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Background: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. Methods: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20–94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. Findings: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4–51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6–7·0; p1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09–0·14; p

Background and purpose Tumor hypoxia is an important cause of radioresistance and is associated with poor outcome. SPECT (Single-photon emission computed tomography) imaging enables visualizing tumor characteristics. We investigated the SPECT-radiotracer [111In]-girentuximab-F(ab’)2 to image Carbonic Anhydrase IX (CAIX), an enzyme upregulated under hypoxic conditions. Materials and methods Athymic mice with subcutaneous FaDu or SCCNij202 head and neck squamous cell carcinoma (HNSCC) xenografts were treated with atovaquone or were housed in a hypoxic chamber (8% O2). Next, [111In]-girentuximab-F(ab’)2 was injected and 24 h later mice were euthanized for ex vivo biodistribution, autoradiography of the tumor, and immunohistochemical staining of the tumor. Tumor sections were analyzed for hypoxia, CAIX expression, vessels, and perfusion. Also, the effect of atovaquone on microSPECT scans was determined in the FaDu model. Results Atovaquone decreased CAIX expression by 69% (p = 0.017) compared with control tumors in FaDu, while in the SCCNij202 tumors no difference was observed. Hypoxic breathing did not increase CAIX expression or hypoxia staining in either tumor model, but did affect the necrotic tumor fraction. Ex vivo tracer uptake in the atovaquone treated group did not differ significantly from the control group, despite the difference in CAIX expression. Furthermore, SPECT imaging with [111In]-girentuximab-F(ab’)2 did not discriminate atovaquone-treated versus control tumors. Conclusion Atovaquone decreased CAIX expression only in the FaDu tumor model. [111In]-girentuximab-F(ab’)2 specifically targets CAIX-expressing areas in HNSCC xenografts, but differences in vessel density and necrosis most likely affected tracer uptake in the tumors and therefore complicated quantification of changes in CAIX expression.

Carbon is the most important biobased material that forms the backbone of life as we know it. Based on this fundamental fact, it is no surprise that carbon-based materials have played an integral role in the development of medical materials. Biobased materials will continue to play an even greater role in medicine as we uncover more of the nuanced mechanisms that determine the multiple roles that carbon plays in biological systems. The purpose of this chapter is to introduce biobased materials and the unique roles that they play in medical products. The important role of carbon will be highlighted while focusing on the role of biobased materials in healthcare and medical products including high surface area adsorbents, recycling of biowaste products, and tailored gut microbiome-based products and therapies that can proactively prevent health challenges.

New findings What is the central question of this study? The study aimed to establish a novel model to study the chronic obstructive pulmonary disease (COPD)-related cardiopulmonary effects of dynamic hyperinflation in healthy subjects. What is the main finding and its importance? A model of expiratory resistance breathing (ERB) was established in which dynamic hyperinflation was induced in healthy subjects, expressed both by lung volumes and intrathoracic pressures. ERB outperformed existing methods and represents an efficacious model to study cardiopulmonary mechanics of dynamic hyperinflation without potentially confounding factors as present in COPD. Abstract Dynamic hyperinflation (DH) determines symptoms and prognosis of chronic obstructive pulmonary disease (COPD). The induction of DH is used to study cardiopulmonary mechanics in healthy subjects without COPD-related confounders like inflammation, hypoxic vasoconstriction and rarefication of pulmonary vasculature. Metronome-paced tachypnoea (MPT) has proven effective in inducing DH in healthy subjects, but does not account for airflow limitation. We aimed to establish a novel model incorporating airflow limitation by combining tachypnoea with an expiratory airway stenosis. We investigated this expiratory resistance breathing (ERB) model in 14 healthy subjects using different stenosis diameters to assess a dose-response relationship. Via cross-over design, we compared ERB to MPT in a random sequence. DH was quantified by inspiratory capacity (IC, litres) and intrinsic positive end-expiratory pressure (PEEPi, cmH2 O). ERB induced a stepwise decreasing IC (means (95% CI): tidal breathing: 3.66 (3.45-3.88), ERB 3 mm: 3.33 (1.75-4.91), 2 mm: 2.05 (0.76-3.34), 1.5 mm: 0.73 (0.12-1.58) litres) and increasing PEEPi (tidal breathing: 0.70 (0.50-0.80), ERB 3 mm: 11.1 (7.0-15.2), 2 mm: 22.3 (17.1-27.6), 1.5 mm: 33.4 (3.40-63) cmH2 O). All three MPT patterns increased PEEPi, but to a far lesser extent than ERB. No adverse events during ERB were noted. In conclusion, ERB was proven to be a safe and efficacious model for the induction of DH and might be used for the investigation of cardiopulmonary interaction in healthy subjects.

