A retrospective study of chemotherapeutic effect without wide-margin surgery or radiation therapy in dogs with oral malignant melanoma.

Background: Effective treatment for canine oral malignant melanoma (e.g., curative-intent surgery) may not be feasible or radiation therapy may be unavailable. However, chemotherapy is usually an option, and more information is needed regarding its use without adequate local treatments. Objective: Our objective was to investigate the efficacy of chemotherapy in canine oral malignant melanoma without adequate local control, using carboplatin with dose reduction in small-breed dogs and metronomic chemotherapy. Animals and procedure: Client-owned dogs with histopathologically diagnosed oral malignant melanoma were retrospectively enrolled from 2016 to 2022. The chemotherapy protocol in each case was determined by the attending clinician. Results: Thirteen dogs were included. The median progression-free interval of all 13 dogs was 42 d (14 to 953 d). The median overall survival time of dogs with chemotherapy as their only systemic treatment was 181 d (50 to 960 d; n = 11). The median dosage of carboplatin was 250 mg/m2. Response to treatment and clinical stage were significant prognostic factors. Conclusion and clinical relevance: As chemotherapy provided a median survival of 6 mo, it could be considered when adequate local control is infeasible. Earlier clinical stages or achievement of at least stable disease during chemotherapy may indicate better survival in dogs.

Une étude rétrospective de l'effet chimiothérapeutique sur le mélanome malin buccal canin dépourvu de chirurgie et de radiothérapie á large marge : le stade clinique et la réponse au traitement prédisent les résultats du patient. Mise en contexte: Des traitements efficaces pour le mélanome malin oral canin, tels que la chirurgie á visée curative, ne sont parfois pas réalisables ou la radiothérapie n'est pas disponible dans certaines régions. La chimiothérapie reste une option de traitement et davantage d'informations devraient être fournies pour les cas qui n'ont pas eu accés á un traitement local adéquat. Objectif: Cette étude visait á étudier l'efficacité de la chimiothérapie dans le mélanome malin oral canin sans contrôle local adéquat, en utilisant le carboplatine avec réduction de dose chez les chiens de petite race et la chimiothérapie métronomique. Animaux et procédure: Treize chiens appartenant á des clients atteints d'un mélanome malin oral diagnostiqué par histopathologie ont été rétrospectivement inscrits de 2016 á 2022. Le protocole de chimiothérapie a été déterminé par le clinicien traitant. Résultats: L'intervalle médian sans progression des treize chiens était de 42 jours (14­953 jours). La durée médiane de survie globale des chiens ayant reçu une chimiothérapie comme seul traitement systémique était de 181 jours (50­960 jours; n = 11). La dose médiane de carboplatine était de 250 mg/m2. La réponse au traitement et le stade clinique étaient des facteurs pronostiques importants. Conclusion et pertinence clinique: La chimiothérapie pouvait encore être envisagée lorsqu'un contrôle local adéquat était impossible. Des stades cliniques plus précoces ou des patients atteignant au moins une maladie stable pendant la chimiothérapie peuvent indiquer une meilleure survie.(Traduit par les auteurs).

Influence of Post-radiation Ocular Surface Disorder on Ocular Surgery: A Case Report and Review of the Literature.

