Technical feasibility of novel immunostimulatory low-dose radiation for polymetastatic disease with CBCT-based online adaptive and conventional approaches.

PURPOSE: A workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = "conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated. METHODS: Using retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc ≥ 95% (acceptable variation (Δ) ≥ 90%), V100% ≥ 95% (Δ ≥ 90%), and D0.03cc ≤ 120% (Δ ≤ 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes. RESULTS: All initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc ≥ 95%, V100% ≥ 95%, and D0.03cc ≤ 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50%), maximum dose at 2 cm from PTV (D2cm), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 = 0.68, 0.63 and 0.69, respectively). CONCLUSIONS: This study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Hepatitis-B virus: replication cycle, targets, and antiviral approaches.

An estimated 257 million people are chronic carriers of hepatitis-B virus (HBV) infection, which resulted in around 1 million deaths, mainly due to hepatocellular carcinoma (HCC). Long-term nucleotide analog treatment of HBV infection is associated with favorable prognosis, no disease progression, and a reduction of HCC risk, but lifelong treatments are required. A better understanding of HBV replication cycle and the host immune response will likely improve the identification of new targets for drug development. Studies are ongoing to determine if it is possible to successfully combine direct-acting antivirals (DAA) with an immunomodulatory therapy to allow increased cure rates. This review will start with summarizing the HBV replication cycle, recall current treatments, and then discuss potential targets and antiviral approaches in development to optimistically reach the HBV cure.

Proteomics of Plasma and Plasma-Treated Podocytes: Application to Focal and Segmental Glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a severe form of idiopathic nephrotic syndrome (INS), a glomerulopathy of presumably immune origin that is attributed to extrarenal pathogenic circulating factors. The recurrence of FSGS (rFSGS) after transplant occurs in 30% to 50% of cases. The direct analysis of patient plasma proteome has scarcely been addressed to date, mainly due to the methodological difficulties associated with plasma complexity and dynamic range. In this study, first, we compared different methods of plasma preparation, second, we compared the plasma proteomes of rFSGS and controls using two preparation methods, and third, we analyzed the early proximal signaling events in podocytes subjected to patient plasma, through a combination of phosphoproteomics and lipid-raft proteomics (raftomics). By combining immunodepletion and high pH fractionation, we performed a differential proteomic analysis of soluble plasma proteins and of extracellular vesicles (EV) obtained from healthy controls, non-INS patient controls, and rFSGS patients (n = 4). In both the soluble- and the EV-protein sets from the rFSGS patients, we found a statistically significant increase in a cluster of proteins involved in neutrophil degranulation. A group of lipid-binding proteins, generally associated with lipoproteins, was found to be decreased in the soluble set from the rFSGS patients. In addition, three amino acid transporters involved in mTORC1 activation were found to be significantly increased in the EV from the rFSGS. Next, we incubated human podocytes for 30 min with 10% plasma from both groups of patients. The phosphoproteomics and raftomics of the podocytes revealed profound differences in the proteins involved in the mTOR pathway, in autophagy, and in cytoskeleton organization. We analyzed the correlation between the abundance of plasma and plasma-regulated podocyte proteins. The observed changes highlight some of the mechanisms involved in FSGS recurrence and could be used as specific early markers of circulating-factor activity in podocytes.

A head and neck treatment planning strategy for a CBCT-guided ring-gantry online adaptive radiotherapy system.

