[Hearing Disorders with Glaucoma]. / Hörstörungen bei Glaukom.

One of the most common sensory impairments of elderly people is hearing loss. Glaucoma is one of the leading causes of blindness worldwide. Hearing and vision loss typically increase with older age. There is scientific evidence that the coincidence of hearing and vision loss is more frequent than expected by the prevalence of individual disorders. With regards to demographic changes and an aging population, in future, it is probable that the incidence of combined hearing and vision impairments will increase, representing a particular challenge not only for doctors and nurses but also a high burden for the private environment of the patients. Therefore, it is of particular importance to diagnose and to treat hearing and vision loss (dual sensory loss) as early as possible. The treatment of hearing disorders and glaucoma as well as possibly underlying systemic diseases such as circulatory disturbances is as important as responsible rehabilitation measures and the supply of hearing and low vision aids. During the last years, knowledge about the molecular biological background of hearing loss and glaucoma has continuously increased but it is currently still at the level of laboratory and animal experiments. Therefore, it remains to be seen whether and to what extent a real therapy for the underlying genetic, immunological and in particular mitochondrial disorders may be accessible in the future.

[Hearing disorders with glaucoma]. / Hörstörungen bei Glaukom.

One of the most common sensory impairments of elderly people is hearing loss. Glaucoma is one of the leading causes of blindness worldwide. Hearing and vision loss typically increase with older age. There is scientific evidence that the coincidence of hearing and vision loss is more frequent than expected by the prevalence of individual disorders. With regards to demographic changes and an aging population, in future, it is probable that the incidence of combined hearing and vision impairments will increase, representing a particular challenge not only for doctors and nurses but also a high burden for the private environment of the patients. Therefore, it is of particular importance to diagnose and to treat hearing and vision loss (dual sensory loss) as early as possible. The treatment of hearing disorders and glaucoma as well as possibly underlying systemic diseases such as circulatory disturbances is as important as responsible rehabilitation measures and the supply of hearing and low vision aids. During the last years, knowledge about the molecular biological background of hearing loss and glaucoma has continuously increased but it is currently still at the level of laboratory and animal experiments. Therefore, it remains to be seen whether and to what extent a real therapy for the underlying genetic, immunological and in particular mitochondrial disorders may be accessible in the future.

[Clinical value of scanning laser polarimetry in glaucoma diagnostics]. / Stellenwert der Scanning Laser Polarimetrie für die Glaukomdiagnostik.

The term glaucoma is used as a melting pot of many different diseases which have in common that the retinal ganglion cells and their axons are damaged. Untreated, apoptosis can be induced causing ganglion cell death which subsequently leads to typical glaucomatous damage at the optic nerve head, scotomas of the visual fields, and in the worst case scenario to blindness. It is well known that patients with glaucoma can suffer a 20 to 50 % loss of retinal ganglion cells before a defect becomes evident in standard white on white perimetry. To prevent glaucomatous damage, it is important to detect changes of the retinal ganglion cells and their nerve fibre layer as early as possible and to monitor their follow-up as closely as possible in order to find an adequate treatment of glaucoma, and to control its efficiency. In the past few years, scanning laser polarimetry by means of GDx technology (Carl Zeiss Meditec, Dublin, USA) could be established as a new method to measure the retinal nerve fibre layer not only qualitatively but even quantitatively. Presently, the GDx plays an important role in actual glaucoma diagnostics on account of its high resolution, the comfort for both patient and user, and its highly reproducible measurements. Especially in difficult evaluable optic nerve heads (e. g., micro- and macrodiscs), tilted discs, and optic disc anomalies (e. g., optic nerve drusen) modern nerve fibre diagnostics by means of GDx technology is a helpful enrichment in clinical routine.

Ruthenium-106 plaque brachytherapy for symptomatic vasoproliferative tumours of the retina.