BACKGROUND: Ocular surface disorder after ocular radiation therapy, even though commonly reported, is often overlooked. Any delay in diagnosis may lead to complications that threaten vision. The presented case highlights the clinical outcome of a severe post-radiation disorder of the ocular surface, the importance of intensive therapy, and the limitations of further surgical interventions. CASE PRESENTATION: A 34-year-old woman was referred for a second opinion due to a years-long history of pain and redness in her right eye (OD) after proton beam therapy for recurrent iris melanoma. The patient then developed post-radiation retinopathy with macula edema, secondary glaucoma, cataract, as well as a severe ocular surface disorder with corneal decompensation and band keratopathy. Several surgical treatments have been attempted, including phacoemulsification with IOL implantation and trabeculectomy with mitomycin C. Due to refractory glaucoma, Baerveldt glaucoma drainage was then necessary. Given the worsening clinical presentation of post-radiation ocular surface disorder with progressing band keratopathy, the possibility of penetrating keratoplasty (PKP) was discussed. CONCLUSION: The continuous worsening of clinical symptoms of the disorder of the ocular surface after proton beam radiotherapy can be the result of a post-radiation syndrome. Gradual expansion of ischemia, vasculitis, and inflammatory mediators compresses the retinal tissue, leading to recurrent macular edema as well as to secondary glaucoma and corneal decompensation. Band keratopathy is occasionally noted and seems to result from severe post-radiation disorder of the ocular surface. However, PKP would typically be indicated in cases of corneal perforation, uncontrolled infectious keratitis, or for improving vision in the presence of corneal opacification, none of which applied to our patient. Furthermore, post-radiation keratopathy implies compromised corneal stromal lymphogenesis and angiogenesis, both of which are now considered essential conditions for allograft rejection. Moreover, a previously performed Baerveldt glaucoma drainage surgery can affect the survival rate of the endothelial cells of the recipient cornea. Therefore, a penetrating or endothelial keratoplasty should be viewed as a high-risk procedure. In this instance, the rigorous treatment of the severe ocular surface disorder was crucial. We managed our patient's complex situation by following the latest guidelines set by the Tear Film & Ocular Surface Society and aimed to alleviate the symptoms as effectively as possible. In conclusion, careful decision-making regarding surgical treatment options should be considered, taking into account the complexities and potential risks involved.

The Role of Radiotherapy for Meningeal Melanocytomas - A 20 Year Update.

BACKGROUND/AIM: Meningeal melanocytomas are rare tumors of the central nervous system and optimal treatment needs further clarification. This study compared subtotal resection (STR), STR plus radiation therapy (RT), gross total resection (GTR), and GTR+RT to better define the role of postoperative RT. PATIENTS AND METHODS: All cases reported in the literature were reviewed. Patients (n=184) with complete data were analyzed for local control (LC) and overall survival (OS). RESULTS: On univariate analysis, GTR (vs. STR) was associated with improved LC (p=0.016). When comparing the treatment regimens, best and worst results were found after GTR+RT and STR alone, respectively (p<0.001). On univariate analysis, GTR resulted in better OS than STR (p=0.041). Moreover, the treatment regimen had a significant impact on OS (p=0.049). On multivariate analyses of LC and OS, extent of resection and treatment regimen were found to be significant factors. After STR, RT significantly improved LC but not OS. After GTR, RT did not significantly improve LC or OS. CONCLUSION: GTR was significantly superior to STR regarding LC and OS. STR+RT resulted in significantly better LC when compared to STR alone.

Equivalent uniform RBE-weighted dose in eye plaque brachytherapy.

BACKGROUND: Brachytherapy for ocular melanoma is based on the application of eye plaques with different spatial dose nonuniformity, time-dependent dose rates and relative biological effectiveness (RBE). PURPOSE: We propose a parameter called the equivalent uniform RBE-weighted dose (EUDRBE) that can be used for quantitative characterization of integrated cell survival in radiotherapy modalities with the variable RBE, dose nonuniformity and dose rate. The EUDRBE is applied to brachytherapy with 125I eye plaques designed by the Collaborative Ocular Melanoma Study (COMS). METHODS: The EUDRBE is defined as the uniform dose distribution with RBE = 1 that causes equal cell survival for a given nonuniform dose distribution with the variable RBE > 1. The EUDRBE can be used for comparison of cell survival for nonuniform dose distributions with different RBE, because they are compared to the reference dose with RBE = 1. The EUDRBE is applied to brachytherapy with 125I COMS eye plaques that are characterized by a steep dose gradient in tumor base-apex direction, protracted irradiation during time intervals of 3-8 days, and variable dose-rate dependent RBE with a maximum of about 1.4. The simulations are based on dose of 85 Gy prescribed to the farthest intraocular extent of the tumor (tumor apex). To compute the EUDRBE in eye plaque brachytherapy and correct for protracted irradiation, the distributions of physical dose have been converted to non-uniform distributions of biologically effective dose (BED) to include the biological effects of sublethal cellular repair, Our radiobiological analysis considers the combined effects of different time-dependent dose rates, spatial dose non-uniformity, dose fractionation and different RBE and can be used to derive optimized dose regimens brachytherapy. RESULTS: Our simulations show that the EUDRBE increases with the prescription depths and the maximum increase may achieve 6% for the tumor height of 12 mm. This effect stems from a steep dose gradient within the tumor that increases with the prescription depth. The simulations also show that the EUDRBE increase may achieve 12% with increasing the dose rate when implant duration decreases. The combined effect of dose nonuniformity and dose rate may change the EUDRBE up to 18% for the same dose prescription of 85 Gy to tumor apex. The absolute dose range of 48-61 Gy (RBE) for the EUDRBE computed using 4 or 5 fractions is comparable to the dose prescriptions used in stereotactic body radiation therapy (SBRT) with megavoltage X-rays (RBE = 1) for different cancers. The tumor control probabilities in SBRT and eye plaque brachytherapy are very similar at the level of 80% or higher that support the hypothesis that the selected approximations for the EUDRBE are valid. CONCLUSIONS: The computed range of the EUDRBE in 125I COMS eye plaque brachytherapy suggests that the selected models and hypotheses are acceptable. The EUDRBE can be useful for analysis of treatment outcomes and comparison of different dose regimens in eye plaque brachytherapy.

