Norbert Bornfeld

Lymphoproliferative lesions of the ocular adnexa: Analysis of 112 cases

OBJECTIVE Lymphoproliferative lesions of the ocular adnexa were analyzed to examine (1) the suitability of the Revised European-American Lymphoma (REAL) classification for the subtyping of the lymphomas in these sites; (2) the predictive value of the REAL classification for the evolution of these tumors; and (3) the frequency and prognostic impact of tumor type, location, proliferation rate (Ki-67 index), p53, CD5 positivity and the presence of monoclonality within these tumors. DESIGN Retrospective review. METHODS The clinical, histomorphologic, immunohistochemical, and molecular biologic (polymerase chain reaction [PCR]) features of lymphoid proliferations of the ocular adnexa were studied. STUDY MATERIALS: The ocular adnexal lymphoproliferative lesions were located as follows: orbit in 52 patients (46%), conjunctiva in 32 patients (29%), eyelid in 23 patients (21%), and caruncle in 5 patients (4%). RESULTS Reactive lymphoid hyperplasia was diagnosed in 12 cases and lymphoma in 99 cases; 1 case remained indeterminate. The five main subtypes of lymphoma according to the REAL classification were extranodal marginal-zone B-cell lymphoma (64%), follicle center lymphoma (10%), diffuse large cell B-cell lymphoma (9%), plasmacytoma (6%), and lymphoplasmocytic lymphoma (5%). Age, gender, and anatomic localization of the lymphomas did not have prognostic significance during a follow-up period of 6 months to 16.5 years (mean, 3.3 years). Extent of disease at time of presentation was the most important clinical prognostic factor: advanced disease correlated with increased risk ratios of having persistent disease at the final follow-up and with lymphoma-related death (P < 0.001). Histomorphologic features and immunohistochemical markers positively correlating with disseminated disease at presentation, stage at final follow-up, and occurrence of lymphoma-related death included cytologic atypia (P < 0.001), MIB-1 proliferation rate (P < 0.001), and tumor cell p53 positivity (P < 0.001). The MIB-1 proliferation rates greater than 20% in extranodal marginal-zone B-cell lymphoma corresponded to at least stage II lymphoma (P < 0.05). CONCLUSION The REAL classification is suitable for the subdivision of the ocular adnexal lymphomas. The MIB-1 proliferation rate and p53 positivity may aid the prediction of disease stage and disease progression, whereas PCR can support the diagnosis and reduce the number of histologically indeterminate lesions.

Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3

Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625.

The possible role of radiofrequency radiation in the development of uveal melanoma.

There are few epidemiologic studies dealing with electromagnetic radiation and uveal melanoma. The majority of these studies are exploratory and are based on job and industry titles only. We conducted a hospital-based and population-based case-control study of uveal melanoma and occupational exposures to different sources of electromagnetic radiation, including radiofrequency radiation. We then pooled these results. We interviewed a total of 118 female and male cases with uveal melanoma and 475 controls matching on sex, age, and study regions. Exposure to radiofrequency-transmitting devices was rated as (a) no radiofrequency radiation exposure, (b) possible exposure to mobile phones, or (c) probable/certain exposure to mobile phones. Exposures were rated independently by two of the authors who did not know case or control status. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found an elevated risk for exposure to radiofrequency-transmitting devices (exposure to radio sets, OR = 3.0, 95% CI = 1.4–6.3; probable/certain exposure to mobile phones, OR = 4.2, 95% CI = 1.2–14.5). Other sources of electromagnetic radiation such as high-voltage lines, electrical machines, complex electrical environments, visual display terminals, or radar units were not associated with uveal melanoma. This is the first study describing an association between radiofrequency radiation exposure and uveal melanoma. Several methodologic limitations prevent our results from providing clear evidence on the hypothesized association.

Long term results after low dose ocular irradiation for choroidal haemangiomas

AIM/BACKGROUND The most common choice of treatment for choroidal haemangiomas (CH) in the past has been the employment of scatter photocoagulation of the surface. This management often requires repetitive treatment or additional invasive management due to massive exudative detachment of the retina. The aim of this retrospective study was to investigate the outcome of the alternative application of low dose external beam irradiation with high energetic photons on these tumours. METHODS A total absorbed dose of 20 Gy was applied to a total of 51 symptomatic eyes: 36 with a circumscribed CH of the posterior pole and 15 with diffuse CH as part of the Sturge–Weber syndrome. The indication for treatment was an exudative retinal detachment including or threatening the fovea. The mean follow up times in each group were 4.5 and 5.3 years, respectively. Out of a group of 33 patients from whom reliable data could be derived, 17 had symptoms lasting longer than 6 months. RESULTS In 23 cases (63.8%) with circumscribed CH complete resolution of the subretinal fluid was achieved; the remaining 13 cases (36.2%) showed residual serous detachment distant to the fovea. The visual acuity improved by two or more lines in 14 cases (38.9%), remained stable in 14 cases (38.9%), and decreased in eight cases (22.2%). The functional success was dependent on the lag duration between onset of first subjective symptoms and treatment. The morphological results with diffuse CH were similar to those of the group of circumscribed CH. The visual acuity (VA) at last examination was improved in seven cases (46.6%); in the remaining eight cases, VA was unchanged or had deteriorated. The poor functional outcome in the latter was mainly attributable to secondary glaucoma. CONCLUSION External beam irradiation is a useful and a low invasive therapeutic option for CH. A successful functional outcome is dependent on the time delay between first onset of symptoms and the beginning of therapy, the formation of subretinal fibrosis, and also on secondary glaucoma in the case of Sturge–Weber syndrome.

