Celia Maschi

Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences

PURPOSE To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT). METHODS AND MATERIALS This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model. RESULTS Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Five factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences. CONCLUSION Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies.

Visual Outcomes of Parapapillary Uveal Melanomas Following Proton Beam Therapy

PURPOSE In parapapillary melanoma patients, radiation-induced optic complications are frequent and visual acuity is often compromised. We investigated dose-effect relationships for the optic nerve with respect to visual acuity after proton therapy. METHODS AND MATERIALS Of 5205 patients treated between 1991 and 2014, those treated using computed tomography (CT)-based planning to 52 Gy (prescribed dose, not accounting for relative biologic effectiveness correction of 1.1) in 4 fractions, with minimal 6-month follow-up and documented initial and last visual acuity, were included. Deterioration of ≥0.3 logMAR between initial and last visual acuity results was reported. RESULTS A total of 865 consecutive patients were included. Median follow-up was 69 months, mean age was 61.7 years, tumor abutted the papilla in 35.1% of patients, and tumor-to-fovea distance was ≤3 mm in 74.2% of patients. Five-year relapse-free survival rate was 92.7%. Visual acuity was ≥20/200 in 72.6% of patients initially and 47.2% at last follow-up. A wedge filter was used in 47.8% of the patients, with a positive impact on vision and no impact on relapse. Glaucoma, radiation-induced optic neuropathy, maculopathy were reported in 17.9%, 47.5%, and 33.6% of patients, respectively. On multivariate analysis, age, diabetes, thickness, initial visual acuity and percentage of macula receiving 26 Gy were predictive of visual acuity. Furthermore, patients irradiated to ≥80% of their papilla had better visual acuity when limiting the 50% (30-Gy) and 20% (12-Gy) isodoses to ≤2 mm and 6 mm of optic nerve length, respectively. CONCLUSIONS A personalized proton therapy plan with optic nerve and macular sparing can be used efficiently with good oncological and functional results in parapapillary melanoma patients.

Treatment of Neovascular Glaucoma after Proton Therapy for Uveal Melanomas with Ranibizumab Injection: Preliminary Results

A last-chance intravitreal injection of ranibizumab was administered alone or in combination with cryotherapy before enucleation for 14 melanomas with neovascular glaucoma (NVG) after proton therapy. These patients were uncontrolled despite medical treatment and experienced pain. All of our patients had a minimum of 4 months of follow-up (ranging from 4 to 22 months). In all of the cases, the neovessels disappeared, and the intra-ocular pressure was normal for 11 out of the 14 patients with or without antiglaucoma drops. No patient experienced pain after the first injection. Tumour regression increased in some patients. However, thus far, the number of cases has been too small to perform any statistical analyses. Although very promising, our results are only preliminary.

Mechanisms of phosphenes in irradiated patients

Anomalous visual perceptions have been reported in various diseases of the retina and visual pathways or can be experienced under specific conditions in healthy individuals. Phosphenes are perceptions of light in the absence of ambient light, occurring independently of the physiological and classical photonic stimulation of the retina. They are a frequent symptom in patients irradiated in the region of the central nervous system (CNS), head and neck and the eyes. Phosphenes have historically been attributed to complex physical phenomena such as Cherenkov radiation. While phosphenes are related to Cherenkov radiation under high energy photon/electron irradiation conditions, physical phenomena are unlikely to be responsible for light flashes at energies used for ocular proton therapy. Phosphenes may involve a direct role for ocular photoreceptors and possible interactions between cones and rods. Other mechanisms involving the retinal ganglion cells or ultraweak biophoton emission and rhodopsin bleaching after exposure to free radicals are also likely to be involved. Despite their frequency as shown in our preliminary observations, phosphenes have been underreported probably because their mechanism and impact are poorly understood. Recently, phosphenes have been used to restore the vision and whether they might predict vision loss after therapeutic irradiation is a current field of investigation. We have reviewed and also investigated here the mechanisms related to the occurrence of phosphenes in irradiated patients and especially in patients irradiated by proton therapy for ocular tumors.Anomalous visual perceptions have been reported in various diseases of the retina and visual pathways or can be experienced under specific conditions in healthy individuals. Phosphenes are perceptions of light in the absence of ambient light, occurring independently of the physiological and classical photonic stimulation of the retina. They are a frequent symptom in patients irradiated in the region of the central nervous system (CNS), head and neck and the eyes. Phosphenes have historically been attributed to complex physical phenomena such as Cherenkov radiation. While phosphenes are related to Cherenkov radiation under high energy photon/electron irradiation conditions, physical phenomena are unlikely to be responsible for light flashes at energies used for ocular proton therapy. Phosphenes may involve a direct role for ocular photoreceptors and possible interactions between cones and rods. Other mechanisms involving the retinal ganglion cells or ultraweak biophoton emission and rhodopsin bleaching after exposure to free radicals are also likely to be involved. Despite their frequency as shown in our preliminary observations, phosphenes have been underreported probably because their mechanism and impact are poorly understood. Recently, phosphenes have been used to restore the vision and whether they might predict vision loss after therapeutic irradiation is a current field of investigation. We have reviewed and also investigated here the mechanisms related to the occurrence of phosphenes in irradiated patients and especially in patients irradiated by proton therapy for ocular tumors.

