PURPOSE: To assess the potential of αvβ6-integrin as a theranostic target in esophageal cancer. METHODS: Membranous β6-integrin (ITGB6) expression was analyzed in 306 specimens of human esophageal squamous cell carcinoma (ESCC) obtained by immunohistochemistry (IHC) from 100 patient cases (1, 37, 58, and 4 of grade G1, G2, G3, and G4, respectively). Ga-68 labeling of D0103 was done manually for preclinical experiments and fully automated for clinical application. Preclinical characterization of Ga-68-D0103 was performed in SCID mice bearing subcutaneous xenografts of H2009 (αvβ6-positive) or MDA-MB-231 (αvβ6-negative) carcinoma cell lines, by ex vivo biodistribution (10, 30, 90, and 180 min p.i) and PET imaging (30, 90, and 180 min p.i.)., without and with co-injection of gelofusine (4% succinylated gelatin). A patient with type-II diabetes (f, 68y, 115 kg) with proximal G2 ESCC was investigated by Ga-68-D0103 PET/CT (193 MBq) at 15, 45, 90, and 104 min p.i.. RESULTS: 99% of ESCC cases were found β6-integrin positive by IHC, of which 48%, 31%, and 20% showed strong, moderate, and low ITGB6 expression, respectively, with no correlation to tumor grade. Ex vivo biodistribution of Ga-68-D0103 in H2009 xenografted mice after 30, 90, and 180 min showed tumor-to-blood ratios of 6.8, 37, and 124, respectively; tumor-to-muscle ratios of 12, 14, and 36, respectively; tumor-to-liver ratios of 10, 17, and 14, respectively; and tumor-to-pancreas ratios of 20, 47, and 56, respectively. Co-administration of gelofusine did not change the tumor uptake but reduced the kidney uptake by 89% (from 178%iA/g to 19.1%iA/g, 90 min p.i.), resulting in an 8.7-fold higher tumor/kidney ratio. µPET imaging in H2009 xenografted mice confirmed a high tumor uptake and low background already 30 min p.i.. Blockade biodistribution and µPET in αvβ6-(-) MDA-MB-231 mice demonstrated target specificity. Clinical PET/CT of a patient with ESCC showed increasing tracer uptake over time in the primary tumor (SUVmax 9.0 and 11.3 at 15 and 104 min p.i., respectively) and in a lymph node metastasis (SUVmax 19.5 and 28.3, respectively), and a decreasing blood pool activity (SUVmean 2.75 and 0.98, respectively). CONCLUSIONS: High (99%) membranous expression frequency and density on tumor cells underscores the potential of αvβ6-integrin as a theranostic target in ESCC, suggesting that αvβ6-integrin PET/CT imaging may adopt a role in re-staging and therapy guidance in this cancer type. The prolonged tumor retention furthermore indicates a therapeutic potential of αvβ6-integrin targeted radiopharmaceuticals when labeled with radionuclides such as lutetium-177, terbium-161, or actinium-225.
- Klíčová slova
- Esophageal Cancer, Integrins, Positron Emission Tomography, Surveillance, Theranostics,
- Publikační typ
- časopisecké články MeSH
PURPOSE: While blocking androgen production and action effectively slows prostate cancer (PCa) progression, it is associated with significant side effects, including an increased risk of cardiovascular disease. Inflammatory activity within atherosclerotic arteries can be assessed using [18F]FDG-PET imaging. Recently, [18F]FDG-PET has also gained relevance in PCa patients - alongside PSMA-targeted PET - for evaluating tumor aggressiveness. This study investigated the effect of hormone therapy on arterial inflammation in PCa patients using [18F]FDG-PET. METHODS: Thirty-two PCa patients receiving hormone therapy were compared to 17 age-matched PCa patients who had not undergone hormonal treatment in the 12 months prior to imaging. All participants underwent [18F]FDG-PET/CT scans. Regions of interest (ROIs) were placed across several arterial segments, as well as in the superior vena cava (SVC), spleen, and bone marrow. To account for background vascular activity, blood-pool activity in the SVC was used for correction, and target-to-background ratios (TBRs) were calculated for each arterial segment. A semi-quantitative calcified plaque (CP) score was also recorded. RESULTS: Patients receiving hormone therapy exhibited significantly higher TBRmax values in the abdominal aorta, ascending aorta, thoracic descending aorta, and in the combined analysis of all arteries (mean TBRmax: 1.6 vs. 1.4; all p < 0.05). Similarly, TBRmean values were significantly elevated in the abdominal and ascending aorta, as well as in the combined arterial analysis (all p < 0.05). No significant differences were observed between groups in age, BMI, total cholesterol, LDL, CRP, or CP scores (all p > 0.05). CONCLUSION: Advanced PCa patients undergoing hormone therapy demonstrate increased arterial inflammation on [18F]FDG-PET imaging compared to non-hormonally treated controls. These findings support a possible mechanistic link between hormone therapy and the elevated cardiovascular risk observed in this patient population.
