Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography

Several radiolabeled fibroblast activation protein targeted inhibitors (FAPI) have been developed for molecular imaging and therapy. A potential correlation of radiotracer uptake in normal organs and extent of tumor burden may have consequences for a theranostic approach using ligands structurally associated with [68Ga]Ga-FAPI, as one may anticipate decreased doses to normal organs in patients with extensive tumor load. In the present proof-of-concept study investigating patients with solid tumors, we aimed to quantitatively determine the normal organ biodistribution of [68Ga]Ga-FAPI-04, depending on the extent of tumor. Except for a trend towards significance in the myocardium, we did not observe any relevant associations between PET-based tumor burden and normal organs. Those preliminary findings may trigger future studies to determine possible implications for theranostic approaches and FAP-directed drugs, as one may expect an unchanged dose for normal organs even in patients with higher tumor load. Abstract (1) Background: We aimed to quantitatively investigate [68Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [68Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUVmean) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUVmax), tumor volume (TV), and fractional tumor activity (FTA = TV × SUVmean). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman’s rank correlation coefficient. (3) Results: Median SUVmean values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUVmax (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUVmax (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUVmax (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [68Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs

In-vivo somatostatin-receptor expression in small cell lung cancer as a prognostic image biomarker and therapeutic target

Background: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT). Methods: A total of 67 patients (26 females; age, 41–80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUVmax) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded. Results: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUVmax was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUVmax vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = −0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively. Conclusions: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patient

Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [68Ga]Ga-PentixaFor PET/CT

BACKGROUND: CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. METHODS: Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [(68)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV(mean)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV(max)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV(mean) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. RESULTS: Median SUV(mean) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV(max) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. CONCLUSIONS: In patients with solid tumors imaged with [(68)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged

Training on reporting and data system (RADS) for somatostatin-receptor targeted molecular imaging can reduce the test anxiety of inexperienced readers

PURPOSE: For somatostatin receptor (SSTR)-positron emission tomography/computed tomography (PET/CT), a standardized framework termed SSTR-reporting and data system (RADS) has been proposed. We aimed to elucidate the impact of a RADS-focused training on reader’s anxiety to report on SSTR-PET/CT, the motivational beliefs in learning such a system, whether it increases reader’s confidence, and its implementation in clinical routine. PROCEDURES: A 3-day training course focusing on SSTR-RADS was conducted. Self-report questionnaires were handed out prior to the course (Pre) and thereafter (Post). The impact of the training on the following categories was evaluated: (1) test anxiety to report on SSTR-PET/CT, (2) motivational beliefs, (3) increase in reader’s confidence, and (4) clinical implementation. To assess the effect size of the course, Cohen’s d was calculated (small, d = 0.20; large effect, d = 0.80). RESULTS: Of 22 participants, Pre and Post were returned by 21/22 (95.5%). In total, 14/21 (66.7%) were considered inexperienced (IR,  1 year). Applying SSTR-RADS, a large decrease in anxiety to report on SSTR-PET/CT was noted for IR (d =  − 0.74, P = 0.02), but not for ER (d = 0.11, P = 0.78). For the other three categories motivational beliefs, reader’s confidence, and clinical implementation, agreement rates were already high prior to the training and persisted throughout the course (P ≥ 0.21). CONCLUSIONS: A framework-focused reader training can reduce anxiety to report on SSTR-PET/CTs, in particular for inexperienced readers. This may allow for a more widespread adoption of this system, e.g., in multicenter trials for better intra- and interindividual comparison of scan results. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11307-022-01712-6

Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo

Cortactin is required for endothelial barrier function and leukocyte recruitment in vivo

Mental health in the slums of Dhaka - a geoepidemiological study

Gruebner O, Khan MH, Lautenbach S, et al. Mental health in the slums of Dhaka - a geoepidemiological study. BMC Public Health. 2012;12(1): 177.Background: Urban health is of global concern because the majority of the world's population lives in urban areas. Although mental health problems (e.g. depression) in developing countries are highly prevalent, such issues are not yet adequately addressed in the rapidly urbanising megacities of these countries, where a growing number of residents live in slums. Little is known about the spectrum of mental well-being in urban slums and only poor knowledge exists on health promotive socio-physical environments in these areas. Using a geo-epidemiological approach, the present study identified factors that contribute to the mental well-being in the slums of Dhaka, which currently accommodates an estimated population of more than 14 million, including 3.4 million slum dwellers. Methods: The baseline data of a cohort study conducted in early 2009 in nine slums of Dhaka were used. Data were collected from 1,938 adults (>= 15 years). All respondents were geographically marked based on their households using global positioning systems (GPS). Very high-resolution land cover information was processed in a Geographic Information System (GIS) to obtain additional exposure information. We used a factor analysis to reduce the socio-physical explanatory variables to a fewer set of uncorrelated linear combinations of variables. We then regressed these factors on the WHO-5 Well-being Index that was used as a proxy for self-rated mental wellbeing. Results: Mental well-being was significantly associated with various factors such as selected features of the natural environment, flood risk, sanitation, housing quality, sufficiency and durability. We further identified associations with population density, job satisfaction, and income generation while controlling for individual factors such as age, gender, and diseases. Conclusions: Factors determining mental well-being were related to the socio-physical environment and individual level characteristics. Given that mental well-being is associated with physiological well-being, our study may provide crucial information for developing better health care and disease prevention programmes in slums of Dhaka and other comparable settings

Are Reports of Psychological Stress Higher in Occupational Studies? A Systematic Review across Occupational and Population Based Studies

This study was funded by the UK Ministry of Defence (MoD)

Wnt/β-catenin signaling regulates CXCR4 expression and [68^{68}Ga] Pentixafor internalization in neuroendocrine tumor cells

Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [$^{68}$Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [$^{68}$Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified