Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.

The tumor-homing property of mesenchymal stem cells (MSC) has lead to their use as delivery vehicles for therapeutic genes. The application of the sodium iodide symporter (NIS) as therapy gene allows noninvasive imaging of functional transgene expression by (123)I-scintigraphy or PET-imaging, as well as therapeutic application of (131)I or (188)Re. Based on the critical role of the chemokine RANTES (regulated on activation, normal T-cell expressed and presumably secreted)/CCL5 secreted by MSCs in the course of tumor stroma recruitment, use of the RANTES/CCL5 promoter should allow tumor stroma-targeted expression of NIS after MSC-mediated delivery. Using a human hepatocellular cancer (HCC) xenograft mouse model (Huh7), we investigated distribution and tumor recruitment of RANTES-NIS-engineered MSCs after systemic injection by gamma camera imaging. (123)I-scintigraphy revealed active MSC recruitment and CCL5 promoter activation in the tumor stroma of Huh7 xenografts (6.5% ID/g (123)I, biological half-life: 3.7 hr, tumor-absorbed dose: 44.3 mGy/MBq). In comparison, 7% ID/g (188)Re was accumulated in tumors with a biological half-life of 4.1 hr (tumor-absorbed dose: 128.7 mGy/MBq). Administration of a therapeutic dose of (131)I or (188)Re (55.5 MBq) in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved survival without significant differences between (131)I and (188)Re. These data demonstrate successful stromal targeting of NIS in HCC tumors by selective recruitment of NIS-expressing MSCs and by use of the RANTES/CCL5 promoter. The resulting tumor-selective radionuclide accumulation was high enough for a therapeutic effect of (131)I and (188)Re opening the exciting prospect of NIS-mediated radionuclide therapy of metastatic cancer using genetically engineered MSCs as gene delivery vehicles.

For PET imaging of mantle cell lymphoma (MCL), [ 18 F]FDG (2-deoxy-2-[ 18 F]fluoro-D-glucose) is the currently recommended radiotracer, although uptake is variable and bone marrow evaluation is limited. In this prospective study, we evaluated the novel CXCR4 (G-protein-coupled C-X-C chemokine receptor type 4) tracer [ 68 Ga]Pentixafor in MCL patients, and compared it to [ 18 F]FDG. Methods: MCL patients underwent [ 68 Ga]Pentixafor-PET/MRI, and, if required for routine purposes, also [ 18 F]FDG-PET/MRI, before treatment. PET was evaluated separately for 23 anatomic regions (12 lymph node stations and 11 organs/tissues), using MRI as the main reference standard. Standardized uptake values (SUV max and SUV mean ) and tumor-to-background ratios (TBR blood and TBR liver ) were calculated. General Estimation Equations (GEE) were used to compare [ 68 Ga]Pentixafor-PET and [ 18 F]FDG-PET sensitivities and positive predictive values (PPV). For bone marrow involvement, where biopsy served as the main reference standard, and splenic involvement, receiver operating characteristic curves were used to determine the optimal SUV and TBR cut-off values, and areas under the curve (AUC) were calculated. Results: Twenty-two MCL patients were included. [ 68 Ga]Pentixafor-PET sensitivity (100%) was significantly higher than for [ 18 F]FDG-PET (75.2%) ( P <0.001), and PPV was slightly, but not significantly lower (94.0%.vs. 96.5%; P =0.21). SUVs and TBRs were significantly higher for [ 68 Ga]Pentixafor-PET than for [ 18 F]FDG-PET ( P <0.001 in all cases); the greatest difference was observed for mean TBR blood , with 4.9 for [ 68 Ga]Pentixafor-PET and 2.0 for [ 18 F]FDG-PET. For bone marrow involvement, [ 68 Ga]Pentixafor-PET SUV mean showed an AUC of 0.92; and for splenic involvement, TBR blood showed an AUC of 0.81. Conclusion: [ 68 Ga]Pentixafor-PET may become an alternative to [ 18 F]FDG-PET in MCL patients, showing clearly higher detection rates and better tumor-to-background contrast.

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. Methods: Within the period of 2014–2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. Results: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. Conclusions: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.

In patients with multivessel disease, a FFR <0.75 identifies a hemodynamically relevant lesion as compared to DSE and SPECT. This study underlines that FFR criteria are also applicable in patients with complex coronary artery disease.