MR-based follow-up after brachytherapy and proton beam therapy in uveal melanoma.

PURPOSE: MRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound. METHODS: Twenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline. RESULTS: Pre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 × 10-3mm2/s increase 12 months after treatment (p = 0.15). CONCLUSION: MR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound.

Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma.

PURPOSE: To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy. DESIGN: Prospective observational, cohort-based, cross-sectional study. PARTICIPANTS: Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM). METHODS: Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins. MAIN OUTCOME MEASURES: Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG. RESULTS: Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients. CONCLUSIONS: A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved.

Prevalence of Myopic Macular Features in Dutch Individuals of European Ancestry With High Myopia.

IMPORTANCE: High myopia incidence and prevalence is increasing worldwide, and the visual burden caused by myopia is expected to rise accordingly. Studies investigating the occurrence of myopic complications in individuals of European ancestry with high myopia are scarce, hampering insights into the frequency of myopic retinal complications in European individuals and their visual burden. OBJECTIVE: To assess the frequency of myopic macular features in individuals of European ancestry with high myopia. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis of the Dutch Myopia Study (MYST) and individuals with high myopia from the Rotterdam Study (RS) included 626 patients with high myopia (spherical equivalent of refractive error [SER] ≤-6 diopters [D] or axial length [AL] ≥26 mm) who underwent an extensive ophthalmic examination including multimodal retinal imaging. In addition to this combination of a population-based cohort study and mix-based high myopia study, a systematic literature review was also performed to compare findings with studies of individuals of Asian ancestry. EXPOSURES: High myopia, age, and AL. MAIN OUTCOMES AND MEASURES: Frequency of myopic macular and optic disc features: tessellated fundus, myopic macular degeneration (MMD), staphyloma, peripapillary intrachoroidal cavitation, peripapillary atrophy (PPA), and "plus" lesions (choroidal neovascularization, Fuchs spot, and lacquer cracks). RESULTS: The mean (SD) SER of the combined study population (MYST and RS) was -9.9 (3.2) D; the mean (SD) age was 51.4 (15.1) years, and 387 (61.8%) were women. The prevalence of MMD was 25.9% and increased with older age (P for trend <.001), lower SER (odds ratio [OR], 0.70; 95% CI, 0.65-0.76; P < .001), and higher AL (OR, 2.53; 95% CI, 2.13-3.06; P < .001). Choroidal neovascularization or Fuchs spot was present in 2.7% (n = 17), both lesions in 0.3% (n = 2), and lacquer cracks in 1.4% (n = 9). Staphyloma, PPA, and MMD were highly prevalent in visual impaired and blind eyes (frequency was 73.9% [20 of 27], 90.5% [19 of 21], and 63.0% [17 of 27] of unilateral blind eyes for MMD, staphyloma, and PPA, respectively). Seven previous studies in Asian populations reported a variable MMD frequency ranging from 8.3% to 64%, but frequencies were similar for comparable risk profiles based on age and SER. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of a highly myopic Dutch population of European ancestry, myopic retinal features were frequent; were associated with age, SER, and AL; and occurred in all visually severely impaired eyes. The absence of treatment options for most of these retinal complications emphasizes the need for effective strategies to prevent high myopia.

Two Late Recurrences of Conjunctival Melanoma.

PURPOSE: To report a patient who developed two late recurrences of conjunctival melanoma (CoM), of which one occurred after orbital exenteration. METHODS: We describe the case of a patient based on clinical and histopathological examination. RESULTS: A 52-year-old patient was treated with local excision and cryotherapy for a CoM with primary acquired melanosis (PAM) near the limbus of the right eye. Twenty-one years later, a recurrence developed in the superior fornix of the same eye in an area with widespread PAM; an orbital exenteration was performed. After another 4 years, a painful nodule developed subcutaneously at the inferior margin of the right orbital socket. Pathology showed a recurrence of CoM with a BRAF V600K mutation, similar to both of the previous lesions (of 25 and 4 years earlier). The nodule was excised without additional therapy. No recurrences or metastases have been observed in the next 2.5 years. The proposed mechanism for the recurrence after surgery could be via dormant tumor cells that have spread prior to the procedure or via residual intraepithelial malignant melanocytes. CONCLUSION: Very late recurrences of CoM are rare but may occur. Our case illustrates the need for long-term awareness of doctors and patients, even after extensive surgical procedures such as orbital exenteration.

