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Background: The choice of a suitable intraocular lens (IOL) and the calculation of postoperative refractive error is one of the most intriguing challenges of modern cataract surgery. This clinical trial compared the accuracy of two laser-assisted optical biometers, the IOL-Master 500 (Carl Zeiss Meditec, Jena, Germany) and the Lenstar LS900 (Haag-Streit, Bern, Switzerland) without taking the postoperative results into consideration., Material and Methods: Artificial lenses (Alcon Pharma) for 114 eyes of 67 patients were measured using both biometric instruments. The deviation of the presumed refractive error from the desired preoperative refractive target was calculated with different formulae (i.e. SRK/T, HofferQ, Haigis and SRKII) based on the intraoperatively chosen IOL. The differences between both instruments were compared using Student's t-test., Results: Using the SRKII formula a mean difference between the IOL-Master and the Lenstar of 0.07 D (p = 0.002) was calculated for 95 eyes, SRK/T used on 47 eyes showed a difference of 0.04 D (p = 0.27), HofferQ measured 0.09 D (p = 0.0001) between both instruments for 88 eyes and the Haigis formula also showed a mean difference of 0.09 D (p = 0.001) based on the calculations of 106 eyes., Conclusion: Both instruments gave reproducible and accurate results with only a small deviation from the desired target refraction and can therefore be considered as comparable for the calculation of IOLs. Statistically significant differences in the results were found when using the SRKII, HofferQ and Haigis formulae but these were too low to have any influence on the choice of IOL to be implanted.

Purpose: To evaluate the effect of intravitreal injection of N-methyl-D-aspartate (NMDA) on brain-derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide-38 (PACAP-38), vasoactive intestinal peptide (VIP) and the VIP-associated glial protein activity-dependent neuroprotective protein (ADNP) in the rat retina. These elements have well-documented neuroprotective properties and may thus be integrated in endogenous neuroprotective mechanisms in the retina which break down in NMDA excitotoxicity., Methods: A volume of 2 μl of 100 nmol NMDA was intravitreally injected into one eye of rats, the untreated eye served as a control. Time-dependent effects of NMDA on VIP, PACAP-38 and BDNF were detected by radioimmunoassay and ELISA, and the effect on the expression of VIP, PACAP-38 and ADNP was evaluated by quantitative RT-PCR 20 days after NMDA injection. Topical flunarizine served to find out whether the effect of NMDA is counteracted., Results: Compared to PACAP-38, VIP levels significantly decreased on days 1, 7, 14, 28 and 56 after NMDA injection indicating that VIPergic cells are more vulnerable than PACAP-38-expressing cells. The expression of VIP and ADNP but not of PACAP-38 was found to be reduced, and application of topical flunarizine counteracted the decrease of VIP. BDNF levels significantly increased after days 1 and 3., Conclusion: The early upregulation of BDNF seems to act neuroprotectively and leads to a delay of ganglion cell loss. Although there is no direct evidence, the decrease of VIP and ADNP - the consequence of the presence of NMDA receptors on these peptide-expressing cells - might contribute to the breakdown of endogenous neuroprotective mechanisms given that the decrease of the VIP-related ADNP runs in parallel with the decrease of VIP. Activating and maintaining these mechanisms must be the primary aim in the therapy of diseases with retinal neuronal degeneration., (© 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.)

There are multiple possible intraocular manifestations in patients with systemic neoplasms. At first line there are uveal, retinal and vitreous metastases from carcinomas, melanomas and lymphomas. In patients with von Hippel Lindau syndrome or familiar adenomatous polyposis coli (FAP), Gardner or Turcot syndromes, fundus examinations can help in the primary diagnosis and thereby facilitate the early detection of systemic neoplasms such as cerebral and spinal haemangioblastoma, kidney or bowel cancer. Furthermore there are rare ocular paraneoplastic syndromes such as the cancer- or melanoma-associated retinopathies (CAR/MAR), the paraneoplastic optic neuropathy (PON) and the bilateral diffuse melanocytic proliferation (BDUMP) that develop secondary to systemic malignancies and can be the primary manifestation., (© Georg Thieme Verlag KG Stuttgart · New York.)

The aim of the study was to investigate the presence and distribution of PE-11, a peptide derived from chromogranin B, in the rat eye. For this purpose, newborn rats were injected with a single dosage of 50mg/kg capsaicin subcutaneously under the neck fold and after three months, particular eye tissues were dissected and the concentration of PE-11-like immunoreactivity was determined by radioimmunoassay. Furthermore, PE-11-like immunoreactivities were characterized in an extract of the rat eye by reversed phase HPLC. Then, the distribution pattern of PE-11 was investigated in the rat eye and rat trigeminal ganglion by immunofluorescence. As a result, PE-11 was present in each tissue of the rat eye and capsaicin pretreatment led to a 88.05% (±7.07) and a 64.26% (±14.17) decrease of the levels of PE-11 in the cornea and choroid/sclera, respectively, and to a complete loss in the iris/ciliary body complex. Approximately 70% of immunoreactivities detected by the PE-11 antiserum have been found to represent authentic PE-11. Sparse nerve fibers were visualized in the corneal and uveal stroma, surrounding blood vessels at the limbus, ciliary body and choroid and in association with the dilator and sphincter muscle. Furthermore, immunoreactivity was present in the corneal endothelium. In the retina and optic nerve, glia was labeled. In the rat trigeminal ganglion, PE-11-immunoreactivity was visualized in small and medium sized ganglion cells with a diameter of up to 30μm. In conclusion, there is unequivocal evidence that PE-11 is a constituent of capsaicin-sensitive sensory neurons innervating the rat eye and the distribution pattern is typically peptidergic in the peripheral innervation but in the retina completely atypical for neuropeptides and unique., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Uveal melanoma primarily metastasizes hematogenously with metastases often confined to the liver. The aim of this study was to investigate the presence of circulating tumor cells (CTC) in patients with metastatic disease as a marker for systemic disease and to determine their prognostic relevance., Methods: Blood samples from 68 patients were collected at the time of initial treatment of metastases. mRNA expression of tyrosinase and MelanA/MART1 as a surrogate marker for the presence of CTC was analyzed by real-time RT-PCR and compared with patient characteristics., Results: CTC were detected in 63% of all patients and in 67% of the 48 patients with only liver metastases. Univariate and multivariate analyses revealed PCR results and serum lactate dehydrogenase as independent prognostic factors for progression-free (hazard ratios 2.2/3.5) and overall survival (hazard ratios 4.0/6.5). Combination of PCR and lactate dehydrogenase divided the patient cohort into 3 groups with distinct prognosis., Conclusion: CTC as evidence for systemic disease can be found in the majority of patients with metastatic uveal melanoma, including patients with visible disease confined to the liver. Detection of CTC-specific mRNA transcripts for tyrosinase and MelanA/MART1 by PCR is a poor prognostic factor for progression-free and overall survival. Characterization of CTC could improve the understanding of their biology., (Copyright © 2011 S. Karger AG, Basel.)

