ga-PSMA-11 PET/CT and 99mTc-MAG3 scintigraphy in close temporal relationship were included in this retrospective study. PSMA-PET-derived SRF was calculated according to the bilateral renal PSMA content (total kidney PSMA = SUVmean × volume), MAG3-based SRF (SRFMAG3) using the common standard integral method of the renal secretion phase. The agreement of SRFPSMA and SRFMAG3 was statistically tested using Pearson correlation and Bland-Altman analysis. The correlation between both SRF assessment methods was highly significant (P < 0.001) with r=0.91. Bland-Altman analysis confirmed agreement of the measurements. High correlation and agreement were also observed in the subgroup analyses of patients with normal and reduced renal function (r=0.81, P < 0.001 and r=0.98, P < 0.001). Renal tubular PSMA expression allows assessment of split renal function by 68Ga-PSMA-11 PET/CT imaging. Additional MAG3 scintigraphy for the purpose of quantifying relative renal function contribution may be spared in settings where PSMA PET is performed; this insight could save time and unnecessary examinations.

Neuron-specific enolase has potential value as a biomarker for [18F]FDG/[68Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients.

BACKGROUND: PSMA-targeted radioligand therapy (PSMA-RLT) yielded impressive results in the metastasized castration-resistant prostate carcinoma (mCRPC) setting. High expression of PSMA is essential for successful PSMA-RLT. However, some patients develop [18F]FDG-avid lesions with low or no PSMA expression ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in the course of treatment. Those lesions are not affected by PSMA-RLT and a change in therapy management is needed. To enable early mismatch detection, possible blood parameters as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT were evaluated. METHODS: Retrospective study of N = 66 advanced mCRPC patients with dual [68Ga]Ga-PSMA-11 and [18F]FDG PET/CT imaging within 4 weeks, who were referred for or received [177Lu]Lu-PSMA-617 radioligand therapy. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP) were tested as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings. Additional to absolute values, relative changes (ΔPSA, ΔNSE, ΔGGT, ΔALP) over a period of 4 ± 1 weeks prior to [18F]FDG PET/CT were analyzed. RESULTS: In total, 41/66 (62%) patients revealed at least one [18F]FDG/[68Ga]Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients by screening for and in 28/41 (68%) patients during PSMA-RLT. NSE serum level (55.4 ± 44.6 µg/l vs. 18.5 ± 8 µg/l, p < 0.001) and ΔNSE (93.8 ± 124.5% vs. 2.9 ± 39.5%, p < 0.001) were significantly higher in the mismatch group than in the non-mismatch group. No significant differences were found for serum PSA (p = 0.424), ΔPSA (p = 0.417), serum ALP (p = 0.937), ΔALP (p = 0.611), serum GGT (p = 0.773), and ΔGGT (p = 0.971). For NSE and ΔNSE, the maximum value of the Youden index in ROC analysis was at a cut-off level of 26.8 µg/l (sensitivity 78%, specificity 96%) and at + 13.9% (sensitivity 84%, specificity 75%), respectively. An introduced scoring system of both parameters achieved a sensitivity of 90% and a specificity of 88% for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch. CONCLUSION: We observed a significantly higher absolute serum concentration and a higher relative increase of NSE in advanced mCRPC patients with [18F]FDG-avid and insufficient PSMA expressing metastases ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in our cohort. NSE might be used as a potential laboratory indicator for [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings, if this observation is confirmed in future, ideally prospective, studies in larger patient cohorts.

Recovery of Renal Function Under PSMA Mediated Radioligand Therapy of Advanced Metastasized Castration Resistant Prostate Cancer.

Radioligand therapy targeting prostate specific membrane antigen (PSMA-RLT) is becoming increasingly important in palliative care of metastasized castration resistant prostate cancer (mCRPC) as a highly effective and low toxicity therapy option. In addition to its overexpression in prostate cancer cells, PSMA is also physiologically expressed in the kidneys which is raising concerns over dose related nephrotoxicity of PSMA-RLT. We describe potential positive short-term effects of PSMA-RLT on renal function with marked recovery of a pretreatment compromised kidney.

Large Paraesophageal Schwannoma With Intense Prostate-Specific Membrane Antigen Expression on 68Ga-PSMA-PET/CT Mimicking Lymph Node Metastasis in a Patient With Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-PET/CT as an emerging modality in molecular imaging will lead to earlier detection and localization of relapse in prostate cancer but will undoubtedly also lead to false-positive findings, as it becomes clear that this new tracer is not as specific as its name would suggest. In this context, we present a case of a large PSMA-expressing schwannoma, a rare nerve sheath tumor mimicking paraesophageal lymph node metastasis in a patient with a history of prostate cancer and biochemical recurrence.

Early metabolic response assessment of breast cancer liver metastases: 4-week posttreatment FDG PET predicts survival after 90Y microsphere radioembolization.

