† People involved in the organization of the challenge. ‡ People contributing data from their institutions.§ Equal senior authors.

Micellen als Ziel: Das cyclische Pentapeptid cRGDfK (rote Dreiecke), das Integrin αvβ3 als Ziel hat, wurde nach der Micellenbildung an die äußere Schale von polymeren Micellen, die mit Doxorubicin (rote Sechsecke) beladen waren, gebunden. Die Internalisierung der modifizierten Micellen durch rezeptorvermittelte Endocytose in Tumor‐Endothelzellen, die den αvβ3‐Rezeptor überexprimieren, war signifikant erhöht (bis zum 30fachen).

BACKGROUND Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high-risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly-diagnosed GBMs. METHODS Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory U, U Miami, Johns Hopkins U) from 9/2017 to 6/2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥ 2x normal was treated to 75 Gy. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. RESULTS Thirty patients were treated on study. Median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median OS and PFS were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least one year after RT. CONCLUSION Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly-diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.

In this study, we report the histological findings of a combined therapy using radiofrequency ablation and intratumoral drug delivery in rat livers, with special attention to wound-healing processes and their effects on drug transport in post-ablated tissue. Doxorubicin-loaded millirods were implanted in rat livers that had undergone medial lobe ablation. Millirods and liver samples were retrieved upon animal sacrifice at time points ranging from 1 h to 8 days. Results demonstrate a clearly defined area of coagulative necrosis within the ablation boundary. The wound-healing response, complete with the appearance of inflammatory cells, neovascularization, and the formation of a fibrous capsule, was also observed. At the 8-day time point, fluorescence imaging analysis showed a higher concentration of doxorubicin localized within the ablation region, with its distribution hampered primarily by fibrous capsule formation at the boundary. Given the variant nature of ablated liver, a mathematical model devised previously by our laboratory describes the data well up to 4 days, but loses reliability at 8 days. These results provide useful mechanistic insights into the wound-healing response after radiofrequency ablation and polymer millirod implantation, as well as the impact this natural corollary has on drug distribution.

Background Low-dose radiotherapy (LD-RT) has produced anti-inflammatory effects in both animal models and early human trials of COVID-19-related pneumonia. The role of whole-lung LD-RT within existing treatment paradigms merits further study. Methods A phase II prospective trial studied the addition of LD-RT to standard drug treatments. Hospitalized and oxygen-dependent patients receiving dexamethasone and/or remdesevir were treated with 1.5 Gy whole-lung LD-RT and compared to a blindly-matched contemporaneous control cohort. Results Of 40 patients evaluated, 20 received drug therapy combined with whole-lung LD-RT and 20 without LD-RT. Intubation rates were 14% with LD-RT compared to 32% without (p=0.09). Intubation-free survival was 77% vs. 68% (p=0.17). Biomarkers of inflammation (C-reactive protein, p=0.02) and cardiac injury (creatine kinase, p<0.01) declined following LD-RT compared to controls. Mean time febrile was 1.4 vs 3.3 days, respectively (p=0.14). Significant differences in clinical recovery (7.5 vs. 7 days, p=0.37) and radiographic improvement (p=0.72) were not detected. On subset analysis, CRP decline following LD-RT was predictive of recovery without intubation compared to controls (0% vs. 31%, p=0.04), freedom from prolonged hospitalizations (21+ days) (0% vs. 31%, p=0.04), and decline in oxygenation burden (56% reduction, p=0.06). CRP decline following 1st drug therapy was not similarly predictive of outcome in controls (p=0.36). Conclusions Adding LD-RT to standard drug treatments reduced biomarkers of inflammation and cardiac injury in COVID-19 patients and may have reduced intubation. Durable CRP decline following LD-RT predicted especially favorable recovery, freedom from intubation, reduction in prolonged hospitalization, and reduced oxygenation burden. A confirmatory randomized trial is now ongoing. Clinical Trial Registration : NCT04366791. Funding : None