Early Stage In Vitro Bioprofiling of Potential Low-Molecular-Weight Organoboron Compounds for Boron Neutron Capture Therapy (BNCT)-Proposal for a Guide.

Given the renewed interest in boron neutron capture therapy (BNCT) and the intensified search for improved boron carriers, as well as the difficulties of coherently comparing the carriers described so far, it seems necessary to define a basic set of assays and standardized methods to be used in the early stages of boron carrier development in vitro. The selection of assays and corresponding methods is based on the practical experience of the authors and is certainly not exhaustive, but open to discussion. The proposed tests/characteristics: Solubility, lipophilicity, stability, cytotoxicity, and cellular uptake apply to both low molecular weight (up to 500 Da) and high molecular weight (5000 Da and more) boron carriers. However, the specific methods have been selected primarily for low molecular weight boron carriers; in the case of high molecular weight compounds, some of the methods may need to be adapted.

Prognostic factors for surgical treatment of radiation-induced scleral necrosis after brachytherapy for uveal melanoma.

PURPOSE: Radiation-induced scleral necrosis (RISN) is a less frequent complication of brachytherapy for uveal melanoma, and may require surgical treatment in selected cases. We aimed to identify the prognostic factors for RISN treatment. METHODS: All patients with brachytherapy for uveal melanoma treated at our institution between 01/1999 and 12/2016 who developed RISN were followed until 02/2021. Various parameters were evaluated through univariable and multivariable Cox regression analysis. The surgical intervention due to RISN was the principal outcome event of this study. RESULTS: Of 115 patients in the final cohort, 51 individuals (44%) underwent RISN treatment (conjunctival revision [n = 2], patching [n = 46] or enucleation [n = 3]) at median 1.80 months after RISN occurrence. Significant RISN characteristics were summarized into a novel RISN severity scale - Grade I: largest diameter ≤ 5 mm and no progression; Grade II: largest diameter > 5 mm or any progression during the follow-up; Grade III: presence of uveal prolapse; and Grade IV: leakage through open eyewall perforation. In the multivariable analysis, the RISN severity scale (aHR = 2.37 per grade increase, p = 0.01) and the time between brachytherapy and RISN occurrence (<15 months, aHR = 6.33, p < 0.0001) were independently associated with the study endpoint. The RISN severity scale showed high diagnostic accuracy for prediction of RISN treatment (AUC = 0.869). CONCLUSIONS: In our series, about the half of RISN cases underwent surgical treatment. The presented novel severity scale for RISN might become a helpful tool for clinical management of individuals with RISN. We recommend external validation of the diagnostic accuracy of the presented scale.

Tumor- and Radiation-Related Complications after Ruthenium-106 Brachytherapy in Small to Medium Uveal Melanomas (Part 1).

PURPOSE: The purpose of this study was to analyze tumor-related complications after ruthenium-106 brachytherapy in patients with uveal melanoma, with respect to local tumor control, insufficient radiation response, enucleation, and metastasis rate. PATIENTS/METHODS AND MATERIALS: This retrospective study included 608 patients treated consecutively with ruthenium-106 brachytherapy between January 2008 and December 2010 at the Department of Ophthalmology, University Hospital Essen. The occurrence of radiation-induced results was analyzed by estimating the risk by applying the Kaplan-Meier method, i.e., the "time to event" analysis. The Cox model test was used for the univariate and multivariate risk factor analyses. The median follow-up was 51 months after primary treatment. RESULTS: Tumor recurrence was found in 21 patients (3.5%) and repeated treatment due to insufficient effect after the initial ruthenium-106 brachytherapy was performed in 40 patients (6.6%). The 5-year cumulative risk of recurrence was 4.0% and that of insufficient effect was 7.3%. Thirteen patients (2.1%) underwent a secondary enucleation; 8 because of a local recurrence and 5 because of severe post-brachytherapy complications. The cumulative enucleation risk was 2.3% after 5 years and 2.9% after 10 years, corresponding to eye preservation of 97.7 and 97.1%, respectively. In forty-two patients (7.2%), metastatic disease was diagnosed during the follow-up. The metastatic rate as calculated by the Kaplan-Meier method was 9.0, and 13.1% at 5 and 10 years, respectively. CONCLUSION: Our study demonstrated that ruthenium-106 brachytherapy is an excellent treatment option for achieving local tumor control and eye preservation in well-selected patients. The metastatic rate is in agreement with that of previous studies analyzing small to medium size uveal melanomas.

