18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results.

INTRODUCTION: Tyrosine kinase (TKI) and checkpoint inhibitors (CI) prolonged overall survival in metastatic renal cell carcinoma (mRCC). Early prediction of treatment response is highly desirable for the individualization of patient management and improvement of therapeutic outcome; however, serum biochemistry is unable to predict therapeutic efficacy. Therefore, we compared 18F-PSMA-1007 PET imaging for response assessment in mRCC patients undergoing TKI or CI therapy compared to CT-based response assessment as the current imaging reference standard. METHODS: 18F-PSMA-1007 PET/CT was performed in mRCC patients prior to initiation of systemic treatment and 8 weeks after therapy initiation. Treatment response was evaluated separately on 18F-PSMA-PET and CT. Changes on PSMA-PET (SUVmean) were assessed on a per patient basis using a modified PERCIST scoring system. Complete response (CRPET) was defined as absence of any uptake in all target lesions on posttreatment PET. Partial response (PRPET) was defined as decrease in summed SUVmean of > 30%. The appearance of new, PET-positive lesions or an increase in summed SUVmean of > 30% was defined as progressive disease (PDPET). A change in summed SUVmean of ± 30% defined stable disease (SDPET). RECIST 1.1 criteria were used for response assessment on CT. Results of radiographic response assessment on PSMA-PET and CT were compared. RESULTS: Overall, 11 mRCC patients undergoing systemic treatment were included. At baseline PSMA-PET1, all mRCC patients showed at least one PSMA-avid lesion. On follow-up PET2, 3 patients showed CRPET, 3 PRPET, 4 SDPET, and 1 PDPET. According to RECIST 1.1, 1 patient showed PRCT, 9 SDCT, and 1 PDCT. Overall, concordant classifications were found in only 2 cases (2 SDCT + PET). Patients with CRPET on PET were classified as 3 SDCT on CT using RECIST 1.1. By contrast, the patient classified as PRCT on CT showed PSMA uptake without major changes during therapy (SDPET). However, among 9 patients with SDCT on CT, 3 were classified as CRPET, 3 as PRPET, 1 as PDPET, and only 2 as SDPET on PSMA-PET. CONCLUSION: On PSMA-PET, heterogeneous courses were observed during systemic treatment in mRCC patients with highly diverging results compared to RECIST 1.1. In the light of missing biomarkers for early response assessment, PSMA-PET might allow more precise response assessment to systemic treatment, especially in patients classified as SD on CT.

Advanced Molecular Imaging in Histologically Verified Metanephric Adenoma.

Metanephric adenoma (MA) describes a rare renal tumor and is generally considered a benign lesion. However, there are cases with regional lymphogenic and distant metastases. Noninvasive diagnosis of MA using conventional imaging remains challenging. Here, we describe a case of histologically verified MA with additional advanced molecular imaging consisting of 18F-PSMA-1007 PET/CT, 99mTc-Sestamibi SPECT and contrast-enhanced ultrasound.

Biodistribution and first clinical results of 18F-SiFAlin-TATE PET: a novel 18F-labeled somatostatin analog for imaging of neuroendocrine tumors.

INTRODUCTION: PET/CT using 68Ga-labeled somatostatin analogs (SSA) targeting somatostatin receptors (SSR) on the cell surface of well-differentiated neuroendocrine tumors (NET) represents the clinical reference standard for imaging. However, economic and logistic challenges of the 68Ge/68Ga generator-based approach have disadvantages over 18F-labeled compounds. Here, we present the first in-human data of 18F-SiFAlin-TATE, a novel 18F-labeled, SSR-targeting peptide. The aim was to compare the intra-individual biodistribution, tumor uptake, and image quality of 18F-SiFAlin-TATE to the clinical reference standard 68Ga-DOTA-TOC. METHODS: Thirteen patients with NET staged with both 68Ga-DOTA-TOC and 18F-SiFAlin-TATE PET/CT have been included in this retrospective analysis. We compared the biodistribution in normal organs and tumor uptake of NET lesions by SUVmean and SUVmax measurement for tracers. Additionally mean and max tumor-to-liver (TLR) and tumor-to-spleen ratios (TSR) have been calculated by division of SUVmean and SUVmax of tumor lesions by the SUVmean of the liver and spleen, respectively. Additionally, image quality was visually rated by 5 blinded readers and an intra-class correlation (ICC) analysis on inter-observer agreement has been performed. RESULTS: Compared with 68Ga-DOTA-TOC, the biodistribution of 18F-SiFAlin-TATE showed somewhat higher, however, statistically not significant higher uptake in the liver, spleen, and adrenal glands. Significantly higher uptake was observed in the kidneys. Tumor uptake was higher in most tumor lesions with significantly higher uptake in common metastatic sites of NET including the liver (SUVmax 18.8 ± 8.4 vs. 12.8 ± 5.6; p < 0.001), lymph nodes (SUVmax 23.8 ± 20.7 vs. 17.4 ± 16.1; p < 0.001) and bone (SUVmax 16.0 ± 10.1 vs. 10.3 ± 5.7; p < 0.01) for 18F-SiFAlin-TATE. The high tumor uptake resulted in favorable TLR and TSR, comparable with that of 68Ga-DOTA-TOC. The ICC analysis on the inter-observer agreement on image quality was substantial and almost perfect. Image quality was rated as excellent in most cases in both 68Ga-DOTA-TOC and 18F-SiFAlin-TATE PET. CONCLUSION: The favorable characteristics of 18F-SiFAlin-TATE with a high image quality, the kit-like labeling procedure, and the promising clinical performance enable improved logistics and diagnostic possibilities for PET imaging of NET. Our first clinical results warrant further systematic studies investigating the clinical use of 18F-SiFAlin-TATE in NET patients.

