Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors-a nationwide, prospective Swedish study.

Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors. Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients. Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35). Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients. Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.

The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group.

Purpose: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group. Methods: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva. Survival was analyzed using Kaplan-Meier estimates. Results: The mean age at diagnosis was 17 years (range 5.0-24.8). A germline BAP1 pathogenic variant was identified in an 18-year-old patient, and a somatic variant, based mainly on immunohistochemistry, in 13 (42%) of 31 available specimens. One tumor had a somatic SF3B1 pathogenic variant. Disomy 3 and the absence of a BAP1 pathogenic variant in the tumor predicted the longest metastasis-free survival. Males showed longer metastasis-free survival than females (P = 0.018). Conclusions: We did not find a stronger-than-average BAP1 germline predisposition for choroidal and ciliary body melanoma among children and young adults compared to adults. Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).

Deferral of Treatment for Small Choroidal Melanoma and the Risk of Metastasis: An Investigation Using the Liverpool Uveal Melanoma Prognosticator Online (LUMPO).

BACKGROUND: We estimated metastatic-death risk when the treatment of small choroidal melanomas is deferred until growth is observed. METHODS: In 24 patients with choroidal melanoma (median diameter 5.85 mm), the exponential growth rate estimated by a mixed-effects model was 4.3% per year. Using the Liverpool Uveal Melanoma Prognosticator Online v.3 (LUMPO3), we measured changes in 15-year metastatic and non-metastatic death risks according to whether the tumor is treated immediately or after observing growth 4 or 12 months later, considering age, sex, and metastasis predictors. RESULTS: In 40-year-old females with 10 mm, disomy 3 and monosomy 3 choroidal melanomas (prevalence 16%), the 15-year absolute risks of metastatic death are 4.2% and 76.6%, respectively, increasing after a 4-month delay by 0.0% and 0.2% and by 3.0% and 2.3% with tumor growth rates of 5.0% and 20.0%, respectively. With 12-month delays, these risks increase by 0.0% and 0.5% and by 1.0% and 7.1%, respectively. Increases in metastatic-death risk are less with smaller tumors and with a higher risk of non-metastatic death. CONCLUSIONS: Deferring treatment of choroidal melanomas until documentation of growth may delay iatrogenic visual loss by months or years and is associated with minimal increase in metastatic mortality, at least with small tumors with usual growth rates of up to 40% per year.

Adenoma of the nonpigmented ciliary epithelium presenting as glaucoma.

Purpose: We describe a case of adenoma of the nonpigmented ciliary epithelium in a 58-year-old male, who presented with glaucoma. Observations: A healthy White male was incidentally found to have an elevated intraocular pressure in his left eye (25 mmHg) during a visit to a local optometrist. After further investigations he was diagnosed with a primary open angle glaucoma (POAG) and treated with drops for two years until he developed a sectorial cataract. During the first dilated eye exam, a pale tan tumor was discovered, that seemed to originate from the superior ciliary body, causing a sectorial-cortical cataract and subluxation of the lens. The eye was enucleated on the suspicion of a rare adult medulloepithelioma, because of multicystic features on B-scan ultrasonography. However, histopathological examination revealed an adenoma of the nonpigmented ciliary epithelium that grew in trabecular papillary patterns, with smaller areas of solid and microcystoid growth. As this is a benign tumor without metastatic potential, the patient was referred back to his home clinic without requirement for radiological staging or screening. Conclusion and Importance: Adenomas of the nonpigmented ciliary epithelium (NPCE adenomas) are benign tumors that are often mistaken for malignant counterparts. Thus, this case report expands on the available literature of this rare entity.

The prognostic implication of visual acuity at the time of uveal melanoma diagnosis.