Treatment-Related Complications and Functional Results after Ruthenium-106 Brachytherapy in Small to Medium Size Uveal Melanomas (Part 2).

PURPOSE: To analyze the treatment-related complications after ruthenium-106 brachytherapy in patients with uveal melanoma in terms of radiation-induced optic neuropathy, maculopathy and retinopathy, radiation-related vitreous hemorrhage, and retinal detachment, as well as secondary glaucoma and radiogenic cataract. In addition, the course of visual acuity was analyzed. PATIENTS/METHODS AND MATERIALS: This retrospective study included 608 patients treated with ruthenium-106 brachytherapy between January 2008 and December 2010 at the Department of Ophthalmology, University Hospital Essen. The follow-up time was 11 years. The occurrence of the radiation-induced complications was analyzed using the Kaplan-Meier method. Cox regression was used for univariate and multivariate risk factor analyses. Hazard ratios were calculated for each variable. RESULTS: Regarding the complications, 34% (N = 207) of the patients had no reported side effects or complications during follow-up. Radiation optic neuropathy was observed in 18.8% (N = 114) of the patients, with a median time to onset of 16 months (range: 3 - 78 months). Radiation maculopathy occurred in 8.2% (N = 50) after a median time of 17 months (range: 3 - 67 months). Radiation retinopathy was observed in 20.1% (N = 122), with a median time to onset of 21 months (range: 6 - 67 months). Secondary glaucoma developed in 9.7% of the patients (N = 53) and radiogenic cataract in 46.8% (N = 227). Vitreous hemorrhage (11.8%, N = 72) and scleral necrosis (2.1%, N = 13) occurred relatively rarely. CONCLUSION: The observed radiogenic complication rate is comparable with that reported in previous studies.

Long-Term Follow-Up of Patients with Conjunctival Lymphoma after Individualized Lens-Sparing Electron Radiotherapy: Results from a Longitudinal Study.

Irradiation with electrons is the primary treatment regime for localized conjunctival low-grade lymphomas. However, radiation-induced cataracts are a major cause of treatment-related morbidity. This study investigates whether lens-sparing electron irradiation produces sufficient disease control rates while preventing cataract formation. All consecutive patients with strictly conjunctival, low-grade Ann Arbor stage IE lymphoma treated with superficial electron irradiation between 1999 and 2021 at our department were reviewed. A total of 56 patients with 65 treated eyes were enrolled with a median follow-up of 65 months. The median dose was 30.96 Gy. A lens-spearing technique featuring a hanging rod blocking the central beam axis was used in 89.2% of all cases. Cumulative incidences of 5- and 10-year infield recurrences were 4.3% and 14.6%, incidences of 5- and 10-year outfield progression were 10.4% and 13.4%. We used patients with involvement of retroorbital structures treated with whole-orbit photon irradiation without lens protection-of which we reported in a previous study-as a control group. The cumulative cataract incidence for patients treated with electrons and lens protection was significantly lower (p = 0.005) when compared to patients irradiated without lens protection. Thus, electrons are an effective treatment option for conjunctival low-grade lymphomas. The presented lens-sparing technique effectively prevents cataract formation.

Strategic Clinical Trial Design for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) involves infusion of cancer patients with a tumor-seeking, boron-loaded compound and irradiation by a beam of neutrons, with an energy range of 1 eV-10 keV. Neutron capture in the 10B atoms results in an effective lethal radiation dose to the tumor cells, while sparing the healthy tissue. Recently available accelerator-based irradiation facilities facilitate developing BNCT to a treatment modality. However, the binary principle of BNCT, together with other points, is challenging in designing clinical trials that allow a timely and safe introduction of this innovative targeted modality into clinical practice. We propose a methodological framework to work toward a systematic, coordinated, and internationally accepted and evidence-based approach.

First clinical implementation of Yttrium-90 Disc Brachytherapy after FDA clearance.