In a recent investigation using the NMDA-excitotoxicity model in the rat retina, we found that, whereas, following intravitreal injection of NMDA, a time-dependent decrease of the levels of a neuropeptide, namely vasoactive intestinal polypeptide (VIP), was fully counteracted by topical treatment with flunarizine eye drops, the levels of pituitary adenylate-cyclase activating peptide-38 (PACAP-38), another neuropeptide, remained unchanged. The aim of the present study was to find out if NMDA causes reduction in the levels of other neuropeptides such as secretoneurin (SN), neurokinin-A/B (NKA/NKB) and substance P (SP), and if so, whether flunarizine has the ability to counteract this effect or prevent such reduction. The reduction of the levels of SN and NKA/NKB 14 days after intravitreal injection of 2 μl of 100 nmol NMDA into one eye was more pronounced than after 7 days; topical flunarizine had a slight counteracting effect, but could not prevent the decrease in the levels of these peptides. Reduction in SP levels after 28 and 56 days was fully counteracted by flunarizine. By enabling a pronounced influx of Ca²+ ions into peptide-expressing cells, NMDA leads to cell death. Since each of these peptides exerts neuroprotective properties in the central nervous system, the drop in their levels caused by acute insult (e.g. NMDA excitotoxicity) or chronic insult (e.g. glaucoma) may cause a breakdown of endogenous neuroprotection in the retina given that these peptides feature neuroprotective properties in the retina as well., (Copyright © 2010 Elsevier B.V. All rights reserved.)

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.

Background: Because of high local recurrence rates after excision of conjunctival melanoma adjuvant local chemotherapy employing mitomycin C (MMC) or irradiation is recommended. Brachytherapy is possible with ruthenium-106-plaques ((106)Ru) or with the strontium-90-plaques ((90)Sr)., Patients and Methods: Fifty-six patients received an excision and adjuvant radiotherapy of conjunctival melanoma between 1992 and 2007. The mean follow-up was 42 months (12 - 151 months). Mean age was 62 (28- 86) years. As an adjuvant radiotherapy 15 patients received X-ray irradiation, 12 patients received (106)Ru-brachytherapy, 4 patients received proton beam therapy and 16 patients with conjunctival melanoma were treated with adjuvant strontium-90 brachytherapy after tumour excision. Four patients received proton beam irradiation and in 13 patients an exenteratio was performed., Results: Twelve patients (21 %) developed tumour recurrences in or adjacent to the irradiated area. Thirteen patients (22 %) showed a recurrence distant from the primary site. Ten patients (18 %) developed systemic metastasis during follow-up. Seven patients (46 %) had no recurrence during the follow-up. Three patients (20 %) had a recurrence in the treated or adjacent areas. Eight patients (53 %) developed new tumours in non-treated areas., Conclusions: Adjuvant radiotherapy allows an acceptable local tumour control rate after excision of conjunctival melanoma. No obvious differences regarding tumour control or systemic metastasis could be seen between the different modes of radiotherapy used., (Copyright Georg Thieme Verlag KG Stuttgart . New York.)

Background: The aim of this study was to characterise the results of a screening for von Hippel-Lindau disease (VHL), angiomatosis retinae (AR) and further VHL lesions in at-risk relatives of ophthalmological VHL index patients., Methods: A retrospective analysis of 20 VHL index patients identified by the presence of angiomatosis retinae and a mutation of the VHL gene was carried out. A molecular genetic test for a VHL mutation and funduscopy was offered to all available at-risk relative. In the case of a positive test result, repeated screening for AR and further VHL lesions were suggested., Results: Fifty-one out of 86 first- and second-degree relatives were screened, and 73 % showed a VHL mutation. At first presentation, asymptomatic AR was present in 55 %, at the end of the study in 72 % of gene carriers. In contrast to the index patients, angiomas were small and could be treated without functional loss. During the study 4 eyes of index patients developed blindness, whereas in the affected relatives no such event occurred. Affected relatives developed further VHL lesions to the same number and extent as the index patients., Conclusions: This study demonstrates the necessity of a screening of at-risk relatives of patients with AR and VHL. Molecular genetic screening allows an early identification of affected relatives. Early and regular screening enables the detection of small retinal angiomas and their treatment without functional loss., ((c) Georg Thieme Verlag KG Stuttgart-New York.)

Background: Today photodynamic therapy (PDT) with Verteporfin is the standard treatment option for symptomatic choroidal haemangiomas. Nevertheless, peripapillary or large haemangiomas pose a therapeutic dilemma, since severe adverse events have been demonstrated in cases where the optic disc was included in the treatment spot. In addition due to the size and the shape of the laser spot, peripapillary and large haemangiomas can only be undertreated or overtreated (with overlapping multiple spots). With the presented new "paint-brush technique" it is possible to treat peripapillary and large choroidal haemangiomas completely without danger for the optic disc and without overtreatment., Material and Methods: With the new technique the application of the laser spot is performed in a "paint-brush fashion" by moving he spot with constant speed excentrically around the lesion's centre over the entire tumour surface. This allows under visual control a complete and confluent PDT of the whole tumour surface without overlapping and/or missing areas or treating the optic disc. In total, 13 eyes of 13 patients (6 with peripapillary and 7 with large choroidal haemangiomas) have been treated. The mean follow-up time was 25.6, respectively, 14.5 months., Results: The PDT with the "paint-brush technique" allows an effective treatment of the leakage in both groups. The mean increase of visual acuity was 1, respectively, 1.4 ETDRS lines 3 months after therapy, which could be maintained over the whole follow-up period. At the last examination visual acuity was unchanged or better in 12 / 13 (92 %) of eyes. After 3 months the tumour height was significantly (p = 0.031 and 0.018) reduced to 1.7 mm (52 %), respectively, 1.3 mm (30 %), which was stable during the whole follow-up. No significant side effects could be detected., Conclusion: The use of the PDT "paint-brush technique" allows complete treatment of choroidal haemangiomas under visual control. Sensitive structures like the optic disc could be excluded from treatment without double- or undertreatment. The functional and anatomic results are good. The technique is a safe and effective amendment in the treatment of symptomatic choroidal haemangiomas., ((c) Georg Thieme Verlag KG Stuttgart-New York.)

