Clinical characteristics and postoperative complications as predictors of radiation toxicity after treatment with I125 Eye Plaque Brachytherapy for Uveal Melanomas.

PURPOSE: I125 Eye Plaque brachytherapy is the standard treatment for medium-sized uveal melanomas (UM). Patients develop radiation toxicities (RTT), including radiation maculopathy (RM), radiation neovascular glaucoma/iris neovascularization (RNGI) and radiation optic neuropathy (RON). We aim to investigate demographics, pretreatment tumor characteristics and posttreatment complications as predictors of RTT. METHODS AND MATERIALS: An IRB-approved single-institution retrospective chart review was performed from 2011 to 2019 for patients with posterior UM treated with brachytherapy. We collected demographics, pretreatment tumor characteristics and posttreatment complications. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using logistic regression model. Hazard ratios (HR) and corresponding p-values were reported. All tests were two-sided; statistical significance was considered when p<0.05. RESULTS: Two hundred and fifty eight patients were evaluated. Median follow-up was 33.50 months (range 3.02-97.31). 178 patients (69.0%) had RTT. 131 patients (50.8%) developed RM. Fifty-six patients (21.7%) developed RON. Nineteen patients (7.4%) developed RNGI. UVA found shorter distance to fovea (DF) (p = 0.04), posttreatment exudative retinal detachment (PERD) (p = 0.001) and posttreatment vitreous hemorrhage (PVH) (p = 0.001) are associated with RTT. MVA found shorter DF (HR=1.03, p = 0.04), PERD (HR=2.52, p = 0.01) and PVH (HR=3.34, p = 0.006) are associated with RTT. MVA found female sex (HR=1.731, p = 0.031) and tumor height (HR=1.13, p = 0.013) are associated with RM and pretreatment retinal detachment (HR=3.41, p<0.001) is associated with RON. CONCLUSIONS: Shorter DF, PERD and PVH are associated with RTT; female sex and tumor height are associated with RM and tumor height is associated with RON. These findings serve as prognostic tools to counsel patients and promote early intervention in management of RTT.

Deep Learning for Per-Fraction Automatic Segmentation of Gross Tumor Volume (GTV) and Organs at Risk (OARs) in Adaptive Radiotherapy of Cervical Cancer.

Background/Hypothesis: MRI-guided online adaptive radiotherapy (MRI-g-OART) improves target coverage and organs-at-risk (OARs) sparing in radiation therapy (RT). For patients with locally advanced cervical cancer (LACC) undergoing RT, changes in bladder and rectal filling contribute to large inter-fraction target volume motion. We hypothesized that deep learning (DL) convolutional neural networks (CNN) can be trained to accurately segment gross tumor volume (GTV) and OARs both in planning and daily fractions' MRI scans. Materials/Methods: We utilized planning and daily treatment fraction setup (RT-Fr) MRIs from LACC patients, treated with stereotactic body RT to a dose of 45-54 Gy in 25 fractions. Nine structures were manually contoured. MASK R-CNN network was trained and tested under three scenarios: (i) Leave-one-out (LOO), using the planning images of N- 1 patients for training; (ii) the same network, tested on the RT-Fr MRIs of the "left-out" patient, (iii) including the planning MRI of the "left-out" patient as an additional training sample, and tested on RT-Fr MRIs. The network performance was evaluated using the Dice Similarity Coefficient (DSC) and Hausdorff distances. The association between the structures' volume and corresponding DSCs was investigated using Pearson's Correlation Coefficient, r. Results: MRIs from fifteen LACC patients were analyzed. In the LOO scenario the DSC for Rectum, Femur, and Bladder was >0.8, followed by the GTV, Uterus, Mesorectum and Parametrium (0.6-0.7). The results for Vagina and Sigmoid were suboptimal. The performance of the network was similar for most organs when tested on RT-Fr MRI. Including the planning MRI in the training did not improve the segmentation of the RT-Fr MRI. There was a significant correlation between the average organ volume and the corresponding DSC (r = 0.759, p = 0.018). Conclusion: We have established a robust workflow for training MASK R-CNN to automatically segment GTV and OARs in MRI-g-OART of LACC. Albeit the small number of patients in this pilot project, the network was trained to successfully identify several structures while challenges remain, especially in relatively small organs. With the increase of the LACC cases, the performance of the network will improve. A robust auto-contouring tool would improve workflow efficiency and patient tolerance of the OART process.

Predictors of Local Recurrence and Progression-Free Survival in Iodine-125 Brachytherapy-Treated Uveal Melanomas: A Modern Institutional Study.