PURPOSE: Herein, we study if high-dose-rate (HDR) yttrium-90 (90Y) brachytherapy could be utilized by medical physicists, radiation oncologists, and ophthalmic surgeons. METHODS AND MATERIALS: Yttrium-90 (90Y) beta-emitting brachytherapy sources received United States Food and Drug Administration clearance for episcleral treatment of ocular tumors and benign growths. Dose calibration traceable to the National Institute of Standards and Technology as well as treatment planning and target delineation methods were established. Single-use systems included a 90Y-disc affixed within specialized, multifunction, handheld applicator. Low-dose-rate to high-dose-rate prescription conversions and depth-dose determinations were performed. Radiation safety was evaluated based on live exposure rates during assembly and surgeries. Clinical data for radiation safety, treatment tolerability, and local control was collected. RESULTS: Practice parameters for the medical physicist, radiation oncologist, and ophthalmic surgeon were defined. Device sterilizations, calibrations, assemblies, surgical methods, and disposals were reproducible and effective. Treated tumors included iris melanoma, iridociliary melanoma, choroidal melanoma, and a locally invasive squamous carcinoma. Mean calculated 90Y disc activity was 14.33 mCi (range 8.8-16.6), prescription dose 27.8 Gy (range 22-30), delivered to depth of 2.3 mm (range 1.6-2.6), at treatment durations of 420 s (7.0 min, range 219 s-773 s). Both insertion and removal were performed during one surgical session. After surgery, each disc-applicator- system was contained for decay in storage. Treatments were well-tolerated. CONCLUSIONS: HDR 90Y episcleral brachytherapy devices were created, implementation methods developed, and treatments performed on 6 patients. Treatments were single-surgery, rapid, and well-tolerated with short-term follow up.

Reporting Dose in Boron Neutron Capture Therapy.

Reporting needs uniformity in definitions and terminology. This is crucial in order to be able to compare and aggregate clinical outcomes data across clinical trials. For decades, there is no standard for reporting dose in boron neutron capture therapy (BNCT). Multiple efforts were made for a common language reporting BNCT, mostly suggesting to report at relevant points the different dose components separately. Although this was accepted by some but not all clinicians, the situation remains an unsatisfactory and cumbersome reporting system, leading to confusion. Another suggestion is made here by proposing not to report the results of calculations that use a site-specific model with certain assumptions, but to report the input parameters needed for such calculations regardless of the model used. This will be mainly the thermal neutron fluence integrated over the irradiation time T and the average 10B concentration integrated over T.

Overview of Boron Neutron Capture Therapy in 2022.

In April 2022, the National Cancer Institute of the United States organized a 3-day seminar, dedicated to boron neutron capture therapy (BNCT). This short article summarizes a presentation from that event, which is intended to provide an overview of activities currently underway worldwide to make BNCT available for patient treatments. This overview does not claim to be exhaustive but shows a great deal of activity in all areas necessary for the complex therapy that is BNCT. A rapid increase in the number of BNCT centers can be expected over the next few years, coupled with the introduction of novel drugs for BNCT. It will be a major challenge to all stakeholders to create clinical networks that can conduct the necessary prospective clinical trials in a short time and in high quality.

A Review of Boron Neutron Capture Therapy: Its History and Current Challenges.

Mechanism of Action: External beam, whether with photons or particles, remains as the most common type of radiation therapy. The main drawback is that radiation deposits dose in healthy tissue before reaching its target. Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when 10B is irradiated with low-energy (0.0025 eV) thermal neutrons. The resulting 10B(n,α)7Li capture reaction produces high linear energy transfer (LET) α particles, helium nuclei (4He), and recoiling lithium-7 (7Li) atoms. The short range (5-9 µm) of the α particles limits the destructive effects within the boron-containing cells. In theory, BNCT can selectively destroy malignant cells while sparing adjacent normal tissue at the cellular levels by delivering a single fraction of radiation with high LET particles. History: BNCT has been around for many decades. Early studies were promising for patients with malignant brain tumors, recurrent tumors of the head and neck, and cutaneous melanomas; however, there were certain limitations to its widespread adoption and use. Current Limitations and Prospects: Recently, BNCT re-emerged owing to several developments: (1) small footprint accelerator-based neutron sources; (2) high specificity third-generation boron carriers based on monoclonal antibodies, nanoparticles, among others; and (3) treatment planning software and patient positioning devices that optimize treatment delivery and consistency.

Scleral necrosis after brachytherapy for uveal melanoma: Analysis of risk factors.

