K. M. Kreusel

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.

Ruthenium-106 Brachytherapy for Peripheral Retinal Capillary Hemangioma

OBJECTIVE This study aimed to evaluate the efficacy and safety of ruthenium-106 brachytherapy of large peripheral retinal capillary hemangiomas. DESIGN A retrospective case series. PARTICIPANTS In 25 eyes of 24 patients, peripheral capillary retinal hemangiomas were treated. INTERVENTION Brachytherapy using 106-ruthenium/106-rhodium plaques was performed. MAIN OUTCOME MEASURES Eyes were reviewed for hemangioma regression after brachytherapy, occurrence of retinal detachment, requirement of additional vitreoretinal surgery, final visual outcome, and final retinal status. RESULTS Preoperative mean visual acuity of all eyes treated was 20/60, mean hemangioma diameter was 3.8 mm, corresponding to approximately 2 disc diameters. In 14 eyes, the retina was attached before surgery, 8 eyes showed an exudative detachment, and 3 eyes showed a traction detachment. Fifteen patients had definite von Hippel-Lindau syndrome. Twenty-three of 25 hemangiomas could be destroyed by single brachytherapy. In 16 eyes, a favorable outcome could be achieved. In nine eyes, outcome was unfavorable, characterized by a severe drop in visual acuity, a persisting exudative retinal detachment, or a recurrent traction detachment. In one eye requiring repeated brachytherapy, irradiation retinopathy occurred. Hemangiomas up to a size of approximately 5.0 mm without preoperative exudative detachment could be treated safely by brachytherapy, whereas a larger hemangioma size or a pre-existing exudative retinal detachment predisposed to an unfavorable outcome. CONCLUSION Solitary peripheral retinal hemangioma can be ablated effectively by ruthenium-106 brachytherapy. A favorable outcome can be expected if the hemangioma diameter is 5.0 mm or smaller and if there is no preoperative exudative retinal detachment.

DIFFERENTIAL STIMULATION OF INTESTINAL MUCIN SECRETION BY CHOLERA TOXIN AND CARBACHOL

Abstract Cholinergic stimulation triggers the secretion of apically stored, preformed mucin from goblet cells but the pathway of cAMP-stimulated mucin secretion is not known. In this study the effect of cholera toxin on mucin secretion in the human colonic goblet cell line HT-29/B6 was investigated and compared to the action of carbachol. PAS staining of mucin blotted onto nitrocellulose served to quantify the secretion of total mucin. Metabolic labelling was used to evaluate the secretion of newly synthesized mucin. The mucinous nature of the detected material was confirmed with an immunoblot employing a well-characterized polyclonal antibody reacting with MUC2-mucin. Cholera toxin caused a 116-fold increase of intracellular cAMP and strongly stimulated the secretion of both preformed and newly synthesized mucin for more than 20 h. Carbachol only triggered the release of preformed mucin immediately after addition. The secretory response to cholera toxin could be partly inhibited by the protein kinase A inhibitor H8 and the microtubule inhibitor colchicine. The action of carbachol was not affected by these agents. In conclusion, we demonstrate a direct cAMP-dependent effect of cholera toxin on mucin secretion by intestinal goblet cells. In contrast to carbachol, the action of cholera toxin involves de novo synthesis of mucin molecules and microtubule-mediated secretion. There seem to be distinct secretion pathways for muscarinic or cAMP-dependent stimulation of mucin secretion.

The outwardly rectifying Cl− channel is not involved in cAMP-mediated Cl− secretion in HT-29 cells: evidence for a very-low-conductance Cl− channel

