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.

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.

Prognostic implications of tenascin C in peripheral blood and primary tumours at the time of uveal melanoma diagnosis.

OBJECTIVE: To examine the prognostic implication of tenascin C (TNC) in posterior uveal melanoma (UM). DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 162 patients diagnosed with posterior UM. METHODS: A peripheral blood sample was obtained from 82 patients at the time of UM diagnosis between 1996 and 1999. Samples were kept frozen at -80°C until the concentration of TNC was measured in 2021. Primary tumour TNC RNA sequencing data were collected from another 80 patients (The Cancer Genome Atlas cohort). Patients were separated based on median TNC values. Cumulative incidences of metastatic death (UM mortality) from competing risks data were calculated as well as Cox regression hazard ratios. RESULTS: Patients with high and low TNC levels had tumours of similar size and American Joint Committee on Cancer stage at Bonferroni-corrected significance levels. The exception was a significantly smaller tumour diameter in patients with high serum TNC levels (p = 0.003). In competing risks analysis, patients with high serum TNC levels (≥7 ng/mL) had a higher UM mortality rate (44% vs 17% at 20 years; p = 0.008). Similarly, patients with higher primary tumour TNC RNA levels (≥1 transcripts per million) had higher UM mortality (83% vs 27% at 5 years; p = 0.003). In multivariate Cox regressions, TNC levels in peripheral blood and primary tumours were predictors of metastatic death independent of American Joint Committee on Cancer stage. CONCLUSIONS: TNC is a prognostic biomarker in UM. At the time of primary tumour diagnosis, it is measured in higher levels in both peripheral blood and tumour tissue from patients who will eventually suffer from metastatic death.

Incidence, risk factors and outcomes of cataract surgery after plaque brachytherapy for posterior uveal melanoma.

Purpose: To examine incidence, risk factors, and outcomes of cataract surgery after plaque brachytherapy for posterior uveal melanoma. Design: Retrospective interventional cohort study contrasted with general population data. Methods: All patients treated with plaque brachytherapy for a posterior uveal melanoma at Sweden's national referral center between 2010 and 2022 were included (n = 933). These patients were cross-referenced with data from the Swedish National Cataract Register. Competing risk incidences and outcomes of cataract surgery were compared with a random sample of 1000 individuals from the general population. Results: The 12-year incidence of cataract surgery after plaque brachytherapy was 27 % (95 % CI 23-31 %), which markedly exceeded the incidence of 16 % in the general population (95 % CI 13-18 %, Gray's P < 0.001). Patients treated with Iodine-125 had significantly higher incidence than patients treated with Ruthenium-106, and the latter had greater incidence than the general population (P < 0.001). In univariate competing risk regressions, older patients, female sex, thick tumors, and Iodine-125 were associated with cataract surgery. In multivariate analysis, older patients and Iodine-125 retained their significance. Outcomes of cataract surgery were overall similar in the plaque brachytherapy and general population, but the general population more often received post op. topical NSAID. Conclusions: In this study, plaque brachytherapy for posterior uveal melanoma was associated with a significantly increased incidence of cataract surgery. Treatment with the gamma emitting isotope iodine-125 and older patient age at the time of brachytherapy emerged as the major risk factors. Outcomes of cataract surgery were comparable to the general population.

Obesity paradox in uveal melanoma: high body mass index is associated with low metastatic risk.

BACKGROUND: Metabolic factors and obesity may influence the development and progression of cancer. In this study, we examine their association with the risk of developing metastases of uveal melanoma. METHODS: Data on metabolic factors, medications, serum leptin levels, tumour leptin receptor RNA expression and clinical outcomes were examined in three cohorts. HRs for metastasis and cumulative incidences of melanoma-related mortality were calculated, and the levels of tumour leptin receptor expression were compared with prognostic factors including BAP1 mutation, and tumour cell morphology. RESULTS: Of 581 patients in the main cohort, 116 (20%) were obese and 7 (1 %) had metastatic disease at presentation. In univariate Cox regressions, tumour diameter, diabetes type II and use of insulin were associated with metastases, but patients with obesity had a lower risk. The beneficial prognostic implication of obesity was retained in multivariate regressions. In competing risk analyses, the incidence of melanoma-related mortality was significantly lower for patients with obesity. Serum leptin levels≥median were associated with a reduced risk for metastasis, independent of patient sex and cancer stage in a separate cohort (n=80). Similarly, in a third cohort (n=80), tumours with BAP1 mutation and epithelioid cells had higher leptin receptor RNA expression levels, which have a negative correlation with serum leptin levels. CONCLUSION: Obesity and elevated serum leptin levels are associated with a lower risk for developing metastases and dying from uveal melanoma.

