Dose escalation to high-risk sub-volumes based on non-invasive imaging of hypoxia and glycolytic activity in canine solid tumors:a feasibility study

INTRODUCTION: Glycolytic activity and hypoxia are associated with poor prognosis and radiation resistance. Including both the tumor uptake of 2-deoxy-2-[(18) F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer copper(II)diacetyl-bis(N(4))-methylsemithio-carbazone (Cu-ATSM) in targeted therapy planning may therefore lead to improved tumor control. In this study we analyzed the overlap between sub-volumes of FDG and hypoxia assessed by the uptake of (64)Cu-ATSM in canine solid tumors, and evaluated the possibilities for dose redistribution within the gross tumor volume (GTV). MATERIALS AND METHODS: Positron emission tomography/computed tomography (PET/CT) scans of five spontaneous canine solid tumors were included. FDG-PET/CT was obtained at day 1, (64)Cu-ATSM at day 2 and 3 (3 and 24 h pi.). GTV was delineated and CT images were co-registered. Sub-volumes for 3 h and 24 h (64)Cu-ATSM (Cu3 and Cu24) were defined by a threshold based method. FDG sub-volumes were delineated at 40% (FDG40) and 50% (FDG50) of SUV(max). The size of sub-volumes, intersection and biological target volume (BTV) were measured in a treatment planning software. By varying the average dose prescription to the tumor from 66 to 85 Gy, the possible dose boost (D( B )) was calculated for the three scenarios that the optimal target for the boost was one, the union or the intersection of the FDG and (64)Cu-ATSM sub-volumes. RESULTS: The potential boost volumes represented a fairly large fraction of the total GTV: Cu3 49.8% (26.8-72.5%), Cu24 28.1% (2.4-54.3%), FDG40 45.2% (10.1-75.2%), and FDG50 32.5% (2.6-68.1%). A BTV including the union (∪) of Cu3 and FDG would involve boosting to a larger fraction of the GTV, in the case of Cu3∪FDG40 63.5% (51.8-83.8) and Cu3∪FDG50 48.1% (43.7-80.8). The union allowed only a very limited D( B ) whereas the intersection allowed a substantial dose escalation. CONCLUSIONS: FDG and (64)Cu-ATSM sub-volumes were only partly overlapping, suggesting that the tracers offer complementing information on tumor physiology. Targeting the combined PET positive volume (BTV) for dose escalation within the GTV results in a limited D( B ). This suggests a more refined dose redistribution based on a weighted combination of the PET tracers in order to obtain an improved tumor control

Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX(3)CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX(3)CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX(3)CL1, CX(3)CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo

Multiple Testing, Cut-Point Optimization, and Signs of Publication Bias in Prognostic FDG–PET Imaging Studies of Head and Neck and Lung Cancer: A Review and Meta-Analysis

Positron emission tomography (PET) imaging with 2-deoxy-2-[18F]-fluorodeoxyglucose (FDG) was proposed as prognostic marker in radiotherapy. Various uptake metrics and cut points were used, potentially leading to inflated effect estimates. Here, we performed a meta-analysis and systematic review of the prognostic value of pretreatment FDG–PET in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), with tests for publication bias. Hazard ratio (HR) for overall survival (OS), disease free survival (DFS), and local control was extracted or derived from the 57 studies included. Test for publication bias was performed, and the number of statistical tests and cut-point optimizations were registered. Eggers regression related to correlation of SUVmax with OS/DFS yielded p = 0.08/p = 0.02 for HNSCC and p < 0.001/p = 0.014 for NSCLC. No outcomes showed significant correlation with SUVmax, when adjusting for publication bias effect, whereas all four showed a correlation in the conventional meta-analysis. The number of statistical tests and cut points were high with no indication of improvement over time. Our analysis showed significant evidence of publication bias leading to inflated estimates of the prognostic value of SUVmax. We suggest that improved management of these complexities, including predefined statistical analysis plans, are critical for a reliable assessment of FDG–PET

An invigorating journey towards better function and well-being: A qualitative study of knee osteoarthritis patients’ experiences with an online exercise and education intervention