BACKGROUND: Visual outcomes after primary tumour treatment of uveal melanoma (UM) have been investigated repeatedly. This study evaluates the correlation between best-corrected visual acuity (BCVA) before treatment with clinicopathological factors and patient survival. SUBJECTS/METHODS: Pre-treatment BCVA was examined in relation to tumour dimensions and location, and survival in a retrospective cohort of 1809 patients who underwent plaque brachytherapy. BCVA was also correlated to tumour histological factors in a second cohort of 137 enucleated eyes. RESULTS: The mean BCVA of the tumour eye prior to plaque brachytherapy was LogMAR 0.42 (SD 0.46). Patients with low BCVA (LogMAR ≥ 1.00) did not differ in age (p = 0.19) and had similar frequency of ciliary body involvement (p = 0.99) but had tumours with greater apical thickness (p < 0.0001), greater diameter (p < 0.0001) and shorter distance to the optic disc and fovea (p < 0.0001). There were no significant relations between low BCVA and any of 13 examined tumour histological factors at a Bonferroni-corrected significance level (p > 0.004). Patients with low BCVA had greater incidence of UM-related mortality in competing risk analysis (p = 0.0019) and shorter overall survival (p < 0.0001). Low BCVA was also associated with increased hazard ratio (HR) for UM-related mortality in univariate analysis (HR 1.5, 95% confidence interval 1.2 to 1.9), but not in multivariate analysis with tumour size and location as covariates. CONCLUSIONS: UM patients with low BCVA before primary tumour treatment have a worse prognosis, likely related to increased tumour dimensions. Future studies should examine the prognostic significance of BCVA in relation to macula-involving retinal detachment and genetic factors.

Trends in Uveal Melanoma Presentation and Survival During Five Decades: A Nationwide Survey of 3898 Swedish Patients.

Background: In contrast to most other cancers, uveal melanoma (UM) is characterized by an absence of major improvements in patient survival during the last several decades. In this study, we examine changes in incidence rates, patient age and tumor size at diagnosis, treatment practices and survival for patients diagnosed in Sweden during the period 1960-2010. Methods: All patients diagnosed with posterior UM between January 1st, 1960, and December 31st, 2009, in Sweden, were included (n = 3898). Trends in incidence, primary treatment modality, patient age and tumor size were analyzed. Disease-specific survival was plotted in Kaplan-Meier curves and the cumulative incidence of UM-related mortality was evaluated in competing risk analysis. Results: Crude (6.5-11.6 cases/million/year) and age-standardized incidence rates (5.6-9.6 cases/million/year) varied between individual years during the study period, but both had a stable linear trend overall (p ≥ 0.12). Gradually, plaque brachytherapy with ruthenium-106 replaced enucleation as the most common primary treatment. The mean patient age at diagnosis increased from 59.8 years in 1960 to 66.0 in 2009. Conversely, the mean tumor size became gradually smaller during the period. In linear regression, the basal diameter and tumor apical thickness decreased with a slope coefficient of -0.03 mm (p = 0.012) and -0.05 mm (p = 1.2 × 10-5) per year after 1960, respectively. Patients diagnosed after 1990 had significantly better disease-specific survival than patients diagnosed before 1990 (p = 2.0 × 10-17). Similarly, the cumulative incidence of UM-related mortality was highest for patients diagnosed 1960-1969 and 1970-1979, with slightly lower incidences for patients diagnosed 1980-1989 and even lower for those diagnosed after 1990 (p = 7.1 × 10-13). The incidence of mortality from other causes than UM did not differ between periods (p = 0.16). Conclusion: In the period from 1960-2010, crude and age-standardized incidence rates of UM have remained stable in Sweden. Several other aspects have changed: Plaque brachytherapy with ruthenium-106 has replaced enucleation as the most common primary treatment modality; patients have become older and their tumors smaller at the time of diagnosis; and their survival has improved. This might indicate a beneficial survival effect of earlier diagnosis and treatment, but the potential influence from lead-time bias should be taken into consideration.

Patients presenting with metastases: stage IV uveal melanoma, an international study.

OBJECTIVE: To analyse ocular and systemic findings of patients presenting with systemic metastasis. METHODS AND ANALYSIS: It is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases. RESULTS: Of 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1-T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category. CONCLUSIONS: Though higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.

Long-term outcomes after enucleation or plaque brachytherapy of choroidal melanomas touching the optic disc.