Improved Staging of Ciliary Body and Choroidal Melanomas Based on Estimation of Tumor Volume and Competing Risk Analyses.

PURPOSE: The current, 8th edition of the American Joint Committee on Cancer (AJCC) anatomic classification and staging model for uveal melanoma does not fully separate survival estimates for patients with advanced stages of the disease (e.g., IIIB and IIIC). Furthermore, some tumors in higher size categories have a smaller volume than tumors in lower categories. Therefore, we developed a novel model for prognostication of metastatic mortality based on estimations of tumor volume. DESIGN: Retrospective, multicenter case series of patients with uveal melanoma involving the choroid, ciliary body, or both. PARTICIPANTS: Six thousand five hundred twenty-eight consecutively registered patients treated at 3 tertiary ocular oncology centers on 2 continents between 1981 and 2022. METHODS: Data on survival, tumor size, and extent were collected for all 6528 patients. Tumor volume was estimated using a simple equation based on largest basal diameter and thickness. Volume-based size categories and stages were developed and validated in independent patient cohorts using competing risk analyses, and correlations with cytogenetic and cytomorphologic features were examined. MAIN OUTCOME MEASURE: Cumulative incidence of metastatic death. RESULTS: The 6528 patients were distributed over 7 stages based on estimated tumor volume and anatomic extent (V stages IA, IB, IIA, IIB, IIIA, IIIB, and IIIC), with a 15-year incidence of metastatic death ranging from 7% to 77%. A new category, V1min, and corresponding stage IA, were introduced, indicating an excellent prognosis. Metastatic mortality in V stage IIIC was significantly higher than that in V stage IIIB (P = 0.03), whereas incidence curves crossed for patients in AJCC stages IIIC vs. IIIB (P = 0.53). Univariable and multivariable competing risk regressions demonstrated higher Wald statistics for V stages compared with AJCC stages (1152 vs. 1038 and 71 vs. 17, respectively). The frequency of monosomy 3, gain of chromosome 8q, and epithelioid cytomorphologic features increased with tumor volume (R2 = 0.70, R2 = 0.50, and R2 = 0.71, respectively; P < 0.001) and showed similar correlations with both AJCC and V stages. CONCLUSIONS: Anatomic classification and staging of ciliary body and choroidal melanomas based on estimation of tumor volume improves prognostication of metastatic mortality. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comprehensive causes of death in uveal melanoma: mortality in 1530 consecutively diagnosed patients followed until death.

BACKGROUND: Uveal melanoma has a high propensity for metastatic spread. Yet, the comprehensive causes of death in a large consecutive cohort followed from diagnosis to death remain unknown. METHODS: All Swedish patients diagnosed with melanoma involving the iris, choroid, and/or ciliary body after January 1, 1960, were assessed for this study. Sequential inclusion was halted upon encountering the first surviving patient during data collection. Causes of death were collected from the National Cause of Death Registry and audited by analysis of up to 15 causative diagnoses. RESULTS: A total of 1530 patients were included, each histopathologically verified with primary uveal melanoma. Mortality from metastatic uveal melanoma was 31% at 5 years, 40% at 10 years, 45% at 20 years, 47% at 30 years, and 48% between 40 and 60 years post-diagnosis. Notably, the longest period between diagnosis and metastatic fatality was 49.6 years. Additionally, 186 other causes of death were recorded, with cardiovascular diseases constituting 26%, other cancers 10%, stroke 6%, dementias 2%, and lower respiratory infections 2% of total mortalities. Mortality from colorectal, lung, prostate, and stomach carcinomas over 60 years were 1.4%, 1.4%, 1.2%, and 0.9%, with metastatic uveal melanoma being the leading cumulative and annual cause of death for the initial 41 and 5 years post-diagnosis, respectively. CONCLUSIONS: In this large consecutive cohort, half of the included patients ultimately succumbed to metastatic uveal melanoma, with deaths occurring up to 50 years after diagnosis. One-quarter and one-tenth of patients died from cardiovascular diseases and other cancers, respectively.