Background COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients. Methods We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age ≥40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded. Results Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV1/FVC

Background Increasing attention has been drawn on the assessment of body composition phenotypes, since the distribution of soft tissue influences cardio-metabolic risk. Dual-energy X-ray absorptiometry (DXA) is a validated technique to assess body composition. European reference values from population-based cohorts are rare. Aims To provide age- and sex-related reference values of body composition parameters and visceral adipose tissue (VAT) mass, and for lean mass index (LMI) with regard to fat mass index (FMI) quantities and BMI categories. Methods GE-Lunar Prodigy DXA scans of 10.894 participants, aged 18–81 years, recruited from 2011 to 2019 by the Austrian LEAD study, a population-based cohort study, have been used to construct reference curves using the LMS method. Parameters assessed are FMI, LMI, appendicular LMI, fat mass ratios android/gynoid and trunk/limbs, and VAT. Results All lean mass and fat mass parameters indicating central fat accumulation were higher in men, whereas other fat mass indices were higher in women. LMI differed between each FMI subgroup (low vs. normal, low vs. high, normal vs. high), and BMI category in all ages and LMI increased with FMI and BMI classes. VAT mass was higher in men compared with women and increased across all age groups within both sexes. Conclusion The present study provides age- and sex-related reference values for European adults aged 18–81 years for body composition parameters and VAT mass for Lunar Prodigy DXA. In addition, this study reports LMI reference values with regard to fat mass quantities, showing a positive association with increasing FMI percentiles and BMI categories., European Journal of Clinical Nutrition, 74 (8), ISSN:0954-3007, ISSN:1476-5640

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition with constantly increasing mortality rates. Interleukin (IL)-33 and its decoy receptor, soluble suppression of tumorigenicity 2 (sST2), play a central role in the inflammatory response during infection. sST2 was suggested as a factor in the pathogenesis of COPD and emerged as a predictor of mortality in other non-communicable diseases. The role of sST2 as a predictor of mortality remains unclear in COPD yet. In this cohort study, we measured circulating concentrations of IL-33 and sST2 in the serum of patients with stable COPD (n = 59), patients with acute exacerbation of COPD (n = 29) and smoking (n = 20) and non-smoking controls (n = 20), using commercially available ELISAs, and investigated the prognostic role of sST2 in stable COPD. sST2 levels were significantly higher in COPD patients and smokers compared with non-smoking controls. We identified systolic blood pressure, forced expiratory volume in 1 s (FEV1% predicted), neutrophil count, lactate dehydrogenase and pack-years index as independent predictors of sST2 levels. During a median follow-up time of 10.6 years, 28 patients (47.5%) died. sST2 was an independent predictor of all-cause mortality in patients with COPD with a hazard ratio of 2.9 (95% CI 1.1–8.4, p = 0.035) per one standard deviation after adjustment for age, sex, pack-years, FEV1% predicted and C-reactive protein (CRP). sST2 concentrations are associated with severity of disease and long-term outcome in patients with COPD.

The impact of body composition on the early origin of chronic diseases is an increasingly appreciated phenomenon. Little is known about the characteristics of children with varying body composition. The aim of this study was to investigate serum lipid profiles and other characteristics in relation to body composition. The data of 1394 participants (aged 6 to, Children, 8 (11), ISSN:2227-9067

Background: Sensitization to aero-allergens is a common condition worldwide and prevalence vary between countries tremendously (17%-69%). Sensitization is related to allergic disease conditions and conflicting data of associated factors exists. Therefore, we aimed to investigate 1.the prevalence of positive SPT including age and sex distribution and 2. associated factors with positive SPT in a broad-aged European general population Methods: 11.283 males and females aged from 6-82 yrs. from the Austrian LEAD general-population cohort have been included with aero-allergen SPT and assessments of socioeconomic status (SES), exposure to tobacco smoke, lifestyle habits, allergic and/or respiratory diseases, body composition, family medical history and pets in household. Results: Positive SPT was higher in males vs. females in both age groups (42.9% vs. 30.5% and 42.2% vs. 33.7%, p House dust mite and grasses mix were the most prevalent allergens in both age groups; however, associated factors with a positive SPT differed in the two age groups (Table1 and Table 2). Conclusion: We found that a positive SPT is a highly prevalent condition in the general population, more prevalent in males vs females, the main allergens are grasses mix and house dust mite, in both age groups. There is a difference in factors associated with SPT between childhood/adolescence and adulthood.

Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. Methods To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1nu/nu) with subcutaneously xenografted LoVo tumors. Results In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm2 and 0.5 μg/μL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. Conclusion Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo.