Métastases en des sites anatomiques raresMetastasis to unusual sites

Metastases are responsible for the majority of deaths from solid cancers. Metastatic phenomenon, complex, is a multi-step process where interactions between cells and with the microenvironment are essential. The organ tropism, that is the propensity of a cancer to metastasize to specific organs, can be explained by several mechanisms that we have described. Apart from the usual metastases, unusual sites can appear with heterogeneous clinical presentations. We describe known to date mechanisms that can explain these unusual metastasis. A summary of these locations has been realized. A rare location should always be considered in front of any atypical symptom.

Métastases en des sites anatomiques rares

Metastases are responsible for the majority of deaths from solid cancers. Metastatic phenomenon, complex, is a multi-step process where interactions between cells and with the microenvironment are essential. The organ tropism, that is the propensity of a cancer to metastasize to specific organs, can be explained by several mechanisms that we have described. Apart from the usual metastases, unusual sites can appear with heterogeneous clinical presentations. We describe known to date mechanisms that can explain these unusual metastasis. A summary of these locations has been realized. A rare location should always be considered in front of any atypical symptom.

Cataract Avoidance With Proton Therapy in Ocular Melanomas

Purpose The lens is a radiosensitive organ. Any dose of cephalic irradiation can give rise to radiation-induced cataracts. Contrary to other forms of radiotherapy, proton therapy (PT) can spare all or part of the lens due to accurate dose deposition. We investigated whether a lens-sparing approach was relevant to avoid cataracts in uveal melanoma patients. Methods Patients were referred for PT from onco-ophthalmologists of private and academic institutions. Patients without preexisting cataracts or implants were entered in a prospective database. Dose thresholds responsible for cataracts were investigated in volumes of lens or lens periphery. Lens opacifications and de novo vision-impairing cataracts (VICs) had biannual follow up by ophthalmologists blinded to lens dose. Correlations between dose-volume relationships and VICs were assessed using univariate/multivariate regressions. Results Between 1991 and 2015, 1696 uveal melanoma patients were consecutively treated with PT. After a median follow up of 48 months, 14.4% and 8.7% of patients had cataracts and VIC within median times of 19 and 28 months, respectively. Median values of mean lens and lens periphery doses were 1.1 (radiobiologically effective [RBE] dose in photon-equivalent grays [GyRBE]) and 6.5 GyRBE, respectively. The lens received no dose in 25% of the patients. At an irradiated lens volume of ≤5%, there was no significantly increased risk for VIC below a dose of 10 GyRBE. Conclusions A lens-sparing approach is feasible and results not only in reduced need for cataract surgery but also in better fundus-based tumor control. Reassessment of radioprotection rules for lens dose thresholds may follow.

Use of hydroxychloroquine in corticodependent and recurrent scleritis.

Dear Editor, Scleritis is a painful inflammatory disease associated with an underlying systemic process in 54% of cases [1]. The control of inflammation often requires systemic glucocorticosteroid therapy and, in up to 25% of cases [2], systemic immunosuppressive therapy is used. Immunosuppressive drugs make it possible to reduce steroid use, but present their own potentially important side-effects. We present hereafter one case of a successful support of a corticodependent scleritis treated with hydroxychloroquine. A 40-year-old man presented with a new episode of anterior nodular scleritis in his left eye. The patient reported a history of recurrent episodes of anterior nodular scleritis (two previous episodes) and posterior scleritis (one episode) in the same eye. At presentation, left visual acuity was 10/10. Slit-lamp examination revealed a nodular redness in the nasal sclera without any peripheral ulcerative keratitis. There was no sign of anterior, intermediate, or posterior uveitis. General physical examination was normal. The patient weighed 67 kg. His height was 174 cm. There wasn’t any clinical sign of vasculitis. A diagnostic evaluation for Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus and other rheumatic or infectious disorders associated with scleritis was initiated: CrP was 3.5 mg/l, ESR was 13/26 mm n. W. and platelet count was 250,000/mm3. The patient had a negative ANCA test result, and there were no circulating immune complexes. The scleritis was difficult to control with topical steroids alone. Oral glucocorticosteroids (prednisone 60 mg/day) were rapidly started. Thanks to this regiment, pain and inflammatory control were achieved. However, the patient developed a secondary uncontrolled hyperglycemia. Therefore, oral glucocorticosteroids were tapered over a 6-month period. The patients scleritis relapsed at 4 mg/day prednisone. Prednisone was increased to 30 mg/day until inflammatory quiescence. Daily dosage was then slowly tapered. At 5 mg/day, the patient presented with a little redness and pain on the nasal side of his left eye. Decision was made to add hydroxychloroquine twice a day as an adjuvant immunosuppressive therapy. After 2 months, the glucocorticosteroid dose was 2 mg/day. Hydroxychloroquine was lowered to one per day because of gastric intolerance. Three months later, the patient was no longer on glucocorticosteroids. Hydroxychloroquine was switched to chloroquine (Nivaquine®), which is generally associated with fewer side-effects. Two years later, inflammatory quiescence is still maintained. Chloroquine treatment is perfectly well-tolerated without any induced side-effects. Recurrent scleritis episodes are often linked to immunologic disorders, and expose the patients to pain, visual impairment, and corneal and intra-ocular complications. They usually respond to oral glucocorticosteroid, but related side-effects or corticodependence can occur [2, 3]. Steroidsparing agents are then needed such as methotrexate [4] azathioprine [5], ciclosporine A [6], mycophenolic acid mycofenolate [7], NSAR [1], infliximab [8] and now rituximab [9]. These therapies are efficient but require a close C. Maschi (*) : P. Gastaud : S. Baillif Service Ophtalmologie, Hopital Saint Roch, CHU-Nice, 5, rue Pierre Dévoluy, Nice 06000, France e-mail: maschi.c@chu-nice.fr