Primary vitrectomy without scleral buckling for rhegmatogenous retinal detachment

Abstract• Background: Pars planta vitrectomy has evolved as an alternative method in the treatment of more complicated rhegmatogenous retinal detachments. We report a series of patients who underwent primary vitrectomy with gas tamponade without the use of additional scleral buckling. • Methods: A retrospective study of 53 patients with a follow-up of 6–45 months (mean 17.8 months) was carried out. Preoperative findings included unusual, multiple or large breaks, vitreous haemorrhage, proliferative vitreoretinopathy and bullous retinal detachment. Preoperative visual acuity was between light perception and 1.0, with 30% (16/53) of patients with 0.4 or better. • Results: Retinal reattachment was achieved in 64% of cases (34/53) with one and in 92% (49/53) with one or more operations. Final visual acuity was between light perception and 1.0, with 41% (22/53) of patients with 0.4 or better. Cataract formation occurred in 86% (37/43) of all patients with a clear lens preoperatively. Macular pucker was noted in 11 % (6/53) and postoperative proliferative vitreoretinopathy causing redetachment in 6% (3/53).• Conclusion: With primary vitrectomy, a high final anatomical success rate with few intraoperative complications can be achieved in more complicated forms of rhegmatogenous retinal detachment. The major drawback of the procedure is the high incidence of post-operative cataract formation.

Implantation and Explantation of a Wireless Epiretinal Retina Implant Device: Observations during the EPIRET3 Prospective Clinical Trial

PURPOSE Visual sensations in patients with blindness and retinal degenerations may be restored by electrical stimulation of retinal neurons with implantable microelectrode arrays. A prospective trial was initiated to evaluate the safety and efficacy of a wireless intraocular retinal implant (EPIRET3) in six volunteers with blindness and RP. METHODS The implant is a remotely controlled, fully intraocular wireless device consisting of a receiver and a stimulator module. The stimulator is placed on the retinal surface. Data and energy are transmitted via an inductive link from outside the eye to the implant. Surgery included removal of the lens, vitrectomy, and implantation of the EPIRET3 device through a corneal incision. The clinical outcome after implantation and explantation of the device was determined. The implant was removed after 4 weeks, according to the study protocol. RESULTS Implantation was successful in all six patients. While the anterior part was fixed with transscleral sutures, the stimulating foil was placed onto the posterior pole and fixed with retinal tacks. The implant was well tolerated, causing temporary moderate postoperative inflammation, whereas the position of the implant remained stable until surgical removal. In all cases explantation of the device was performed successfully. Adverse events were a sterile hypopyon effectively treated with steroids and antibiotics in one case and a retinal break in a second case during explantation requiring silicone oil surgery. CONCLUSIONS The EPIRET3 system can be successfully implanted and explanted in patients with blindness and RP. The surgical steps are feasible, and the postoperative follow-up disclosed an acceptable range of adverse events.

Primary vitrectomy for rhegmatogenous retinal detachment: an analysis of 512 cases

BackgroundPrimary pars plana vitrectomy (PPPV) has gained widespread popularity in the treatment of rhegmatogenous retinal detachments (RRD). However, the surgical procedure is still flawed by a significant rate of anatomical and functional failures. The study was conducted to analyse the risk factors for a dissatisfying postoperative outcome.MethodsWe carried out a retrospective study of 512 cases of PPPV with a minimum follow-up of 3 months from one institution over a 9-year period. Preoperatively, 24.8% of patients (127 out of 512) were pseudophakic, 16.4% (84 out of 512) highly myopic, 19.9% (102 out of 512) had preoperative proliferative vitreoretinopathy (PVR) and 14.6% (75 out of 512) had vitreous haemorrhage.ResultsThe follow-up period ranged from 3 to 108 months (median 14.8). Retinal reattachment was achieved with one operation in 70.7% (362 out of 512) and after one or more operations in 97.5% of cases (499 out of 512). The major reasons for redetachments were new retinal breaks, followed by a combination of new breaks and PVR, and PVR without apparent breaks. Postoperative visual acuities of ≥0.1 and ≥0.4 were achieved in 82.8% (424 out of 512) and 48.2% (247 out of 512) respectively. Out of 376 phakic patients at study entry, 66.4% (250 out of 376) underwent cataract surgery either in combination with PPPV or during the postoperative course. Factors that were significantly associated with either anatomical or functional failure included duration of symptoms, low preoperative visual acuity, myopia, amblyopia, hypotony, macular detachment, preoperative PVR, extent of detachment, involvement of inferior quadrants, no detectable breaks, large breaks, breaks posterior to the equator, surgeon, level of surgical training, endocryotherapy, and combined scleral buckling surgery.ConclusionPrimary pars plana vitrectomy is still flawed by a relatively high primary redetachment rate following the initial procedure. The advantages of the technique are a high final reattachment rate and relatively good functional results in a subset of patients with more complicated types of RRD. The risk factors for postoperative failures following PPPV for RRD match to a large extent those following scleral buckling surgery (SBS). Future improvements of the technique will have to focus on modifiable risk factors, such as details of the surgical procedures, surgical training and case selection, to distinguish it from SBS.

Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma

Aim: To investigate the safety and efficacy of photodynamic therapy with verteporfin in patients with choroidal haemangioma. Methods: A non-randomised, prospective clinical investigation of 19 patients with symptomatic circumscribed choroidal haemangioma was performed. Unsuccessful pretreatment (external beam irradiation, laser photocoagulation) was performed in four patients. Patients were included when (1) subretinal exudation involving the fovea, (2) a decrease in visual function, and (3) additional symptoms (for example, metamorphopsia) were present. Photodynamic therapy (PDT) was performed with verteporfin at a concentration of 6 mg/m2 body surface area and a light dose of 100 J/cm2 at 692 nm. Results: The mean follow up time was 10.6 months (2–24 months). The mean number of treatment sessions was 2.15 (range 1–5). Visual acuity improved by at least one line in 73.3%, by at least two lines in 42.1%, was stable in 21.1%, and decreased by one line in 5.2% of the patients. Exudation was completely resolved in 94.8% of the cases. Regression of tumour height was documented in all 19 tumours. Patients receiving any pretreatment before PDT, a visual acuity of 0.1 and less, a history of more than 30 months, and no significant response after the first PDT session, did not show any significant improvement. Cox regression analysis revealed that the number of PDT treatment sessions was inversely associated with the improvement in visual acuity of at least two lines. No recurrences and no local or systemic side effects were observed during the follow up time. Conclusion: PDT using verteporfin is a safe and effective therapy for the treatment of symptomatic choroidal haemangioma even in tumours located beneath the fovea.

Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation

We present cytogenetic data of 12 new cases of uveal melanoma. One case showed a hypotetraploid chromosome number; the others were near-diploid. Underrepresentation or monosomy of chromosome 3 as well as multiplication of chromosomes 8, 8q, or regions of 8q was found in five cases. Both anomalies were observed in three cases. In two of these, multiplication of 8q resulted from isochromosome formation. The smallest multiplicated region seemed to be 8q23-24-->qter. Chromosome 6 anomalies were found in five cases without monosomy 3. Aberrations of chromosome 21 were seen in five cases and found to be the only cytogenetic change in two of them. These anomalies may define a subgroup of uveal melanoma. An anomaly of chromosome 1 was found in three cases. Anomalies of other chromosomes were detected in at most two cases each. Nonclonal centromeric or telomeric associations were seen in one case and different nonclonal ring chromosomes in another. Underrepresentation of chromosome 3 was seen exclusively in tumors with ciliary body involvement, while anomalies of chromosome 6 were detected only in pure choroideal melanomas. A review of the published cytogenetic data of untreated uveal melanoma supports our finding that monosomy 3 is frequently associated with multiplication of 8q but rarely with anomalies of chromosome 6, whereas the opposite is true for tumors with disomy 3, and that isochromosomes are closely associated with monosomy 3. Thus, cells with monosomy 3 seem to predispose to isochromosome formation.

Frequency of asymptomatic choroidal metastasis in patients with disseminated breast cancer: results of a prospective screening programme

AIM To determine the frequency of visually asymptomatic choroidal metastasis in patients with disseminated breast cancer and its dependence on the incidence of metastasis by number and site of other organ metastases. METHODS From January 1995 until April 1997 120 patients irradiated for disseminated breast cancer underwent ophthalmological screening for choroidal metastasis. No patient was symptomatic for ocular disease. 68 out of 120 patients were found to have metastases in one organ and 52 patients had metastases in more than one organ. 80% of the patients had bone metastases, 25% lung metastases, 22% liver metastases, 15% brain metastases, and 22% had metastases in other organs. RESULTS Six patients (5%) were found to have asymptomatic choroidal metastases. Five patients had unilateral and one patient bilateral metastases. 52 patients with more than one involved organ had a significantly higher risk for asymptomatic choroidal metastasis (6/52, 11%) than 68 patients with metastases in only one organ (0/68) (p=0.006). In univariate analysis a significantly higher risk was seen for patients with lung metastases (14% choroidal metastases versus 2% in patients without lung metastases, p=0.03) and for patients with brain metastases (17% choroidal metastases versus 3% in those without brain metastases, p=0.04). CONCLUSION In disseminated breast cancer the incidence of asymptomatic choroidal metastases was 5% and increased to 11% when more than one organ was involved in metastatic spread. Risk factors for choroidal metastases were dissemination of disease in more than one organ and the presence of lung and brain metastases.