Nicotinamide Prevents Retinal Vascular Dropout in a Rat Model of Ocular Hypertension and Supports Ocular Blood Supply in Glaucoma Patients.

Purpose: To investigate whether nicotinamide (NAM) modulates retinal vasculature in glaucoma. Methods: This was a prospective controlled clinical trial investigating animal and human histopathology. Participants included normotensive and ocular hypertensive rats, postmortem human ocular tissue, glaucoma patients (n = 90), and healthy controls (n = 30). The study utilized histopathology, computer-assisted retinal vasculature analysis, optical coherence tomography angiography (OCTA), and NAM treatment. The main outcome measures included retinal vascular parameters in rats as assessed by AngioTool; retinal vasculature integrity in rats and humans as assessed by histopathology, antibody-staining, and ImageJ-based measurements; and retinal perfusion density (PD) and flux index in humans as assessed by OCTA. Results: A number of vessel parameters were altered in ocular hypertension/glaucoma compared to healthy controls. NAM treatment improved the retinal vasculature in ocular hypertensive rats, with an increase in mean vessel area, percentage area covered by vessels, total vessel length, total junctions, and junction density as assessed by AngioTool (all P < 0.05); vessel wall integrity as assessed by VE-cadherin antibody staining was also improved (P < 0.01). In humans, as assessed by OCTA, increases in PD in the optic nerve head and macula complete image (0.7%, P = 0.04 and 1.0%, P = 0.002, respectively) in healthy controls, and an increase in the temporal quadrant of the macula (0.7%, P = 0.02) in glaucoma patients was seen after NAM treatment. Conclusions: NAM can prevent retinal vascular damage in an animal model of glaucoma. After NAM treatment, glaucoma patients and healthy controls demonstrated a small increase in retinal vessel parameters as assessed by OCTA.

Delays between Uveal Melanoma Diagnosis and Treatment Increase the Risk of Metastatic Death.

PURPOSE: To investigate if the interval between diagnosis and treatment of posterior uveal melanoma (UM) is associated with metastatic death. DESIGN: Retrospective, single-center cohort study. PARTICIPANTS: A total of 1145 patients consecutively diagnosed with posterior UM at St. Erik Eye Hospital, Stockholm, Sweden, from 2012 to 2022, with recorded dates of diagnosis and primary treatment. This cohort represents 81% of all diagnosed patients in Sweden during this period. METHODS: Data on the interval between diagnosis and treatment were collected for all patients. Its prognostic importance was examined with univariate and multivariate competing risks regressions, and cumulative incidence analyses. MAIN OUTCOME MEASURES: Incidence of metastatic death (UM mortality) for patients with prompt (< 1 month from diagnosis) versus delayed treatment (≥ 1 month) and subdistribution hazard ratios (exp(ßj)) for every additional 10-day delay in treatment. RESULTS: The mean interval between diagnosis and treatment was 34 days (SD, 56, range, 0-932). Patients treated promptly had larger tumors at diagnosis, but there were no differences in patient age, tumor distance to the optic disc, rates of ciliary body involvement (CBI) or extraocular extension (EXE), or symptom duration before diagnosis. Those who were treated more than 1 month after diagnosis had greater UM mortality in American Joint Committee on Cancer (AJCC) stage II and III. In stage I, UM mortality for delayed treatment was lower for the first 10 years, followed by a marked spike in the 11th year. In multivariate competing risks regressions of all 1145 patients with tumor diameter, thickness, CBI, and EXE as covariates, the risk for UM mortality increased with 1% for every additional 10-day delay in treatment (exp(ßj) 1.01). Among 355 patients treated with enucleation, this delay was associated with UM mortality, independent of AJCC stage, cytomorphology, and level of immunohistochemical BAP-1 expression. CONCLUSIONS: Increasing time between diagnosis and treatment of UM is associated with a higher risk of metastatic death. These results challenge a central concept in the understanding of metastatic progression and may indicate the existence of late metastatic seeding. They also underscore the importance of prompt treatment. Validation in independent cohorts is recommended. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Brachytherapy With 15- Versus 20-mm Ruthenium 106 Plaques Without Verification of Plaque Position Is Associated With Local Tumor Recurrence and Death in Posterior Uveal Melanoma.