Incidence of Strabismus Post-Plaque Brachytherapy in Patients With Uveal Melanoma.

PURPOSE: To determine the incidence and type of strabismus in patients with uveal melanoma treated with plaque brachytherapy. DESIGN: Multicenter, retrospective incidence estimation study. METHODS: A total of 438 eyes of 438 patients with uveal melanoma treated with plaque brachytherapy between October 2011 and May 2021. Intervention was Iodine 125, and Palladium 103 plaque brachytherapy. The variables reviewed included incidence of nonresolving strabismus post-plaque brachytherapy, type of strabismus developed, extraocular muscles operated, and modality of treatment received. RESULTS: A total of 438 patients underwent plaque brachytherapy treatment for uveal melanoma. Eleven patients developed strabismus post-plaque brachytherapy (2.5%, n = 11/438). Of these patients, 5 (1.1%, n = 5/438) developed strabismus immediately postoperation. Specifically, 2 patients (0.5%, n = 2/438) developed strabismus immediately postoperation due to slipped muscles, 2 patients (0.5%, n = 2/438) due to decompensated phorias, and 1 patient (0.5%, n = 1/438) due to a fibrotic muscle. Six patients (1.4%, n = 6/438) developed late-onset sensory strabismus. A total of 355 patients (81.1%, n = 355/438) had their extraocular muscles disinserted during surgery, with the lateral rectus being the most common, accounting for 45.4% (n = 161/355), followed by the superior rectus at 26.8% (n = 95/355). Strabismus surgery was the most common treatment modality, comprising 72.7% (n = 8/11) of patients. CONCLUSIONS: The incidence of strabismus after plaque brachytherapy treatment for uveal melanoma was low and primarily classified as late-onset sensory strabismus. Previous studies may underestimate the long-term incidence of strabismus after plaque brachytherapy by focusing primarily on strabismus present immediately postoperatively.

A practical method of estimating medium-heterogeneity corrected dose without a Monte Carlo calculation in ocular brachytherapy using 125I COMS plaques.

PURPOSE: To provide a practical method of estimating medium-heterogeneity corrected dose without a Monte Carlo (MC) calculation in ocular brachytherapy using 125I Collaborative Ocular Melanoma Study (COMS) plaques. METHODS AND MATERIALS: Using egs_brachy, MC simulations (1) under task group-43 assumptions with fully loaded seed configurations in water (HOMO) and (2) with effects of plaque backing, insert and inter-seed interactions (HETERO) were performed for seven 125I COMS plaques (10 mm-22 mm in diameter), and homogeneous dose (DHOMO) and heterogeneous dose (DHETERO) for central-axis and off-axis points were determined. For DHOMO, 85 Gy was normalized to a depth of 5 mm. Central-axis heterogeneity correction factors (HCFs) from a depth of 0 mm (inner sclera) to 22 mm (opposite retina) were derived from a ratio of DHETERO to DHOMO. Off-axis HCFs for optic disc/macula and lens as a function of distance from optic disc/macula (DT/MT) for various basal dimensions of tumor (BD/BM) were derived from DHETERO/DHOMO. RESULTS: Central-axis HCF varied with a dose reduction of 10.3-19.8% by heterogeneity. Off-axis HCF for optic disc/macula varied significantly depending on DT/MT and BD/BM with a dose reduction of 11.3-38.3%. Off-axis HCF for lens had a dependence on MT and BM with its variation of 11.0-19.0%. A clinical example of using HCFs to estimate DHETERO was presented. CONCLUSIONS: The practical method of using depth-dependent central-axis HCF and DT/MT- and BD/BM-dependent off-axis HCF provided in this study will facilitate a heterogeneous dose estimate for 125I COMS plaques without MC calculations.

