Purpose: The objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration.
Methods: NAT-SLNs were prepared using the emulsification-ultrasonication technique. Box- Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X1], surfactant concentration [X2], and sonication frequency [X3]) on particle size (R1), zeta potential (ZP; R2), and drug entrapment efficiency (EE%) (R3) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated.
Results: The optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached ~85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (Papp) and steady-state flux (Jss) reached 11.59×10-2 cm h-1 and 3.94 mol h-1, respectively, in comparison with 7.28×10-2 cm h-1 and 2.48 mol h-1 for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against Aspergillus fumigatus ATCC 1022 and a Candida albicans clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate, that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues.
Conclusion: Thus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.
MATERIALS AND METHODS: A retrospective study of patients diagnosed as benign bone tumours according to the Enneking classification who underwent simple or extended curettage at Menoufia university-Orthopedic Oncology Division (with or without grafting or filling) during the surgical treatment (Jan 2015 to Feb 2020). A review of the medical records was done. Lesions' size (length, width and depth) was measured on plain radiographs using the image j program. When applicable, degrees of filling of the resultant cavity were classified into four categories, according to Modified Neer's classification. Functional evaluation using the musculoskeletal tumour society (MSTS) score was reviewed.
RESULTS: Overall, 88 patients diagnosed with a primary bone tumour and who received the surgical intervention were included in the study. The mean age of the patients was 22.61+13.497 (3-58) years. There were 48 males and 40 females (54 right and 34 left). The mean follow-up period was 28.09+16.13 months. The most common location was the distal femur in 15 patients, the proximal femur in 10 patients and the proximal tibia in 12 patients. The most common diagnosis was giant cell tumour in 20 patients, followed by UBC in 19 patients, ABC in 15 patients and enchondroma in 13 patients. Twenty-three patients had simple curettage, while 65 patients had extended curettage. Mean MSTS was 28.78±1.68. Fifty-five lesions were classified according to modified Neer's classification.Thirtty-two patients were classified as type 1 with complete healing,22 patient was classified as type 2 with partial healing, and only one was classified as a recurrent lesion. Seven patients (7.9%) developed local recurrences.
CONCLUSION: Filling the resulting cavity after the removal of the pathological tissues is usually necessary but not always required. This is determined by the type of lesion and the size of the resulting cavity following curettage. Individualised surgery is required; additional fixation should be considered.
METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098.
FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab.
INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully.
FUNDING: F Hoffmann-La Roche/Genentech.