BACKGROUND: Radiation-induced scleral necrosis (RISN) is a rare, but a serious complication of brachytherapy for uveal melanoma. We aimed at analysing the incidence, timing and risk factors associated with development of RISN in a large institutional series. METHODS: All consecutive cases with brachytherapy for uveal melanoma treated by the Departments of Ophthalmology and Radiotherapy at University Hospital Essen between 1999 and 2016 were eligible. Development of RISN during the post-treatment follow-up was recorded. A 1:2 propensity score matched case-control study was performed for the evaluation of the prognostic value of different tumour- and treatment-associated parameters. RESULTS: RISN was documented in 115 (2.9%) of 3960 patients with uveal melanoma included in the final analysis, and occurred at the mean 30.3 months (range: 1.26-226 months) after brachytherapy. In the whole cohort, younger age (p = 0.042), plaque type (p = 0.001) and ciliary body involvement (p < 0.0001) were independently associated with the RISN occurrence. In the case-control study, multivariable weighted proportional hazard analysis discovered the association of the following additional tumour- and treatment-associated characteristics with RISN: posterior tumour margin anterior to equatorial region (p = 0.0003), extraocular tumour extension (p = <0.0001), scleral contact dose (p = <0.0001), conjunctival dehiscence after therapy (p = 0.0001), disinsertion of the superior rectus muscle (p = 0.001) and the glaucoma medication (p = 0.014). CONCLUSIONS: Our study confirms RISN as a rare complication, which might occur even years later after the brachytherapy for uveal melanoma. Alongside with scleral dose five other tumour and therapy related factors predict the risk of RISN after brachytherapy for uveal melanoma were established.

Theranostics in Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: 10B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of 10B in the tumor but also on the organs at risk. It is not yet possible to determine the 10B concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the 10B concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of 10B from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the 10B concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach.

Practice Considerations for Proton Beam Radiation Therapy of Uveal Melanoma During the Coronavirus Disease Pandemic: Particle Therapy Co-Operative Group Ocular Experience.

Uveal melanoma (UM) is a rare but life-threatening cancer of the eye. In light of the coronavirus disease (COVID-19) pandemic, hospitals and proton eye therapy facilities must analyze several factors to ensure appropriate treatment protocols for patients and provider teams. Practice considerations to limit COVID-19 transmission in the proton ocular treatment setting for UM are necessary. The Particle Therapy Co-Operative Group is the largest international community of particle/proton therapy providers. Participating experts have current or former affiliation with the member institutions of the Particle Therapy Co-Operative Group Ocular subcommittee with long-standing high-volume proton ocular programs. The practices reviewed in this document must be taken in conjunction with local hospital procedures, multidisciplinary recommendations, and regional/national guidelines, as each community may have its unique needs, supplies, and protocols. Importantly, as the pandemic evolves, so will the strategies and recommendations. Given the unique circumstances for UM patients, along with indications of potential ophthalmologic transmission as a result of health care providers working in close proximity to patients and intrinsic infectious risk from eyelashes, tears, and hair, practice strategies may be adapted to reduce the risk of viral transmission. Certainly, providers and health care systems will continue to examine and provide as safe and effective care as possible for patients in the current environment.

Monte Carlo Simulation of the Treatment of Uveal Melanoma Using Measured Heterogeneous 106Ru Plaques.

BACKGROUND/AIMS: Ruthenium plaques are used for the treatment of ocular tumors. The aim of this work is the comparison between simulated absorbed dose distributions tallied in an anthropomorphic phantom, obtained from ideal homogeneous plaques, and real eye plaques in which the actual heterogeneous distribution of 106Ru was measured. The placement of the plaques with respect to the tumor location was taken into consideration to optimize the effectiveness of the treatment. METHODS: The generic CCA and CCB, and the specific CCA1364 and CCB1256 106Ru eye plaques were modeled with the Monte Carlo code PENELOPE. To compare the suitability of each treatment for an anterior, equatorial and posterior tumor location, cumulative dose-volume histograms for the tumors and structures at risk were calculated. RESULTS: Eccentric placements of the plaques, taking into account the inhomogeneities of the emitter map, can substantially reduce the dose delivered to structures at risk while maintaining the prescribed dose at the tumor apex. CONCLUSIONS: The emitter map distribution of the plaque and the computerized tomography of the patient used in a Monte Carlo simulation allow an accurate determination of the plaque position with respect to the tumor with the potential to reduce the dose to sensitive structures.

Proton radiotherapy in advanced malignant melanoma of the conjunctiva.

