BackgroundThe possibility to combine Low Intensity UltraSound (LIUS) and Nanoparticles (NP) could represent a promising strategy for drugs delivery in tumors difficult to treat overcoming resistance to therapies. On one side the NP can carry drugs that specifically target the tumors on the other the LIUS can facilitate and direct the delivery to the tumor cells. In this study, we investigated whether Very Low Intensity UltraSound (VLIUS), at intensities lower than 120 mW/cm2, might constitute a novel strategy to improve delivery to tumor cells. Thus, in order to verify the efficacy of this novel modality in terms of increase selective uptake in tumoral cells and translate speedily in clinical practice, we investigated VLIUS in three different in vitro experimental tumor models and normal cells adopting three different therapeutic strategies.MethodsVLIUS at different intensities and exposure time were applied to tumor and normal cells to evaluate the efficiency in uptake of labeled human ferritin (HFt)-based NP, the delivery of NP complexed Firefly luciferase reported gene (lipoplex-LUC), and the tumor-killing of chemotherapeutic agent.ResultsSpecifically, we found that specific VLIUS intensity (120 mW/cm2) increases tumor cell uptake of HFt-based NPs at specific concentration (0.5 mg/ml). Similarly, VLIUS treatments increase significantly tumor cells delivery of lipoplex-LUC cargos. Furthermore, of interest, VLIUS increases tumor killing of chemotherapy drug trabectedin in a time dependent fashion. Noteworthy, VLIUS treatments are well tolerated in normal cells with not significant effects on cell survival, NPs delivery and drug-induced toxicity, suggesting a tumor specific fashion.ConclusionsOur data shed novel lights on the potential application of VLIUS for the design and development of novel therapeutic strategies aiming to efficiently deliver NP loaded cargos or anticancer drugs into more aggressive and unresponsive tumors niche.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1018-6) contains supplementary material, which is available to authorized users.

Background Obesity was recently identified as a major risk factor for worse COVID-19 severity, especially among the young. The reason why its impact seems to be less pronounced in the elderly may be due to the concomitant presence of other comorbidities. However, all reports only focus on BMI, an indirect marker of body fat. Aim To explore the impact on COVID-19 severity of abdominal fat as a marker of body composition easily collected in patients undergoing a chest CT scan. Methods Patients included in this retrospective study were consecutively enrolled among those admitted to an Emergency Department in Rome, Italy, who tested positive for SARS-Cov-2 and underwent a chest CT scan in March 2020. Data were extracted from electronic medical records. Results 150 patients were included (64.7% male, mean age 64 ± 16 years). Visceral fat (VAT) was significantly higher in patients requiring intensive care ( p = 0.032), together with age ( p = 0.009), inflammation markers CRP and LDH ( p < 0.0001, p = 0.003, respectively), and interstitial pneumonia severity as assessed by a Lung Severity Score (LSS) ( p < 0.0001). Increasing age, lymphocytes, CRP, LDH, D-Dimer, LSS, total abdominal fat as well as VAT were found to have a significant univariate association with the need of intensive care. A multivariate analysis showed that LSS and VAT were independently associated with the need of intensive care (OR: 1.262; 95%CI: 1.0171–1.488; p = 0.005 and OR: 2.474; 95%CI: 1.017–6.019; p = 0.046, respectively). Conclusions VAT is a marker of worse clinical outcomes in patients with COVID-19. Given the exploratory nature of our study, further investigation is needed to confirm our findings and elucidate the mechanisms underlying such association.

Radioactive 90 Y-selective internal radiation (SIR) sphere therapy is increasingly used for the treatment of nonresectable hepatocellular carcinoma (HCC). However, the maximum delivered dose is limited by severe injury to the nontarget tissue, including liver parenchyma. Our study aimed to implement radiobiologic models for both tumor control probability (TCP) and normaltissue complication probability (NTCP) to describe more effectively local response and the liver toxicity rate, respectively. Methods: Patients with documented HCC, adequate bone marrow parameters, and regular hepatic and pulmonary function were eligible for the study. Patients who had pulmonary shunt greater than 20% of 99m Tc-labeled macroaggregated albumin or any uncorrectable delivery to the gastrointestinal tract, reverse blood flow out of the liver, or complete portal vein thrombosis were excluded. Patients received a planned activity of the 90 Y-SIR spheres, determined using the empiric body surface area method. The dose distribution was determined using posttreatment (3-dimensional) activity distribution and Monte Carlo dose voxel kernel calculations, and the mean doses to healthy liver and tumor were calculated for each patient. Response was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) and recommendations of the European Association for the Study of the Liver (EASL). Criteria were used to assess possible liver toxicities. The parameters of TCP and NTCP models were established by direct maximization of the likelihood. Results: Seventy-three patients were treated. With an average dose of 110 Gy to the tumor, complete or partial response was observed in 74% and 55% of patients according to the EASL guideline and RECIST, respectively, and the predicted TCPs were 73% and 55%, respectively. With a median liver dose of 36 Gy (range, 6-78 Gy), the $grade 2 (G2), $grade 3 (G3), and $grade 4 (G4) liver toxicities were observed in 32% (23/73), 21% (15/73), and 11% (8/73) of patients, respectively. The parameters describing the $G2 liver toxicity data using the NTCP model were a tolerance dose of the whole organ leading to a 50% complication probability of 52 Gy (95% confidence interval, 44-61 Gy) and a slope of NTCP versus dose of 0.28 (95% confidence interval, 0.18-0.60), assuming n 5 1. Conclusion: The radiobiologic approach, based on patient-specific dosimetry, could improve the 90 Y-microsphere therapeutic approach of HCC, maintaining an acceptable liver toxicity.

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