The treatment of large uveal melanomas poses a therapeutic challenge, due to the expected treatment-related side-effects. After sole radiotherapy the majority of patients are faced with radiogenic complications secondary to the large amount of tumour necrosis. Alternative treatment modalities addressing this issue are transscleral resection in arterial hypotension in anteriorly located tumours and endoresection via pars plana vitrectomy in posteriorly located tumours. A surgical resection treatment was applied in 292 patients with large uveal melanomas. In 150 patients the tumour was treated by transscleral resection and postoperative adjuvant (106)ruthenium brachytherapy and 142 patients were treated by primary proton beam irradiation and secondary endoresection. The mean follow-up time was 3.8 and 2.5 years, respectively. Local tumour control was achieved in 76 % and 98 %, respectively. The 5-year metastatic rates were 28 % and 21 % and eye retention was achieved in 82 % and 97 %, respectively. Surgical resection of uveal melanomas with adjuvant radiotherapy is the treatment of choice in cases of large tumours, avoiding enucleation in the vast majority of cases in the long term, without increasing the incidence of tumour-related risks., ((c) Georg Thieme Verlag KG Stuttgart-New York.)

By means of highly sensitive radioimmunoassays, the levels of substance P (SP) and secretoneurin (SN) were detected in vitreous aspirates of patients with macular holes which served as controls, in patients with nonproliferative diabetic retinopathy (DR), active proliferative diabetic retinopathy (active PDR), inactive PDR, rhegmatogenous retinal detachment and proliferative vitreoretinopathy (PVR). Furthermore, SN-like immunoreactivities were characterized by reversed phase-HPLC. The concentration of SN was more than 20-fold higher in macular holes when compared with SP and reversed phase HPLC revealed evidence that the vitreous levels of SN represent authentic SN. SN was significantly decreased in patients with nonproliferative DR, active PDR and inactive PDR by more than 70% which seems to result from a reduced expression and/or secretion from the cilary epithelium and a reduced release from the retina both due to diabetes mellitus. By contrast SP was increased in rhegmatogenous retinal detachment most obviously due to an enhanced outflow of the peptide through retinal breaks. Despite their proangiogenic activities, SP and SN are unlikely to be involved in the pathogenesis of neovascularizations in DR because of their unchanged and reduced levels, respectively, but the low levels of both peptides may facilitate the regression of vasoproliferations following laser photocoagulation.

Background: Because of the high local recurrence rates after excision of conjunctival melanomas, adjuvant local chemotherapy or irradiation is recommended. Strontium-90 brachytherapy is one radiotherapeutic option due to its low penetration depth., Methods: 15 patients with conjunctival melanoma were treated with adjuvant strontium-90 brachytherapy after tumour excision. The treatment was fractionated into 9 irradiation sessions with 6 Gy each. The mean follow-up was 35 months (12-60 months)., Results: Seven patients (46%) had no recurrence during the follow-up. Three patients (20%) had a recurrence in the treated or adjacent area. Eight patients (53%) developed new tumours in non-treated areas., Conclusions: Strontium-90 brachytherapy is a useful adjuvant in the treatment of conjunctival melanomas. Regular ophthalmoscopic controls are necessary because of the high rate of new tumours in non-irradiated areas, especially in cases with primary acquired melanosis.

Background: Tamoxifen is used in the treatment of selected patients with breast carcinoma. Rarely, it has been shown to cause ocular toxic effects including crystalline retinopathy., Methods: Retrospective analysis of clinical and functional (visual acuity, visual field, colour vision) data of a case series of eight female patients under tamoxifen therapy with electrophysiological examination., Results: Seven of eight patients complained of visual disturbances. In one case, examination showed crystalline deposits in the cornea and macular area. Three patients revealed changes in full-field and multifocal electroretinogram, and two had a pathological multifocal electroretinogram only. In six cases we applied a desaturated panel D-15 colour vision test; five of these showed some disorders., Conclusions: Most tamoxifen patients who complained of visual disturbances showed electrophysiological changes, particularly in the multifocal electroretinogram and often without a certain morphological correlate. We recommend electrophysiological examination for patients with unclear visual deterioration who are receiving tamoxifen therapy.

A case of juxtapapillary capillary retinal angioma associated with a vascularized epiretinal membrane of the macula in a 6-year-old girl is presented. Von-Hippel-Lindau-Syndrome was revealed by molecular genetic methods, and further family members were identified as gene carriers. The retinal angioma embedded in an epiretinal membrane was removed completely with the membrane by pars plana vitrectomy with a good functional result. Histopathology confirmed the diagnosis of capillary angioma.

Purpose: The purpose of this work was to evaluate the characteristic appearance of untreated retinoblastoma on a large sample in comparison to the histological findings after therapeutical enucleation., Materials and Methods: In a prospective clinical trial 46 children with retinoblastoma in 63 affected untreated eyes were examined under general anesthesia on MRI using a 1.5-T system. The examinations were performed with a special surface coil applying an examination protocol including fast T2- and T1-weighted spin echo sequences and additional fast T1-WI after intravenous injection of Gd-DTPA in different planes. The imaging results were compared to the histopathological findings in 29 patients with 30 affected eyes., Results: Comparing MRI findings and histopathological results, optic nerve infiltration was detected with a sensitivity of 53.8% and a specificity of 82.3% on MRI, infiltration of the choroid with a sensitivity of 75.0% and a specificity of 100.0%, and the degree of tumor calcification with a sensitivity of 91.7% and a specificity of 88.9%. In this study the characteristic MR appearance of untreated retinoblastoma was evaluated., Conclusion: MRI was helpful in relevant aspects of pretherapeutical retinoblastoma staging, deficits remain regarding optic nerve infiltration.

Background: Metastatic uveal melanoma has a poor prognosis and limited therapeutic options. Proteoglycans are involved in tumor cell invasion and metastatic behavior. The mAbB5 stains a chondroitin sulphate proteoglycan (CSPG) on cutaneous melanoma cells. Here, we compare the B5-staining of CSPG in primaries and metastases of uveal melanoma., Material and Methods: Immunohistopathological staining was performed in 15 cutaneous and 39 uveal melanoma samples. A score for intracellular and surface staining was established. B5 staining was compared in primaries and metastases of uveal melanoma using Student's t-test., Results: Eight of 11 (73%) uveal melanoma metastases were positive for B5-staining whereas only 5 of 28 (18%) primary uveal melanoma samples were B5-positive (P < 0.001). Nine of 15 cutaneous melanoma samples (60%) were B5-positive without significant difference between primary and metastatic lesions. Surface staining was found both on uveal melanoma metastases and cutaneous melanomas., Conclusions: CSPG was expressed significantly more often in metastases than in primaries of uveal melanoma. It potentially may be one factor associated with metastatic spread. Further studies are needed to determine its use as prognostic factor. The mAbB5 may also be a promising tool for immunotherapy due to its strong staining of CSPG on the surface of cutaneous and metastatic uveal melanoma cells.

