Rumana N. Hussain

Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach

Background Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow. Methods Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications. Results The cohort comprised 232 patients with UM having a median age of 59 years (range, 25–82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1–20.8) and tumour height was 3.4 mm (range, 0.7–10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery. Conclusions Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases. Precis Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively.

Prognostic Biopsy of Choroidal Melanoma after Proton Beam Radiation Therapy

Figure 1. Metastatic mortality according to chromosome 3 status. Choroidal melanoma is fatal in almost 50% of patients. A large majority of patients with this cancer want to know their prognosis, even if there is no effective treatment for metastatic disease. Those with a good prognosis are reassured. Special measures, such as more intensive surveillance, can be targeted at high-risk patients, who either may ultimately undergo liver surgery or be given systemic or localized hepatic chemotherapy. Metastatic disease develops almost exclusively in patients whose tumor shows chromosome 3 loss, with or without changes in chromosome 8q, and/or a class 2 gene expression profile. Genetic tumor analysis greatly enhances estimation of survival probability, especially if clinical and histologic predictors are included in the multivariate analysis. Most patients are treated with proton beam radiotherapy (PBR) or plaque brachytherapy, so that biopsy is required for prognostication. Complications, such as vitreous hemorrhage, can complicate the radiotherapy treatment; furthermore, there are concerns that the biopsy might seed the tumor to other parts of the eye and extraocularly. For these reasons, for several years we have offered patients prognostic tumor biopsy after radiotherapy. The aim of this study was to correlate metastatic mortality with multiplex ligationdependent probe amplification (MLPA) or microsatellite analysis (MSA) performed on choroidal melanoma biopsy samples obtained soon after completion of PBR. Patients were included if they resided in the UK and had a successful transretinal biopsy of choroidal melanoma within 1 month of PBR completion. The National Health Service Cancer Registry is populated with every patient with a staged tumor diagnosis; the registry is commissioned to report to the referring oncology unit at the time of death, along with the death certificate issued by local physicians, and it is from this registry that survival data were obtained. Proton beam radiotherapy (56 Gy over 4 consecutive days) was administered at the Clatterbridge Cancer Center, located 14 km from the Liverpool Ocular Oncology Center, where all ophthalmic care was delivered. Biopsy was performed as soon as possible after PBR. Tumor samples were obtained with a 25-gauge vitreous cutter, the cytospin stained with May Grunewald Giemsa, and assessed histologically by an experienced ophthalmic pathologist (S.E.C.) for cell content and type. DNA extraction, DNA quality assessment and quantification and identification of chromosome aberrations by MLPA or MSA were performed as described previously. This study was conducted in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice Guidelines. The service evaluation was approved by the Royal Liverpool and Broadgreen University Hospital Trust (Reference number: TA0517). The study cohort included 102 patients, who comprised 47 females and 55 males with a mean age of 57.3 years (range, 25e82; Table 1, available at www.aaojournal.org). The tumors had a mean largest basal diameter 12.0 mm (range, 5.4e19.3) and a median tumor thickness of 3.5 mm (range, 0.9e10.3). Twentyfour tumors involved the ciliary body and 8 extended to anterior chamber and angle. Tumor biopsy was performed on the last day of PBR treatment in 70 patients (69%), after 1 through 7 days in 28 patients, and 8 through 20 days in 4 patients. Diagnosis of melanoma was confirmed cytologically in all cases (Fig 2, available at www.aaojournal.org). Genetic analysis was performed by MLPA in 74 patients and MSA in 28 cases. Chromosomal analysis demonstrated monosomy 3 in 39 (38%) and disomy 3 in 63 (62%). Other chromosomal alterations included chr.6p gain in 49%, chr.8q gain in 40%, and chr.1p loss in 16%. The median follow-up was 3.6 years (range, 0.3e8.6). By study close, 12 patients died (11.8%), 9 from metastatic disease. Actuarial rates of metastatic death at 7 years were 0% in disomy 3 patients and 35% in monosomy 3 patients (Fig 1). To our knowledge, this is the largest study yet performed on genetic typing of choroidal melanoma samples obtained after radiotherapy. We previously compared preradiotherapy and postradiotherapy MLPA/MSA data from the same tumors in 4 patients, showing concordance in all tumors. Similarly, array CGH of 5 tumors preradiotherapy and postradiotherapy showed no change in chromosome 3 status because of treatment. Dogrusöz et al performed karyotyping and/or fluorescence in-situ hybridization in 36 enucleated eyes with previously irradiated choroidal melanoma and found frequent, complex and extensive chromosomal abnormalities in irradiated tumors. Their genetic studies were performed many months after radiotherapy, when tumors had developed necrosis and inflammation and when clonal expansion of any surviving melanoma cells may have occurred; therefore, their results cannot be extrapolated to our tumors, which were biopsied within a month of PBR.

