Neoadjuvant proton beam irradiation followed by transscleral resection of uveal melanoma in 106 cases.

AIMS: To describe results after neoadjuvant proton beam irradiation followed by transscleral resection of large uveal melanoma. METHODS: Retrospective interventional case series, including 106 consecutive patients. Local tumour control, enucleation and metastasis development were assessed with survival curves. Predictors of local recurrence and metastasis were investigated with log-rank testing. RESULTS: Mean follow-up was 3.2 years. Local recurrence occurred in five cases with an estimated risk of 4.2% and 10.4% at 3 and 5 years after treatment, respectively. Enucleation was performed in 10 cases with an estimated risk of 9.2% and 18.4% at 3 and 5 years, respectively. Significant risk factors for local recurrence were not evident. Metastasis was estimated to occur in 28.4% at 3 years and 40.3% at 5 years, correlating with patient's age only (p=0.01). Seventy four patients (69.8%) underwent vitreoretinal surgery for complications after tumour resection. Median visual acuity (VA) was 20/50 at diagnosis and 20/400 in the third year after treatment. VA preservation of 20/200 or better was achieved in 33 patients (31.1%). CONCLUSION: Neoadjuvant proton beam irradiation may help to prevent local recurrence after transscleral resection. Additional vitreoretinal surgery was frequently needed in the presented series. The majority of patients avoided enucleation and functional blindness.

Proton beam radiotherapy of diffuse iris melanoma in 54 patients.

BACKGROUND: Treatment modalities in iris melanoma include excision, plaque radiotherapy, photon or proton beam therapy and enucleation. In extensive tumours and diffuse seeding, radiotherapy remains as an alternative to enucleation. METHODS: This study is a retrospective, consecutive, interventional, single-institutional case series. 54 patients with a diffuse and non-resectable iris melanoma diagnosed from September 1998 to June 2012 were included. A 68-megaelectron volt proton beam was used to treat the anterior segment with a total dose of 4×12.5 cobalt grey equivalent. The cases were evaluated for local tumour control, eye retention, functional outcome and local complications after treatment. RESULTS: During a mean follow-up of 62.7 months (median 54.8 months, range 5.5-159.6 months), local tumour control was achieved in 96.3% of the patients. Cataract and glaucoma were the main complications developing after irradiation in 42.6% and 55.6%, respectively. In 34 of 44 patients (77.3%) who underwent cataract removal, a visual acuity of 20/40 or better following surgery was preserved. Enucleation was performed in three patients. The reason was suspected tumour recurrence in one and glaucoma in two. Hepatic metastasis occurred in one patient. CONCLUSIONS: As an alternative to enucleation, whole anterior segment fractionated proton beam radiotherapy offered excellent local tumour control in diffuse iris melanoma. Given the limited alternatives, the rate of complications appears acceptable and visual function could be preserved in the majority of the patients during follow-up.

Proton beam therapy of parapapillary choroidal melanoma.

PURPOSE: To analyze the functional outcome with regard to the development of visual acuity and radiation-induced optic neuropathy of patients with parapapillary choroidal melanoma treated with proton beam therapy. DESIGN: Clinical case series, retrospective study. METHODS: We evaluated 147 consecutive patients with parapapillary choroidal melanoma who received proton beam therapy as primary tumor treatment at the Helmholtz Center in Berlin from 1998 to 2005. A cumulative dose of 60 Cobalt Gray Equivalents (CGE) was delivered to the tumor and the optic disc received a minimum of 50 CGE. Kaplan-Meier analysis was used to assess ocular outcome and survival rates. For trend analysis of functional development, Wilcoxon-Mann-Whitney U test was used to compare the medians of 2 groups and Kruskal-Wallis test was used in the case of more than 2 groups. RESULTS: The mean follow-up time was 6.5 years (range 0.3-11.7 years). The most common side effects were radiation-induced optic neuropathy, retinopathy, and cataract. The median visual acuity before and within the first year after therapy was 0.4 logMAR (20/50), lapsing to 1.3 logMAR (20/400) after 3 years and 1.4 logMAR (20/500) after 5 years. During follow-up, no light perception developed in 17 cases (11.6%), mostly attributed to radiation-induced retinopathy, optic neuropathy, and secondary glaucoma. Enucleation was carried out in 14 patients (9.5%) because of local recurrence or severe side effects. CONCLUSION: Radiation-induced optic neuropathy is an expected issue after proton beam therapy of parapapillary choroidal melanoma, and visual impairment is common during long-term follow-up, but some useful vision can be preserved in a considerable number of patients.