Epigenetic regulation identifies RASEF as a tumor-suppressor gene in uveal melanoma.

PURPOSE: Recently, a segregation study in families with uveal and cutaneous melanoma identified 9q21 as a potential locus harboring a tumor-suppressor gene (TSG). One of the genes in this area, RASEF, was then analyzed as a candidate TSG, but lack of point mutations and copy number changes could not confirm this. In this study, the RASEF gene was investigated for potential mutations and gene silencing by promoter methylation in uveal melanoma. METHODS: Eleven uveal melanoma cell lines and 35 primary uveal melanoma samples were screened for mutations in the RASEF gene by high-resolution melting-curve and digestion analysis. Expression of RASEF was determined by real-time RT-PCR in all cell lines and 16 primary uveal melanoma samples, and the methylation status of the promoter of the RASEF gene was analyzed and confirmed by direct sequencing. RESULTS: Mutation screening revealed a known polymorphism (R262C; C-->T) in exon 5 of the RASEF gene that displayed a normal frequency (54%). Of the primary uveal melanomas, 46% presented a heterozygous genotype, and 10 (91%) of 11 cell lines showed a homozygous genotype. Melting-curve analysis indicated loss of heterozygosity in at least two primary tumors. Low RASEF expression in the cell lines and primary tumors correlated with methylation of the RASEF promoter region. Homozygosity and methylation of the RASEF gene in primary tumors were associated with decreased survival (P = 0.019). CONCLUSIONS: Homozygosity, in combination with methylation, appears to be the mechanism targeting RASEF in uveal melanoma, and allelic imbalance at this locus supports a TSG role for RASEF.

Pyrophosphorolysis detects B-RAF mutations in primary uveal melanoma.

PURPOSE: Mutations in the genes that control cell proliferation in cutaneous melanoma are generally uncommon in uveal melanoma. Despite the absence of known activating mutations, the RAF-MEK-ERK, or mitogen-activated protein kinase (MAPK), pathway is usually activated in uveal melanoma. An assay with increased potential to identify mutations is now available, and this study was therefore conducted to reanalyze uveal melanoma cell lines and primary tumors for this mutation. METHODS: Eleven uveal melanoma cell lines and 45 primary uveal melanomas were analyzed for mutations in exon 15 of the B-RAF gene by using pyrophosphorolysis-activated polymerization (PAP). Mutations were validated by sequencing of the PAP product. RESULTS: B-RAF mutations were detected in cell lines OCM-1 and -3 (V600E) and in six primary uveal melanomas. The V600K mutation was detected in one primary uveal melanoma, for which the V600E assay turned out to be sensitive as well. Direct sequencing of the exon 15 PCR product did not reveal the mutations found with the PAP-assay, indicating a low frequency of the mutant allele in primary samples. CONCLUSIONS: Because of the very sensitive PAP technology, B-RAF mutations were found in cell lines and primary uveal melanomas, which suggests that they may occasionally play a role in the activation of the MAPK pathway in uveal melanoma and indicates a higher prevalence of B-RAF mutations in uveal melanoma than was reported earlier. However, the relative scarcity of the B-RAF mutation excludes an elemental role for this mutation in uveal melanoma.

Long-term follow-up of endothelial cell change after Artisan phakic intraocular lens implantation.