AIM: To investigate the safety and efficacy of beta ray brachytherapy in treatment of vasoproliferative tumours of the retina (VTR). METHODS: 35 consecutive patients with symptomatic VTR were treated with a ruthenium-106 ((106)Ru) plaque. Three tumours had been treated previously (two with cryotherapy; one with transpupillary thermotherapy). 32 VTR (91.4%) were located in the lower half of the retina and all of them were found between the mid-periphery and the ora serrata. The mean tumour thickness was 2.8 mm. An exudative retinal detachment was present in 25 eyes (71.4%) and in 15 cases (42.9%) hard exudates were found in the macula. The major symptom was loss of vision (77.1%). RESULTS: Brachytherapy was well tolerated by every patient. The mean applied dose was 416 Gy at the sclera and 108 Gy at the tumour apex. In all but four eyes (88.6%), it was possible to control the VTR activity. The median follow up time was 24 months. Three of the above mentioned four eyes with treatment failure had had secondary glaucoma before therapy. There was no case of radiation induced neuropathy or retinopathy. Cataract surgery was necessary for five patients. The development of epiretinal gliosis was the most common event during follow up (n = 10, 28.6%). The mean visual acuity decreased slightly (0.33 before and 0.29 after brachytherapy). Multivariate analysis showed that the presence of macular pathology before treatment was associated with a 6.1-fold risk of vision of 0.25 or better (p = 0.03). CONCLUSIONS: beta ray brachytherapy with (1106)Ru plaques was able to control the activity of VTR and retain vision. Cases with secondary glaucoma before treatment had a very poor prognosis.

[Analysis of ocular surface alterations following proton beam radiation in eyes with conjunctival malignant melanoma]. / Analyse der okulären Oberfläche nach Protonenbestrahlung bei malignem Melanom der Bindehaut.

BACKGROUND: In cases of large, diffuse or multilocular growth pattern of conjunctival melanoma, proton beam irradiation can serve as an alternative therapy to exenteration. In extended tumours, ocular surface problems can result after therapy. In this study we examined ocular surface integrity of ten patients who underwent proton beam radiation between 1996 and 2002. METHODS: The patients were examined during their follow-up. Eight of the ten cases who underwent proton radiotherapy were recurrent tumours, which were previously treated with other adjuvant therapies. We performed a standard ophthalmological examination and detailed tear film diagnostics. RESULTS: The follow-up was 17-87 months (mean: 40.9+/-20.1). In six cases more than 50% of the upper and lower eyelids were included in the radiation field. All of these cases showed moderate to severe sicca symptoms. The impression cytology revealed squamous metaplasia of conjunctival cells in nine of ten cases. CONCLUSIONS: Squamous metaplasia of conjunctival epithelia indicates a radiogenic, persisting disturbance of differentiation of the conjunctival epithelial cells. The tear film instability correlates with the loss of mucin-secreting goblet cells and meibomian gland dysfunction.

Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma.

Uveal melanoma is the most common form of primary eye cancer. Monosomy 3, which is an unusual finding in tumors but is present in approximately 50% of uveal melanomas, is significantly correlated with metastatic disease. To obtain positional information on putative tumor suppressor genes on this chromosome, we have investigated tumors from 333 patients by comparative genomic hybridization, microsatellite analysis, or conventional karyotype analysis. A partial deletion of the long arm was found in eight tumors, and the smallest region of deletion overlap (SRO) spans 3q24-q26. We found six tumors with a partial deletion of the short arm and were able to define a second SRO of about 2.5 Mb in 3p25. This SRO does not overlap with the VHL gene. Our finding suggests a role for two tumor suppressor genes in metastasizing uveal melanoma and may explain the loss of an entire chromosome 3 in these tumors.

Expression of VLA-2, VLA-3, and alpha(v) integrin receptors in uveal melanoma: association with microvascular architecture of the tumour and prognostic value.

BACKGROUND: The interaction of the integrin receptors with their ligands (collagen, laminin, fibronectin, and others) has a crucial role during the reorganisation of the extracellular matrix and the metastatic process. The presence of particular vascular patterns in uveal melanoma is associated with the development of metastases. There is some evidence that interactions between the tumour cells and the extracellular matrix are responsible for the shape of these patterns. METHODS: The expression of VLA-2, VLA-3, and alpha(v) integrin receptors was examined by immunohistochemistry on paraffin embedded tumour specimens from 92 uveal melanomas (iris melanomas excluded). Possible correlations between these results and the tumour vascular patterns, the histological features of the tumours as well as the clinical outcome of the patients, were investigated. RESULTS: The expression of VLA-2 in tumours was associated with the presence of vascular networks (p = 0.05). Tumours with less than 25% VLA-3 positive cells infiltrated the sclera more frequently than those with more than 25% VLA-3 cell positivity (p = 0.05). Tumours expressing less than 50% alpha(v) positive cells were associated with the mixed or epithelioid cell type (p = 0.05) and, with less statistical precision, with the presence of extraocular growth (p = 0.07). The univariate logistic regression analysis showed that the risk of developing metastases within the first 5 years after diagnosis did not depend on the expression of the integrin receptors investigated. CONCLUSION: The potential biological importance of the associations between integrin expression and the histopathological features of the tumours found in the present study remains to be elucidated in future experiments. The immunohistochemical detection of VLA-2, VLA-3, and alpha(v) integrins had no prognostic value in our preliminary report.