GEC-ESTRO survey of 106Ru eye applicator practice for ocular melanoma - Physicist survey.

AIM: 106Ru eye plaque brachytherapy (BT, interventional radiotherapy) is an eye-preserving treatment for uveal melanoma performed in about 100 clinics worldwide. Despite this relatively low number, there is a considerable variation in clinical practice. In 2022, the BRAPHYQS and Head & Neck and Skin GEC-ESTRO working groups conducted a survey to map the current clinical practice. The survey consisted of a physicist and a physician part. This paper describes the physicist results. However, three physician questions with overlapping interest are included here as well. MATERIALS AND METHODS: The survey questions pertained to commissioning and quality control (QC) of the plaques, treatment planning, radiobiological correction, as well as more general questions on practice improvement. The questions overlapping with the physician survey were related to dose prescription and margins. RESULTS: Sixty-five physicist responses were included. A majority of the centres do not perform an independent measurement of the absorbed dose at reference depth, percentage depth dose (PDD) and off-axis data. A lack of calibration services and suitable equipment are the main reasons. About one third of the centres indicated that they do image based treatment planning. The use of margins and dose prescription showed a large variability, despite the availability of guidelines [1]. Many respondents expressed a strong wish for improvement in a wide range of aspects of clinical practice. CONCLUSION: The physics survey showed a wide variability regarding quality control of the 106Ru sources and treatment planning practice.

Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

SIRT7 sustains tumor development and radioresistance by repressing endoplasmic reticulum stress-induced apoptosis in cutaneous melanoma.

Cutaneous melanoma is one of the most malignant human tumors and possesses strong resistance to radiotherapy. However, the mechanisms contribute to such radioresistance of melanoma is unclear. In this study, SIRT7 is identified to be higher-expressed in melanoma and positively correlated with melanoma staging. Under ionizing radiation (IR)-treatment condition, loss of SIRT7 compromised the survivability of melanoma cells showed by decreased proliferation, colony formation, migration, but enhancing apoptosis. Transcriptomic sequencing analysis indicated the apoptosis induced after SIRT7 knockdown is tightly related with the induction of endoplasmic reticulum stress (ER stress) by IR treatment. Loss of SIRT7 enhanced EIF2α acetylation and activated its phosphorylation to induce the expression of ER stress proteins including DDIT3, XBP1 and GRP78, among which DDIT3 is responsible for apoptosis induction. SIRT7 depletion enriched ER stress-activated transcription factor ATF4 at the promoter region of DDIT3 gene to transactivate its expression and induces apoptotic cascade in both mock- and IR-treatment conditions. Consistently, SIRT7 is highly upregulated in radioresistant melanoma cell strain and still modulates the ER-stress responsive genes to maintain the homeostasis of melanoma. Collectively, SIRT7 negatively regulates ER stress-activated apoptosis to enhance the survivability of melanoma cells in both non-IR- and IR-treatment conditions. Our study highlights the role of SIRT7 in repressing ER stress and the following apoptosis to sustain tumor development and mediate radioresistance in melanoma, which may suggest a novel intervention target for melanoma therapy.

Disinsert, retract and rotate technique of plaque brachytherapy.