Purpose Detection of residual or recurrent vital renal tumor on follow-up (FU) cross-sectional imaging after ablative therapy is challenging. The specific and high expression levels of carbonic anhydrase IX (CAIX) in clear cell renal cell carcinoma (ccRCC) makes it a suitable target for imaging using radiolabeled anti-CAIX antibody girentuximab. The objective of this study was to evaluate the feasibility of targeted FU imaging 1 month after cryoablation of ccRCC using single photon emission computed tomography (SPECT) after 111In-labeled girentuximab administration. Methods In this prospective study 16 patients underwent 111In-girentuximab-SPECT before MR-guided renal cryoablation between February 2015 and September 2018. In case of tumor targeting 111In-girentuximab-SPECT was repeated 1 month following MR-guided cryoablation. Presence of residual or recurrent vital tumor was assessed on contrast-enhanced cross-sectional imaging during further FU. The standard FU imaging protocol consisted of MRI/CT scans at 1, 3, 6, 12, and 18 months and annually thereafter. Results A total of 10 (63%) patients showed positive tumor targeting on 111In-girentuximab-SPECT before cryoablation and 9 ( 56%) were eligible to undergo FU SPECT. Of the 9 111In-girentuximab-SPECT FU scans, 8 (89%) were considered negative. One (11%) scan showed uptake suggestive for residual vital tumor. Six months after treatment, FU CT showed contrast enhancement suggestive for residual/recurrent disease in the ablated zone at the site of the 111In-girentuximab uptake after treatment. During a mean FU of 21 months (range 1–33) no other cases with residual/recurrent disease were detected. Conclusion FU imaging with 111In-girentuximab-SPECT is feasible after ccRCC cryoablation and may contribute to early detection of residual or recurrent disease.

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.

Background Analysis of cell-free DNA from blood could provide an alternative method for identifying genomic changes in the tumors of patients with advanced lung adenocarcinoma. Objective We compared the performance of droplet digital PCR (ddPCR) and Cobas® EGFR Mutation Test v2 (Cobas) for detecting EGFR mutations in cell-free plasma DNA. Patients and Methods Plasma samples from patients with advanced EGFR-mutated lung adenocarcinoma were analyzed for EGFR T790M, exon 19 deletions, and L858R mutations by both ddPCR and Cobas. Results T790M testing was performed in 354 plasma samples collected from 129 patients. The concordance rate between ddPCR and Cobas for T790M, sensitivity, and specificity were 86, 100, and 85%, respectively. Exon 19 deletions were analyzed in 196 plasma samples obtained from 71 of the 129 patients using both platforms. The concordance rate between ddPCR and Cobas for exon 19 deletions, sensitivity, and specificity were 90, 92, and 89%, respectively. L858R mutations were studied in 124 plasma samples obtained from 44 of the 129 patients using both assays. The concordance rate between ddPCR and Cobas for L858R, sensitivity, and specificity were 90, 91, and 89%, respectively. In patients who progressed under treatment with an EGFR TKI (n = 50), the T790M positivity rate was 66% using ddPCR, but only 24% using Cobas. Conclusions We observed a high concordance between ddPCR and Cobas in detecting EGFR mutations in plasma samples of patients with advanced EGFR-mutated lung adenocarcinoma, but ddPCR was more sensitive than Cobas.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are the major reason for COPD hospitalization and increased risk for readmissions. The organizational structure of Austrian hospitals provides the opportunity to investigate the impact of specialized respiratory care compared to general care on adherence to guidelines and readmission in AECOPD.The data from the European COPD audit, a prospective observational non-interventional cohort trial were analyzed. In total, 823 patients admitted due to AECOPD in 26 hospitals (specialized respiratory care vs. general care) within Austria were included. Patients characteristics and outcomes (length of stay, readmission rate, and mortality) were analyzed in relation to hospital resources (personnel and equipment) and adherence to international guidelines.Patients admitted to general care had more comorbidities (Charlson comorbidity index: 2.6 ± 1.7 vs. 2.0 ± 1.4; p 0.05) and a shorter length of stay (10.7 ± 7.8 days vs. 12.0 ± 10.2 days; p 0.05). Patients admitted to specialized respiratory care more often underwent blood gas analysis and non-invasive ventilation (98.4% vs. 81.5% and 68.6% vs. 26.7%, p 0.01; respectively). In multivariate analysis, the risk for AECOPD readmission was lower (odds ratio, OR 0.72 [0.51;0.91]; p 0.05) in patients admitted to specialized respiratory care.A greater adherence to COPD guidelines with respect to blood gas analysis and non-invasive ventilation and decreased AECOPD readmission risk was observed for patients admitted to specialized respiratory care. Adherence to guidelines may have the potential to decrease COPD readmission rates.

