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.

Surgical Outcome After Treatment of Radiation-Induced Scleral Necrosis in Patients With Uveal Melanoma.

PURPOSE: Surgical repair might be required in patients with uveal melanoma (UM) that develop advanced forms of radiation-induced scleral necrosis (RISN). In this monocentric long-term observational study, we aimed at analyzing the treatment outcome after RISN surgery. METHODS: All consecutive cases with UM who underwent surgical intervention for RISN between 1999 and 2020 were included. Achievement of the tectonic stability and evaluation of incidence and the risk factors for a repetitive patch surgery (RPS) were the main endpoints. RESULTS: The final analysis included 57 patients (mean age: 58.7 years; 63.2% female patients), where 55 individuals underwent a patch grafting, and 2 cases were treated with conjunctival reconstructive surgery. The mean follow-up time after grafting was 38.5 months (0.03-221.1 months). Tectonic stability was achieved in 56 (98.3%) patients. Scleral graft (38/55, 69.1%) was the most frequent patching material, followed by Tutopatch (7/55, 12.7%), corneal graft (7/55, 12.7%), dura graft (2/55, 3.6%), and fascia lata (FL) graft (1/55, 1.8%). Eleven patients (20%) underwent RPS after the mean time of 12.9 months (0.3-50.3 months). In the final multivariate Cox regression analysis, the use of Tutopatch (5/7; 71.4%, adjusted hazard ratio = 4.66, P = 0.044) and RISN progression after patch grafting (9/11; 81.8%, adjusted hazard ratio = 9.67, P = 0.008) were independent risk factors for RPS. CONCLUSIONS: RISN surgery maintains long-term tectonic stability in most of the cases underwent surgical repair for RISN after brachytherapy for UM. Depending on graft material and, particularly, further RISN progression, an RPS might be necessary in certain cases.

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.

Release of Cell-Free Tumor DNA in the Plasma of Uveal Melanoma Patients Under Radiotherapy.

Purpose: Uveal melanoma (UM) is a tumor of the eye that metastasizes in approximately half of cases. Prognostic testing requires accessibility to tumor tissue, which is usually not available with eye-preserving therapies. Noninvasive approaches to prognostic testing that provide valuable information for patient care are therefore needed. The aim of this study was to evaluate the use of circulating cell-free plasma DNA analysis in UM patients undergoing brachytherapy. Methods: The study recruited 26 uveal melanoma patients referred to the department between February and October 2020. Blood samples were collected at various time points before, during, and after treatment, and deep amplicon sequencing was used to identify oncogenic variant alleles of the GNAQ and GNA11 genes, which serve as indicators for the presence of circulating tumor DNA (ctDNA). Results: The results showed that all patients were ctDNA negative before brachytherapy. In 31% of patients, ctDNA was detected during therapy. The variant allele fraction of GNAQ or GNA11 alleles in ctDNA positive samples ranged from 0.24% to 2% and correlates with the largest basal diameter and thickness of the tumor. Conclusions: The findings suggest that brachytherapy increases the presence of tumor DNA in the plasma of UM patients. Thus ctDNA analysis may offer a noninvasive approach for prognostic testing. However, efforts are still required to lower the limit of detection for tumor-specific genetic alterations.

Analysis of uveal melanomas and paired constitutional DNA for exclusion of a BAP1-tumor predisposition syndrome.

Uveal melanoma (UM) is a rare tumor originating from melanocytic cells in the eye. Familial aggregation of UM is rare and can occur as part of the tumor predisposition syndrome BAP1-TPDS. However, family history alone will only identify a subset of patients with BAP1-TPDS. In the present study, we used sequential testing of tumor and blood DNA from UM patients for differential diagnosis of BAP1-TPDS. The study group was an unselected prospective cohort of patients from whom UM tissue was available. First, chromosome 3 status in tumor DNA was determined in all 140 patients who consented to participate. As tumors with disomy 3 rarely show BAP1 alterations, sequence analysis of this gene was performed in the 72 tumors with monosomy 3 (M3) or partial M3 only. We identified oncogenic BAP1 alterations in 52 of these tumors (72%). Targeted sequencing of DNA from matched peripheral blood showed pathogenic variants in two patients (3.8%) thus proving BAP1-TPDS. Only one of these two patients also had a medical history suggestive of this syndrome. Conversely, in three patients known to have had additional tumors before diagnosis of UM, constitutional heterozygosity for a BAP1 mutation was excluded. Altogether, in 50 patients we could exclude BAP1-TPDS with high diagnostic certainty. The results of our study support that genetic testing for BAP1-TPDS should be offered to all patients with UM. Moreover, as genetic information from the tumor can help exclude heritable risk, the strategy for analysis should include efforts to obtain tumor samples for testing.