BACKGROUND: Plaque brachytherapy is commonly used in the management of choroidal melanomas. The surgical steps usually involve creating a conjunctival peritomy, fixing the recti muscles, with or without disinserting them based on the location of the lesion, and placing the plaque. The inferior oblique muscle is attached close to the macula, and in cases of perimacular or peripapillary lesions, the muscle needs to be sacrificed. PURPOSE: The authors here demonstrate a novel technique of placing radioactive plaque without disinserting the inferior oblique muscle in cases of perimacular or peripapillary choroidal melanomas. SYNOPSIS: The video demonstrates how the "disinsert, retract, and rotate technique" of brachytherapy plaque placement can be performed and what are the fundamentals behind this technique. The authors have performed this procedure multiple times and there has been no incidence of plaque tilt or migration. HIGHLIGHTS: In perimacular and peripapillary choroidal melanoma brachytherapy plaque placement, the inferior oblique muscle can be spared. The simple technique does not lead to any tilt or migration of the radioactive plaque. VIDEO LINK: https://youtu.be/YMIg3rYyp2o.

Curative carbon ion radiotherapy in a head and neck mucosal melanoma series: Facing the future within multidisciplinarity.

PURPOSE: To evaluate efficacy and toxicity of carbon ion radiotherapy (CIRT) in locally advanced head and neck mucosal melanoma (HNMM) patients treated at our Institute. MATERIALS AND METHODS: Between June 2013 and June 2020, 40 HNMM patients were treated with CIRT. Prescription dose was 65.6-68.8 Gy relative biological effectiveness [RBE] in 16 fractions. Twelve (30%) patients received only biopsy, 28 (70%) surgical resection before CIRT. Immunotherapy was administered before and/or after CIRT in 45% of patients, mainly for distant progression (89%). RESULTS: Median follow-up was 18 months. 2-year Local Relapse Free Survival (LRFS), Overall Survival (OS), Progression Free Survival (PFS) and Distant Metastasis Free Survival (DMFS) were 84.5%, 58.6%, 33.2% and 37.3%, respectively. At univariate analysis, LRFS was significantly better for non-recurrent status, < 2 surgeries before CIRT and treatment started < 9 months from the initial diagnosis, with no significant differences for operated versus unresected patients. After relapse, immunotherapy provided longer median OS (17 months vs 3.6, p-value<0.001). Late toxicity ≥ G3 (graded with CTCAE 5.0 scale) was reported in 10% of patients. CONCLUSION: CIRT in advanced HNMM patients is safe and locally effective. Prospective trials are warranted to assess the role of targeted/immune- systemic therapy to improve OS.

Central subfield thickness predicts visual acuity outcomes in plaque-irradiated eyes with choroidal melanoma.

OBJECTIVE: To determine the association between pre-operative central subfield thickness (CST) and post-radiotherapy visual acuity (VA), cystoid macular edema (CME), and intravitreal anti-vascular endothelial growth factor (VEGF) requirement. DESIGN: Single-center retrospective study. PARTICIPANTS: Patients with plaque-irradiated extramacular choroidal melanoma treated between 11/11/2011 and 4/30/2021. Pre-operative CST difference between the affected and unaffected eye was used. Kaplan-Meier analysis and hazard ratios were calculated. RESULTS: Of 85 patients, pre-operative CST was greater in the melanoma-affected eye (vs. fellow eye) by mean of 20.4 µm (median 14.0, range - 60.0-182.0). Greater CST at presentation (vs. fellow eye) was associated with larger tumor diameter (p = 0.02), greater tumor thickness (p < 0.001), and more frequent tumor-related Bruch's membrane rupture (p = 0.006). On univariate analysis of outcome data, greater CST at presentation (vs. fellow eye) was associated with higher 5-year risk (1.09 [1.02-1.17], p = 0.02) of VA 20/200 or worse and increased (1.10 [1.01-1.20], p = 0.03) likelihood for anti-VEGF injections after plaque irradiation. There was no significant association with CME. The association between CST and VA outcome remained significant on multivariate analysis accounting for impact of tumor thickness and radiation dose to optic disc, while tumor distance to fovea was the only significant factor on multivariate analysis for anti-VEGF injections. CONCLUSION: Greater CST at presentation (vs. fellow eye) was associated with worse VA outcome following plaque radiotherapy for choroidal melanoma. Large-sized tumors may contribute to a higher intraocular VEGF burden, potentially leading to greater preoperative CST, which correlates with poor VA outcome post-plaque radiotherapy.

Generation and comparison of 3D dosimetric reference datasets for COMS eye plaque brachytherapy using model-based dose calculations.