Photodynamic therapy as initial treatment for small choroidal melanomas

PURPOSE To evaluate Verteporfin photodynamic therapy (PDT) as primary treatment for small, posterior choroidal melanoma. DESIGN Retrospective cohort review. SUBJECTS, PARTICIPANTS AND CONTROLS Retrospective case note review of 20 patients with small juxtapapillary and juxtafoveal choroidal melanomas treated with PDT at the Liverpool Ocular Oncology Clinic. METHODS Patient and tumour characteristics, PDT session details, visual acuity and B-scan ultrasonography measurements as well as colour fundus photographs at each examination were collated and analysed. MAIN OUTCOME MEASURES Local tumour control and Best Corrected Visual Acuity (BCVA). RESULTS The 20 patients (14 male, 6 female) had a mean age of 61.2 years (range, 40-85) and were treated between 2001 and 2012. Seven tumours were amelanotic, while 13 were pigmented. Of 20 melanomas, 11 (55%) showed complete regression on B-scan ultrasonography and colour photography; five (25%) showed partial regression; four (20%) remained unchanged and two (10%) showed further growth, for which alternative standard treatment was required. Baseline BCVA was 0.1 logMAR (mean; range 0.0-0.6) compared to a post-PDT BCVA of 0.4 logMAR (mean; range -0.2 to 1.7) over a follow-up of 60.0 months (mean; range 25-156 months). CONCLUSIONS PDT can induce tumour regression in a significant proportion of small, posterior, choroidal melanomas but is less reliable than other forms of therapy. It may have a role in patients with special visual requirements if they accept the increased risk of treatment failure requiring radiotherapy.

Verteporfin photodynamic therapy for the treatment of sporadic retinal capillary haemangioblastoma.

PURPOSE To assess the effectivity of photodynamic therapy (PDT) for the treatment of retinal capillary haemangiomas METHOD Retrospective case note analysis of all patients with retinal angiomas treated with PDT between 2003 and 2010. RESULTS Six eyes of 6 patients (3 male, 3 female) with a mean age of 50 years (range, 23-78) were identified in our database. The follow up period was between 24 and 60 months (mean, 36). Tumor regression was evident in two patients; three tumors showed no demonstrable response to treatment on ophthalmoscopy or ultrasonography and one tumor progressed despite PDT and subsequent cryotherapy. One patient developed retinal neovascularisations following a period of inattendence to our clinic. Visual acuity improved in two patients following PDT, deteriorated in three patients and remained stable in a one patient. CONCLUSION The response of retinal haemangioblastomas to PDT is inconsistent. Other treatment modalities ought to be utilized for peripheral lesions, however PDT may be tried in juxtapapillary lesions where radiotherapy or cryotherapy is likely to result in concurrent visual loss.

In vitro experiment to elucidate the mechanism of the ‘soft shell technique’ for preventing subretinal migration of perfluoro-octane

Aim Perfluorocarbon liquid (PFCL) can migrate into subretinal space in detached and stiffened retina with open holes during vitreoretinal surgery. An innovative ‘soft shell’ technique was introduced to reduce the complication using hyaluronate (HA) to ‘cover’ the retinal hole. This study aims to study the effectiveness of this technique in vitro. Methods Ex vivo porcine retina was mounted on a transwell insert. Beneath the retina was an aqueous solution. Two retinal holes were made using needle punctures. One of the two retinal holes was covered with HA. Perfluoro-n-octane (PFO) was added above the retina incrementally using a syringe pump. The height of PFO required to cause the migration of PFO through the retinal holes was measured. The ‘pendant drop’ method was carried out to measure the interfacial tensions between the PFO and aqueous, and between PFO and four different concentrations of HA solution. Results A statistically higher PFO level was required to cause the migration of PFO through the retinal hole with HA coating than without HA coating (Tobit regression with p<0.05). The use of HA was associated with 2.39-fold increase in hydrostatic pressure before the collapse of the PFO interface at the retinal holes. The interfacial tension between PFO and HA solution with concentrations of 0.05%, 0.25%, 0.5% and 1% were 54.2±0.6, 55.3±0.6, 59.5±1.5 and 68.3±1.3 mN/m, respectively (mean±SD). The interfacial tension between PFO and aqueous with 1% HA coating (68.3±1.3 mN/m) was significantly higher than that without (37.4±3.4 mN/m) (p<0.05). Conclusions The interfacial tension between HA and PFO is higher than that between aqueous and PFO. This is a plausible physical explanation of how the ‘soft shell’ technique might work to prevent subretinal migration of PFCL.