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/m(2) body surface area and a light dose of 100 J/cm(2) 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.

Altered expression of beta 1 integrins in renal carcinoma cell lines exposed to vinblastine.

BACKGROUND: Cellular expression of P-glycoprotein (P-gp) which mediates a well characterized mechanism of multidrug resistance (MDR) has been reported previously to be associated with an enhanced tumor dissemination. Since adhesion receptors of the beta 1 integrin family play a substantial role in tumor spread, we studied expression of VLA-1 to -6 in a total of four renal carcinoma cell (RCC) lines prior to and after induction of MDR via exposure to vinblastine. MATERIAL AND METHODS: Surface expression of P-gp and VLA-1 to -6 was determined immunocytochemically in untreated pre-established renal carcinoma cell lines (Caki-1, Caki-2, A498) and a cell line derived from a RCC patient who had received a vinblastine-containing therapy regimen prior to the resection of a local relapse of the tumor (EH). Resistant sublines were cultivated in the presence of 1 ng/ml and 10 ng/ml of vinblastine sulfate, respectively. RESULTS: In all cell lines examined, an increased number of P-gp expressing cells was observed upon exposure to vinblastine. Significant changes of beta 1 integrin expression were observed in three of four RCC cell lines. A de novo expression of VLA-1, VLA-2, and VLA-4 as detected by immunocytochemistry occurred in resistant Caki-1 cells. A498 cells showed an increasing number of VLA-2 positive cells in drug resistant sublines. In contrast, a decrease of VLA-2 and VLA-5 expression was found in EH cells, the only cell line exhibiting P-gp expression prior to vinblastine exposure. Caki-2 cells showed no significant changes of surface integrin expression upon treatment with vinblastine. CONCLUSIONS: Our results demonstrate that induction of drug resistance can be associated with substantial changes of the integrin phenotype in renal carcinoma cell lines. In our experiments, among all VLAs studied, VLA-2 was most frequently altered in expression by RCC cell lines. The significance of these observations for aberrant metastatic properties of multidrug resistant tumor cells will be the subject of further studies.

Active specific immunotherapy of renal cell carcinoma: cellular and humoral immune responses.

We investigated the effect of vaccinating renal cell carcinoma (RCC) patients with irradiated autologous or allogeneic tumor cells and Newcastle disease virus (NDV) as adjuvant on cellular and humoral antitumor immunity. By Western blot analysis, we found that vaccination induced antibody formation in 33 of 34 patients against NDV proteins but not against tumor cell related antigens. NDV proteins detected had molecular weights of 53 kDa, 55-56 kDa, and 66 kDa. ADCC by patients' isolated PBMC and patients' sera against autologous or allogeneic tumor cells was not enhanced after vaccine treatment in a nonradioactive cytotoxicity assay. Target cells infected with NDV were lysed more effectively (p < 0.05) in ADCC after vaccination than noninfected targets. Natural cellular cytotoxicity of patients' isolated PBMC was not altered during vaccine treatment. Specific lysis rates against autologous and allogeneic RCC cells not exceeded 10% (effector:target ratio 50:1). Specific lysis of K-562 cells was > 20%; a slight decrease in lysis during vaccination was not significant. Numbers of lymphocyte subsets from patients' peripheral blood analyzed by FACS revealed significant expression of CD20+ (p < 0.02) and CD39+ (p < 0.03) cell numbers by vaccine therapy. Cytokine detection in patients' sera by ELISA showed significant increases (p < 0.05) for IFN-gamma and TNF-alpha but not for IFN-alpha four h post vaccination. Thus, immunomodulation with autologous or allogeneic RCC tumor cell vaccines is mainly due to cytokine induction, whereas tumor specific humoral or cellular responses are not detectable in patients' peripheral blood.

