Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent

Seroprevalence of 34 Human Papillomavirus Types in the German General Population

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life

Differentiation of Hamartomas and Malignant Lung Tumors in Single-Phased Dual-Energy Computed Tomography

This study investigated the efficacy of single-phase dual-energy CT (DECT) in differentiating pulmonary hamartomas from malignant lung lesions using virtual non-contrast (VNC), iodine, and fat quantification. Forty-six patients with 47 pulmonary lesions (mean age: 65.2 ± 12.1 years; hamartomas-to-malignant lesions = 22:25; male: 67%) underwent portal venous DECT using histology, PET-CT and follow-up CTs as a reference. Quantitative parameters such as VNC, fat fraction, iodine density and CT mixed values were statistically analyzed. Significant differences were found in fat fractions (hamartomas: 48.9%; malignancies: 22.9%; p ≤ 0.0001) and VNC HU values (hamartomas: −20.5 HU; malignancies: 17.8 HU; p ≤ 0.0001), with hamartomas having higher fat content and lower VNC HU values than malignancies. CT mixed values also differed significantly (p ≤ 0.0001), but iodine density showed no significant differences. ROC analysis favored the fat fraction (AUC = 96.4%; sensitivity: 100%) over the VNC, CT mixed value and iodine density for differentiation. The study concludes that the DECT-based fat fraction is superior to the single-energy CT in differentiating between incidental pulmonary hamartomas and malignant lesions, while post-contrast iodine density is ineffective for differentiation

Myocardial lipid content in Fabry disease: a combined 1^1H-MR spectroscopy and MR imaging study at 3 Tesla

Background Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by $^1$H magnetic resonance spectroscopy (MRS) at 3 Tesla. Methods Myocardial lipid content was quantified in vivo by $^1$H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined $^1$H-MRS with cardiac cine imaging and LGE MRI in a single examination. Results Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076). Conclusions This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by $^1$H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; $^1$H-MRS; T$_1$ mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease

The effect of tin prefiltration on extremity cone-beam CT imaging with a twin robotic X-ray system

Introduction: While tin prefiltration is established in various CT applications, its value in extremity cone beam CT relative to optimized spectra has not been thoroughly assessed thus far. This study aims to investigate the effect of tin filters in extremity cone-beam CT with a twin-robotic X-ray system. Methods: Wrist, elbow and ankle joints of two cadaveric specimens were examined in a laboratory setup with different combinations of prefiltration (copper, tin), tube voltage and current-time product. Image quality was assessed subjectively by five radiologists with Fleiss' kappa being computed to measure interrater agreement. To provide a semiquantitative criterion for image quality, contrast-to-noise ratios (CNR) were compared for standardized regions of interest. Volume CT dose indices were calculated for a 16 cm polymethylmethacrylate phantom. Results: Radiation dose ranged from 17.4 mGy in the clinical standard protocol without tin filter to as low as 0.7 mGy with tin prefiltration. Image quality ratings and CNR for tin-filtered scans with 100 kV were lower than for 80 kV studies with copper prefiltration despite higher dose (11.2 and 5.6 vs. 4.5 mGy; p < 0.001). No difference was ascertained between 100 kV scans with tin filtration and 60 kV copper filtered scans with 75% dose reduction (subjective: p = 0.101; CNR: p = 0.706). Fleiss' kappa of 0.597 (95% confidence interval 0.567-0.626; p < 0.001) indicated moderate interrater agreement. Conclusion: Considerable dose reduction is feasible with tin prefiltration, however, the twin-robotic Xray system's low-dose potential for extremity 3D imaging is maximized with a dedicated low-kilovolt scan protocol in situations without extensive beam-hardening artifacts. Implications for practice: Low-kilovolt imaging with copper prefiltration provides a superior trade-off between dose reduction and image quality compared to tin-filtered cone-beam CT scan protocols with higher tube voltage. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of The College of Radiographers. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)