Early detection of metastatic uveal melanoma by the analysis of tumor-specific mutations in cell-free plasma DNA.

BACKGROUND: Eye salvaging therapy of malignant melanomas of the uvea can preserve the eye in most cases, but still about half of patients die from metastatic disease. Previous analyses of cell-free DNA from plasma had shown detectable levels of tumor-specific GNAQ/GNA11 mutations in patients with the clinical diagnosis of progressive disease. However, data on the time span that elapses from the detection of ctDNA in plasma to the clinical detection of metastases (diagnostic lead time) are missing. METHODS: We examined 135 patients with uveal melanoma. Cell-free DNA was isolated from a total of 807 blood samples which were taken over a period of up to 41 months and analyzed for the presence of GNAQ/GNA11 mutations by deep amplicon sequencing. RESULTS: Twenty-one of the 135 patients developed metastases or recurrence. A ctDNA signal was identified in the plasma of 17 of the 21 patients. In 10 patients, this ctDNA signal preceded the clinical diagnosis of metastasis by 2-10 months. In 10 other patients, a ctDNA signal was only detected in samples obtained shortly before or after radiotherapy. The presence of a ctDNA signal in 16 of the remaining 125 patients was linked to clinical manifestation of metastases (n = 14) or tumor recurrence (n = 2) with a sensitivity and specificity of 80% and 96%, respectively. CONCLUSION: Detection of ctDNA in plasma can provide a diagnostic lead time over the clinical diagnosis of metastases or tumor recurrence. Longer lead times are to be expected if intervals between sampling are shortened.

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.

Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria.

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013-2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in DICER1 was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.

Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3's performance using discrimination and calibration methods. LUMPO3's ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.

Psychosocial impact of prognostic genetic testing in uveal melanoma patients: a controlled prospective clinical observational study.

BACKGROUND: The risk of metastases in uveal melanoma can accurately be estimated through genetic analysis of the tumor. A growing number of patients decide to receive information on their prognosis, although this can be extremely burdensome. Studies on the psychosocial impact of testing are sparse. The objective of this study was to examine traits of patients opting for prognostication, to investigate its psychosocial impact and the use of psycho-oncological services over time. We further examined characteristics of patients utilizing these services and risk factors of prolonged psychological distress. DESIGN AND METHODS: This study is a non-randomized controlled prospective clinical observational trial. Patients availing for prognostication formed the test group, while those who opted out constituted the observational group. The psychosocial impact of genetic testing was assessed with the following variables: resilience, social support, fear of tumor progression, depression, general distress, health-related quality of life, estimation of the perceived risk, and the utilization of psycho-oncological interventions. Data were assessed at five different time points over a period of 12 months. We applied binary logistic regression analysis, multiple linear regressions and a mixed model. RESULTS: Of 175 patients, 63 decided to obtain prognostic information. Treatment method (enucleation > brachytherapy), lower social support and higher general distress could significantly predict patient's choice for prognostic testing. After result announcement, perceived risk of metastases was significantly increased in patients with poor prognosis, while it decreased in those with good prognosis. Overall, a significant decrease over time appeared concerning fear of progression, general distress, depression and anxiety. Mental quality of life increased over time. The utilization of psycho-oncological interventions increased significantly after prognostication; however, this was equivalent in the test and observational groups. Female sex, higher general distress and higher anxiety predicted greater use of psycho-oncological interventions. DISCUSSION: Availing of prognostic testing is not associated with poorer subsequent psychological well-being. It rather may help to alleviate distress and promote a more realistic risk perception. However, psychological support should be available to all patients, independent of prognosis and treatment, especially considering that patients with low social support and high distress increasingly opt for prognostication.

GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma.

Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11. Circumscribed choroidal hemangioma is a benign tumor that becomes symptomatic in adulthood. In some patients, morphologic examination of biopsies is required for differential diagnosis between amelanotic choroidal melanoma and circumscribed choroidal hemangioma. Here, we report the results of GNAQ/GNA11 mutation analysis in samples from circumscribed choroidal hemangioma. Deep amplicon sequencing (Illumina MiSeq, San Diego, CA, USA) of positions R183 and Q209 of GNAQ and GNA11 in tissue samples from 33 patients with histologically diagnosed circumscribed choroidal hemangioma. All patients underwent biopsy or enucleation at our clinic between 2008 and 2018. To enable detection of variant alleles at low fractions, read depth exceeded 15,000-fold. DNA for genetic analysis was prepared from either snap-frozen (n = 22) or FFPE (n = 11) tissue samples. Samples from 28/33 patients (85%) showed a somatic missense mutation of GNAQ (c.626 A > G) predicted to result in p.Q209R. Variant allele fraction was variable (range 2.3% to 28%). Variants of GNAQ resulting in p.Q209 are characteristic for circumscribed choroidal hemangiomas. It appears that the GNAQ mutation spectrum in this tumor is narrow, possibly restricted to p.Q209R. Moreover, the spectrum is distinct from that of uveal melanoma, in which alterations resulting in p.Q209R are very rare.