Verteporfin photodynamic therapy for the treatment of choroidal haemangioma associated with Sturge-Weber syndrome.

PURPOSE Choroidal haemangiomas associated with Sturge Weber syndrome most commonly affect the posterior pole and consequently result in amblyopia. Treatment is often challenging but usually unwarranted unless there is visual deterioration caused by exudative or neovascular complications. The main objective is to demonstrate the effectivity of photodynamic therapy in this context. DESIGN AND METHODS Retrospective analysis of prospectively collected data regarding verteporfin photodynamic therapy (PDT) in the treatment of patients with choroidal haemangiomas associated with Sturge Weber syndrome. RESULTS Six patients (4 male, 2 female) with a median age of 28 years (range, 23-67) had a mean tumour belly diameter of 12.2mm (range, 9-16.8). There was regression of the tumour in all cases, albeit after 3 treatments in a single case. The exudative retinal detachment resolved in 2 out of 3 patients. Visual outcome improved in 3 patients, remaining poor but stable in the other three, due to pre-existing amblyopia. CONCLUSIONS PDT is an effective and safe treatment for patients with choroidal haemangioma associated with Sturge-Weber syndrome.

Polydimethyl Siloxane as an Internal Tamponade for Vitreoretinal Surgery

Purpose: To report the efficacy and safety of polydimethyl siloxane (Siluron Xtra®) as an internal tamponade. Design: Audit and adverse event screening of procedures (March 2014-2015). Methods: Patients who had undergone vitreoretinal procedures with Siluron Xtra® tamponade were retrospectively analysed with respect to anatomical outcome, visual outcomes, and perioperative complications, in particular intraocular pressure. Inclusion Criteria: all patients who had undergone Siluron Xtra® tamponade. Exclusion Criteria: No cases were excluded; however, there were no paediatric or pregnant patients within this cohort. All vitreoretinal cases were included, including retinal detachments, but also trauma, endophthalmitis, and intraocular foreign bodies. Results: Twenty-eight patients had polydimethyl siloxane as an intraocular tamponade; 24 retinal detachments (83% complicated by proliferative vitreoretinopathy ≥grade C), 12 had previous failed surgery, and 4 had procedures for intraocular lymphoma, endophthalmitis, or trauma. Follow-up was 14-20 months, and mean duration of tamponade was 6.8 months (3-12 months). Anatomical success was 79% after polydimethyl siloxane injection, 58% 3 months following removal (14/24), 5 remain with long-term tamponade, and 5 with redetachment under tamponade required further intervention. Five required topical anti-glaucomatous agents, and 1 following trauma required glaucoma surgery. Cataract developed in 3/6 phakic patients, and visible emulsification occurred in a single patient. Conclusion: Polydimethyl siloxane seems to be an acceptable alternative tamponade agent for the management of complex retinal detachments with comparable anatomical success and comparable rates of raised intraocular pressure to other low-viscosity silicone oil agents, but more importantly, with a lower rate of emulsified oil-related complications, which is important particularly for cases requiring long-term tamponade.

The Use of a Polyetheretherketone (peek) Implant to Reconstruct the Midface Region.

A good functional and cosmetic result after midfacial reconstructive surgical procedures is of paramount importance. We describe the use of a Polyetheretherketone (PEEK) implant to reconstruct the midface area, after extensive mutilating surgery due to an infiltrative skin tumor. A 67-year-old male patient underwent multiple and extensive surgeries to the left cheek and lower lid because of a highly aggressive metatypical basal cell carcinoma. Complete resection of the recurrent tumor resulted in a cosmetically evident absent cheek contour and facial deformity. The PEEK implant was used to restore the bony cheek contour, with good aesthetic outcome and restoration of the facial symmetry. Preoperative planning with 3-dimensional CT scans allow for customization of the implant. PEEK implants have been scantily described in the periorbital region. The material has a very low reported morbidity and also has the advantage of improving intraoperative predictability and reducing surgical time in complex reconstructive procedures.