PURPOSE: Brachytherapy with episcleral plaques is the most common primary tumor treatment for uveal melanoma. This study aimed to compare the risk of tumor recurrence and metastatic death between 2 frequently used ruthenium 106 plaque designs: CCB (20.2 mm) and CCA (15.3 mm). METHODS AND MATERIALS: Data were obtained from 1387 consecutive patients treated at St. Erik Eye Hospital, Stockholm, Sweden between 1981 and 2022 (439 with CCA and 948 with CCB plaques). During the period, scleral transillumination was performed to delineate tumor margins before plaque insertion, but accurate plaque positioning was not verified after scleral attachment, and no minimum scleral dose was used. RESULTS: Patients treated with CCA plaques had smaller tumors than those treated with CCB plaques (mean diameter, 8.6 vs 10.5 mm; P < .001). There were no differences in patient sex, age, tumor distance to the optic disc, tumor apex dose, dose rate, or in rates of ciliary body involvement, eccentric plaque placement, or adjunct transpupillary thermotherapy (TTT). The average difference between plaque and tumor diameter was greater with the CCB plaque, and a smaller difference was an independent predictor of tumor recurrence. The 15-year incidence of tumor recurrence was 28% and 15% after treatment with CCA and CCB plaques, respectively (competing risk analysis, P < .001). Multivariate Cox regression analysis revealed a lower risk for tumor recurrence with CCB plaques (hazard ratio, 0.50). Similarly, patients treated with CCB plaques had a lower risk for uveal melanoma-related mortality (hazard ratio, 0.77). The risk for either outcome was not lower for patients treated with adjunct TTT. Uni- and multivariate time-dependent Cox regressions demonstrated that tumor recurrence was associated with uveal melanoma-related and all-cause mortality. CONCLUSIONS: Compared with 20-mm plaques, brachytherapy with 15-mm ruthenium plaques is associated with a higher risk for tumor recurrence and death. These adverse outcomes may be avoided by increasing safety margins and implementing effective methods to verify accurate plaque positioning.

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.

Multiorgan Involvement of Dormant Uveal Melanoma Micrometastases in Postmortem Tissue From Patients Without Coexisting Macrometastases.

OBJECTIVES: Almost half of all patients diagnosed with uveal melanoma will die of metastatic disease. This has been attributed to early seeding of micrometastases. We investigate the presence, density, organ involvement, and characteristics of micrometastases of uveal melanoma in tissue obtained at autopsy of patients with and without coexisting macrometastases. METHODS: Patients diagnosed with primary uveal melanoma at a national referral center between 1960 and 2020 (n = 4,282) were cross-referenced with autopsy registers at nearby hospitals. Eleven patients were included. Formalin-fixed, paraffin-embedded tissue samples obtained during autopsy were examined with routine histology, immunohistochemistry, and immunomagnetic separation. RESULTS: Micrometastases were detected in 5 of 5 patients with and in 5 of 6 patients without coexisting macrometastases. Micrometastases were identified in several sites, including lungs, kidneys, myocardium, and bone marrow. Their highest density per mm2 of tissue was seen in the liver. Of 11 examined patients, 2 had at least 1 BAP-1-positive metastasis. All micrometastases had immune cell infiltrates and no or very low proliferative activity. CONCLUSIONS: We demonstrate multiorgan involvement of apparently dormant micrometastases in patients with uveal melanoma. This suggests that micrometastases are present in nearly all patients diagnosed with primary uveal melanoma, regardless of coexisting macrometastases.

Digital morphometry and cluster analysis identifies four types of melanocyte during uveal melanoma progression.