OBJECTIVE: To report endothelial cell densities (ECDs) and their correlation to anterior chamber depth (ACD) after implantation of the Artisan intraocular phakic lens. DESIGN: Prospective observational case series. PARTICIPANTS: Three hundred eighteen eyes of 173 myopic patients treated with the Artisan iris-fixated phakic intraocular lens (IOL). METHODS: Eyes with an ACD ranging between 2.89 and 4.5 mm were implanted with the Artisan phakic IOL. Endothelial cell density measurements were performed preoperatively and at each follow-up examination using a noncontact specular microscope. MAIN OUTCOME MEASURES: Endothelial cell density (cells per square millimeter). RESULTS: Follow-up ranged between 1 (82 eyes) and 7 years (13 eyes) (mean, 35.3+/-20.7 [standard deviation] months per eye). After 3 years, there was a significant loss in ECD (P< or =0.03). At 5 years, mean observed endothelial cell loss was 8.3% (5.3% corrected for a natural endothelial cell loss of 0.6% a year). Endothelial cell density loss remained progressive throughout our follow-up period. After 3 years, a significant negative correlation between ACD and endothelial cell loss was revealed (P< or =0.03). Patient age, gender, refractive error, incision size, and side of the eye were not correlated to ECD loss. All corneas remained clear throughout the study. CONCLUSION: After 3 years, a significant ECD loss was revealed. This ECD loss was significantly negatively correlated to the ACD. We therefore suggest that eyes just meeting the minimum ECD requirement have greater ACDs to compensate for possible greater endothelial cell loss and that patients with shallow anterior chambers have higher ECDs. Artisan phakic lens implantation in young eyes narrowly meeting the minimum criteria of endothelial cell density (2,000 cells/mm(2)) and ACD (2.6 mm) should perhaps be reevaluated, due to longer exposure to higher rates of endothelial cell loss.

Tear cytokine and ocular surface alterations following brief passive cigarette smoke exposure.

PURPOSE: To prospectively investigate the effects of acute passive cigarette smoke exposure on the ocular surface and tear film in healthy non-smokers. METHODS: Twelve right eyes of 12 subjects without any ocular diseases were examined before, 5 min, and 24h after 5 min of passive cigarette smoke exposure in a controlled smoke chamber. Tear samples were obtained before, 5 min and 24 h after smoke exposure to detect tear hexanoyl-lysine (HEL), acrolein and inflammatory cytokine concentrations. Tear evaporation rate, DR-1 tear film lipid layer interferometry, tear film break-up time (TBUT), ocular surface fluorescein staining (FS) and Rose Bengal staining (RB), Schirmer I test were performed before, 5 min, and 24h after smoke exposure. Conjunctival impression cytology (IC) and brush cytology (BC) were carried out before and 24h after smoke exposure. RESULTS: Tear evaporation rate, tear lipid spread time, tear film break-up time, and vital staining scores showed significant worsening with passive smoke exposure. Tear HEL and IL-6 concentrations increased significantly 24 h after smoke exposure. Tear acrolein level showed an insignificant increase at 5 min. IC and RT-PCR revealed a significant reduction in goblet cell density, a shift toward higher squamous metaplasia grades and a significant downregulation of MUC5AC mRNA expression at 24 h. CONCLUSION: Even brief passive exposure to cigarette smoke in healthy non-smoker subjects was associated with adverse effects on the ocular surface health as evidenced by an increase of tear inflammatory cytokines, tear lipid peroxidation products and decrease of mucosal defense resulting in tear instability and damage to the ocular surface epithelia.

Increased expression of p73Deltaex2 transcript in uveal melanoma with loss of chromosome 1p.

The loss of chromosome 1p and chromosome 3 is associated with metastatic disease and decreased survival of uveal melanoma (UM) patients. The p53 homologues, p73 and p63, are located on chromosomes 1p and 3q, respectively. Both are able to activate p53 target genes, resulting in growth arrest, apoptosis and differentiation. N-terminally truncated isoforms of these genes may act as dominant negative inhibitors of wild-type p53 and transactivating activity. Although, p53 is frequently involved in several malignancies it does not play a major role in UM. Altered expression has been reported for both p63 and p73 in various malignancies. In this study, fluorescent in-situ hybridization was performed to identify gains or losses of p63 and p73 loci in UM. The expression of the different p63 and p73 isoforms was evaluated by reverse transcriptase PCR followed by Southern blot analysis. Furthermore, the expression pattern of the various DeltaTAp73 transcripts was analysed in seven primary UMs and 11 UM-derived cell lines using isoform-specific real-time PCR. Our results indicated that the isoform p73Deltaex2/3 was abundantly expressed and a relative loss of the p73 locus was associated with the upregulation of p73Deltaex2 and TAp73 transcripts. N-terminal transactivation forms of both p73 and p63 were observed in primary and metastasis-derived cell lines, as well as in primary melanomas, but in only one of the cell lines a DeltaNp63 mRNA transcript was observed. Our data suggest a potential function of p73 deletion transcripts in UM progression.