Cataract formation: a possible complication of intra-arterial chemotherapy for retinoblastoma.

PURPOSE: To delineate and discuss a not yet described possible ocular complication of selective intra-arterial chemotherapy (SIAC) for treatment of retinoblastoma. METHODS: A 23-month-old girl with a large unilateral retinoblastoma was treated with repeated SIAC using 5 mg melphalan between July 2010 and January 2012. Clinical course of tumor and further ocular changes after therapy and histopathologic findings are described. RESULTS: In total, 5 SIAC were performed over a time period of 18 months. After the last SIAC, diffuse dense cataract prevented further funduscopy. In addition, anterior chamber seeding was obvious, leading to the decision to enucleate the eye. Histopathologically, nearly complete regression of the main tumor mass with prominent calcifications, but vital tumor seeding in the vitreous, on the lens surface, on the ciliary body, and in the anterior chamber, was observed. Peculiar vacuolation of the lens epithelial cells, liquefaction of the subepithelial lens fibers, and diffuse small vacuoles within the lens were striking. CONCLUSIONS: Repeated SIAC with melphalan may induce cataract formation, possibly as a toxic effect of the chemotherapeutic to the lens, maybe combined with radiation exposure during fluoroscopy. This ocular complication should be taken into consideration as a limitation of the number of feasible repeated treatments.

Intraoperative localization of tantalum markers for proton beam radiation of choroidal melanoma by an opto-electronic navigation system: a novel technique.

PURPOSE: External beam proton radiation therapy has been used since 1975 to treat choroidal melanoma. For tumor location determination during proton radiation treatment, surgical tantalum clips are registered with image data. This report introduces the intraoperative application of an opto-electronic navigation system to determine with high precision the position of the tantalum markers and their spatial relationship to the tumor and anatomical landmarks. The application of the technique in the first 4 patients is described. METHODS AND MATERIALS: A navigated reference base was attached noninvasively to the eye, and a navigated pointer device was used to record the spatial position of the tantalum markers, the tumor, and anatomical landmarks. Measurement accuracy was assessed on ex vivo porcine eye specimen by repetitive recording of the tantalum marker positions. The method was applied intraoperatively on 4 patients undergoing routine tantalum clip surgery. The spatial position information delivered by the navigation system was compared to the geometric data generated by the EYEPLAN software. RESULTS: In the ex vivo experiments, the maximum repetition error was 0.34 mm. For the intraoperative application, the root mean square error of paired-points matching of the marker positions from the navigation system and from the EYEPLAN software was 0.701-1.25 mm. CONCLUSIONS: Navigation systems are a feasible tool for accurate localization of tantalum markers and anatomic landmarks. They can provide additional geometric information, and therefore have the potential to increase the reliability and accuracy of external beam proton radiation therapy for choroidal melanoma.

Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival.