[Pulmonary carcinoids and carcinoids of the small intestine]. / Karzinoide der Lunge und im Abdomen.

CLINICAL/METHODICAL ISSUE: Pulmonary carcinoids and carcinoids of the small intestine (jejunum and ileum) are often asymptomatic and can affect various parts of the body, which makes diagnosis difficult. STANDARD RADIOLOGICAL METHODS: Contrast-enhanced computed tomography (CE-CT) is commonly used for primary diagnostics. In case of concomitant pulmonary consolidation (e.g., atelectasis or pneumonia), tumor lesions can be obscured. In addition, differentiation between atypical (AC) and typical carcinoids (TC) is not possible using CT. Small tumors of the small intestine are easily overlooked (sensitivity: 50-85%, specificity: 25-97%, based on the literature). Additional functional imaging evaluation using hybrid imaging techniques can be applied, e.g., positron emission tomography/computed tomography (PET/CT). METHODICAL INNOVATIONS/PERFORMANCE: Depending on the histological characteristics of the tumor, PET/CT scans can be performed with different tracers. Since most carcinoids (e.g., TC) express somatostatin receptors (SSR), 68 gallium-radiolabeled PET tracers (e.g. 68 Ga-DOTA-TOC) are commonly used (sensitivity: 88-93%, specificity: 88-95%, based on the literature). Poorly differentiated carcinoids (e.g., AC) demonstrate lower SSR expression; thus, use of 18F­FDG (sensitivity: 37-72%, based on the literature) is indicated. In principle, these methods enable a noninvasive prognostic differentiation based on SSR expression and 18F­FDG uptake. However, the diagnosis must always be histologically confirmed. ACHIEVEMENTS/PRACTICAL RECOMMENDATIONS: Hybrid imaging with CE-CT and PET is useful to detect pulmonary carcinoids and carcinoids of the small intestine, respectively, and can be utilized for primary diagnostics and restaging.

Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival.

BACKGROUND: NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression. METHODS: Thirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method. RESULTS: The median PFS after initial PRRT was 33 months (95% CI: 30-36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5-47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0-16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92-119) and 51 months (95% CI: 41-61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively. CONCLUSIONS: Salvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET.

Pre-therapeutic factors for predicting survival after radioembolization: a single-center experience in 389 patients.

PURPOSE: To determine pre-therapeutic predictive factors for overall survival (OS) after yttrium (Y)-90 radioembolization (RE). METHODS: We retrospectively analyzed the pre-therapeutic characteristics (sex, age, tumor entity, hepatic tumor burden, extrahepatic disease [EHD] and liver function [with focus on bilirubin and cholinesterase level]) of 389 consecutive patients with various refractory liver-dominant tumors (hepatocellular carcinoma [HCC], cholangiocarcinoma [CCC], neuroendocrine tumor [NET], colorectal cancer [CRC] and metastatic breast cancer [MBC]), who received Y-90 radioembolization for predicting survival. Predictive factors were selected by univariate Cox regression analysis and subsequently tested by multivariate analysis for predicting patient survival. RESULTS: The median OS was 356 days (95% CI 285-427 days). Stable disease was observed in 132 patients, an objective response in 71 (one of which was complete remission) and progressive disease in 122. The best survival rate was observed in patients with NET, and the worst in patients with MBC. In the univariate analyses, extrahepatic disease (P < 0.001), large tumor burden (P = 0.001), high bilirubin levels (>1.9 mg/dL, P < 0.001) and low cholinesterase levels (CHE <4.62 U/I, P < 0.001) at baseline were significantly associated with poor survival. Tumor entity, tumor burden, extrahepatic disease and CHE were confirmed in the multivariate analysis as independent predictors of survival. Sex, applied RE dose and age had no significant influence on OS. CONCLUSIONS: Pre-therapeutic baseline bilirubin and CHE levels, extrahepatic disease and hepatic tumor burden are associated with patient survival after RE. Such parameters may be used to improve patient selection for RE of primary or metastatic liver tumors.

Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) as a Biomarker in the Mouse Model of Experimental Autoimmune Myocarditis (EAM).

Vascular cell adhesion molecule-1 (VCAM-1) is strongly upregulated in hearts of mice with coxsackie virus-induced as well as in patients with viral infection-triggered dilated cardiomyopathy. Nevertheless, the role of its soluble form as a biomarker in inflammatory heart diseases remains unclear. Therefore, we investigated whether plasma levels of soluble VCAM-1 (sVCAM-1) directly correlated with disease activity and progression of cardiac dysfunction in the mouse model of experimental autoimmune myocarditis (EAM). EAM was induced by immunization of BALB/c mice with heart-specific myosin-alpha heavy chain peptide together with complete Freund`s adjuvant. ELISA revealed strong expression of cardiac VCAM-1 (cVCAM-1) throughout the course of EAM in immunized mice compared to control animals. Furthermore, sVCAM-1 was elevated in the plasma of immunized compared to control mice at acute and chronic stages of the disease. sVCAM-1 did not correlate with the degree of acute cardiac inflammation analyzed by histology or cardiac cytokine expression investigated by ELISA. Nevertheless, heart to body weight ratio correlated significantly with sVCAM-1 at chronic stages of EAM. Cardiac systolic dysfunction studied with positron emission tomography indicated a weak relationship with sVCAM-1 at the chronic stage of the disease. Our data provide evidence that plasma levels of sVCAM-1 are elevated throughout all stages of the disease but showed no strong correlation with the severity of EAM.