BACKGROUND: The management of conjunctival melanoma is challenging and frequently ends in exenteration. The aim of this retrospective study was to evaluate the long-term results of proton beam radiation with regard to various clinical parameters. METHODS: Eighty-nine patients with extended conjunctival melanoma (≥T2) and multifocal bulbar located tumors (T1c/d) were treated consecutively with proton radiotherapy (dose 45 Gy). The following parameters were assessed: TNM stage, tumor origin, local recurrence, performance of exenteration, occurrence of metastases, overall survival, and potential complications. A time-to-event analysis was preformed to the primary endpoints: relapse, metastasis, exenteration, and death by use of Kaplan-Meier cumulative survival estimates and Cox proportional hazards regression that provides hazard ratios and 95% confidence intervals. RESULTS: The median follow-up time was 4.2 years (max. 21.7 years). Local recurrence and metastatic disease occurred in 33% and 16% of patients, respectively. Exenteration-free survival and overall survival tended to be worse in T3 melanoma. No association between tumor origin and local recurrence, metastatic disease, or overall survival was observed. Main complications after proton radiotherapy were sicca-syndrome (30%), secondary glaucoma (11%), and limbal stem cell deficiency (8%). CONCLUSIONS: In summary, proton radiotherapy in conjunctival melanoma is an effective alternative to exenteration, with a 5-year cumulative probability of eye preservation of 69%.

Urinary Proteomics Profiles Are Useful for Detection of Cancer Biomarkers and Changes Induced by Therapeutic Procedures.

Boron neutron capture therapy (BNCT) is a binary cancer treatment modality where two different agents (10B and thermal neutrons) have to be present to produce an effect. A dedicated trial design is necessary for early clinical trials. The concentration of 10B in tissues is an accepted surrogate to predict BNCT effects on tissues. Tissue, blood, and urines were sampled after infusion of two different boron carriers, namely BSH and BPA in the frame of the European Organisation for Research and Treatment of Cancer (EORTC) trial 11001. In this study, urine samples were used to identify protein profiles prior and after drug infusion during surgery. Here, an approach that is based on the mass spectrometry (MS)-based proteomic analysis of urine samples from head and neck squamous cell carcinoma (HNSCC) and thyroid cancer patients is presented. This method allowed the identification of several inflammation- and cancer-related proteins, which could serve as tumor biomarkers. In addition, changes in the urinary proteome during and after therapeutic interventions were detected. In particular, a reduction of three proteins that were involved in inflammation has been observed: Galectin-3 Binding Protein, CD44, and osteopontin. The present work represents a proof of principle to follow proteasome changes during complex treatments based on urine samples.

18 F-FDG PET/MRI vs MRI in patients with recurrent adenoid cystic carcinoma.

OBJECTIVES: To evaluate and compare the diagnostic potential of 18 F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18 FDG-PET/MRI) and MRI for recurrence diagnostics after primary therapy in patients with adenoid cystic carcinoma (ACC). METHODS: A total of 32 dedicated head and neck 18 F-FDG PET/MRI datasets were included in this analysis. MRI and 18 F-FDG PET/MRI datasets were analyzed in separate sessions by two readers for tumor recurrence or metastases. RESULTS: Lesion-based sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 96%, 84%, 90%, 93%, and 91% for 18 F-FDG PET/MRI and 77%, 94%, 95%, 73%, and 84% for MRI, resulting in a significantly higher diagnostic accuracy of 18 F-FDG PET/MRI compared to MRI (P < .005). CONCLUSION: 18 F-FDG PET/MRI is superior to MRI in detecting local recurrence and metastases in patients with ACC of the head and neck. Especially concerning its negative predictive value, 18 F-FDG PET/MRI outperforms MRI.

Dose Distributions and Treatment Margins in Ocular Brachytherapy with 106Ru Eye Plaques.

Brachytherapy with 106Ru eye plaques is the most common treatment modality for small to medium-sized uveal melanomas in Europe. So far, no standardized or widely accepted dose prescription protocol for the irradiation of intraocular tumors with 106Ru eye plaques has been defined. For 125I plaques, the minimum dose required for tumor control should be at least 85 Gy. Concerning 106Ru plaques, the dose prescriptions at the University Hospital of Essen foresees minimum doses of 700 Gy to the tumor base and 130 Gy to the tumor apex. These dose prescriptions are expected to ensure sufficient treatment margins. We apply these dose prescriptions to different eye plaque types and tumor sizes and discuss the resulting treatment margins. These investigations are based on Monte Carlo simulations of dose distributions of 3 different eye plaque types. The treatment margin in apical direction has an expansion of at least 0.8 mm for all investigated eye plaques. For symmetrically formed eye plaques, the treatment margin at the base of the tumor goes beyond the visible edge of the plaque. This study focuses on the shape of 85-Gy isodose lines and on treatment margins for different eye plaque types and tumor sizes and shall help exchange knowledge for ocular brachytherapy.