- Klíčová slova
- Arterial inflammation, Atherosclerosis, Hormone therapy, PET/CT, Prostate cancer, [18F]FDG,
- Publikační typ
- časopisecké články MeSH
BACKGROUND: PSMA-targeted radioligand therapies (PSMA RLT) are an effective and safe option for metastatic castration-resistant prostate cancer, but responsive subtypes and their biomarkers are not fully defined. METHODS: Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I&T. CfDNA underwent whole-genome sequencing to establish copy number variation (CNV) profiles and circulating-tumor DNA (ctDNA) levels and compared between prostate-specific antigen (PSA) response- and 1-year overall survival (1YOS) groups. RESULTS: Non-responders exhibited higher degrees of cfDNA CNV burden (P = 0.048) and higher ctDNA levels (P = 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847). CONCLUSION: Unresponsive patients exhibited higher levels of cfDNA genomic instability and ctDNA levels, warranting genome-wide CNV profiling studies next to targeted approaches for mechanistic radiobiological insights and their value as response biomarkers for PSMA RLTs.
- Klíčová slova
- CNV, CtDNA, Liquid biopsy, PSMA RLT, Prostate cancer,
- Publikační typ
- časopisecké články MeSH
PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.
- Klíčová slova
- Kidneys, PSMA, Prostate cancer, Radioligand therapy, Salivary glands,
- MeSH
- antigeny povrchové * metabolismus MeSH
- glutamátkarboxypeptidasa II * metabolismus MeSH
- krysa rodu Rattus MeSH
- ledviny * účinky léků diagnostické zobrazování metabolismus účinky záření MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- radioprotektivní látky * farmakologie farmakokinetika MeSH
- slinné žlázy * účinky léků diagnostické zobrazování metabolismus účinky záření MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny povrchové * MeSH
- FOLH1 protein, human MeSH Prohlížeč
- glutamátkarboxypeptidasa II * MeSH
- radioprotektivní látky * MeSH
Radioguidance that makes use of β-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of β-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of β-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation.
- Klíčová slova
- Beta emitting Radionuclides, Image guided surgery, Radiation exposure, Radioguidance, Radiotracers,
- MeSH
- beta částice * škodlivé účinky MeSH
- chirurgie s pomocí počítače * škodlivé účinky metody normy MeSH
- lidé MeSH
- nukleární lékařství * metody normy MeSH
- radiační ochrana metody normy MeSH
- radiofarmaka * aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- směrnice pro lékařskou praxi MeSH
- Názvy látek
- radiofarmaka * MeSH
BACKGROUND: Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. METHODS: One hundred thirty men with confirmed PCa (70.5 ± 8.0 years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7 MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. RESULTS: PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). CONCLUSION: These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.
- Klíčová slova
- Liquid biopsy, PET/CT, PSMA, Prostate cancer, ctDNA,
- MeSH
- cirkulující nádorová DNA * krev genetika MeSH
- EDTA * analogy a deriváty MeSH
- izotopy gallia * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prostaty * diagnostické zobrazování genetika krev MeSH
- oligopeptidy MeSH
- PET/CT * MeSH
- prognóza MeSH
- průřezové studie MeSH
- radioizotopy galia * MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- cirkulující nádorová DNA * MeSH
- EDTA * MeSH
- gallium 68 PSMA-11 MeSH Prohlížeč
- izotopy gallia * MeSH
- oligopeptidy MeSH
- PSMA-11 MeSH Prohlížeč
- radioizotopy galia * MeSH
- MeSH
- jednofotonová emisní výpočetní tomografie metody MeSH
- kadmium MeSH
- koronární cirkulace fyziologie MeSH
- lidé MeSH
- nemoci koronárních tepen * diagnostické zobrazování MeSH
- prognóza MeSH
- telur MeSH
- zobrazování myokardiální perfuze * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- Názvy látek
- kadmium MeSH
- telur MeSH
- MeSH
- celková dávka radioterapie MeSH
- lidé MeSH
- nukleární lékařství * metody MeSH
- průzkumy a dotazníky MeSH
- radiometrie * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
- úvodníky MeSH
PURPOSE: Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population. METHODS: In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC. RESULTS: Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone. CONCLUSION: Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.
- Klíčová slova
- Artificial intelligence, Biomarkers, Cancer genomics, Head and neck cancer, Machine learning, Radiomics,
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku diagnostické zobrazování genetika MeSH
- genetické markery MeSH
- hodnocení rizik MeSH
- lidé MeSH
- nádory hlavy a krku * diagnostické zobrazování genetika MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- spinocelulární karcinom * patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- Názvy látek
- genetické markery MeSH