[Prognostically relevant markers of malignant melanoma of the uvea]. / Prognostisch relevante Marker bei malignem Melanom der Uvea.

In addition to classic risk factors such as tumor size, tumor location, and histological cell type, a range of other potentially prognostic parameters have been discovered in the past few years. Many of these have only been described once so that they cannot be considered established markers. A few, however, such as vascular patterns or monosomy 3, were independently identified by several groups and now constitute recognized prognostic markers. The association of these factors with the disease course provides us with ever-new insights into the biology of this tumor. In particular, with the aid of new technologies such as microarray analysis, researchers around the globe hope that new and exciting discoveries will be made that can also modify therapy concepts.

[Endoscopic resection of malignant melanomas of the uvea after preoperative stereotactic single dose convergence irradiation with the Leksell gamma knife]. / Endoresektion maligner Melanome der Uvea nach präoperativer stereotaktischer Einzeldosis-Konvergenzbestrahlung mit dem Leksell-Gamma-knife.

In cases of large volume and highly prominent melanomas of the uvea, it is rare for conventional methods of radiation therapy to enable salvage of the globe or even residual functionality of the affected eye. Complications due to the massive amount of accumulated necrotic tissue often necessitate subsequent enucleation of the blinded eye. Tumor-destroying, single-dose convergence irradiation (radiosurgery) of such tumors applied shortly before endoresection can represent a possible therapeutic alternative in these types of cases.

Influence of latanoprost on retinal microcirculation in glaucoma.

PURPOSE: To test whether latanoprost has an influence on ocular haemodynamics, considering the general reputation of prostaglandins which is frequently associated with vasoconstriction. The effect of latanoprost on the retinal blood supply of treatment-naïve glaucoma patients was tested. MATERIALS AND METHODOLOGY: 13 patients (7 male, 6 female) who had just recently been diagnosed with primary open-angle glaucoma (POAG) were treated with latanoprost (0.005%). The average age of our study group was 63.8 years (+/- 2.9 years). The drug's effect on retinal autoregulation was assessed by flicker test using the Dynamic Vessel Analyzer (DVA). Examinations took place before initializing treatment, after 4 weeks and once again after 4 to 6 months. RESULTS: In our group of POAG patients, the IOP under treatment was significantly reduced about 25%. No intraindividual differences in systemic blood pressure and heart rate were observed. In DVA measurements of glaucoma patients, the maximum flicker dilation of the arteries was significantly lower than reported for healthy volunteers. Beyond that, POAG patients did not show significant differences in vessel diameters, peak amplitudes as well as maximum dilations of retinal arteries and veins before and under treatment with latanoprost (0.005%). CONCLUSION: Latanoprost markedly lowered the IOP but it did not exert a significant effect on retinal haemodynamics. There was neither a tendency towards vasoconstriction nor towards vasodilation. Sustaining reperfusion damage after topical latanoprost therapy thus seems to be highly unlikely. Further studies must show if sole IOP lowering or a dual positive effect - IOP lowering and improvement of retinal vessel autoregulation - have a more positive impact on the long term follow-up of glaucoma patients.

[Endoresection of large uveal melanomas after pretreatment by single-dose stereotactic convergence irradiation with the leksell gamma knife--first experience on 46 cases]. / Endoresektion grosser Melanome der Uvea nach stereotaktischer Single-dose-Vorbestrahlung mit dem Leksell Gamma-Knife -- Erste Erfahrungen an 46 Fällen.

BACKGROUND: The aim of this non-comparative, consecutive case series is to evaluate the short-term results after endoresection of large uveal melanomas in combination with pretreatment with stereotactic gamma knife radiosurgery. METHODS: Between March 2000 and November 2002, forty-six patients with large uveal melanomas underwent stereotactic radiosurgery followed by endoresection of the tumour via a standard three-port vitrectomy including laser photocoagulation and silicone oil tamponade. The average tumour height was 9.5 mm. The minimum dose delivered to the tumour volume was 25 Gy. RESULTS: The median follow-up time was 410 days. In 40 cases (87 %), the eye was retained with a VA of 20/200 or better in 30 cases (65.2 %) and 20/63 or better in ten cases (21.7 %). In 12 eyes with a follow-up of >/= 0.5 years, the median VA was 20/80 after silicone oil removal and cataract surgery had been performed. Six eyes (13 %) were enucleated due to serious complications caused by the radiosurgery (3 cases) or endoresection (3 cases). In 13 patients (28.2 %), additional major surgery was required. Seven patients developed liver metastases during follow-up and six patients died. No local tumour recurrences were observed. CONCLUSIONS: Eyes with large uveal melanomas can be salvaged by stereotactic radiotherapy followed by endoresection.