PURPOSE: To investigate local and systemic outcomes after enucleation, brachytherapy with ruthenium-106, iodine-125, notched and non-notched plaques and transpupillary thermotherapy (TTT) of choroidal melanomas touching the optic disc. METHODS AND MATERIALS: All patients treated for choroidal melanoma touching the optic disc at St. Erik Eye Hospital, Stockholm, Sweden between 1984 and 2015 (n = 165) were included. Retrospective clinicopathological data was collected and 3D dosimetry performed. RESULTS: Ninety-five patients (58 %) had been treated with ruthenium-106 brachytherapy, 21 (13 %) with iodine-125 brachytherapy and 49 (30 %) with enucleation. Median follow-up was 12.3 years. In simulations, some tumor areas were underdosed with non-notched plaques. Fifty of 116 patients (43 %) underwent a secondary brachytherapy (n = 5), enucleation (n = 29) or TTT (n = 16). In multivariate Cox Regressions, there were no significant differences in the risk for tumor progression or lack of regression between radioisotopes and notched and non-notched plaques. Adding TTT did not reduce the risk for a second treatment. The number of clock hours of circumpapillary tumor growth did not correlate to the risk for treatment failure or mortality. There were no significant differences in melanoma-related mortality for any treatment including enucleation. Kaplan-Meier disease-specific survival was 77 % at 5 years, 72 % at 10 years and 67 % at 20 years. CONCLUSION: Plaque brachytherapy of choroidal melanomas touching the optic disc entails a two to threefold increased risk for treatment failure. This risk is similar between radioisotopes, notched and non-notched plaque designs and if TTT is used or not. The high rate of treatment failure does not lead to increased mortality.

Effect of plaque brachytherapy dose and dose rate on risk for disease-related mortality in 1238 patients with choroidal melanoma.

BACKGROUND: Episcleral brachytherapy is the most common treatment for medium-sized choroidal melanomas. Although controversial, inadequate brachytherapy dose and dose rates have at least a hypothetical implication on patient survival. METHODS: All patients who received ruthenium-106 or iodine-125 brachytherapy for choroidal melanoma at St. Erik Eye Hospital 1996 to 2016 were included (n=1238). Cox regression hazard ratios for melanoma-related mortality across deciles, quartiles and individual integers of apex radiation doses (Gy) and dose rates (Gy/hour) were calculated, adjusted for tumour size and location. RESULTS: The average radiation dose at the tumour apex ranged from 73.0 Gy in the first decile to 108.6 Gy in the tenth. Decreasing apex dose by 1 Gy increments or by decile or quartile group was not associated with melanoma-related mortality (p>0.2) The average radiation dose rate at the tumour apex ranged from 0.5 Gy/hour in the first decile to 2.8 Gy/hour in the tenth. Similarly, decreasing apex dose rate by 1 Gy/hour increments or by decile or quartile groups was not associated with melanoma-related mortality (p>0.5). CONCLUSION: There are no increased hazards for choroidal melanoma-related mortality after brachytherapy with decreasing doses between 108.6 and 73.0 Gy, or with decreasing dose rates between 2.8 and 0.5 Gy/hour.

Conjunctival melanoma treatment outcomes in 288 patients: a multicentre international data-sharing study.

BACKGROUND: To relate conjunctival melanoma characteristics to local control. METHODS: Retrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. RESULTS: 288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2-8.9%), 19.3% (14.4-25.5%) and 36.9% (26.5-49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence. CONCLUSION: This multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.

Ruthenium-106 versus iodine-125 plaque brachytherapy of 571 choroidal melanomas with a thickness of ≥5.5 mm.