BACKGROUND: Several types of benign and malignant uveal melanocytes have been described based on their histological appearance. However, their characteristics have not been quantified, and their distribution during progression from normal choroidal melanocytes to primary tumors and metastases has not been reported. METHODS: A total of 1,245,411 digitally scanned melanocytes from normal choroid, choroidal nevi, primary uveal melanomas, and liver metastases were entered into two-step cluster analyses to delineate cell types based on measured morphometric characteristics and expression of protein markers. RESULTS: Here we show that a combination of the area and circularity of cell nuclei, and BAP-1 expression in nuclei and cytoplasms yields the highest silhouette of cohesion and separation. Normal choroidal melanocytes and three types of uveal melanoma cells are outlined: Epithelioid (large, rounded nuclei; BAP-1 low; IGF-1R, IDO, and TIGIT high), spindle A (small, elongated nuclei; BAP-1 high; IGF-1R low; IDO, and TIGIT intermediate), and spindle B (large, elongated nuclei; BAP-1, IGF-1R, IDO, and TIGIT low). In normal choroidal tissue and nevi, only normal melanocytes and spindle A cells are represented. Epithelioid and spindle B cells are overrepresented in the base and apex, and spindle A cells in the center of primary tumors. Liver metastases contain no normal melanocytes or spindle A cells. CONCLUSIONS: Four basic cell types can be outlined in uveal melanoma progression: normal, spindle A and B, and epithelioid. Differential expression of tumor suppressors, growth factors, and immune checkpoints could contribute to their relative over- and underrepresentation in benign, primary tumor, and metastatic samples.

In this study, we take a close look on more than a million cells of the type that makes pigment inside the eye. Sometimes these cells become cancers called uveal melanomas, that have a high risk of killing the patient. The cells were digitally scanned and we measured their size, shape, and content of different proteins that are important for how they behave. We find that four types of cells are present in different proportions in normal tissue, moles, eye tumors, and tumor tissue that has spread to other parts of the body. This knowledge is important as it improves our understanding of what cells form uveal melanomas, and of how they are distributed over different stages of the disease. In turn, this could help researchers focus on the right type of cells in our pursuit of effective treatments.

A Prognostic Score for the Prediction of Local Treatment Failure in Plaque Brachytherapy of Uveal Melanoma.

Purpose: To develop a prognostic score that correlates to a low, medium, and high incidence of treatment failure after plaque brachytherapy of uveal melanoma (UM). Methods and Materials: All patients who have received plaque brachytherapy for posterior UM at St. Erik Eye Hospital in Stockholm, Sweden from 1995 through 2019 were included (n = 1636). Treatment failure was defined as tumor recurrence, lack of tumor regression, or any other condition requiring a secondary transpupillary thermotherapy (TTT), plaque brachytherapy, or enucleation. The total sample was randomized into 1 training and 1 validation cohort, and a prognostic score for the risk for treatment failure was developed. Results: In multivariate Cox regression, low visual acuity, tumor distance to the optic disc ≤2 mm, American Joint Committee on Cancer (AJCC) stage, and a tumor apical thickness of >4 (for Ruthenium-106) or >9 mm (for Iodine-125) were independent predictors of treatment failure. No reliable threshold could be identified for tumor diameter or cancer stage. In competing risk analyses of the validation cohort, the cumulative incidence of treatment failure, as well as of secondary enucleation, increased with the prognostic score: In the low, intermediate, and high-risk classes, the 10-year incidence of treatment failure was 19, 28, and 35% and of secondary enucleation 7, 19, and 25 %, respectively. Conclusions: Low visual acuity, American Joint Committee on Cancer stage, tumor thickness, and tumor distance to the optic disc are independent predictors of treatment failure after plaque brachytherapy for UM. A prognostic score was devised that identifies low, medium, and high risk for treatment failure.

Increasing demand for ophthalmic pathology: time trends in a laboratory with nationwide coverage.

PURPOSE: To report the time trends in basic patient characteristics and the number of specimens received at a national referral center for ophthalmic pathology. METHODS: Data on patient sex, age at surgical resection and geographical location of the referring unit were obtained for all specimens received at the St. Erik Ophthalmic Pathology laboratory, Stockholm, Sweden, between January 1st, 1959, and December 31st, 2021. RESULTS: A total of 33 057 specimens had been received, of which 14 560 (44%) came from men and 18 477 (56%) from women (for 20 patients, the sex was not specified). The average annual percent change (AAPC) in the number specimens received was + 10.5%, whereas the Swedish population increased with 0.5% per year. Patients became older throughout the period, with an average yearly increase of patient age at surgery of 0.3 years (AAPC 0.2%). Overall, women were three years older than men at surgery (59.4 versus 56.4 years, P < 0.0001) The number of specimens increased with patient age from the first to the 8th decade, after which it decreased to zero in the 11th decade. The largest portion of patients had undergone their surgery in one of the hospitals or clinics in the capital region, with four of the five largest sources corresponding to the most populous counties in the country. CONCLUSIONS: During six decades, the growth in number of specimens sent to our national referral center for ophthalmic pathology has greatly outpaced the growth of the population, indicating an increasing demand for subspecialized services. Throughout the period, patients have become older, and a higher number of specimens have been submitted from female patients.