Background: To determine the effectiveness and risk profile of combined ruthenium- (Ru)-106-brachytherapy and transpupillary thermotherapy (TTT) of the tumour apex for the treatment of large choroidal melanoma., Methods: A consecutive series of 31 large choroidal melanoma treated by Ru-106-brachytherapy and adjuvant TTT was studied. TTT was performed 1 day prior to plaque removal and up to 3 times (mean: 1.8) during follow-up. Evaluation comprised tumour regression, treatment-related adverse events, necessity of additional treatment and visual results., Results: Mean follow-up was 21.6+/-7.8 (10.8-38.3) months. Mean tumour thickness was 6.8+/-1.0 (5.0-8.9) mm prior to treatment. Mean residual tumour thickness at the end of follow-up was 2.5+/-1.0 mm. Relevant adverse treatment effects were exudative maculopathy or macula oedema (22.6%), vitreous haemorrhage (16.1%), optic neuropathy (16.1%) and retinal detachment (9.7%). One tumour recurrence occurred during follow-up, and was treated by enucleation., Conclusions: The combination of Ru-106-brachytherapy with TTT allows for the treatment of large posterior choroidal melanoma. The rate of treatment-related adverse events appears to be acceptable.

Background: Several trials demonstrated efficacy of the gemcitabine/treosulfan (GeT) combination in metastatic uveal melamoma. This randomized phase II trial compared the GeT combination versus treosulfan alone (T) in this rare disease., Patients and Methods: Chemotherapy-naive patients with proven metastatic uveal melanoma were randomly assigned to receive 1000 mg/m(2) of gemcitabine plus 3500 mg/m(2) of treosulfan (GeT) or 3500 mg/m(2) of T. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. Primary end point was rate of responses and disease stabilizations., Results: Forty-eight patients were randomized. Seven confirmed stable diseases (SDs) and one partial remission (PR) were observed in 24 patients treated with the GeT regimen, whereas no PR and only three SDs were observed in the T arm (P = 0.08). Median progression-free survival (PFS) was 3 months (95% CI 1.1-4.9) and 2 months (95% CI 1.7-2.3) in the GeT and T arm (P = 0.008, log-rank). Six and 12 months PFS was 34.8% and 17.9% and 16.7% and 0% always favoring the GeT arm., Conclusions: This first randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over T.

Background: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has not yet been defined. The study assesses ifosfamide (IFO) and trofosfamide (TRO) for treating IOL., Patients and Methods: We prospectively evaluated the efficacy and aqueous penetration of intravenous IFO, oral TRO and their active 4-hydroxy (4-OH) metabolites in 10 patients with IOL. Doses varied from 1500 to 2000 mg/m2/day on days 1-3 for IFO and from 150 to 400 mg/day (continuous or intermittent administration) for TRO. Four patients had newly diagnosed disease, and six had relapsed after pretreatment., Results: All patients responded to first treatment with IFO or TRO, and both of two patients responded to re-treatment with IFO on ocular relapse. Progression-free survival from the first treatment with IFO or TRO was > or = 6-18 months. In six of six patients, 4-OH metabolites were detected in the aqueous humor at a concentration of 0.32-1.56 microM immediately after IFO infusion with an aqueous/serum ratio of 0.19-0.54. 4-OH metabolites could be detected in one of three patients at a concentration of 7.2 microM 3-16 h after ingestion of TRO., Conclusions: IFO and TRO are active in IOL. IOL patients evidence aqueous penetration of 4-OH metabolites after intravenous administration of IFO.

Background: The aim of this study was to evaluate whether photodynamic therapy (PDT) with verteporfin is able to induce tumor cell necrosis in human uveal melanomas., Methods: On four eyes with an uveal melanoma, PDT with verteporfin was performed on the tumor 2-3 days before planned enucleation. The eyes were evaluated histologically., Results: In two melanomas with only mild pigmentation some effects after PDT were detected on tumor tissue in a depth up to 2.5 mm at light doses > or =100 J/cm(2). Histologically, vascular occlusion and thrombosis in tumor vessels were observed. In the heavily pigmented melanoma no tumor necrosis was induced with the above-mentioned parameters., Conclusion: Depending on treatment parameters and tumor pigmentation, PDT with verteporfin is able to induce tumor necrosis in human uveal melanomas. Based on these results it is possible that PDT can become an adjuvant treatment method for uveal melanoma.

Background: Dry eye symptoms can often be observed following vitreo-retinal operations, however, little is known about the frequency and severity of these postoperative problems., Methods: Examination of 140 patients following vitreo-retinal surgery ( n=31), brachytherapy ( n=76), proton beam radiation ( n=33) and controls ( n=54) using a questionnaire together with a clinical examination of the anterior segment, tear break-up time and a Schirmer test., Results: Of the treated patients 63% complained of dry eye symptoms versus 40% of the controls ( p=0.004). The tear break-up time was decreased in treated patients ( p<0.001, medians: 15 vs. 20 s). No significant difference was seen on the Schirmer test ( p=0.825; medians: 12 vs. 12 mm)., Conclusions: Dry eye symptoms are a common postoperative complication following vitreo-retinal surgery and ocular tumour therapy.

This trial was performed to define the maximum tolerated dose (MTD) of treosulfan administered in combination with a fixed dose of gemcitabine in uveal melanoma patients. Preclinical studies suggested synergistic activity against uveal melanoma. Gemcitabine (1 g/m2) and treosulfan (2.5-4 g/m2) were administered on days 1 and 8, and cycles were repeated on day 29 for a maximum of six cycles. For treosulfan, dose escalation cohorts of 2-4 patients were enrolled. An additional 25 patients were entered at treosulfan dose levels II (3 g/m2) and III (3.5 g/m2). Thirty three patients with uveal melanoma and six patients with other histologies were accrued. Side-effects were predominantly haematological. The MTD was 3.5 g/m2 of treosulfan together with 1 g/m2 of gemcitabine. In the uveal melanoma patients, one partial response (PR) and 15 stablisations of disease (SD) were recorded and whether this translates into a survival gain should be explored further.