PURPOSE: A joint Working Group of the American Association of Physicists in Medicine (AAPM), the European Society for Radiotherapy and Oncology (ESTRO), and the Australasian Brachytherapy Group (ABG) was created to aid in the transition from the AAPM TG-43 dose calculation formalism, the current standard, to model-based dose calculations. This work establishes the first test cases for low-energy photon-emitting brachytherapy using model-based dose calculation algorithms (MBDCAs). ACQUISITION AND VALIDATION METHODS: Five test cases are developed: (1) a single model 6711 125 I brachytherapy seed in water, 13 seeds (2) individually and (3) in combination in water, (4) the full Collaborative Ocular Melanoma Study (COMS) 16 mm eye plaque in water, and (5) the full plaque in a realistic eye phantom. Calculations are done with four Monte Carlo (MC) codes and a research version of a commercial treatment planning system (TPS). For all test cases, local agreement of MC codes was within ∼2.5% and global agreement was ∼2% (4% for test case 5). MC agreement was within expected uncertainties. Local agreement of TPS with MC was within 5% for test case 1 and ∼20% for test cases 4 and 5, and global agreement was within 0.4% for test case 1 and 10% for test cases 4 and 5. DATA FORMAT AND USAGE NOTES: Dose distributions for each set of MC and TPS calculations are available online (https://doi.org/10.52519/00005) along with input files and all other information necessary to repeat the calculations. POTENTIAL APPLICATIONS: These data can be used to support commissioning of MBDCAs for low-energy brachytherapy as recommended by TGs 186 and 221 and AAPM Report 372. This work additionally lays out a sample framework for the development of test cases that can be extended to other applications beyond eye plaque brachytherapy.

Clinically Driven Alpha/Beta Ratios for Melanoma Brain Metastases and Investigation of Biologically Effective Dose as a Predictor for Local Control After Radiosurgery: A Proof of Concept in a Retrospective Longitudinal Series of 274 Consecutive Lesions.

BACKGROUND AND OBJECTIVES: Brain metastases (BM) develop in nearly half of the patients with advanced melanoma. The aim of this retrospective historical cohort study was to analyze radiological response of melanoma BM to single-fraction Gamma Knife radiosurgery (GKRS), in relation to biologically effective dose (BED) for various alpha/beta ratios. METHODS: Included in the study were 274 lesions. Primary outcome was local control (LC). Mean marginal dose was 21.6 Gy (median 22, range 15-25). Biologically effective dose was calculated for an alpha/beta ratio of 3 (Gy 3 ), 5 (Gy 10 ), 10 (Gy 10 ), and 15 (Gy 15 ). RESULTS: Receiver operating characteristic value for LC and BED was 85% (most statistically significant odds ratio 1.14 for BED Gy 15 , P = .006), while for LC and physical dose was 79% ( P = .02). When comparing equality of 2 receiver operating characteristic areas, this was statistically significant ( P = .02 and .03). Fractional polynomial regression revealed BED (Gy 10 and Gy 15 ) as statistically significant ( P = .05) with BED of more than 63 Gy 10 or 49 Gy 15 as relevant, also for higher probability of quick decrease in volume first month after GKRS and lower probability of radiation necrosis. Shorter irradiation time was associated with better LC ( P = .001), particularly less than 40 minutes (LC below 90%, P = .05). CONCLUSION: BED Gy 10 and particularly Gy 15 were more statistically significant than physical dose for LC after GKRS for radioresistant melanoma BM. Irradiation time (per lesion) longer than 40 minutes was predictive for lower rates of LC. Such results need to be validated in larger cohorts.

Long-Term Intracranial Outcomes With Combination Dual Immune-Checkpoint Blockade and Stereotactic Radiosurgery in Patients With Melanoma and Non-Small Cell Lung Cancer Brain Metastases.

PURPOSE: The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone. METHODS AND MATERIALS: Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. RESULTS: Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts. CONCLUSIONS: The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs.

Survival Benefit of Stereotactic Radiotherapy in the Complex Management of Metastatic Melanoma.