Tumor hypoxia plays a major role in radio- and chemotherapy resistance in solid tumors. Carbonic Anhydrase IX (CAIX) is an endogenous hypoxia-related protein, which is associated with poor patient outcome. The quantitative assessment of CAIX expression of tumors may steer cancer treatment by predicting therapy response or patient selection for antihypoxia or CAIX-targeted treatment. Recently, the single-photon emission computerized tomography (SPECT) tracer [111In]In-DTPA-girentuximab-F(ab′)2 was developed and validated for targeting CAIX. The aim of this study was to optimize quantitative microSPECT/CT of CAIX expression in vivo in head and neck tumor models. Athymic mice with subcutaneous SCCNij153 and SCCNij202 head and neck squamous cell carcinoma xenografts were injected with [111In]In-DTPA-girentuximab-F(ab′)2. First, the protein dose, timing, and image acquisition settings were optimized. Tracer uptake was determined by quantitative SPECT, ex vivo radioactivity counting, and by autoradiography of tumor sections. The same tumor sections were immunohistochemically stained for CAIX expression and hypoxia. Highest tumor-normal-tissue contrast was obtained at 24 h after injection of the tracer. A protein dose of 10 μg resulted in the highest tumor-to-muscle ratio at 24 h p.i. Ex vivo biodistribution studies showed a tumor uptake of 3.0 ± 0.6%ID/g and a tumor-to-muscle ratio of 8.7 ± 1.4 (SCCNij153). Quantitative analysis of the SPECT images enabled us to distinguish CAIX antigen blocked from nonblocked tumors, fractions positive for CAIX expression: 0.22 ± 0.02 versus 0.08 ± 0.01 (p < 0.01). Immunohistochemical, autoradiographic, and microSPECT/CT analyses showed a distinct intratumoral spatial correlation between localization of the radiotracer and CAIX expression. Here, we demonstrate that [111In]In-DTPA-girentuximab-F(ab′)2 specifically targets CAIX-expressing cells in head and neck cancer xenografts. SPECT imaging with indium-labeled girentuximab-F(ab′)2 allows quantitative assessment of the fraction of CAIX positive tissue in head and neck cancer xenografts. These results indicate that [111In]In-DTPA-girentuximab-F(ab′)2 is a promising tracer to image hypoxia-related CAIX expression.

Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies.

Background DXA is a widely used technique to assess body composition. Reference values based on a large general population cohort of European children and adolescents were missing. The aim of this study was to provide age‐ and sex‐specific reference percentiles of body composition parameters for European children and adolescents and to compare them to the American NHANES cohort. Additionally, exponents accounting best for height biases were analysed. Methods DXA scans of 1573 participants, aged 6 to 18 years, recruited from 2011 to 2019 by the Austrian LEAD study, a representative population‐based cohort, have been used to create reference charts using the LMS model. Results Reference charts displaying percentile curves and the corresponding reference values are provided. Fat mass parameters were higher in females, while lean mass parameters were higher in males. Compared to the NHANES cohort medians of FMI and LMI were always lower. For FMI , BMI , LMI and ALMI the best fitting exponent were 2.5, 3, 3 and 3.5 respectively Conclusions The present study provides reference charts for children and adolescents aged 6 to 18 years, for body composition parameters assessed by DXA. The charts enable comparison to a European general‐population cohort and indicate that reference populations should be chosen with caution., Pediatric Obesity, 16 (1)

Background Serological tests are widely used in various medical disciplines for diagnostic and monitoring purposes. Unfortunately, the sensitivity and specificity of test systems is often poor, leaving room for false positive and false negative results. However, conventional methods used to increase specificity decrease sensitivity and vice versa. Using SARS-CoV-2 serology as an example, we propose here a novel testing strategy: the "Sensitivity Improved Two-Test" or "SIT2" algorithm. Methods SIT2 involves confirmatory re-testing of samples with results falling in a predefined retesting-zone of an initial screening test, with adjusted cut-offs to increase sensitivity. We verified and compared the performance of SIT2 to single tests and orthogonal testing (OTA) in an Austrian cohort (1,117 negative, 64 post-COVID positive samples) and validated the algorithm in an independent British cohort (976 negatives, 536 positives). Results The specificity of SIT2 was superior to single tests and non-inferior to OTA. The sensitivity was maintained or even improved using SIT2 when compared to single tests or OTA. SIT2 allowed correct identification of infected individuals even when a live virus neutralization assay could not detect antibodies. Compared to single testing or OTA, SIT2 significantly reduced total test errors to 0.46% (0.24-0.65) or 1.60% (0.94-2.38) at both 5% or 20% seroprevalence. Conclusion For SARS-CoV-2 serology, SIT2 proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy to apply algorithm and can potentially be helpful for the serology of other infectious diseases.

Background: European population cohorts continue to expand our understanding of chronic airways disease and inter-study collaboration may help address the inevitable limitations of study size, duration, era and geography. Towards this aim, CADSET has collated data from ten major general population European cohorts: Asklepios; Copenhagen City Heart Study; Copenhagen General Population Study; ECRHS; HUNT; LEAD; Lifelines, OLIN, Rotterdam Study and WSAS. We included males and females aged 20 to 95 years with baseline demographic and spirometry data.Results: Data from 262,829 individuals (44% male) from multiple European countries provided good coverage across all adult ages (Fig.1A). Recruitment occurred in every year from 1976 through 2020. 23% were current-smokers and 42% were never-smokers, a pattern varying with advancing age (Fig.1B). The prevalence of airflow limitation varied according to whether lower limit of normal (LLN) or Interpretation: These results fit with previous reports, however the size, geographical reach and span of recruitment provided by this collaboration provides a unique opportunity to explore chronic airways disease development. Together, we are now pursuing research questions previously beyond the scope of individual cohort studies.