A serum protein signature at the time of Uveal Melanoma diagnosis predicts long-term patient survival.

PURPOSE: To develop a prognostic test based on a single blood sample obtained at the time of uveal melanoma diagnosis. METHODS: 83 patients diagnosed with posterior uveal melanoma between 1996 and 2000 were included. Peripheral serum samples were obtained at diagnosis and kept at -80 °C until this analysis. Protein profiling of 84 cancer-related proteins was used to screen for potential biomarkers and a prognostic test that stratifies patients into metastatic risk categories was developed (serUM-Px) in a training cohort and then tested in a validation cohort. RESULTS: Low serum leptin levels and high osteopontin levels were found to identify patients with poor prognosis and were therefore selected for inclusion in the final test. In the validation cohort, patient sex and American Joint Committee on Cancer stages were similarly distributed between the low, intermediate, and high metastatic risk categories. With increasing metastatic risk category, patients had shorter metastasis-free- and overall survival, as well as greater cumulative incidence of uveal melanoma-related mortality in competing risk analysis (P = 0.007, 0.018 and 0.029, respectively). In multivariate Cox regression, serUM-Px was an independent predictor of metastasis with tumor size and patient sex as covariates (hazard ratio 3.2, 95% CI 1.5-6.9). CONCLUSIONS: A prognostic test based on a single peripheral venous blood sample at the time of uveal melanoma diagnosis stratifies patients into low, intermediate, and high metastatic risk categories. Prospective validation will facilitate its clinical utility.

Adjuvant melatonin for uveal melanoma (AMUM): protocol for a randomized open-label phase III study.

BACKGROUND: Uveal melanoma is the most common primary intraocular tumor in adults. In Sweden, at least 100 patients are diagnosed with the disease each year. Almost half of the patients develop metastases, with a median survival time of 1 year once metastases are detected. The primary ocular tumor is typically treated with either enucleation or brachytherapy, and no adjuvant treatment is added. Melatonin is an indolamine hormone that has improved survival in previous trials with patients diagnosed with various cancers, including advanced cutaneous melanoma. Side effects have been mild. We aim to investigate if adjuvant treatment with melatonin for 5 years following diagnosis of non-metastasized uveal melanoma can decrease the occurrence of metastases. METHODS: An open-label, prospective, 5-year randomized clinical trial (RCT) will be conducted at St. Erik Eye Hospital. One hundred patients recently diagnosed with non-metastatic uveal melanoma will be randomized to either treatment with adjuvant melatonin 20 mg (4 tablets of 5 mg) at 10 pm for 5 years, or to standard follow-up (control group). The primary outcome measurement is the relative risk for having developed metastases 5 years after randomization. The secondary outcomes are overall survival, risk of developing other cancers, overall survival after detection of metastases, and differences in the occurrence of adverse events (AE) and serious adverse events (SAE) between the groups. DISCUSSION: Melatonin has been found to positively impact our immune system, inhibit angiogenesis, stimulate apoptosis in malignant cells, and act as a potent antioxidant. Previous clinical trials have used similar doses of melatonin with positive results, particularly in advanced stages of cancer. Previous animal and human studies have found the toxicity of the hormone to be low. Considering the potential benefits and limited risks of melatonin, as well as its global availability, it may be a suitable candidate for an adjuvant treatment in patients with uveal melanoma. TRIAL REGISTRATION: Our trial protocol has been approved and registered by the Swedish Medical Products Agency on June 22, 2022 (EudraCT 2022-500,307-49-00). Our trial registration number is NCT05502900, and the date of registration is August 16, 2022.