Ruthenium-106 brachytherapy for iris and iridociliary melanomas.

BACKGROUND AND PURPOSE: To evaluate ruthenium-106 (Ru106) brachytherapy as eye-conserving treatment of iris melanomas (IMs) and iridociliary melanomas (ICMs). MATERIALS AND METHODS: Eighty-eight patients received Ru106 brachytherapy between 2006 and 2016. Primary outcome was local control, and secondary outcomes were metastasis, survival, eye preservation, complications and visual acuity (VA). RESULTS: Overall median follow-up was 36 months. Of 88 patients, 58 (65.9%) had IM and 30 (34.1%) had ICM. ICM were on average larger and more advanced than IM. Local failure-free survival at 3years was 98.9% (SE 1.2%). Metastasis-free survival was 98.2% (SE 1.8%) at 3years; no deaths due to melanoma occurred during follow-up. Eye preservation rate was 97.7%. Treatment-related toxicities were mostly mild and observed in 80.7% of the patients. Common toxicities were worsening of pre-existing or new cataract (51.1%), dry eyes (29.5%) and glaucoma (20.5%). VA was not affected by Ru106 brachytherapy, with only 2.3% having VA <0.33 (low vision) at follow-up. CONCLUSIONS: Ru106 for IM and ICM yielded excellent local control (98.9%) and eye preservation (97.7%). Toxicities were common, but mostly mild and transient. Moreover, Ru106 did not affect visual acuity.

Digital PCR-Based T-cell Quantification-Assisted Deconvolution of the Microenvironment Reveals that Activated Macrophages Drive Tumor Inflammation in Uveal Melanoma.

Uveal melanoma progression can be predicted by gene expression profiles enabling a clear subdivision between tumors with a good (class I) and a poor (class II) prognosis. Poor prognosis uveal melanoma can be subdivided by expression of immune-related genes; however, it is unclear whether this subclassification is justified; therefore, T cells in uveal melanoma specimens were quantified using a digital PCR approach. Absolute T-cell quantification revealed that T-cell influx is present in all uveal melanomas associated with a poor prognosis. However, this infiltrate is only accompanied by differential immune-related gene expression profiles in uveal melanoma with the highest T-cell infiltrate. Molecular deconvolution of the immune profile revealed that a large proportion of the T-cell-related gene expression signature does not originate from lymphocytes but is derived from other immune cells, especially macrophages. Expression of the lymphocyte-homing chemokine CXCL10 by activated macrophages correlated with T-cell infiltration and thereby explains the correlation of T-cell numbers and macrophages. This was validated by in situ analysis of CXCL10 in uveal melanoma tissue with high T-cell counts. Surprisingly, CXCL10 or any of the other genes in the activated macrophage-cluster was correlated with reduced survival due to uveal melanoma metastasis. This effect was independent of the T-cell infiltrate, which reveals a role for activated macrophages in metastasis formation independent of their role in tumor inflammation. IMPLICATIONS: The current report uses an innovative digital PCR method to study the immune environment and demonstrates that absolute T-cell quantification and expression profiles can dissect disparate immune components.

ECCO essential requirements for quality cancer care: Melanoma.

BACKGROUND: ECCO essential requirements for quality cancer care (ERQCC) are explanations and descriptions of challenges, organisation and actions that are necessary to give high-quality care to patients who have a specific type of cancer. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. MELANOMA: ESSENTIAL REQUIREMENTS FOR QUALITY CARE: CONCLUSION: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for melanoma. The ERQCC expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams and specialised treatments is guaranteed to all patients with melanoma.