Rationale: Metabolic syndrome (MetS), in particular increased central obesity is associated with cardiovascular events but also lung function (LF) impairment. The aim was to investigate whether LF impairment is associated with increased levels of visceral adipose tissue (VAT). Methods: Data was obtained from the Austrian LEAD Study, an observational, population-based cohort study. Adults aged 25-82 years with valid LF and metabolic data, including waist circumference (WC) for central obesity, and DXA Scans for VAT (n=9.157) were included in this analysis. LF was assessed by spirometry pre- and post-bronchodilation (BD). Abnormal LF was defined as FEV1 pre BD Results: Table 1 shows odds ratios of MetS components and VAT associated with impaired LF pattern. Increased VAT was associated with both, obstructive (OR 1.5 [1.3-1.8]) and restrictive (OR 2.4 [1.8-3.0]) LF pattern, while increased WC was not. Conclusion: VAT showed a consistent association with LF impairment independent of the type of impairment, in contrast to the different components of the MetS.

Background: Perception of global health status may differ between COPD patients and their physicians. Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners in Austria. The St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Furthermore, we asked, independent from each other, the patient as well as the treating physician to estimate the global health status of the patient (excellent, good, fair, poor, very poor). Inclusion criteria were a physician’s diagnosis of COPD and age ≥ 40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded. Results: Of 1,175 COPD patients, 248 did not fulfill the GOLD criteria for COPD (FEV1/FVC≥0.7) and 77 were excluded due to missing data. In 48.7% of study participants, patients and physicians disagreed on the global health status. In 29.7% it was estimated better by the physician than by the patient (overrated patients), and in 19.0% it was underrated. Multivariate regression analysis indicated that overrated patients had a statistically significant better lung function (FEV1), less exacerbations and a lower total SGRQ-C score compared to underrated patients. Conclusion: In stable COPD outpatients the global health status tends to be overestimated in patients with milder airway obstruction and less exacerbations and vice versa.

Reprogramming of energy metabolism in the development of prostate cancer can be exploited for a better diagnosis and treatment of the disease. The goal of this study was to determine whether differences in glucose and pyruvate metabolism of human prostate cancer cells with dissimilar aggressivenesses can be detected using hyperpolarized [1‐13C]pyruvate MRS and [18F]FDG‐PET imaging, and to evaluate whether these measures correlate. For this purpose, we compared murine xenografts of human prostate cancer LNCaP cells with those of more aggressive PC3 cells. [1‐13C]pyruvate was hyperpolarized by dissolution dynamic nuclear polarization (dDNP) and [1‐13C]pyruvate to lactate conversion was followed by 13C MRS. Subsequently [18F]FDG uptake was investigated by static and dynamic PET measurements. Standard uptake values (SUVs) for [18F]FDG were significantly higher for xenografts of PC3 compared with those of LNCaP. However, we did not observe a difference in the average apparent rate constant k pl of 13C label exchange from pyruvate to lactate between the tumor variants. A significant negative correlation was found between SUVs from [18F]FDG PET measurements and k pl values for the xenografts of both tumor types. The k pl rate constant may be influenced by various factors, and studies with a range of prostate cancer cells in suspension suggest that LDH inhibition by pyruvate may be one of these. Our results indicate that glucose and pyruvate metabolism in the prostate cancer cell models differs from that in other tumor models and that [18F]FDG‐PET can serve as a valuable complementary tool in dDNP studies of aggressive prostate cancer with [1‐13C]pyruvate., Differences in energy metabolism in murine xenografts of prostate cancer are found using hyperpolarized MR and PET. A significant negative correlation was seen between PET‐derived SUVs and 13C‐MR‐derived k pl values for the xenografts of both tumor types. Standard uptake values (SUV) for [18F]FDG were significantly higher for PC3 compared to LNCaP. Energy metabolism in prostate cancer cell models differ from other tumor models and [18F]FDG‐PET can serve as a complementary tool in dDNP studies of aggressive prostate cancer with [1‐13C]pyruvate.

Background In the context of the COVID-19 pandemic, numerous new serological test systems for the detection of anti-SARS-CoV-2 antibodies rapidly have become available. However, the clinical performance of many of these is still insufficiently described. Therefore, we compared 3 commercial CE-marked, SARS-CoV-2 antibody assays side by side. Methods We included a total of 1154 specimens from pre-COVID-19 times and 65 samples from COVID-19 patients (≥14 days after symptom onset) to evaluate the test performance of SARS-CoV-2 serological assays by Abbott, Roche, and DiaSorin. Results All 3 assays presented with high specificities: 99.2% (98.6–99.7) for Abbott, 99.7% (99.2–100.0) for Roche, and 98.3% (97.3–98.9) for DiaSorin. In contrast to the manufacturers’ specifications, sensitivities only ranged from 83.1% to 89.2%. Although the 3 methods were in good agreement (Cohen’s Kappa 0.71–0.87), McNemar tests revealed significant differences between results obtained from Roche and DiaSorin. However, at low seroprevalences, the minor differences in specificity resulted in profound discrepancies of positive predictive values at 1% seroprevalence: 52.3% (36.2–67.9), 77.6% (52.8–91.5), and 32.6% (23.6–43.1) for Abbott, Roche, and DiaSorin, respectively. Conclusion We found diagnostically relevant differences in specificities for the anti-SARS-CoV-2 antibody assays by Abbott, Roche, and DiaSorin that have a significant impact on the positive predictive values of these tests.