Introduction: Iodine-125 brachytherapy is an effective eye-sparing treatment for uveal melanoma. Previous work has shown that uveal melanomas cluster into distinct molecular classes based on gene expression profiles - discriminating low-grade from high-grade tumors. Our objective was to identify clinical and molecular predictors of local recurrence (LR) and progression-free survival (PFS). Methods: We constructed a retrospective database of uveal melanoma patients from the University of Miami's electronic medical records that were treated between January 8, 2012, and January 5, 2019, with either COMS-style or Eye Physics plaque. Data on tumor characteristics, pretreatment retinal complications, post-plaque treatments, LR, and PFS were collected. Univariate and multivariate Cox models for cumulative incidence of LR and PFS were conducted using SAS version 9.4. Results: We identified 262 patients, with a median follow-up time of 33.5 months. Nineteen patients (7.3%) had LR, and 56 patients (21.4%) were classified as PFS. We found that ocular melanocytosis (hazard ratio = 5.55, p < 0.001) had the greatest impact on PFS. Genetic expression profile did not predict LR outcomes (hazard ratio = 0.51, p = 0.297). Conclusion: These findings help physicians identify predictors for short-term brachytherapy outcomes, allowing better shared decision making with patients preoperatively when deciding between brachytherapy versus enucleation. Patients stratified to higher risk groups based on preoperative characteristics such as ocular melanocytosis should be monitored more closely. Future studies must validate these findings using a prospective cohort study.

Proton therapy for thoracic malignancies: a review of oncologic outcomes.

Introduction: Radiotherapy is an integral component in the treatment of the majority of thoracic malignancies. By taking advantage of the steep dose fall-off characteristic of protons combined with modern optimization and delivery techniques, proton beam therapy (PBT) has emerged as a potential tool to improve oncologic outcomes while reducing toxicities from treatment.Areas covered: We review the physical properties and treatment techniques that form the basis of PBT as applicable for thoracic malignancies, including a brief discussion on the recent advances that show promise to enhance treatment planning and delivery. The dosimetric advantages and clinical outcomes of PBT are critically reviewed for each of the major thoracic malignancies, including lung cancer, esophageal cancer, mesothelioma, thymic cancer, and primary mediastinal lymphoma.Expert opinion: Despite clear dosimetric benefits with PBT in thoracic radiotherapy, the improvement in clinical outcomes remains to be seen. Nevertheless, with the incorporation of newer techniques, PBT remains a promising modality and ongoing randomized studies will clarify its role to determine which patients with thoracic malignancies receive the most benefit. Re-irradiation, advanced disease requiring high cardio-pulmonary irradiation volume and younger patients will likely derive maximum benefit with modern PBT.

Ceftriaxone-induced radiation recall dermatitis.

BACKGROUND: Radiation recall dermatitis (RRD) is an acute inflammatory skin reaction occurring in a skin area previously exposed to radiotherapy and triggered by subsequent intake of a drug, most commonly a chemotherapeutic agent. RRD secondary to antibiotics has also been reported but is a rare phenomenon overall and there are no reports of RRD in association with ceftriaxone exposure. METHODS: We report on a 59-year-old patient who had received radiotherapy to the neck bilaterally and who developed RRD 6 months later after a single dose of intramuscular ceftriaxone. RESULTS: The patient's rash resolved without further intervention over the ensuing 2 days following administration of a single dose of ceftriaxone. CONCLUSION: This case illustrates that while RRD secondary to antibiotic exposure is rare, it is part of the differential diagnosis to be considered for acute dermatitis when there is a past history of radiotherapy to the same skin area.

Influence of tumor shape and location in eye plaque brachytherapy dosimetry.

PURPOSE: A common treatment planning technique for eye plaque brachytherapy is to model the tumor as an ellipse. For posterior tumors near the optic disc and fovea, this approach may lead to overlap between tumor and the organ at risk (OAR). We hypothesized that a superior plan can be generated by modeling the actual tumor shape. MATERIALS AND METHODS: Forty eye plaque patients with tumors <1 cm from the optic disc and fovea were selected. Two treatment plans were generated for each patient: an elliptical tumor model plan and a true tumor model plan. Dosimetric data were collected for each plan, and Wilcoxon signed-rank tests were used to asses any statistically significant differences. RESULTS: Equivalent tumor coverage was confirmed between the elliptical and true tumor plans for all patients. Qualitative analysis showed greater dosimetric differences between plans as the distance from the OARs increased from 0 to 2 mm but the largest differences were observed between 2 and 4 mm. Minimal differences between models were seen beyond 4 mm. Statistically significant dosimetric improvements were found for tumors <4 mm from the fovea and <2 mm from the optic disc. CONCLUSIONS: Intuitively, accurate modeling of the tumor accounting for irregularities in the shape should result in a more conformal plan and an overall reduction in OAR dose. However, this technique is only beneficial for tumors that are within 4 mm of the fovea or optic disc. An elliptical tumor model allows for an acceptable plan unless the tumor is located posteriorly and has an irregular shape.

How Does Brainstem Involvement Affect Prognosis in Patients with Limited Brain Metastases? Results of a Matched-Cohort Analysis.