In vivo distribution of integrins in renal cell carcinoma: integrin-phenotype alteration in different degrees of tumor differentiation and VLA-2 involvement in tumor metastasis.

We studied 23 renal cell carcinomas and two normal kidney tissues by immunohistochemistry using monoclonal antibodies against subunits of the VLA integrins (VLA-1 to VLA-6) and CD51. All integrins investigated in our study, except VLA-4 (ubiquitous negative), were distributed in different patterns in tumors assayed. We found a correlation between VLA-2 expression and site of tissue; primary tumor cells expressed no VLA-2 integrin, whereas tumor cells from metastatic tissues exhibited VLA-2 positivity (P < .009). Additionally, the expression of VLA-3 and VLA-5 correlated with tumor grading; both integrins were undetectable in G1 tumors but widely expressed in G2 and G3 tumors (VLA-3, p < .000; VLA-5, p < .005). Our results suggest that VLA-2 integrin is involved in metastasis of RCC and that poorly differentiated tumor cells have a different integrin phenotype when compared to normal or highly differentiated tumor cells.

Expression of Fas and Fas ligand in uveal melanoma: biological implication and prognostic value.

The interaction between Fas and Fas ligand is one possible immune escape mechanism used by tumour cells. In the present study, melanoma tissue from 103 patients who underwent enucleation for malignant uveal melanoma (iris melanomas excluded) was stained by immunohistochemistry with monoclonal antibodies specific for Fas, Fas ligand, CD3, CD8, and CD68. Histological and clinical data for these tumours were assessed. Both Fas and Fas ligand were detected in uveal melanomas. Cells of the monocyte/macrophage lineage rather than T-cells were the predominant group of tumour-infiltrating cells. The metastasis-free 5-year survival rates in the univariate analyses were considerably lower in patients with tumours that lacked Fas ligand expression (< 35% of the tumour cells), in the presence of more than 50 CD8-positive cells in 20 high-power fields and in the presence of more than 100 CD3-positive cells in 20 high-power fields. Fas and Fas ligand expression was associated with scleral infiltration. After adjustment for scleral infiltration, the predictive value of both Fas and Fas ligand expression was markedly decreased. In addition, the CD3- and CD8-positive cell count was positively associated with the histological cell type. Cox proportional hazards models showed that the presence of CD3- and CD8-positive cells was not an independent prognostic factor after adjusting for histological cell type. This preliminary observation deserves further investigation, which may shed more light on the immune escape mechanisms of this tumour and thus enable novel therapeutic strategies. The clinical relevance of this observation is limited, as more predictive parameters have been described for uveal melanoma.

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.

Expression of the cell adhesion molecules ICAM-1, VCAM-1 and NCAM in uveal melanoma: a clinicopathological study.

To investigate the relationship between the expression of the cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) in uveal melanoma and the metastatic spread in the first 5 years after diagnosis, we performed a hospital-based case-control study with human tissue from 90 patients who underwent enucleation for primary uveal melanoma (iris melanoma excluded). Thirty-five patients developed metastasis within the first 5 years, and 55 patients lived metastasis-free for at least 5 years after enucleation. The paraffin-embedded and formalin-fixed globes were studied by immunohistochemistry with monoclonal antibodies for ICAM-1, VCAM-1 and NCAM. A strong ICAM-1 positivity (more than 75% of the tumor cells stained positive) was detected in 73 tumors (81%). The expression of 75% or less ICAM-1 positive cells in tumors was strongly associated with the development of metastases (odds ratio: 7.5, p = 0.001). Multiple logistic regression models showed that ICAM-1 is an independent risk factor for metastasis even after control for important prognostic markers like extraocular growth, ciliary body involvement, scleral infiltration and cell type. VCAM-1 was expressed in 24 out of 88 tumors (27.3%) and NCAM only in 14 out of 87 tumors (16%). Only spindle cells stained positive with anti-NCAM. NCAM and VCAM-1 expression was not related to metastasis. Our results show that the loss of ICAM-1 expression is associated with an increased risk of metastasis within the first 5 years after diagnosis.