There is growing interest in blood eosinophil counts in the management of chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). Despite this, typical blood eosinophil levels in the general population, and the impact of potential confounders on these levels have not been clearly defined.We measured blood eosinophil counts in a random sample of 11 042 subjects recruited from the general population in Austria. We then: 1) identified factors associated with high blood eosinophil counts (>75th percentile); and 2) excluded subjects with these factors to estimate median blood eosinophil counts in a “healthy” sub-population (n=3641).We found that: 1) in the entire cohort, age ≤18 years (OR 2.41), asthma (OR 2.05), current smoking (OR 1.72), positive skin prick test (OR 1.64), COPD (OR 1.56), metabolic syndrome (OR 1.41), male sex (OR 1.36) and obesity (OR 1.16) were significantly (pversus 100 (30–310) cells·µL−1, respectively) and did not change with age.Median blood eosinophil counts in adults are considerably lower than those currently regarded as normal, do not change with age beyond puberty, but are significantly influenced by a variety of factors which have an additive effect. These observations will contribute to the interpretation of blood eosinophil levels in clinical practice.

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195mPt BP co-localized with calcium in the trabeculae of mice tibia.

Background Based on biological and behavioural diversity sex and gender may affect comorbidities associated with prediabetes and diabetes. Besides evaluating the prevalence of prediabetes and diabetes (using fasting plasma glucose and HbA1(c) levels), the primary aim of the study is to investigate sex and gender differences in the prevalence of comorbidities in subjects with prediabetes and diabetes and to identify possible risk factors associated with prediabetes and diabetes.Design This observational, population-based cohort study included 11.014 subjects aged 6-80 years. Examinations included blood samples, ankle-brachial index, ECG, dual-energy X-ray absorptiometry scan and an interviewer-administered questionnaire.Results Across all ages, prevalence of prediabetes was 20.2% (male 23.6%; female 17.1%), and 5.4% for diabetes (male 7.3%; female 3.7%). The prevalence of prediabetes ranged from 4.4% (6

Background and objective Cardiovascular risk is substantially increased in patients with COPD and can be quantified via arterial stiffness. The PDE-IV inhibitor roflumilast revealed a potential reduction of COPD-related cardiovascular risk. We aimed to investigate the effects of roflumilast on arterial stiffness by quantification of pulse wave velocity (PWV) in stable COPD. Methods In this randomized placebo-controlled trial, 80 COPD patients received roflumilast or placebo for 24 weeks. The primary outcome was the change in cf-PWV. Secondary outcomes comprised markers of vascular function (e.g. Aix and RHI), systemic inflammation (e.g. IL-6 and TNF-α) and clinical characteristics of COPD (e.g. CAT and 6MWT). Results A total of 33 and 34 patients completed the roflumilast and placebo arm, respectively (age, median (IQR): 64.5 (61-69.5) vs 64.5 (56-72) years; FEV1 , median (IQR): 34.5 (25.5-48.6) vs 35.3 (27-46.8) % predicted; 6MWT, median (IQR): 428 (340-558) vs 456 (364-570) m). Change from baseline PWV did not show a significant difference between roflumilast and placebo (+5.0 (95% CI: -2.0 to +13.0) vs 0.0 (95% CI: -7.0 to +7.0)%, P = 0.268). Roflumilast did not improve markers of vascular function or systemic inflammation. We observed a significant improvement in change from baseline 6MWT with roflumilast versus placebo (+53.0 (95% CI: +19.1 to +86.9) vs -0.92 (95% CI: -35.1 to +33.3) m, P = 0.026). Conclusion Our study revealed no beneficial effects of roflumilast on arterial stiffness. Further studies are needed to test a potential improvement of exercise capacity with roflumilast in COPD.