Hypoxia and its down-stream activated pathways are commonly involved in tumor progression. Genes involved in angiogenesis and glycolysis, i.e. vascular endothelial growth factor (VEGF) and lactase dehydrogenase A (LDHA), respectively, are transcriptionally controlled by the hypoxia inducible factors 1α and 2α (HIF1α and HIF2α). A series of 60 uveal melanomas were immunohistochemically assessed for the expression of VEGF and the phosphorylated/activated form of VEGF receptor 2 (pVEGFR2/KDR), after binding to VEGF. The expression of HIF1α, HIF2α and LDH5 was also investigated. Uveal melanomas overexpressing HIF2α (but not that of HIF1α) were significantly associated with high VEGF (P = 0.005), pVEGFR2/KDR (P < 0.0001) and LDH5 (P ≤ 0.0001). High LDH5 was linked with tumor necrosis (P = 0.01) and increased tumor size (P = 0.03). High VEGF was linked with phosphorylated pVEGFR2/KDR receptors. In univariate analysis high pVEGFR2/KDR receptor expression was significantly related with poor prognosis (P = 0.02). It is concluded that HIF2α plays an important role in the progression of uveal melanomas possibly by promoting the autocrine loop VEGF-pVEGFR2/KDR, and by enhancing the expression of LDHA gene, conferring thus a growth advantage. As pVEGFR2/KDR expression was significantly related with poor prognosis, inhibitors of this receptor may improve the clinical outcome of patients with pVEGFR2/KDR overexpressing uveal melanomas.

Endogenous filamentous fungal endophthalmitis--single-centre survey in patients with acute leukaemia or postallogeneic stem cell transplantation and review of the literature.

Endogenous endophthalmitis caused by filamentous fungi has been infrequently described and its prognosis in immunocompromised patients is largely unknown. Patients were identified through a single-centre database containing patients with endophthalmitis. Cases published since 2002 were reviewed. Clinical and treatment features as well as outcomes were analysed. Six patients were identified from the database. Underlying conditions were haematological malignancies (HM) and/or allogeneic haematopoietic stem cell transplantation (HSCT). Three patients underwent vitrectomy. None of the patients survived and the median time from first evidence of endophthalmitis until death was 33 days. The median time from first evidence of an invasive fungal infection to endophthalmitis was only 5 days. Fifty-six patients were identified from the literature. The majority of these patients underwent vitrectomy (27) or enucleation (10) and received intraocular antifungal therapy (28). Only 13 (23%) of 56 patients experienced an improved vision. The survival rate was 52% in all 56 patients but was significantly less in patients with HM or post-HSCT when compared with all others (26% vs. 70%, respectively; P = 0.003). Endogenous endophthalmitis caused by filamentous fungi is frequently associated with a permanent decrease or loss of vision. This type of fungal infection carries a particular poor prognosis in patients with profound immunosuppression, requiring improved treatment strategies.

Autophagy patterns and prognosis in uveal melanomas.

Autophagy is a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. It has been claimed that, under certain conditions, such a process may be associated with tumor progression. In this study, the autophagic activity was investigated in a series of 99 uveal melanomas after immunohistochemical staining for the autophagy-associated proteins MAP1LC3A and BECN1, most commonly known as LC3A and Beclin 1, respectively. These were assessed in parallel with the hypoxia-inducible factor 1α (HIF1A) and its downstream protein lactate dehydrogenase 5 (composed by five LDHA subunits). Increased autophagic reactivity, detected by MAP1LC3A or BECN1, was associated with intense pigmentation and tumor hypoxia. Uveal melanomas with extensive overexpression of BECN1 or those with underexpression of this protein were associated with the worst prognosis, but the former manifested metastases much earlier than the latter; only 58% of patients with extensive BECN1 overexpression were alive at 4 years, compared with 80% of patients with underexpressed patterns. It is concluded that autophagy is commonly upregulated in uveal melanomas, and may be associated with hypoxia and intense pigmentation. There is a strong association between extensive BECN1 overexpression and early metastases/poor prognosis, and between underexpression of this protein and late metastases/better prognosis.

Transarterial chemoembolization of liver metastases from uveal melanoma after failure of systemic therapy: toxicity and outcome.