Objective: To explore what it means for patients with knee osteoarthritis (OA) to engage in online delivered exercise and education. Method: We combined participant observations and focus group interviews with knee OA patients who engaged in an 8-week program (12 exercise sessions and 2 education sessions) delivered online. Data underwent a three-level phenomenological-hermeneutic interpretation inspired by Ricoeur's narrative and interpretation theory. Results: We performed 17 participant observations during online group-based exercise sessions with twenty individuals with knee OA (12 females), median age 71 years (range: 48 to 81), and five focus group interviews with fifteen of the individuals. The following three themes emerged from the data analysis: 1. Exercise engagement portrays an experience of ownership of the exercise-based treatment, leading to better function and well-being and raising hope for the future 2. A good start but only halfway supported portrays perceived well-guided in performing knee OA exercise, however also some unmet support needs in the online format, and 3. Beneficial peer companionship with online constraints portrays a socially engaging peer forum that, at times, was limited by the online format. Conclusions: This phenomenological-hermeneutic study reflects that supervised online exercise and education facilitate identity mobility, potentially increasing self-efficacy to adopt weekly exercise habits in patients with knee OA. However, the program may benefit from enabling a more interactive approach between peer participants and combining the online format with physical group classes. Moreover, further individualization and focus on a gradual approach toward self-management are encouraged

Prognostic Value of Urokinase-Type Plasminogen Activator Receptor PET/CT in Head and Neck Squamous Cell Carcinomas and Comparison with ¹⁸F-FDG PET/CT:A Single-Center Prospective Study

The aim of this phase II clinical trial (NCT02965001) was to evaluate the prognostic value of urokinase-type plasminogen activator receptor (uPAR) PET/CT with the novel ligand (68)Ga-NOTA-AE105 in head and neck cancer and compare it with (18)F-FDG. Methods: Patients with head and neck squamous cell carcinoma referred for curatively intended radiotherapy were eligible and prospectively included in this study. (68)Ga-uPAR and (18)F-FDG PET/CT were performed before initiation of curatively intended radiotherapy, and the SUV(max) of the primary tumor was measured on both PET/CT studies by 2 independent readers. Relapse-free survival (RFS) and overall survival (OS) were calculated, and optimal cutoffs were established for (68)Ga-uPAR and (18)F-FDG PET independently and compared using log rank and Kaplan–Meier statistics, as well as univariate and multivariate analysis in a Cox proportional-hazards model. Results: In total, 57 patients were included and followed for a median of 33.8 mo (range, 2.30–47.2, mo). The median SUV(max) of the primary tumors was 2.98 (range, 1.94–5.24) for (68)Ga-uPAR and 15.7 (range, 4.24–45.5) for (18)F-FDG. The optimal cutoffs for (68)Ga-NOTA-AE105 SUV(max) in the primary tumor were 2.63 for RFS and 2.66 for OS. A high uptake of (68)Ga-NOTA-AE105 (SUV(max) above cutoff) was significantly associated with poor RFS and OS (log-rank P = 0.012 and P = 0.022). (68)Ga-NOTA-AE105 uptake in the primary tumor was significantly associated with poor RFS in univariate analysis (hazard ratio [HR], 8.53 [95% CI, 1.12–64.7]; P = 0.038), and borderline-associated with OS (HR, 7.44 [95% CI, 0.98–56.4]; P = 0.052). For (18)F-FDG PET, the optimal cutoffs were 22.7 for RFS and 22.9 for OS. An (18)F-FDG SUV(max) above the cutoff was significantly associated with reduced RFS (log-rank P = 0.012) and OS (log-rank P = 0.000). (18)F-FDG uptake was significantly associated with reduced RFS (HR, 3.27 [95% CI, 1.237–8.66]; P = 0.017) and OS (HR, 7.10 [95% CI, 2.60–19.4]; P < 0.001) in univariate analysis. In a multivariate analysis including (68)Ga-uPAR SUV(max), (18)F-FDG SUV(max), TNM stage, and p16 status, only (68)Ga-uPAR SUV(max) remained significant (HR, 8.51 [95% CI, 1.08–66.9]; P = 0.042) for RFS. For OS, only TNM stage and (18)F-FDG remained significant. Conclusion: The current trial showed promising results for the use of (68)Ga-uPAR PET SUV(max) in the primary tumor to predict RFS in head and neck squamous cell carcinoma patients referred for curatively intended radiotherapy when compared with (18)F-FDG PET, TNM stage, and p16 status. (68)Ga-uPAR PET could potentially become valuable for identification of patients suited for deescalation of treatment and risk-stratified follow-up schemes