Arteriovenous malformations (AVMs) have an inherent capacity to form new blood vessels, resulting in excessive lesion growth, and this process is further triggered by the release of angiogenic factors. 68Ga-labeled arginine-glycine-aspartate tripeptide sequence (RGD) PET/CT imaging may provide insight into the angiogenic status and treatment response of AVMs. This clinical feasibility study was performed to demonstrate that 68Ga-RGD PET/CT imaging can be used to quantitatively assess angiogenesis in peripheral AVMs. Methods: Ten patients with a peripheral AVM (mean age, 40 y; 4 men and 6 women) and scheduled for endovascular embolization treatment were prospectively included. All patients underwent 68Ga-RGD PET/CT imaging 60 min after injection (mean dose, 207 ± 5 MBq). Uptake in the AVM, blood pool, and muscle was quantified as SUVmax and SUVpeak, and a descriptive analysis of the PET/CT images was performed. Furthermore, immunohistochemical analysis was performed on surgical biopsy sections of peripheral AVMs to investigate the expression pattern of integrin αvβ3. Results:68Ga-RGD PET/CT imaging showed enhanced uptake in all AVM lesions (mean SUVmax, 3.0 ± 1.1; mean SUVpeak, 2.2 ± 0.9). Lesion-to-blood and lesion-to-muscle ratios were 3.5 ± 2.2 and 4.6 ± 2.8, respectively. Uptake in blood and muscle was significantly higher in AVMs than in background tissue (P = 0.0006 and P = 0.0014, respectively). Initial observations included uptake in multifocal AVM lesions and enhanced uptake in intraosseous components in those AVM cases affecting bone integrity. Immunohistochemical analysis revealed cytoplasmatic and membranous integrin αvβ3 expression in the endothelial cells of AVMs. Conclusion: This feasibility study showed increased uptake in AVMs with angiogenic activity, compared with surrounding tissue without angiogenic activity, suggesting that 68Ga-RGD PET/CT imaging can be used as a tool to quantitatively determine angiogenesis in AVMs. Further studies will be conducted to explore the potential of 68Ga-RGD PET/CT imaging for guiding current treatment decisions and for assessing response to antiangiogenic treatment.

Background Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce. Objective To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib. Patients and Methods In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib. Results Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number. Conclusion EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

Apples can suffer from significant mechanical injury in the form of bruise damage. The discrete element method (DEM) allows for individual particle contacts and the dynamic behaviour of a group of particles to be studied. Successfully applying this method to apples allows for future investigations into postharvest mechanical damage to be performed on a range of fruit and vegetables. A contact model that closely replicated the visco-elastic nature of apples was used and the material properties were successfully determined using a pendulum device. Bruise damage models (in the form of bruise volume, bruise area and bruise depth) were coupled to the peak impact forces available through DEM. Bruise formations resulting from multiple impacts and variable time durations between impacts were studied. A detailed multi-sphere particle shape representation along with a realistic contact point loading scheme was implemented. Overlapping bruises were studied and accounted for on a post process level. The resulting DEM model was successfully validated and extended to include run-time bruise visualisation. Qualitatively the model accurately predicted the dynamic bulk behaviour of the apples. Quantitatively, the model succeeded in predicting the contact forces experienced by apples to within 11%. The model predicted the mean bruise damage of a single apple for realistic situations within an accuracy of 47% in terms of mean bruise volume, 35% for bruise area and 30% for bruise depth.

Introduction Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non–small-cell lung cancer who have been pre-treated with EGFR–tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. Methods From April 2015 to November 2016, we included 119 patients with advanced EGFR -mutated non–small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. Results T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1–12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number ( p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89–5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. Conclusion Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.

Anaplastic thyroid cancer (ATC) is a rare malignancy that accounts for 1%-2% of all thyroid cancers. ATC is one of the most aggressive human cancers, with rapid growth, tumor invasion, and development of distant metastases. The median survival is only 5 mo, and the 1-y survival is less than 20%. Moreover, as a result of severe dedifferentiation, including the loss of human sodium iodide symporter (hNIS) expression, radioactive iodide (RAI) therapy is ineffective. Recently, we have demonstrated beneficial effects of autophagy-activating digitalislike compounds (DLCs) on redifferentiation and concomitant restoration of iodide uptake in RAI-refractory papillary and follicular thyroid cancer cell lines. In the current study, the effects of DLCs on differentiation and proliferation of ATC cell lines were investigated. Methods: Autophagy activity was assessed in ATC patient tissues by immunofluorescent staining for the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3). In addition, the effect of autophagy-activating DLCs on the proliferation, gene expression profile, and iodide uptake capacity of ATC cell lines was studied. Results: Diminished autophagy activity was observed in ATC tissues, and in vitro treatment of ATC cell lines with DLCs robustly restored hNIS and thyroglobulin expression and iodide uptake capacity. In addition, proliferation was strongly reduced by induction of cell cycle arrest and, to some extent, cell death. Mechanistically, reactivation of functional hNIS expression could be attributed to activation of the transcription factors activating transcription factor 3 and protooncogene c-fosConclusion: DLCs could represent a promising adjunctive therapy for restoring iodide avidity within the full spectrum from RAI-refractory dedifferentiated to ATC.