PURPOSE: A planning strategy was developed and the utility of online-adaptation with the Ethos CBCT-guided ring-gantry adaptive radiotherapy (ART) system was evaluated using retrospective data from Head-and-neck (H&N) patients that required clinical offline adaptation during treatment. METHODS: Clinical data were used to re-plan 20 H&N patients (10 sequential boost (SEQ) with separate base and boost plans plus 10 simultaneous integrated boost (SIB)). An optimal approach, robust to online adaptation, for Ethos-initial plans using clinical goal prioritization was developed. Anatomically-derived isodose-shaping helper structures, air-density override, goals for controlling hotspot location(s), and plan normalization were investigated. Online adaptation was simulated using clinical offline adaptive simulation-CTs to represent an on-treatment CBCT. Dosimetric comparisons were based on institutional guidelines for Clinical-initial versus Ethos-initial plans and Ethos-scheduled versus Ethos-adapted plans. Timing for five components of the online adaptive workflow was analyzed. RESULTS: The Ethos H&N planning approach generated Ethos-initial SEQ plans with clinically comparable PTV coverage (average PTVHigh V100%  = 98.3%, Dmin,0.03cc  = 97.9% and D0.03cc  = 105.5%) and OAR sparing. However, Ethos-initial SIB plans were clinically inferior (average PTVHigh V100%  = 96.4%, Dmin,0.03cc  = 93.7%, D0.03cc  = 110.6%). Fixed-field IMRT was superior to VMAT for 93.3% of plans. Online adaptation succeeded in achieving conformal coverage to the new anatomy in both SEQ and SIB plans that was even superior to that achieved in the initial plans (which was due to the changes in anatomy that simplified the optimization). The average adaptive workflow duration for SIB, SEQ base and SEQ boost was 30:14, 22.56, and 14:03 (min: sec), respectively. CONCLUSIONS: With an optimal planning approach, Ethos efficiently auto-generated dosimetrically comparable and clinically acceptable initial SEQ plans for H&N patients. Initial SIB plans were inferior and clinically unacceptable, but adapted SIB plans became clinically acceptable. Online adapted plans optimized dose to new anatomy and maintained target coverage/homogeneity with improved OAR sparing in a time-efficient manner.

Success of Endoscopic Laser Cyclophotocoagulation vs Repeat Transscleral Treatment after Prior Transscleral Cycloablation.

Aim: To compare the efficacy of endoscopic cyclophotocoagulation (ECP) vs repeat transscleral cyclophotocoagulation (TCP) in eyes with persistent glaucoma despite prior treatment with TCP. Materials and methods: This was a retrospective chart review of glaucoma patients at the American University of Beirut Medical Center over 10 years who underwent ECP or repeat TCP. We reported qualified and complete success; success was defined as postoperative intraocular pressure (IOP) ≤21 mm Hg, with (qualified) or without medications (complete) and without procedure-related complications. Results: This study included 23 eyes of 21 patients with various forms of uncontrolled glaucoma who had failed TCP. A total of 13 eyes of 12 patients underwent ECP with a mean age of 39.9 ± 23.2 years, and 10 eyes of nine patients underwent repeat TCP with a mean age of 27.2 ± 22.6 years. A significant decrease in IOP was observed from 38.5 ± 7.9 mm Hg preoperatively to 25.2 ± 8.8 mm Hg postrepeat TCP (p = 0.006) and from 33.0 ± 9.5 to 12.8 ± 3.9 mm Hg post-ECP (p < 0.001), noted at a mean follow-up time of 39.2 ± 44.4 and 41.5 ± 37.4 months, respectively. The mean number of antiglaucoma medications decreased in the two groups (from 3.8 ± 1.0 preoperatively to 1.8 ± 0.9 postoperatively for ECP and from 3.5 ± 1.3 to 3.1 ± 0.9 postoperatively for TCP); however, the drop was only statistically significant post-ECP. Qualified success was significantly higher after ECP vs repeat TCP (91.7 vs 40%, respectively). Complete success was achieved only in 1/12 (8.3%) eyes in the ECP group. Conclusion: Endoscopic cyclophotocoagulation (ECP) performed in glaucomatous eyes previously treated with transscleral cycloablation provided more IOP control as compared to repeat TCP by directly treating viable tissue in previously skipped ciliary processes and in between processes. Clinical significance: In glaucomatous eyes previously treated with transscleral cycloablation, ECP attained better IOP control than repeat transscleral cycloablation. How to cite this article: Al-Haddad C, Barikian A, Moussawi ZE, et al. Success of Endoscopic Laser Cyclophotocoagulation vs Repeat Transscleral Treatment after Prior Transscleral Cycloablation. J Curr Glaucoma Pract 2023;17(4):191-196.