The liver is the predominant site of metastases in the majority of patients with uveal melanoma, suggesting the evaluation of regional treatment approaches. Here we report our experience with transarterial chemoembolization (TACE) in uveal melanoma patients with pretreated liver metastases. Twenty-five patients were treated with fotemustine-based or cisplatin-based TACE after treatment failure of systemic therapy between 2003 and 2008 at our institution. Grade III toxicity consisted of gastric ulcer (n=1), fever (n=3), splenic infarction (n=1), and thrombocytopenia (n=1). No grade IV toxicity or catheter-associated complications were observed. Fourteen of 25 patients (56%) had stable disease for at least 2 months and four had partial remission. The median progression-free survival (PFS) was 3 months (95% confidence interval: 2-4 months) and the median overall survival (OS) was 6 months (95% confidence interval: 5-7 months), with 15% of patients alive at 1 year. Both PFS and OS were significantly longer, when pretreatment lactate dehydrogenase was below the two-fold upper limit of normal (n=11): PFS 5 versus 2 months (P<0.001) and OS 11 versus 5 months (P=0.012). All patients with lactate dehydrogenase less than 2xupper limit of normal had a clinically detectable benefit. TACE is well tolerated and effective in pretreated patients with liver metastases from uveal melanoma. TACE should further be evaluated as first-line therapy in prospective randomized clinical trials.

Ten-year results of transscleral resection of large uveal melanomas: local tumour control and metastatic rate.

AIMS: To describe the long-term tumour control and metastatic rate after transscleral resection (TSR) of large uveal melanomas in a single-centre study. METHODS: The sample included 210 patients with large uveal melanomas. Univariate analysis of local tumour control and metastatic risk by Kaplan-Meier survival curves and log-rank testing. Cox proportional HR analysis with forward and backward selection was used to identify independent prognostic factors in patients submitted to TSR of a large uveal melanoma. RESULTS: A residual tumour was diagnosed in 6% of the patients. The 5- and 10-year local tumour recurrence rates were 24% and 32%, respectively. Older age, a large basal tumour diameter, the lack of adjuvant ruthenium brachytherapy and retinal detachment led to a 2.6, 2.4, 4.4 and 7.8 times higher risk of melanoma recurrence, respectively. The 5- and 10-year metastatic rates were 28% and 44%, respectively, and were statistical significantly affected by extraocular spread, tumour thickness and local tumour recurrence. CONCLUSIONS: TSR is an alternative to enucleation for the treatment of large uveal melanomas. Results should improve with better patient selection and more effective methods of adjuvant radiotherapy.

Retinal detachment after phacoemulsification in high myopia: analysis of 2356 cases.

PURPOSE: To determine the incidence of and risk factors for rhegmatogenous retinal detachment (RD) in highly myopic eyes after cataract surgery. SETTING: Two ophthalmology centers in Munich and Ahaus, Germany. METHODS: This retrospective medical chart review comprised 1519 consecutive patients (2356 eyes) with an axial length (AL) greater than 27.0 mm who had planned phacoemulsification and intraocular lens implantation in the capsular bag. In addition, all patients and/or the referring ophthalmologist were contacted regarding the occurrence of RD and laser capsulotomy and the date of occurrence. RESULTS: Follow-up was longer than 24 months in 84% of eyes. Because some cases of RD were questionably related to the preceding cataract surgery, the absolute incidence of postoperative RD was determined as highest (2.2%) and lowest (1.5%). Sex, history of laser capsulotomy, and increasing AL had no statistically significant effect on the rate of RD. The risk for postoperative RD was significantly higher in eyes of younger patients and eyes with preoperative prophylactic treatment for retinal degeneration. CONCLUSIONS: The risk for postoperative RD in this study (1.5% to 2.2%) corresponds to the incidence of pseudophakic RD and idiopathic RD in myopia described in the literature. The risk profile for postoperative RD in this series cannot be distinguished from the risk profile for idiopathic RD in myopia of this extent. The true effect of prophylactic treatment of degenerative lesions remains to be elucidated.