ObjectiveCardiac disease is the leading cause of indirect maternal mortality. The aim of this study was to analyse to what extent socioeconomic factors influence the outcome of pregnancy in women with heart disease.MethodsThe Registry of Pregnancy and Cardiac disease is a global prospective registry. For this analysis, countries that enrolled ≥10 patients were included. A combined cardiac endpoint included maternal cardiac death, arrhythmia requiring treatment, heart failure, thromboembolic event, aortic dissection, endocarditis, acute coronary syndrome, hospitalisation for cardiac reason or intervention. Associations between patient characteristics, country characteristics (income inequality expressed as Gini coefficient, health expenditure, schooling, gross domestic product, birth rate and hospital beds) and cardiac endpoints were checked in a three-level model (patient–centre–country).ResultsA total of 30 countries enrolled 2924 patients from 89 centres. At least one endpoint occurred in 645 women (22.1%). Maternal age, New York Heart Association classification and modified WHO risk classification were associated with the combined endpoint and explained 37% of variance in outcome. Gini coefficient and country-specific birth rate explained an additional 4%. There were large differences between the individual countries, but the need for multilevel modelling to account for these differences disappeared after adjustment for patient characteristics, Gini and country-specific birth rate.ConclusionWhile there are definite interregional differences in pregnancy outcome in women with cardiac disease, these differences seem to be mainly driven by individual patient characteristics. Adjustment for country characteristics refined the results to a limited extent, but maternal condition seems to be the main determinant of outcome.

A non-invasive imaging method to monitor islet grafts could provide novel and improved insight into the fate of transplanted islets and, potentially, monitor the effect of therapeutic interventions. Therefore, such an imaging method could help improve long-term transplantation outcome. Here, we investigated the use of [ 123 I]IBZM for insulin positive graft volume quantification and longitudinal graft monitoring. SPECT images were acquired 6 weeks after islet transplantation in the calf muscle of rats. For longitudinal graft analysis, rats were monitored by SPECT for 10 weeks. After animals were euthanized, graft containing muscles were dissected for ex vivo analysis and insulin-positive graft volume determination. Six weeks after transplantation, a clear signal was observed in all grafts by SPECT imaging. Moreover, the intensity of the SPECT signal correlated linearly with insulin-positive graft volume, as determined histologically. Longitudinal graft follow-up showed a clear SPECT signal of the transplant from 3 until 10 weeks after transplantation. In this study, we demonstrate for the first time the successful application of a radiotracer, [ 123 I]IBZM, for non-invasive, in vivo graft volume quantification and longitudinal graft monitoring.

Contains fulltext : 177175.pdf (Publisher’s version ) (Open Access) Calcium phosphate cement (CPC) is used in bone repair because of its biocompatibility. However, high similarity between CPC and the natural osseous phase results in poor image contrast in most of the available in vivo imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). For accurate identification and localization during and after implantation in vivo, a composition with enhanced image contrast is needed. In this study, we labeled CPC with perfluoro-15-crown-5-ether-loaded (PFCE) poly(latic-co-glycolic acid) nanoparticles (hydrodynamic radius 100 nm) and gold nanoparticles (diameter 40 nm), as 19F MRI and CT contrast agents, respectively. The resulting CPC/PFCE/gold composite is implanted in a rat model for in vivo longitudinal imaging. Our findings show that the incorporation of the two types of different nanoparticles did result in adequate handling properties of the cement. Qualitative and quantitative long-term assessment of CPC/PFCE/gold degradation was achieved in vivo and correlated to the new bone formation. Finally, no adverse biological effects on the bone tissue are observed via histology. In conclusion, an easy and efficient strategy for following CPC implantation and degradation in vivo is developed. As all materials used are biocompatible, this CPC/PFCE/gold composite is clinically applicable.

Purpose: The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases. Procedures: Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [18F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression. Results: 5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [18F]FLT SUVmean and SUVmax were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUVmax at days −1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [18F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats. Conclusion: This study suggests that 5-FU treatment induces a flare in [18F]FLT uptake of responsive CC531 tumors in the liver, while the ADCmean did not change significantly. Future studies in larger groups are warranted to further investigate whether [18F]FLT PET can discriminate between disease progression and treatment response.

Contains fulltext : 165740.pdf (Publisher’s version ) (Closed access) Up to 20%-30% of patients with metastatic non-medullary thyroid cancer have persistent or recurrent disease resulting from tumor dedifferentiation. Tumor redifferentiation to restore sensitivity to radioactive iodide (RAI) therapy is considered a promising strategy to overcome RAI resistance. Autophagy has emerged as an important mechanism in cancer dedifferentiation. Here, we demonstrate the therapeutic potential of autophagy activators for redifferentiation of thyroid cancer cell lines. Five autophagy-activating compounds, all known as digitalis-like compounds, restored hNIS expression and iodide uptake in thyroid cancer cell lines. Upregulation of hNIS was mediated by intracellular Ca2+ and FOS activation. Cell proliferation was inhibited by downregulating AKT1 and by induction of autophagy and p21-dependent cell-cycle arrest. Digitalis-like compounds, also designated as cardiac glycosides for their well-characterized beneficial effects in the treatment of heart disease, could therefore represent a promising repositioned treatment modality for patients with RAI-refractory thyroid carcinoma. Mol Cancer Ther; 16(1); 169-81. (c)2016 AACR. 13 p.