Ruthenium-106 brachytherapy for choroidal melanoma without transpupillary thermotherapy: Similar efficacy with improved visual outcome.

PURPOSE: To evaluate efficacy and toxicity of two different protocols for eye-conserving treatment of patients with small to intermediate-sized choroidal melanomas; the current ruthenium-106 (Ru106) brachytherapy protocol and the preceding protocol of Ru106-brachytherapy with transpupillary thermotherapy (Ru106/TTT). METHODS AND MATERIALS: Long-term outcomes of 449 consecutive patients, of whom 196 (43.6%) treated using Ru106/TTT and 253 (56.3%) treated using Ru106, were compared in terms of local control, survival, eye preservation and visual outcome. RESULTS: Median follow-up was 82.8 months. Patients in the Ru106-group had smaller, less centrally located tumours and better pre-treatment visual acuity (VA). Five-year cumulative incidence of local failure was 11.2% for Ru106/TTT and 5.2% for Ru106, which was not statistically significant after correction for differences in baseline characteristics (hazard ratio for Ru106 = 0.57, p = 0.14). Cumulative incidence of distant metastases was 11.2 versus 6.2%, and cumulative incidence of cause-specific death was 22.4 versus 5.5% for Ru106/TTT and Ru106 respectively. Enucleation was performed in 9.2 versus 4.0% for Ru106/TTT versus Ru106; 5.1 versus 3.2% for local failure and 2.6 versus 0.8% for complications. At one year of follow-up, significantly more patients had lost useful vision (VA < 0.33) in the Ru106/TTT-group than in the Ru106-group (50.0 versus 24.5%). After two and three years, the differences decreased (54.6 versus 34.0% and 61.7 versus 45.8%, respectively) and lost statistical significance. CONCLUSIONS: Both the current Ru106 and the preceding Ru106/TTT-protocols provided excellent tumour control, cosmetic and functional eye preservation and vital prognosis. The Ru106-protocol yielded prolonged preservation of VA and should be regarded the current standard of treatment.

Isolated (hypoxic) hepatic perfusion with high-dose chemotherapy in patients with unresectable liver metastases of uveal melanoma: results from two experienced centres.

Uveal melanoma patients have a poor survival after the diagnosis of metastatic disease. Isolated hepatic perfusion (IHP) was developed to treat patients with unresectable metastases confined to the liver. This retrospective analysis focuses on treatment characteristics, complications, toxicity and survival after IHP. Patients with uveal melanoma metastases confined to the liver treated with IHP in two experienced hepato-pancreatic-biliary surgery centres (Erasmus MC Cancer Institute and Leiden University Medical Center) were included. Between March 1999 and April 2009, 30 patients were treated with IHP. The duration of surgery was 3.7 h (Erasmus MC Cancer Institute) versus 8.7 h (Leiden University Medical Center) and also the dosage of melphalan differed: 1 mg/kg body weight (n=12) versus a dose of 170-200 mg (n=18) or melphalan (100 mg) combined with oxaliplatin (50 or 100 mg) (n=3). The length of hospital stay was 10 days. Two patients developed occlusion of the hepatic artery and died, respectively, 3 days and 1.5 months after surgery. Progression-free survival was 6 (1-16) months and recurrences occurred mainly in the liver. The median overall survival was 10 (3-50) months. IHP is a potentially beneficial treatment modality resulting in a reasonable overall survival for uveal melanoma patients. Because of considerable morbidity related to the open procedure, a percutaneous system has been developed and is currently being investigated.

Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma.