BACKGROUND: Episcleral brachytherapy is the most common eye-preserving treatment for medium-sized choroidal melanomas. γ-emitting iodine-125 (125I) and ß-emitting ruthenium-106 (106Ru) are widely used. The latter is however generally reserved for thinner tumours (<6 mm). In this study, we compare ocular and patient survival in thicker tumours treated with the respective radioisotope. METHODS: All patients with ≥5.5 mm thick choroidal melanomas who were treated with plaque brachytherapy at a single institution between 1 November 1979 and 31 December 2015 were included (n=571). Size-controlled Cox regression HRs for postbrachytherapy enucleation, repeated brachytherapy and melanoma-related mortality were calculated, as well as Kaplan-Meier disease-specific survival and relative 10-year survival in matched subgroups. RESULTS: 317 patients were treated with 106Ru and 254 with 125I. The rate of repeated brachytherapy was significantly higher among patients treated with 106Ru (8%) than with 125I (1%, p<0.001). Size-controlled Cox regression HRs for postbrachytherapy enucleation (125I vs 106Ru 0.7, p=0.083) and melanoma-related mortality were not significant (125I vs 106Ru 1.1, p=0.63). Similarly, Kaplan-Meier disease-specific and relative 10-year survival was comparable in matched groups of 5.5-7.4 mm (relative survival 106Ru 59%, 125I 56%) and ≥7.5 mm thick tumours (relative survival 106Ru 46%, 125I 44%). CONCLUSIONS: Rates of repeated brachytherapy were significantly higher among patients treated with 106Ru versus 125I for thick choroidal melanomas. There were, however, no significant differences in rates of enucleation or patient survival.

No Gender Differences in Long-Term Survival after Brachytherapy of 1,541 Patients with Uveal Melanoma.

BACKGROUND: In several malignancies, gender-based survival differences after specific therapeutic interventions have been demonstrated. It is not known whether such differences exist after plaque brachytherapy of uveal melanoma. METHODS: All patients who received brachytherapy for uveal melanoma at St. Erik Eye Hospital from November 1, 1979 through November 20, 2017 were included (n = 1,541). Retrospective data were retrieved including baseline patient and tumor characteristics, brachytherapy nuclide (ruthenium-106 or iodine-125), radiation dose, treatment duration, tumor relapses, date of metastasis, and cause of death. RESULTS: A total of 775 men and 766 women were treated with plaque brachytherapy. There were no significant differences between the genders in baseline characteristics, treatment, or follow-up. Men and women had similar rates of tumor relapses, hazard for repeated brachytherapy (men vs. women 0.8, p = 0.47), enucleation-free survival, and survival after detection of metastasis. Five-, 10-, and 15-year melanoma-related mortality was 14, 24, and 27% for men and 15, 26, and 32% for women, respectively. There were no significant differences in hazard for melanoma-related mortality (men vs. women 0.9, p = 0.32), median Kaplan-Meier disease-specific survival (men 18.2 years, women 15.5 years, p = 0.22), or median overall survival (men 13.5 years, women 12.6 years, p = 0.60). CONCLUSION: There are no relevant differences between men and women in ocular or patient survival after brachytherapy for uveal melanoma.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN: Retrospective, multicenter observational study. PARTICIPANTS: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Auditory event-related potentials (P300) and mesial temporal sclerosis in temporal lobe epilepsy patients.

AIMS: To investigate the role of centrally recorded P300 in patients suffering from mesial temporal sclerosis-temporal lobe epilepsy (MTS-TLE). METHODS: Sixteen patients (3 men and 13 women; median age: 32.5 years old) suffering from TLE with MTS and 43 healthy controls (12 men and 31 women; median age: 35 years old) participated in the study. P300 was elicited using an auditory two-stimulus oddball paradigm. In order to address the aim of the study, we adopted two statistical approaches; hierarchical linear regression analyses and ROC curves. RESULTS: After adjusting for age, MTS patients had a mean reduction of P300 amplitude by 6.93 µV and a mean increase of P300 latency by 38.78 ms, compared to controls. Age and MTS-TLE status accounted for 32 and 16% of the variance of latency and amplitude, respectively. Diagnostic analyses to detect MTS-TLE status revealed a sensitivity and specificity of 88 and 65% for amplitude and 81 and 70% for latency, respectively. No association between duration of disease and P300 characteristics were found. CONCLUSIONS: This study, along with other studies, contributes to our understanding and clinical significance of centrally recorded P300s in MTS-TLE patients. Future studies should focus on the association of these P300s with cognition in such patients.