Longterm visual prognosis of patients with ocular Adamantiades-Behçet's disease treated with interferon-alpha-2a.

OBJECTIVE: Relapsing ocular involvement is one of the major manifestations in Adamantiades-Behçet's disease (ABD). Combining systemic corticosteroids with cyclosporin A is currently the treatment of choice. Interferon-alpha (IFN-alpha) has proven to be effective in mucocutaneous ABD and has been reported to improve ocular lesions. We examined the longterm effects of IFN-alpha-2a in a case series of 45 patients with ocular involvement. METHODS: Since 1988, 45 patients (79 eyes of 90 eyes) with ocular involvement in ABD have been treated with IFN-alpha (3 x 6-9 Mio IU per wk). In the initial acute phase of the disease, patients additionally received short-term corticosteroids (oral prednisolone 100 mg/day), tapered to a maintenance dose of 10 mg/day within 2 weeks. IFN-alpha-2a was administered as longterm therapy with a mean duration of 30 months (range 1.1-101 mo). RESULTS: IFN-alpha-2a/prednisolone treatment was effective against vasculitis, optic nerve neuropathy, and iritis. Sixty-four eyes had no recurrence under therapy. To date, recurrences have been seen in 26 eyes under IFN-alpha treatment. Flu-like symptoms were recorded in nearly all patients (n = 43). Further side effects were dose-dependent reversible thrombocytopenia (n = 1), psychosis (n = 3), depression (n = 13), thyroiditis (n = 1), and reversible diffuse alopecia (n = 7). In our series, 92% of all eyes showed stable or improved visual acuity in longterm followup. CONCLUSION: Longterm remission of ocular inflammation can be achieved with the combination of IFN-alpha and low-dose corticosteroids.

Incidence and clinical characteristics of symptomatic choroidal metastasis from lung cancer.

PURPOSE: To determine the clinical characteristics of symptomatic choroidal metastasis (CM) resulting from metastatic lung cancer. METHODS: Twenty-two consecutive patients with symptomatic CM resulting from lung cancer were retrospectively reviewed for ocular findings, medical history and systemic disease. All patients underwent a complete screening for further organ metastasis by computed tomography (CT) and bone scintigraphy. Annual frequency of CM was determined and compared with the incidence predicted from ocular screening studies. RESULTS: In eight of 22 (36%; 95% confidence interval [CI] 17-59) patients, lung cancer had been diagnosed before occurrence of CM, with a median interval of 13 months. In 14 patients lung cancer was detected after diagnosis of CM, with a median interval of 1 month. Choroidal metastasis was unilateral, solitary and located close to or at the posterior pole in the majority of patients. Further organ metastasis with a median number of three affected organ systems was present in 19 (86%; 95% CI 65-97) patients. Median survival after diagnosis of symptomatic CM was 13 months, by contrast with 2 months in lung cancer patients with CM identified in an ocular screening study. The mean number of patients in Berlin diagnosed with symptomatic CM was 1.4 per year, which was two orders of magnitude less than predicted from screening studies. CONCLUSIONS: Symptomatic choroidal lung cancer metastasis in the majority of patients presents as a solitary tumour before diagnosis of lung cancer in patients with multiple organ systems affected by metastatic disease. Contrary to predictions from ocular screening studies, it is a rare clinical entity.

Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment: a prospective randomized multicenter clinical study.