PURPOSE: To study the effectiveness and acute side effects of fractionated stereotactic radiation therapy (fSRT) for uveal melanoma. METHODS AND MATERIALS: Between 1999 and 2003, 38 patients (21 male, 17 female) were included in a prospective, nonrandomized clinical trial (mean follow-up of 25 months). A total dose of 50 Gy was given in 5 consecutive days. A blinking light and a camera (to monitor the position of the diseased eye) were fixed to a noninvasive relocatable stereotactic frame. Primary end points were local control, best corrected visual acuity, and toxicity at 3, 6, 12, and 24 months, respectively. RESULTS: After 3 months (38 patients), the local control was 100%; after 12 months (32 patients) and 24 months (15 patients), no recurrences were seen. The best corrected visual acuity declined from a mean of 0.21 at diagnosis to 0.06 2 years after therapy. The acute side effects after 3 months were as follows: conjunctival symptoms (10), loss of lashes or hair (6), visual symptoms (5), fatigue (5), dry eye (1), cataract (1), and pain (4). One eye was enucleated at 2 months after fSRT. CONCLUSIONS: Preliminary results demonstrate that fSRT is an effective and safe treatment modality for uveal melanoma with an excellent local control and mild acute side effects. The follow-up should be prolonged to study both long-term local control and late toxicity.

Reduced melanoma-related mortality in uveal melanoma by preenucleation radiotherapy.

BACKGROUND: Radiotherapy of an eye before enucleation, so called preenucleation radiotherapy (PER), of patients with uveal melanoma was initiated to reduce enucleation-induced systemic metastasis. Earlier studies with a short follow-up period have not demonstrated a significant effect on survival. OBJECTIVE: To study the effect of PER on melanoma-related mortality after more than 9 years of follow-up. DESIGN: In a prospective study, 167 patients with uveal melanoma were treated between 1978 and 1992 by irradiation with 800 rad (8 Gy) given in 2 fractions 2 days before enucleation. A group of 108 patients with uveal melanoma treated between 1971 and 1992 by enucleation only in the same hospital served as a historical control group. Patients were followed up until December 2002 or death. RESULTS: Melanoma-related death occurred in 32.3% of the PER-treated group and in 40.7% of the enucleation only group. Mean follow-up was 9.25 years. After 48 months of follow-up, a significant difference in survival became evident in favor of the PER group. The estimated 15-year survival rates for patients with melanoma in the PER group and enucleation only group were 63.7% and 51.0%, respectively. For patients dying of all causes, these percentages were 47.5% and 25.2%, respectively. In both groups, women had a better prognostic outcome than men. CONCLUSION: This study suggests that PER improves long-term survival in patients with uveal melanoma.

Digital PCR validates 8q dosage as prognostic tool in uveal melanoma.

BACKGROUND: Uveal melanoma (UM) development and progression is correlated with specific molecular changes. Recurrent mutations in GNAQ and GNA11 initiate UM development while tumour progression is correlated with monosomy of chromosome 3 and gain of chromosome 8q. Hence, molecular analysis of UM is useful for diagnosis and prognosis. The aim of this study is to evaluate the use of digital PCR (dPCR) for molecular analysis of UM. METHODS: A series of 66 UM was analysed with dPCR for three hotspot mutations in GNAQ/GNA11 with mutation specific probes. The status of chromosomes 3 and 8 were analysed with genomic probes. The results of dPCR analysis were cross-validated with Sanger sequencing, SNP array analysis, and karyotyping. RESULTS: Using dPCR, we were able to reconstitute the molecular profile of 66 enucleated UM. With digital PCR, GNAQ/GNA11 mutations were detected in 60 of the 66 UM. Sanger sequencing revealed three rare variants, and, combined, these assays revealed GNAQ/GNA11 mutations in 95% of UM. Monosomy 3 was present in 43 and chromosome 8 aberrations in 52 of the 66 UM. Survival analysis showed that increasing 8q copy numbers were positively correlated with metastasis risk. CONCLUSION: Molecular analysis with dPCR is fast and sensitive. Just like the recurrent genomic aberrations of chromosome 3 and 8, hotspot mutations in GNAQ and GNA11 are effectively detected in heterogeneous samples. Increased sensitivity contributes to the number of mutations and chromosomal aberrations detected. Moreover, quantification of copy number with dPCR validated 8q dosage as a sensitive prognostic tool in UM, of which implementation in disease prediction models will further improve prognostication.