Purpose: Large uveal melanomas located close to the optic nerve and/ or to the fovea have an unfavourable prognosis with regard to visual preservation and eye retention, due to the high incidence of radiation and tumour necrosis induced complications. Endoresection of the tumour after proton beam irradiation, is an alternative approach, aiming to reduce the incidence of ocular morbidity caused by tumour necrosis after sole radiotherapy., Patients and Methods: 32 patients with large uveal melanomas (mean tumour thickness: 9.1 mm, mean tumour volume: 0.77 cc), received a primary proton beam irradiation (60 CGE) and underwent subsequent endoresection via a 3-port pars plana vitrectomy. The median pretreatment visual acuity was 0.2. The mean follow-up was 13.9 months., Results: The postoperative visual acuity after 12 months was 0.12 (median, mean visual acuity loss 0.08). The probability of developing radiation retinopathy or papillopathy within the first year after treatment was 35% and 28% respectively and the probability of enucleation was 9% within the first postoperative year. No tumour recurrences were observed and 2 patients developed liver metastases., Conclusions: Endoresection following irradiation of large uveal melanomas located close to the optic nerve and/ or the fovea seems to be a useful and safe alternative to the traditional irradiation or enucleation. The incidence of complications following our approach seems to be lower when compared to radiation alone, where tumour necrosis is a substantial problem.

Background: Choroidal metastasis (CM) is the most common malignant intraocular tumor. The aim of this study was the characterization of the ophthalmoscopic aspect, the underlying tumor disease and differential diagnosis of this entity., Study Design: Retrospective observational case series., Patients and Methods: A total of 71 consecutive patients with CM were evaluated. Special attention was given to ocular symptoms, the ophthalmoscopic and sonographic aspects and the characteristics of the underlying tumor disease. All patients had undergone screening (CCT, CT of thorax and abdomen; bone scintigraphy) for the primary tumor and further organ metastases., Results: Of the patients 95% had symptomatic CM, in 5% of the patients CM was detected by chance, 60% had a single CM, 40% showed multiple (2-14) lesions and 18% ( n=13) had no history of tumor disease. In 12 of these patients lung cancer could be diagnosed. In 53% of the patients the primary tumor was breast cancer, in 26% lung cancer, in 3% kidney cancer, bowel cancer, choroidal or cutaneous melanoma and in single patients cervical, ovarian, thymus or prostate cancer. In one patient who died from disseminated metastases, no definite primary tumor could be detected. Of the patients 96% had further metastases, CM occurred with a mean interval after diagnosis of the primary of 9 months in lung cancer and 68 months in breast cancer. CM was the first clinical sign of tumor disease in 58% of patients with lung cancer and the first clinical sign of metastatic disease in 28% of patients with breast cancer., Conclusions: Choroidal metastasis occurs almost exclusively in metastatic disease. In breast cancer it typically occurs years after diagnosis of the primary tumor and may be the first sign of metastatic disease. In lung cancer choroidal metastasis may be the first sign of the tumor disease.

Purpose: The determination of tumor volume in ocular tumors is very important for the planning and success of radiation therapy. This study uses an animal model to evaluate the accuracy of MR-based volumetry of ocular tumors., Materials and Methods: In a total of 25 porcine eyes obtained from the slaughterhouse, ocular tumors were produced by injecting a mixture of hand creme and Gd-DTPA under ophthalmoscopic guidance. The injected volume varied between 0.05 ml and 2.7 ml. The eyes were examined with a 1.5 Tesla scanner and a 4 cm circular surface coil especially developed for ocular MRI. After data transfer to a separate workstation, volumetric analysis was carried out by three independent radiologists using semiautomated software. The determined volume was compared with the injected volume., Results: Of the 25 prepared porcine eyes, 23 were suitable for volumetric analysis. The injection of the mixture of hand creme and Gd-DTPA produced two different types of tumors. Ophthalmoscopically, 14 ellipsoid and 9 lobulated to mushroom-shaped tumors were found and confirmed by MRI. Minor deviation was found between injected volume and volume calculated by MRI, with a correlation coefficient of 0.96., Conclusion: Using appropriate technique, MRI is capable of determining small tumor volumes with high accuracy in an animal model. Minor differences can be expected when transferring the results to clinical studies.

Background/aims: Diagnosis of retinoblastoma is mainly based on indirect ophthalmoscopy, but additional imaging techniques are indispensable for the staging of the disease. A new high resolution magnetic resonance imaging (MRI) technique for the examination of the eye was evaluated. A new surface coil with a diameter of 5 cm allows a field of view of 60 mm with an in-plane resolution of 0.8 mm. We compared preoperative MRI scans with the histology after enucleation in 21 cases of retinoblastoma. Parameters studied were appearance of retinoblastoma, choroidal and scleral infiltration, extraocular extension, optic nerve infiltration, and vitreous seeding., Results: All retinoblastomas could be visualised as hypointense to vitreous on T2 weighted images and slightly hyperintense to vitreous on plain T1 weighted images with a moderate enhancement after contrast application. Histology revealed seven cases with infiltration of the optic disc or optic nerve. Preoperative MRI scans depict juxtapapillary tumour masses, but it was impossible to differentiate between a juxtapapillary retinoblastoma, a prelaminar infiltration of the optic disc, or a just postlaminar optic nerve infiltration. In five of 14 cases with a proved tumour infiltration of the choroid, MRI scans showed an inhomogeneous contrast enhancement of the choroid in enhanced T1 weighted sequences beneath the retinoblastoma. Whether this sign is specific for a choroidal infiltration or is just an artefact remains unclear. High resolution MRI scans did not allow the exclusion of this form of intraocular tumour extension. All nine cases with proved vitreous seeding were not detected by MRI scans. None of these cases showed scleral infiltration or orbital tumour extension. Therefore, it is not possible to judge the rank of this technique in detecting orbital tumour growth., Conclusion: The new MRI technique is of limited value in visualisation of prelaminar or postlaminar infiltration of the optic nerve. Advanced choroidal infiltration might be visualised by contrast enhanced T1 weighted MRI scans, but the available spatial resolution did not allow the exclusion this critical form of tumour growth by MRI scans. Nevertheless, high resolution MRI with the new surface coil has superior contrast and spatial resolution compared to computed tomograph (CT) or other available imaging techniques. MRI cannot replace CT in detecting tumour calcification but with increasing experience with this new technique it should be possible to renounce CT scans in the majority of cases of retinoblastoma.

Background: Up to now the diagnosis of choroidal tumors was mainly based on ophthalmoscopy and ultrasound examination. Indocyanine green angiography allows the identification of vascular patterns in these tumors, which could be helpful in the differential diagnosis. The aim of the study was to characterize the staining patterns of choroidal metastases., Methods: In the years 1996-2000 we performed ICG-A of 15 choroidal metastasis using the scanning laser ophthalmoscope from Rodenstock. The mean tumor height was 3.7 mm (2.0-9.0). These angiographies were compared to the angiographies of 38 choroidal malignant melanomas with a mean height of 3.6 mm (1.4-6-6)., Results: All metastases showed a blockage of the background staining and a patchy staining of the tumor surface. Intratumoral vessels could be detected in 13% of all cases of metastases. The choroidal melanomas examined showed a blockage of the background staining in all cases and tumor vessels in 89%., Conclusion: The angiographic picture of the metastatic lesions was characteristic. Intratumoral vessels could not be detected using ICG-A. Most of the metastases showed a patchy staining of the tumor surface.