Chromosome 3 is a valid marker for prognostic testing of biopsy material from uveal melanoma later treated by brachytherapy.

PURPOSE: Monosomy 3 (M3) in uveal melanoma (UM) obtained after enucleation is significantly associated with metastatic death. With improved biopsy techniques, samples from patients treated with eye-preserving methods have become available. As the choice of treatment depends on tumour size, patients treated with eye-preserving brachytherapy tend to have smaller tumours. It has to be determined if M3 is a valid marker for prognosis of these patients. METHODS: Follow-up and clinical data were collected from a total of 451 UM patients: 291 patients were treated by brachytherapy. Tumour tissue was sampled by transretinal biopsy using the 23-gauge Essen biopsy forceps prior to therapy in 114 of them. Chromosome 3 status was determined by microsatellite analysis. Data were compared to those from 160 patients treated by enucleation. RESULTS: Chromosome 3 status correlates significantly with disease-related survival in both patient groups. The proportion of tumours with M3 is lower in the brachytherapy group compared to patients treated with enucleation (25/77 32% and 102/144 71%, respectively). CONCLUSIONS: M3 is a valid marker for poor prognosis in uveal melanoma later treated by brachytherapy. The higher proportion of D3 tumours might explain, at least in part, the more favourable prognosis of patients treated by brachytherapy.

[Primary Intraocular Lymphoma: Relevance of Diagnostic Vitrectomy]. / Primäres intraokuläres Lymphom: Relevanz der diagnostischen Vitrektomie.

Primary intraocular lymphomas are rare tumours that can be further subdivided into primary vitreoretinal and the even rarer primary uveal lymphoma. The incidence of primary vitreoretinal lymphoma (PVRL) has increased during the last few decades. Differential diagnostic distinction between lymphoma and posterior uveitis is often difficult, so that adequate diagnosis and treatment is often delayed. This is fatal, because PVRL is often associated with primary central nervous lymphoma. To confirm the diagnosis, prior treatment of cytological or histological detection of lymphoma cells is the gold standard. Therefore, a diagnostic vitrectomy should be performed with vitreous biopsy and sometimes transretinal biopsy. Cytokine analysis, as well as flow cytometry and molecular tests, are only additional methods that can be employed in case enough tumour material is available. After the diagnosis has been made, an interdisciplinary treatment concept must be developed by oncologists and ophthalmologists together.

Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center.

BACKGROUND: Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined. PROCEDURE: This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment. RESULTS: The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0-10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population). CONCLUSIONS: Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.

How Eye-Preserving Therapy Affects Long-Term Overall Survival in Heritable Retinoblastoma Survivors.

PURPOSE: Intraocular retinoblastoma is curable, but survivors with a heritable predisposition are at high risk for second malignancies. Because second malignancies are associated with high mortality, prognostic factors for second malignancy influence long-term overall survival. This study investigates the impact of all types of eye-preserving therapies on long-term survival in the complete German cohort of patients with heritable retinoblastoma. PATIENTS AND METHODS: Overall survival, disease staging using international scales, time period of diagnosis, and treatment type were analyzed in the 633 German children treated at the national reference center for heritable retinoblastoma. RESULTS: The 5-year overall survival of children diagnosed in Germany with heritable retinoblastoma between 1940 and 2008 was 93.2% (95% CI, 91.2% to 95.1%), but long-term mortality was increased compared with patients with nonheritable disease. Overall survival correlated with tumor staging, and 92% of patients were diagnosed with a favorable tumor stage (International Retinoblastoma Staging System stage 0 or I). Despite a 5-year overall survival of 97.4% (95% CI, 96.0% to 98.8%) in patients with stage 0 or I, only 79.5% (95% CI, 74.2% to 84.8%) of these patients survived 40 years after diagnosis. Long-term overall survival was reduced in children treated with eye-preserving radiotherapy compared with enucleation alone, and adding chemotherapy aggravated this effect. CONCLUSION: The benefits of preserving vision must be balanced with the impact of eye-preserving treatments on long-term survival in heritable retinoblastoma, and the genetic background of the patient influences choice of eye-preserving treatment. Germline RB1 genetic analysis is important to identify heritable retinoblastoma among unilateral retinoblastoma cases. Eye-preserving radiotherapy should be carefully considered in patients with germline RB1 mutations. Life-long oncologic follow-up is crucial for all retinoblastoma survivors, and less detrimental eye-preserving therapies must be developed.