BACKGROUND/AIM: Targeted therapy and immunotherapy, with additional stereotactic radiation therapy (SRT) have revolutionized the management of metastatic malignant melanoma (mMM). We aimed to analyze the effectiveness and safety of SRT and determine its role in the complex management of mMM. PATIENTS AND METHODS: We treated 24 patients with solitary metastasis, 15 with oligometastatic disease and one with multiple metastases. The primary endpoint was to investigate the possible effect of stereotactic radiotherapy for metastatic lesions on patients' survival taking the systemic therapy into consideration. RESULTS: The median overall survival (OS) for the entire group was 30.07 months; 50% of them received immunotherapy, 32% received targeted therapy. Complete remission of the irradiated lesions was observed in six patients, partial tumor response was achieved in 13, while stable disease was detected in 10; tumor progression occurred in four cases. Compartmental recurrence (recurrence in the brain in a not previously irradiated region) developed in seven patients. OS was significantly longer in those with extracranial metastases treated with stereotactic body radiotherapy in comparison to brain SRT. We found a strong correlation between tumor response and mean OS (42.5 months after complete or partial remission versus 11.8 months in those with stable or progressive disease). No OS difference was observed according to the number of irradiated lesions or type of systemic therapy before SRT (no therapy: 43.6 months, with therapy: 25.7 months). Significant OS advantage was shown when immunotherapy was administered post-SRT (mean OS: with immunotherapy: 39.6 months, no immunotherapy: 18.5 months). CONCLUSION: In the case of oligometastatic MM, SRT can be used safely and with good efficiency in addition to targeted therapy/anti-programmed cell death protein 1 therapy. Improved survival warrants including SRT in the complex management of mMM, however, further studies are needed for SRT optimization.

Iodine-125 brachytherapy for choroidal melanoma by using Ocuprosta seeds with indigenous non-collimated plaques: Our initial experience.

PURPOSE: Brachytherapy is the gold-standard treatment for choroidal melanoma. This study evaluated iodine-125 brachytherapy by using Ocuprosta seeds with indigenous non-collimated plaques in Asian patients. METHODS: Retrospective single-center study in a tertiary care hospital of 12 eyes with choroidal melanoma in 12 Asian patients who underwent brachytherapy with Ocuprosta seeds fixed on non-collimated plaques and had a follow-up of at least 32 months (mean: 42.4 ± 9.5 months; median: 40 months). Radiotherapy was planned after developing the digital 3D model of the tumor within the eye by using radiological images and clinical pictures. Ocuprosta iodine-125 seeds were used on indigenous non-collimated gold plaques to deliver the radiation for precalculated time. "Successful outcome" was taken as a decrease in the volume of the tumor, and "unsuccessful outcome" was defined as no change in the tumor volume or increase in the tumor volume at 24 months after brachytherapy. RESULTS: The mean decrease in tumor volume was 21% (914.5 ± 912.2 mm3 to 495.7 ± 633.6 mm3) after brachytherapy, which correlated with the baseline volume of the tumor. Ten eyes (83.3%) showed a reduction in tumor volume, whereas two eyes showed an increase in the volume of the tumor after brachytherapy. One of the cases with a reduction in tumor size developed neovascular glaucoma. Enucleation was done in three eyes. A globe salvage rate of 75% and tumor regression rate of 83% were seen in the present study using Ocuprosta seeds. CONCLUSIONS: Iodine-125 brachytherapy with uncollimated indigenous gold plaques is an effective treatment modality for choroidal melanomas in Asian patients.

Stereotactic radiosurgery of brain metastases: a retrospective study.