OBJECTIVE: Although brainstem metastases are thought to portend an inferior prognosis compared to non-brainstem brain metastases, there is limited evidence to support this claim, particularly in the modern radiosurgical era. METHODS: We collected the clinical data for 500 patients with brain metastases treated at our institution with stereotactic radiosurgery (SRS). All patients received SRS to at least one brain metastasis, and all brainstem metastases underwent SRS. After propensity score matching, clinical characteristics and overall survival were calculated and compared between groups. RESULTS: Three hundred sixteen patients with brain metastases were analyzed after matching (143 with brainstem involvement and 173 without). Patients with brainstem metastases lived shorter after first SRS than patients without brainstem metastases did (median 4.4 and 6.5 months, respectively; P = 0.01), and they were more likely to have received whole brain irradiation (P = 0.003). Patients with a single metastasis did not survive longer than patients with multiple brain metastases if there was brainstem involvement (P = 0.45). The incidence of new extracranial disease and severe toxicity after SRS did not differ between groups. CONCLUSIONS: The survival of patients with brain metastases is inferior after a metastatic lesion develops within the brainstem, despite favorable local control with brainstem SRS. The brainstem location should be considered a negative prognostic factor for survival after SRS, and it could result from the eloquence of this location. Future research could identify the clinically life-limiting component of brainstem metastases.

Brainstem metastases treated with stereotactic radiosurgery: safety, efficacy, and dose response.

The safety and efficacy of stereotactic radiosurgery (SRS) in the brainstem is questioned by some over concern of violating historical brainstem SRS dose tolerance. Our purpose was to report on the clinical outcomes of patients treated at our institution with radiosurgery for brainstem metastases. Patients with metastatic tumors within or directly abutting the brainstem from 1992 to 2014 were analyzed. Patient and tumor characteristics, SRS parameters, and toxicity were recorded and analyzed for associations with local control and survival. Multivariate statistical analysis was performed using Cox proportional hazards modeling. One-hundred and eighty-nine (189) brainstem metastases from 161 patients were included in our analysis. Whole brain irradiation was administered prior to SRS in 52 % of patients. The median margin dose was 18 Gy prescribed to the 50 % isodose line. Median imaging follow up was 5.4 months and median survival was 5.5 months after SRS. At last follow up, local control was achieved in 87.3 % of brainstem lesions treated. There were 3 recorded events of grade 3-5 toxicity (1.8 %). On multivariate analysis, a margin dose ≥16 Gy was associated with improved local control (p = 0.049) and greater KPS score was associated with improved overall survival following SRS (p = 0.024). Patients with brainstem metastases who have limited intracranial disease and/or who have received whole brain irradiation should be considered for SRS. Margin doses of at least 16 Gy are associated with superior local control, and serious radiation toxicity in SRS for brainstem metastasis appears rare.

Central composite design for the formulation and optimization of a multi-unit potential colonic drug delivery system of budesonide for ulcerative colitis.

Budesonide is a potent glucocorticoid with high affinity for the glucocorticoid receptor, which is used for the treatment of inflammatory bowel diseases. Current oral formulations of budesonide present low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. The objective of this study was to develop a colon specific delivery system for budesonide to increase the efficacy in the treatment of ulcerative colitis using a statistical procedure. Pellets were prepared by powder layering of budesonide on nonpareils (0.5-0.6 mm) in a coating pan. Drug-layered pellets were coated with an inner layer of a combination of Eudragit RL PO and RS PO and an outer layer of Eudragit FS in a fluidized-bed apparatus. Central composite design was used to study the effect of three independent variables. The independent variables selected were amount of Eudragit FS outer coating (X1), proportion of Eudragit RL PO in the inner coating (X2), amount of Eudragit RL PO-RS PO inner coating (X3). Fifteen batches were prepared and evaluated for amount of drug released in 6 h (Y1), amount of drug released in 12h (Y2). The proportion of the more hydrophilic polymer Eudragit RL PO had the most significant effect on drug release - higher proportion gave faster release; the amount of inner and outer coat did not have a significant effect on the rate of drug release at either 6 or 12 h in the range studied. The computer optimization process and contour plots predicted the levels of independent variables X1, X2, and X3 (0.79, 0.69 and 0.35 respectively), for colon targeting.

Box-Behnken experimental design in the development of pectin-compritol ATO 888 compression coated colon targeted drug delivery of mesalamine.

The aim of this study was to investigate the combined influence of 3 independent variables in the compression coated tablet of mesalamine for ulcerative colitis. A 3-factor, 3-level Box-Behnken design was used to derive a second order polynomial equation and construct contour plots to predict responses. The independent variables selected were: percentage of polymers (pectin and compritol ATO 888) in compression coating (X(1)), coating mass (X(2)) and coating force (X(3)). Fifteen batches were prepared and evaluated for percent of drug released in 5 h (Y(5)), time required for 50 % mesalamine to dissolve (t(50)) with rat cecal (RC) content and without rat cecal content (t(50)), percent of drug released in 24 h in the presence of rat cecal content (Y(24) with RC). Transformed values of independent and dependent variables were subjected to multiple regressions to establish a full-model second-order polynomial equation. F was calculated to confirm the omission of insignificant terms from the full-model equation. The computer optimization process and contour plots predicted the levels of independent variables X(1), X(2), and X(3) (0, 0.2 and -0.15, respectively) for colon targeting and total percent of drug released up to 24 h.