The treatment modality of primary uveal melanoma has up to now had no direct influence on the evolution of metastatic disease. Novel adjuvant treatment modalities are being developed on the basis of identifying significant prognostic factors for survival. The development of vaccination protocols targeting specific melanoma and/or tumor antigens has gained increasing importance and is currently being evaluated. Up to date the median survival of patients with metastases of uveal melanoma used to be approx. 5 months. In the last years median survival of selected patients with metastatic disease could be increased to 14 months by intrahepatic fotemustin influsions. Novel systemic chemotherapy protocols are currently being evaluated based on chemosensitivity studies. Furthermore, immunotherapeutical modalities are entering clinical evaluation as treatment for metastatic uveal melanoma.

Background: The treatment of large uveal melanomas is always a challenge to the ophthalmic oncologist due to the expected long-term complications. The purpose of this study was to compare 125Iodine plaque brachytherapy with transscleral resection of large uveal melanomas in terms of preserving visual function and avoiding secondary enucleation., Patients and Methods: A total of 135 patients with similar tumor features were selected from a group of 211 patients with uveal melanomas where the tumor height was greater than 7.5 mm. Of these patients 87 were treated by 125Iodine brachytherapy and 48 patients by transscleral tumor resection. The mean follow-up time was 26 months., Results: After transscleral resection 58% of the patients and after 125Iodine-brachytherapy 15% of the patients retained a visual acuity of > or = 0.1 after a follow-up of 28 months. Following iodine-brachytherapy there was a sixfold higher rate of secondary glaucoma. No difference was found with respect to the eye retention and mortality rate., Conclusion: Patients with large melanomas eligible for transscleral local resection have a better visual function than those treated by 125Iodine brachytherapy.

Purpose: The purpose of our study was to evaluate the use of the galactose microbubble-based contrast agent Levovist in color Doppler sonography of uveal melanomas. We also evaluated the use of the resistance index and pulsatility index in differentiating tumor-associated vessels from normal vessels in patients with uveal melanomas., Methods: In this prospective study, 40 patients with uveal melanoma were examined with color Doppler sonography before and after the administration of the contrast agent Levovist. The Doppler signals were recorded from both the tumor and the orbit and were evaluated quantitatively and qualitatively., Results: Tumor-associated vessels were detected without contrast enhancement in 36 of 40 patients and with contrast enhancement in 38 of 40 patients. The spectral characteristics of the Doppler signals did not change after the injection of Levovist. There were no differences-qualitative or quantitative-in Doppler signals between normal and tumor-associated vessels., Conclusions: The injection of Levovist slightly improved the detection of small vessels in uveal melanomas and the orbit but did not help to differentiate between normal vessels and tumoral vessels. The differentiation of a solid tumor from subretinal hemorrhage or effusion was improved., (Copyright 2001 John Wiley & Sons, Inc.)

Background: Little is known about the risks, effects and results of phacoemulsification following treatment with different modalities of choroidal melanoma., Methods: In a retrospective study, records were evaluated of 72 patients who underwent cataract surgery after treatment of choroidal melanoma (35 were treated with iodine-125 plaques, 27 with ruthenium-106 plaques, eight by tumor excision, and two with proton beam irradiation). The data were analyzed with respect to complications, effects on postoperative tumor care and visual outcome., Results: Phacoemulsification was performed at a mean interval of 21.5 months after primary tumor therapy. An intraocular lens (IOL) was implanted in 93% of the cases. The mean postoperative follow-up time was 16.2 months. Preoperative problems were rubeosis iridis (30.5%), secondary glaucoma (34.7%) and posterior synechiae (41.6%). Intraoperatively, defects of the posterior capsule occurred in 12.5%. Visual acuity equal to or better than preoperative vision was found in 95.8% of the patients as the best postoperative measurement and in 72.2% at the last follow-up measurement. A deterioration of more than two lines in visual acuity was observed in 4.2% as the best postoperative vision and in 27.8% at the last documented examination. Phacoemulsification was not the cause of deterioration in any of the cases. After cataract surgery, tumor retreatment was necessary in 19.4%. Treatment of radiation retinopathy was performed for the first time in 13.8%. Metastases developed in six patients (8.3%)., Conclusion: Phacoemulsification following treatment for choroidal melanoma is both possible and advisable. The majority of patients have enhanced visual acuity. No decrease of vision occurred as a result of cataract extraction. The postoperative care of intraocular tumors and the treatment of radiation retinopathy is improved by timely cataract surgery.

Background: To evaluate the significance of angioma number (single or multiple) for the presence of von Hippel-Lindau (VHL) disease in patients presenting with capillary retinal angioma., Methods: Forty-one nonrelated patients presenting with capillary retinal angioma were evaluated. An ophthalmic workup, screening for other organ lesions, and molecular genetic screening for a mutation of the VHL gene was performed. The diagnosis of VHL was made on the basis of the personal and family history, the presence of other VHL-associated organ lesions, or the presence of a mutation of the VHL gene., Results: Thirteen patients (32%) presented with a single angioma and 28 patients (68%) presented with multiple angiomas. In 81% of all patients, VHL could be diagnosed. Diagnosis of VHL could be readily made by the personal or family history in 51% of all patients. In another 27% of all patients, VHL disease was evidenced by screening for other VHL-associated lesions. In two patients (3%) VHL could be diagnosed by molecular genetics only. All patients with multiple retinal angiomas had VHL disease and, in 38% of patients with a single angioma, VHL was present. Reasons for a missing family history in patients with VHL disease were the presence of a de novo mutation (15% of VHL patients) or clinical anticipation of VHL disease (18% of VHL patients)., Conclusion: The presence of multiple retinal angiomas strongly suggests VHL disease, which, however, can be obscured by presence of a de novo mutation or by clinical anticipation of VHL disease in affected families. A single retinal angioma may be sporadic as well as the presenting sign of VHL. Diagnosis and screening for this multitumor syndrome is substantially supported by molecular genetics.