OBJECTIVE: To compare scleral buckling surgery (SB) and primary pars plana vitrectomy (PPV) in rhegmatogenous retinal detachments of medium complexity. DESIGN: Prospective randomized multicenter clinical trial (the Scleral Buckling versus Primary Vitrectomy in Rhegmatogenous Retinal Detachment Study), separated into phakic or aphakic/pseudophakic eyes. Patients were enrolled over a 5-year period. There was 1-year follow up in the study, and the primary outcome was assessed at 1 year. PARTICIPANTS: Forty-five surgeons (25 centers, 5 European countries) recruited 416 phakic and 265 pseudophakic patients. Completion of follow-up was achieved in 93% of the phakic and 89% of the pseudophakic patients. INTERVENTION: Scleral buckling surgery with the potential use of multiple sponges, encircling elements, drainage, and intraocular injections. Primary vitrectomy included 3-port vitrectomy with sulfur hexafluoride-air tamponade; additional SB was left to the surgeon's decision. MAIN OUTCOME MEASURES: Primary study end point: change in best-corrected visual acuity (BCVA); secondary end points: primary and final anatomical success, proliferative vitreoretinopathy, cataract progression, and number of reoperations. RESULTS: In the phakic trial, the mean BCVA change was significantly (P = 0.0005) greater in the SB group (SB, -0.71 logarithm of the minimum angle of resolution [logMAR], standard deviation [SD] 0.68; PPV, -0.56 logMAR, SD 0.76). In the pseudophakic trial, changes in BCVA showed a nonsignificant difference of 0.09 logMAR. In phakic patients, cataract progression was greater in the PPV group (P<0.00005). In the pseudophakic group, the primary anatomical success rate (defined as retinal reattachment without any secondary retina-affecting surgery; SB, 71/133 [53.4%]; PPV, 95/132 [72.0%]) was significantly better (P = 0.0020), and the mean number of retina-affecting secondary surgeries (SB, 0.77, SD 1.08; PPV, 0.43, SD 0.85) was lower (P = 0.0032) in the PPV group. Redetachment rates were 26.3% (SB; 55/209) and 25.1% (PPV; 52/207) in the phakic trial and 39.8% (SB; 53/133) and 20.4% (PPV; 27/132) in the pseudophakic trial. CONCLUSIONS: The study shows a benefit of SB in phakic eyes with respect to BCVA improvement. No difference in BCVA was demonstrated in the pseudophakic trial; based on a better anatomical outcome, we recommend PPV in these patients.

Incidence and clinical characteristics of symptomatic choroidal metastasis from breast cancer.

PURPOSE: To determine the clinical incidence and characteristics of symptomatic choroidal metastasis (CM) in breast cancer. METHODS: Forty-six consecutive patients with CM from breast cancer were retrospectively reviewed in respect of ocular findings, medical history and systemic disease. Clinical incidence of CM was determined and compared with the incidence predicted from prevalence data obtained in ocular screening studies. RESULTS: Choroidal metastasis occurred with a median interval of 42.4 months after diagnosis of breast cancer and was predominantly unilateral (63% patients) and solitary (57% affected eyes). A total of 32% of patients had no history of metastatic tumour disease, but systemic screening with CT and scintigraphy revealed metastatic disease in 100% of patients. A median number of three other organs were affected by metastasis. Median survival from diagnosis of CM was 13.1 months. The mean number of local patients diagnosed with CM was 2.9 per year, which was one order of magnitude less than predicted from clinical screening studies. CONCLUSIONS: Choroidal metastasis occurs in advanced metastatic breast cancer, indicating a grave vital prognosis. In a minority of patients (32%) it is the first sign of metastatic disease. The clinical incidence of CM is far smaller than predicted from prevalence data obtained from ocular screening studies.

Intraocular surgery under systemic interferon-alpha therapy in ocular Adamantiades-Behçet's disease.