BACKGROUND: Single-fraction stereotactic radiosurgery (SRS) is an established standard for radiation therapy of brain metastases although recent developments indicate that multi-fractionated stereotactic radiotherapy (FSRT) results in lower radiation necrosis especially for larger metastases, and the same or even better local control in comparison to SRS. METHODS: Seventy-two patients with 111 brain metastases received SRS with a single dose of 18 Gy between September 2014 and December 2021. The dose prescription was either 18 Gy given to the enclosing 80% isodose with a normalization to Dmax = 100% of 22.5 Gy (part I) or 18 Gy = D98, while D0.03 cc of 21.6-22.5 Gy was accepted (part II). The study retrospectively evaluated local progression-free survival (LPFS), response on the first follow-up magnetic resonance imaging (MRI), and radiation necrosis. RESULTS: Melanoma brain metastases (n = 44) were the most frequent metastases. The median gross tumor volume (GTV) was 0.30 cm³ (IQR, 0.17-0.61). The median follow-up time of all patients was 50.8 months (IQR, 30.4-64.6). Median LPFS was 23.5 months (95%CI 17.2, 29.8). The overall LPFS rates at 12-, 18-, 24- and 30 months were 65.3%, 56.3%, 46.5%, and 38.8%. Brain metastases with radioresistant histology (melanoma, renal cell cancer, and sarcoma) showed a 12-month LPFS of 60.2%, whereas brain metastases with other histology had a 12-month LPFS of 70.1%. The response of brain metastases on first follow-up MRIs performed after a median time of 47 days (IQR, 40-63) was crucial for long-term local control and survival. Eight brain metastases (7.2%) developed radiation necrosis after a median time of 18.4 months (IQR, 9.4-26.5). In multivariate analyses, a GTV > 0.3 cm³ negatively affected LPFS (HR 2.229, 95%CI 1.172, 4.239). Melanoma, renal cell cancers, and sarcoma had a lower chance of LPFS in comparison to other cancer types (HR 2.330, 95%CI 1.155, 4.699). CONCLUSIONS: Our results indicate a reasonable 1-year local control of brain metastases with radiosensitive histology. Radioresistant metastases show a comparatively poor local control. Treatment refinements merit exploration to improve local control of brain metastases. TRIAL REGISTRATION: This study is retrospectively registered (ethics approval number 23-3451-104).

Radiotherapy with or without immunotherapy in metastatic melanoma: efficacy and tolerability.

INTRODUCTION: Radiotherapy (RT) is primarily considered as a palliative treatment in patients with metastatic melanoma. However, observations suggest that when RT is combined with immune checkpoint inhibitors (ICI), it can induce an immune response leading to an anti-tumoral effect also distant from the irradiated area - a phenomenon called 'abscopal effect'. The frequency and circumstances of abscopal effect among metastatic melanoma patients remains uncertain and further research is necessary. MATERIAL AND METHOD: This retrospective study included all metastatic melanoma patients who received non-stereotactic RT in Stockholm, Sweden in 2015-2020. Patients were grouped depending on if RT was given at start of ICI (RT + ICI(start)), at ICI progression (RT + ICI(salvage)) or without ICI (RT(only)). Response rates in irradiated (RR(irradiated)) and overall response rates in non-irradiated (ORR(non-irradiated)) metastases were evaluated together with survival and toxicity in each cohort. RESULTS: In the RT + ICI(start) (n = 47), RT + ICI(salvage) (n = 41) and RT(only) (n = 55) cohorts, RR(irradiated) was 70.7%, 67.5% and 43.1% (p = 0.018) while the ORR(non-irradiated) was 36.1%, 14.8% and 0.0% (p = 0.003), and the median overall survival was 18.2, 15.0 and 7.2 months, respectively (p = 0.014). Local response to RT was in all cohorts associated with longer survival (p < 0.001). The frequency of grade ≥3 immune-related adverse events was 17.0% and 19.5% in the RT + ICI(start) and RT + ICI(salvage) cohorts. No increased frequency of RT-related adverse events was seen in the RT + ICI cohorts, compared to the RT(only) cohort. CONCLUSION: This retrospective study showed that melanoma patients receiving RT in combination with ICI had a superior antitumoral response in both irradiated and non-irradiated lesions as compared to patients receiving only RT. Additionally, a subgroup of patients receiving RT when progressing on ICI experienced tumor regression also in non-irradiated areas.

Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models.

Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. The aim of this study is to evaluate whether and to what extent blockade of VISTA, an immune checkpoint, can potentiate the tumor control ability of radiation therapy. Our study is novel in that it is the first comparison of two VISTA-blocking methods (antibody inhibition and genetic knockout) in combination with RT. VISTA was blocked either through genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine flank tumor models (B16 and MC38). Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. When combined with a single 15Gy radiation dose, VISTA blockade via genetic knockout in the B16 model and via anti-VISTA antibodies in the MC38 model significantly improved survival compared to RT alone by an average of 5.5 days and 6.3 days, respectively (p < 0.05). The gene expression data suggest that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune-mediated cytotoxicity. VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15Gy radiation through increased expression and stimulation of cell-mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.