AIM: To evaluate the feasibility of early metabolic response assessment with 18F-FDG PET/CT in patients with breast cancer liver metastases 4 weeks after radioembolization with Yttrium-90 labeled microspheres. METHODS: 25 patients (mean age 58y, range 40-74) with advanced stage liver metastases of breast cancer were treated with 1.9 ± 0.4 GBq of 90Y-microspheres in the salvage setting and underwent 18F-FDG PET/CT at baseline and 4 weeks post-radioembolization. 14 patients (56 %) had an excessive hepatic tumor burden (> 50 % of total liver volume), 21 patients (84 %) had extrahepatic disease. Liver lesions with the highest SUVmax were selected as target lesions and a cut-off was set at 50 % reduction to separate responders from non-responders. The predictive impact of metabolic response on overall survival (OS) was investigated along with other prognostic factors. RESULTS: The median OS in this highly advanced metastatic cohort was 7 months (95 % CI, 5-9). All patients had a reduction in SUVmax (mean ΔSUVmax: -49 ± 26 %) at 4 weeks post-treatment. Patients with > 50 % SUVmax reduction survived longer (median OS 13 mo, 95 % CI 8-18) than the remaining patients (median OS 4 mo, 95 % CI 2-6; p = 0.001). From all investigated baseline factors including age, performance status, and presence of extra-hepatic disease, only the hepatic tumor burden had a significant impact on OS (p = 0.02). CONCLUSIONS: This is the first preliminary evidence in breast cancer that early post-radioembolization molecular response assessment of treated liver metastases - as early as 4 weeks posttreatment - may predict survival. If confirmed by larger series, FDG PET/CT could be considered for early response-adapted treatment modifications.

Differences between neonates and adults in carbohydrate sequences and reaction kinetics of plasmin and alpha(2)-antiplasmin.

This study investigates reaction kinetics by slow-binding kinetics methods of both adult and fetal plasmin (Types 1 and 2) with adult and fetal alpha(2)-antiplasmin. In addition, carbohydrate sequences of Fetal and Adult Plasminogen Types 1 and 2, as well as fetal and adult alpha(2)-antiplasmin, were determined by mass spectrometric analysis. All curves of plasmin-alpha(2)-antiplasmin interaction followed the same pattern, indicating reversible slow-binding inhibition with an initial loose complex and a following tight complex. Differences between fetal and adult plasmin reactions with alpha(2)-antiplasmin were predominantly due to the initial loose complex. Values for K(i initial) in the reaction with adult alpha(2)-antiplasmin were 1.5 and 1.6 nM for Fetal Plasmin Types 1 and 2, respectively; compared to 0.3 and 0.7 nM for the corresponding adult types. Increasing concentrations of tranexamic acid resulted in a continuous increase of K(i initial) until a plateau was reached which was similar for all plasmin types. Almost identical values could be obtained when fetal alpha(2)-antiplasmin was used instead of adult alpha(2)-antiplasmin. Mass spectrometric analyses of the glycans present on plasminogen revealed a higher level of truncated N-glycans on the fetal material compared to the adult. The O-glycans of fetal and adult plasminogen were closely similar and only minor differences were observed between N-glycans of fetal and adult alpha(2)-antiplasmin. In conclusion, both fetal plasmin isoforms are less inhibited by alpha(2)-antiplasmin compared to the adult plasmin variants. These findings are important for the understanding of the physiology of the fibrinolytic system in neonates and provide further evidence that differences in glycosylation could be associated with marked effects on protein function.

Influence of soluble fibrin on reaction kinetics of plasmin type 1 and type 2 with alpha2-antiplasmin.

This study investigates, by slow binding kinetics methods, reaction kinetics of both plasmin types 1 and 2 with alpha -antiplasmin in the presence of increasing concentrations of either epsilon-amino-caproic acid (EACA) or soluble fibrin. All curves of plasmin-alpha -antiplasmin interaction followed the same pattern, indicating reversible slow binding inhibition with an initial loose complex and a following tight complex. Without soluble fibrin or EACA, differences between plasmin types 1 and 2 could be seen in the initial loose complex formation. The presence of increasing concentrations of EACA slowed down the first step of the reaction (without any effect on the second step), resulting in increasing values for K. Plasmin type 1 demonstrated a steep slope of K at an EACA concentration of 1 mmol/l. In plasmin type 2, the increase of K started at higher EACA concentrations. The value for K at a high EACA concentration (100 mmol/l) was the same for both plasmin types. In contrast to EACA, increasing concentrations of soluble fibrin slowed down both reaction steps. At high concentrations of soluble fibrin, the inhibitory effect of alpha -antiplasmin was almost completely abolished. Our data demonstrate that the effect of soluble fibrin and the lysine analogue EACA on plasmin-antiplasmin reactions are different and that the use of lysine analogues does not mimic fibrin in laboratory analyses of plasmin inhibition. In addition, our data indicate theoretical differences between plasmin type 1 and plasmin type 2, when used for local thrombolytic therapy.(2) (2) (i initial) (i initial) (i initial) (i initial) (2)