BACKGROUND: Adamantiades-Behçet's disease (ABD) is a multi-system disorder with recurrent oral and/or genital ulcerations, skin lesions and ocular involvement. Eye involvement is a common manifestation that affects the patients' quality of life more than any other. Left untreated, it leads to blindness and often to loss of the eye through secondary complications like phthisis or painful glaucoma. In some cases, such as tractional retinal detachment, secondary glaucoma or secondary cataract formation, intraocular surgery is required. METHODS: A prospective study of patients with ocular ABD who underwent intraocular surgery under systemic treatment with interferon-alpha was conducted. From 1999 to 2005, we treated eight eyes from five patients with pars plana vitrectomy (n = 1), phacoemulsification (n = 6) and trabeculectomy (n = 1). The mean follow-up was 49 months (range 5-94 months). RESULTS: Seven out of eight eyes had better visual acuity following surgery. One eye did not benefit from cataract surgery because of optic nerve atrophy. Only one eye showed prolonged inflammation following phacoemulsification. None of the patients showed a recurrence during follow-up. The failure of conservative glaucoma treatment necessitated trabeculectomy in one eye; the patient has had no further recurrence for 6 years under monotherapy with interferon-alpha. CONCLUSION: Interferon-alpha is a potent therapy for Adamantiades-Behçet's disease with ocular involvement. It also provides a basis for safe and reliable surgical interventions. In seven of eight eyes, there was no intra- or peri-operative recurrence of inflammation, which is a common complication after these procedures. Only one eye showed acute and prolonged inflammation following cataract surgery.

Solitary juxtapapillary capillary retinal angioma and von Hippel-Lindau disease.

BACKGROUND: The aim of this study was to evaluate patients with solitary juxtapapillary capillary retinal angioma for the presence of von Hippel-Lindau disease (VHL). METHODS: A retrospective case series of 11 patients, each presenting with a solitary juxtapapillary capillary retinal angioma, was examined. Patients were evaluated for type of angioma, presence of other VHL lesions, and mutations of the VHL gene. RESULTS: Juxtapapillary angioma was exophytic in 7 patients and endophytic in 4 patients. VHL could be diagnosed in 7 patients (64%). Four patients were affected by VHL-related lesions as distinct from ocular angioma. A mutation of the VHL gene could be detected in 6 patients; in 1 of these patients, this mutation of the VHL gene was the only evidence of VHL. There was no difference in the age at manifestation or the type of juxtapapillary angioma in VHL patients compared with non-VHL patients. INTERPRETATION: A solitary juxtapapillary angioma may indicate the presence of VHL in a majority of patients, irrespective of the growth pattern of the tumour. Molecular genetic diagnostics is the most effective method of detecting VHL. Because of the high risk of the presence of other VHL lesions, thorough screening for VHL is mandatory for patients presenting with a solitary juxtapapillary angioma.

Circulating tumor cells as prognostic factor for distant metastases and survival in patients with primary uveal melanoma.

PURPOSE: The aim of this study was to determine in patients with high-risk primary uveal melanoma whether the detection of circulating tumor cells by quantitative reverse transcription-PCR (RT-PCR) is of prognostic relevance. EXPERIMENTAL DESIGN: Blood samples from 110 patients with high-risk nonmetastatic uveal melanoma were collected on the occasion of primary treatment or follow-up visit. mRNA expression of tyrosinase and MelanA/MART1 were analyzed by real-time RT-PCR and compared with clinical data at presentation and follow-up by univariate and multivariate analyses. RESULTS: The RT-PCR assay yielded a positive result in 11 of 110 patients, with five positive findings for tyrosinase and five for MelanA/MART1, and one sample positive for both markers. At a median follow-up of 22 months, 25% of patients had developed metastases and 15% had died. Univariate statistical analysis revealed RT-PCR and the largest tumor diameter as important prognostic factors for the development of metastases and for survival. In a Cox proportional hazard model, RT-PCR result and largest tumor diameter predicted metastases (hazard ratios 7.3 and 2.6, respectively), whereas PCR result, largest tumor diameter, and Karnofsky performance status were significant variables for disease-specific survival (hazard ratios 22.6, 4.7, and 6.0, respectively). Analysis of individual RT-PCR results revealed both tyrosinase and MelanA/MART1 transcripts as independent prognostic factors. CONCLUSION: The presence of tyrosinase or MelanA/MART1 transcripts is an independent prognostic factor in patients with high-risk primary uveal melanoma for subsequent development of metastases and for survival and can be used to select patients for adjuvant treatment studies.