Background: Vasoproliferative tumours of the retina (VPTR) are benign tumours of unknown origin, occurring mostly in otherwise healthy patients. VPTR may be associated with other chorioretinal diseases, such as uveitis. The tumours, which histologically represent reactive gliovascular proliferations, are characterised by a pink to yellow appearance on funduscopy and are accompanied by exudative and haemorrhagic changes of the retina., Methods: 22 cases of VPTR in 21 patients were examined with a follow up period between 1 month and 6 years. Ophthalmological changes associated with VPTR were intraretinal and subretinal exudations (n=18), exudative detachments of the surrounding sensory retina (n=13), intraretinal and subretinal haemorrhages (n=10), exudative changes within the macula (n=10), hyperpigmentation of the retinal pigment epithelium at the border of the exudative retinal changes (n=9), and vitreous haemorrhages (n=4). Tumour biopsy was performed in two cases. Treatment consisted of plaque radiotherapy (n=14), plaque radiotherapy and cryotherapy (two), cryotherapy only (two), observation (three), and enucleation in one case of a blind and painful eye., Results: Regression of the tumour and the associated exudative changes could be observed in all treated cases. Visual acuity at last follow up improved two lines or more in two cases, remained within two lines of the initial visual acuity in 15 cases, and worsened in the remaining five. Histopathological examination of the biopsy specimens and the tumour of the enucleated eye showed massive capillary proliferation with perivascular spindle-shaped glial cells of retinal origin., Conclusion: The correct diagnosis of VPTR is of importance as these lesions may lead to visual loss. Further, VPTR must be differentiated from angiomas associated with von Hippel-Lindau disease as well as from ocular and systemic malignancies. Regression of tumour thickness and associated retinal changes can be achieved with brachytherapy or cryotherapy.

Objective: To describe the cytologic transformation and tumor progression in a series of uveal melanomas., Methods: Fifteen cases of uveal melanoma, treated by primary transscleral local resection without primary adjuvant treatment, needed enucleation because of local tumor recurrence. Cytologic and cell morphometric features of the primary tumor and the intraocular recurrence were compared, with evaluation of the amounts of intermediate cells, epithelioid cells, mitotic figures, and nucleolar area., Results: The cases were categorized into 2 groups, according to their cytologic characteristics. In the first group (5 cases), there was no cytopathological transformation in the recurrent tumor. The nucleolar area was increased in only 1 case. In the second group (10 cases), the recurrent tumors showed transformation into a more epithelioid cell type. In all but 1 case there was an increase in epithelioid cells in the tumor recurrence. The nucleolar area was increased significantly in all cases. The mean local recurrence interval in all cases was 15.3 months, with no difference between the groups. Death from metastases occurred in 7 cases in which the nucleolar area was 4.2 microm(2) in the primary tumor., Conclusions: These findings demonstrate that, in an individual tumor, the cytologic phenotype can change considerably even after a relatively short time, resulting in an increase in tumor-related mortality., Clinical Relevance: Studies on the natural course of uveal melanoma have been very limited and based purely on observations on the progression of melanomas in terms of size and alteration of various clinical characteristics.

Purpose: The possible role of protein kinase C (PKC) inhibitors in novel pressure-lowering drugs is currently under investigation. To gain further insight into regulation of contractility by PKC in trabecular meshwork (TM) and ciliary muscle (CM), the effects of various PKC inhibitors and activators were tested., Methods: Isometric tension measurements of bovine TM and CM strips were performed. PKC was stimulated by phorbol ester and by the diacylglycerol analogue diC8. PKC blockade was accomplished using H7 and myristoilated PKC substrate (mPKC). Western blot analysis was used to identify specific PKC isoforms in human trabecular meshwork (HTM), human ciliary muscle (HCM), and bovine TM and CM., Results: In tissues precontracted by carbachol PKC antagonist H7 led to a relaxation of TM (25+/-7.2 versus 100%; n = 8) with no effect on CM. mPKC substrate selectively blocks PKC. This substance led to relaxation of TM (32.8+/-7.4 versus 100%, n = 7), whereas CM was not affected. PMA at concentrations of 10(-6) M led to a slow contraction of both tissues that was more marked in TM. DiC8 and 4alpha-phorbol had no effect on contractility. Western blot analysis revealed expression of calcium-dependent PKC-alpha and calcium-independent PKC-epsilon isoforms in HTM and HCM. PKC-epsilon expression was more pronounced in HTM than in HCM. Similar PKC isoform expression was found in native bovine tissue., Conclusions: PKC isoforms show different tissue distributions in human and bovine TM and CM. Contractility differences exist in both tissues in response to PKC antagonists and agonists. The data indicate that PKC may be involved in regulation of aqueous humor outflow by the TM. Thus, inhibition of PKC may represent a new way of influencing outflow facility through isolated relaxation of TM.

Hypotension caused by hypovolemic, hemorrhagic shock induces disturbances in the immune system that may contribute to an increased susceptibility to sepsis. The effect of chemically induced hypotension on circulating cytokines and adhesion molecules has not been investigated yet. In 21 patients scheduled for resection of malignant choroidal melanoma of the eye the perioperative serum levels of the cytokines IL-1beta, IL-6, IL-10, TNF-alpha, and the adhesion molecules sE-Selectin and sICAM-1 were investigated. Moderate hypothermia of 32 degrees C was induced in all patients. In 14 patients profound hypotension (mean arterial blood pressure 35-40 mmHg, hypotension group) was induced by enalapril and nitroglycerin for a mean duration of 71 min. In 7 patients the tumor was not resectable, and hypotension was not induced (controls). We did not detect significant differences in serum levels of cytokines or sE-Selectin perioperatively in patients with profound hypotension compared with controls. In both groups IL-6 serum levels increased significantly and reached a maximum after rewarming (17 +/- 6 and 16 +/- 5 pg/dL, respectively, P < 0.001). IL-1beta, IL-10, and TNF-alpha did not change perioperatively in both groups. On the first postoperative day sICAM-1 serum levels were significantly increased in both groups (mean increase of 96 and 54 ng/mL, respectively, P < 0.01 and P < 0.05). We conclude from this study that profound normovolemic arterial hypotension does not seem to have effects on serum levels of circulating IL-1beta, IL-6, IL-10, TNF-alpha, and sE-Selectin. Perioperative moderate hypothermia may be the reason for the postoperative increase in sICAM-1 levels independent of the blood pressure.