Dutch Translation and Psychometric Testing of the 9-Item Shared Decision Making Questionnaire (SDM-Q-9) and Shared Decision Making Questionnaire-Physician Version (SDM-Q-Doc) in Primary and Secondary Care.

PURPOSE: The SDM-Q-9 and SDM-Q-Doc measure patient and physician perception of the extent of shared decision making (SDM) during a physician-patient consultation. So far, no self-report instrument for SDM was available in Dutch, and validation of the scales in other languages has been limited. The aim of this study was to translate both scales into Dutch and assess their psychometric characteristics. METHODS: Participants were patients and their treating physicians (general practitioners and medical specialists). Patients (N = 182) rated their consultation using the SDM-Q-9, 43 physicians rated their consultations using the SDM-Q-Doc (N = 201). Acceptability, reliability (internal consistency), and the factorial structure of the instruments were determined. For convergent validity the CPSpost was used. RESULTS: Reliabilities of both scales were high (alpha SDM-Q-9 0.88; SDM-Q-Doc 0.87). The SDM-Q-9 and SDM-Q-Doc total scores correlated as expected with the CPSpost (SDM-Q-9: r = 0.29; SDM-Q-Doc: r = 0.48) and were significantly different between the CPSpost categories, with lowest mean scores when the physician made the decision alone. Principal Component Analyses showed a two-component model for each scale. A confirmatory factor analysis yielded a mediocre, but acceptable, one-factor model, if Item 1 was excluded; for both scales the best indices of fit were obtained for a one-factor solution, if both Items 1 and 9 were excluded. CONCLUSION: The Dutch SDM-Q-9 and SDM-Q-Doc demonstrate good acceptance and reliability; they correlated as expected with the CPSpost and are suitable for use in Dutch primary and specialised care. Although the best model fit was found when excluding Items 1 and 9, we believe these items address important aspects of SDM. Therefore, also based on the coherence with theory and comparability with other studies, we suggest keeping all nine items of the scale. Further research on the SDM-concept in patients and physicians, in different clinical settings and different countries, is necessary to gain a better understanding of the SDM-construct and its measurement.

The RAS-BRAF kinase pathway is not involved in uveal melanoma.

An activating mutation has been recently observed in cutaneous melanoma in a downstream component of RAS-BRAF. The most common mutation, occurring in 80% of cutaneous melanoma samples, is a T-to-A transition resulting in a single amino acid substitution (V599E). Since cutaneous and uveal melanoma (UM) have a common origin, we aimed to establish whether activation of the BRAF proto-oncogene is also an important factor in the development of UM. Exons 11 through 18 of the BRAF gene were screened from 33 primary UMs and 11 UM cell lines. Genomic polymerase chain reaction products were evaluated using single-strand conformation polymorphism analysis, followed by sequencing of aberrant products. The most common mutation, T1796A in the kinase domain of BRAF, was not observed in any of the primary UM samples. This mutation was also absent in 10 of the 11 UM cell lines. In one of the UM cell lines, OCM1, the T1796A mutation was present. We conclude that, in contrast to cutaneous melanoma, BRAF does not appear to be involved in the pathogenesis of UM.

Concomitant choroidal melanoma and non-hodgkin lymphoma in two adult patients: case report.

OBJECTIVE: To report two cases of concomitant choroidal melanoma and intraocular non-Hodgkin lymphoma in two patients. DESIGN: Case report. PARTICIPANTS: Two patients with yellow creamy infiltrates in fundo. INTERVENTION: Both patients had a complete ophthalmologic evaluation and histology was obtained after enucleation of the affected eye. MAIN OUTCOME MEASURES: Histology findings of the enucleated eyes. RESULTS: One patient showed a choroidal melanoma with a primary non-Hodgkin lymphoma located solely in the affected eye. The other patient showed a systemic non-Hodgkin lymphoma with ocular manifestations concomitant with a choroidal melanoma. CONCLUSIONS: In the presence of yellow creamy infiltrates one should include a choroidal lymphoma in the differential diagnosis even if there is another clear pathologic condition. Furthermore in those cases systemic disease should be excluded.