Purpose: To evaluate whether the different signal intensities at magnetic resonance (MR) imaging of melanoma are associated with a higher content of melanin., Materials and Methods: In a prospective study, MR imaging and ophthalmoscopic examination findings in 42 patients (19 women, 23 men; age range, 30-87 years) with uveal melanoma were compared with histopathologic examination findings obtained after enucleation. MR imaging was performed with 2-mm sections by using a 5-cm surface coil. T1- and T2-weighted images were obtained before and after contrast material administration., Results: In 33 (79%) of the patients, there was homogeneous tumor pigmentation, whereas in nine (21%) patients, there was inhomogeneous bipartite tumor pigmentation. Compared with the histopathologic data, the results of qualitative evaluation were accurate in 29 (58%) of 50 and in 26 (53%) of 49 tumorous areas on T1- and T2-weighted images, respectively. Quantitative evaluation yielded better results, especially at T1-weighted imaging; an 86% correlation was found. Because of methodological reasons, only the superficial pigmentation of inhomogeneous tumors could be evaluated with ophthalmoscopy., Conclusion: Thin-section MR imaging of the eye enables an accurate prediction of melanomatous pigmentation with quantitative evaluation of plain T1-weighted images and is superior to ophthalmoscopy in cases of inhomogeneous pigmentation.

Purpose: Choroidal melanomas usually present a characteristic appearance in MRI. Differing characteristics can cause problems in differential diagnosis between melanomas and other masses in the globe. The purpose of this study was to evaluate the appearance of choroidal melanomas with MRI in a large consecutive patient group., Methods: In a prospective study, 200 patients with choroidal melanomas were investigated with MRI using a 1.5 T scanner and a 5 cm surface coil. Both quantitative and qualitative evaluation of the resulting images was performed., Results: 78.5% of the melanomas presented with homogeneous signal intensities within the tumor due to a homogeneous pigmentation whereas 21.5% of the melanomas demonstrated a mixed pigmentation. Signal intensities of the homogeneous melanomas in the plain T1-WI were moderately or markedly hyperintense compared to the vitreous in 29.3% and moderately or markedly hypointense in the T2-WI in 37.1%. An accompanying retinal detachment was found in 65.5% and an extraocular growth in 7.0%., Conclusions: In 10% to 37% we observed the typical well known MR appearance, including homogeneous high signal in the T1-WI and low signals in the T2-WI. For further differentiation, morphological criteria (e.g. shape, size, and position) were used, which are also discussed.

Background/aims: A checkpoint mechanism in late G1, whose regulation via loss of retinoblastoma protein (pRB) or p16, or overexpression of cyclin D1 or cyclin dependent kinase 4 (CDK4), has been proposed to constitute a common pathway to malignancy. The aims of this study were (a) to compare markers of cell cycle G1-S phase transition in an intraocular tumour with known pRB deficiency (retinoblastoma) and compare it with one with an apparently functional pRB (uveal melanoma); (b) to determine if one of these markers may have a role in the pathogenesis of uveal melanoma; and (c) to determine if there is a difference in cell cycle marker expression following treatment of uveal melanoma and retinoblastoma., Methods: 90 eyes were enucleated from 89 patients for retinoblastoma (n = 24) or for choroidal or ciliary body melanoma (n = 66). Conventional paraffin sections were assessed for cell type and degree of differentiation. Additional slides were investigated applying standard immunohistochemical methods with antibodies specific for cyclin D1 protein, pRB, p53, p21, p16, BCL-2, and MIB-1., Results: Cyclin D1 protein and pRB were negative in retinoblastoma using the applied antibodies. In contrast, cyclin D1 protein expression was observed in 65% of uveal melanomas; a positive correlation between cyclin D1 cell positivity and tumour cell type, location, growth fraction, as well as with pRB positivity was observed. p53, p21, and p16 could be demonstrated in both tumours. An inverse relation between p53 and p21 expression was demonstrated in most choroidal melanomas and in some retinoblastomas. Apart from a decrease in the growth fractions of the tumours as determined by MIB-1, a significant difference in the expression of G1-S phase transition markers in vital areas of uveal melanoma and retinoblastoma following treatment with radiotherapy and/or chemotherapy was not observed., Conclusion: Retinoblastomas and uveal melanomas, two tumours of differing pRB status, differ also in their immunohistochemical pattern for markers of the G1-S phase transition of the cell cycle. The results of the present study support the concept of (a) an autoregulatory loop between pRB and cyclin D1 in tumours with a functional pRB and the disruption of this loop in the presence of pRB mutation, as well as (b) a checkpoint mechanism in late G1, whose regulation via loss of p16 or pRB, or overexpression of cyclin D1 constitutes a common pathway to malignancy. Further, the results raise the possibility of cyclin D1 overexpression having a role in the pathogenesis of uveal melanoma.

Background: Primary chemotherapy is a new treatment approach in retinoblastoma, aiming to avoid radiogenic adverse effects, such as second tumor-associated mortality, as observed following external beam irradiation., Objective: To describe the clinical and histopathologic regression pattern after primary chemotherapy in retinoblastoma., Methods: Five patients with sporadic bilateral retinoblastoma underwent planned enucleation of their functionally blind eye after 2, 3 (in 2 patients), 4, and 6 courses of primary chemotherapy with carboplatin, etoposide, cyclophosphamide, and vincristine. The eyes were examined histopathologically, using light microscopy and immunohistochemical analysis with proliferation markers., Results: One patient had a type 1 (cottage cheese) regression and 4 patients had either a type 2 (fish flesh) or a type 3 (combined) regression pattern. Histopathologic examination revealed a complete tumor necrosis in 1 patient with type 1 regression after 3 courses of chemotherapy and in 1 patient with type 3 regression after 4 courses of chemotherapy. The remaining 3 patients with type 2 or type 3 regression had histologically still active proliferative tumor cells after 2, 3, and 6 courses of chemotherapy., Conclusion: This article correlates histopathologically the clinically described efficacy of primary chemotherapy in the treatment of retinoblastoma, underlining, however, the necessity of careful observation and the use of ancillary treatment whenever there is no complete tumor regression.

A possible selective therapeutic approach to corneal graft rejection will aim at IL-2 receptor-bearing antigen-activated T-lymphocytes with monoclonal anti IL-2R antibodies. In a rat penetrating keratoplasty model (Lewis x Lewis-BN) comparing to controls (median, 8 days), a significant delay of the allograft reaction was achieved by applying a therapeutic dose (15 mg/kg bw) of cyclosporin A (median, 18 days; p < 0.01), an intraperitoneal (1.0 mg/kg bw) (median, 13.5 days; p < 0.05) or a subconjunctival injection of IL-2R mab (0.5 mg/kg bw ART-18) (median, 16 days; p < 0.01) with low-dose Cyclosporin A (1.5 mg/kg bw). In pharmacokinetic experiments, the corneal radioactivity 24 h after intraperitoneal injection of 125I-labeled ART-18 was < 1% (p < 0.01) of the values obtained by subconjunctival injection, whereas the serum radioactivity values (p > 0.05) were in the same range. The above results suggest that the onset of an allograft reaction in perforating keratoplasty seems to depend on the locally achievable antibody concentration and can be delayed with a high level of IL-2 R mab present in the immediate surrounding of the foreign antigen-expressing cells.