The patch-clamp technique and transepithelial current measurements in conjunction with analysis of transepithelial current noise were employed in order to clarify the role of the outwardly rectifying, depolarization-induced Cl− channel (ORDIC) during cAMP-mediated Cl− secretion in HT-29/B6 cells. Confluent monolayers growing on permeable supports were used in order to ensure the apical location of measured Cl− channels. The ORDIC needed to be activated by excision and/or depolarization, and was found in both cAMP-stimulated and non-stimulated cells. Both 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) and 4,4′-dinitro-2,2′-stilbenedisulphonate (DNDS) induced fast flickery-type blocks of the ORDIC at low, micromolar blocker concentrations and were used as a probe for ORDIC. However, these substances were ineffective in blocking transepithelial forskolin-induced Cl− secretion of monolayers in Ussing chambers. No inhibitory effect at all was detected for DNDS up to 1 mmol/l. NPPB blocked the ORDIC at low concentrations (IC50=0.5±0.3 μmol/l) by reducing its open probability, but NPPB did not block forskolin-induced Cl− secretion unless high concentrations were used (IC50=240±10 μmol/l). In order to exclude effects of NPPB other than on the apical Cl− channel, trans-epithelial measurements were performed in basolaterally amphotericin-permeabilized, forskolin-stimulated preparations, and a serosal-to-mucosal Cl− gradient was applied as a driving force. Under these conditions, NPPBs inhibitory effects were also very small. Noise analysis of this gradient-driven Cl− current showed a very-low-frequency Lorentzian noise component (fc=1.4±0.2 Hz), which was not compatible with Lorentzians predicted from single-channel gating of ORDIC. As revealed from fura-2 fluorescence measurements, forskolin-stimulated Cl− secretion occurred in the absence of changes in intracellular Ca2+. Thus, we conclude that there is an apical Cl− channel in HT-29/B6 that is activated through the cAMP-mediated pathway and is insensitive to NPPB and DNDS, and the kinetics of which are incompatible with ORDIC kinetics. Therefore, despite its prevalence in isolated patches and even in cell-attached recordings, the ORDIC appears not to be involved in cAMP-mediated Cl− secretion by HT-29/B6 cells. From noise analysis, a very-small-conductance (probably below 1 pS), slow-gating Cl− channel was calculated as the conductive site in the apical membrane during forskolin stimulation.

Radiotherapy of unilateral choroidal metastasis: unilateral irradiation or bilateral irradiation for sterilization of suspected contralateral disease?

Radiotherapy is the highly effective standard in the treatment of choroidal metastasis. Visual acuity can be stabilized or increased in about 70-80% of eyes treated, thus prevailing the quality of life in these worse prognostic patients. In about 30-40% bilateral macroscopic disease is found at diagnosis. The best treatment for unilateral metastasis remains controversial: unilateral or bilateral irradiation for sterilization of suspected contralateral metastasis or unilateral irradiation without irradiation of the contralateral choroidea. In the analysis of a prospective study (ARO 95-08) 35 out of 50 patients with choroidal metastasis had unilateral disease and received unilateral irradiation with a lateral field using 6 MeV-photons (40 Gy in 20 fractions) without sparing the contralateral choroidea. Therefore the posterior contralateral choroidea received 50-70% of the total dose (20-28 Gy) for suspected micrometastasis. None of these patients developed contralateral choroidal metastasis during the median follow up time of 11.5 months. A unilateral field with 40 Gy for unilateral choroidal metastasis without sparing the contralateral choroidea seems to be effective in destroying contralateral micrometastasis with a lower risk of late side effects compared with bilateral fields.

Tight junctions and paracellular permeability in cultured bovine corneal endothelial cells

Intramembrane specializations of cultured bovine corneal endothelial cells were studied with thin section and freeze-fracture electron microscopy and related to the paracellular permeability and the transendothelial resistance (Rt) of the monolayers. The following intercellular junctions were found: single and discontinuous networks of tight junctions (TJ) which girdle the apico-lateral cell perimeter incompletely, gap junctions, and membrane undulations suggesting intermediate junctions. The macromolecular tracer ruthenium red penetrated into the lateral intercellular space beyond the level of the incomplete belt of TJ. Rt of these monolayers was 20.9±1.0 º · cm2 Protamine induced a reversible increase of Rt to 118±5 % of its control value. We conclude that incomplete belts of TJ may be the morphological counterpart of the high paracellular permeability of this monolayer and functionally and morphologically resemble those of their native endothelium. Cultured corneal endothelial cells are an excellent model for studying the influence of incomplete belts of TJ on paracellular permeability of cells.

Recurrence Rate Following Adjuvant Strontium-90 Brachytherapy after Excision of Conjunctival Melanoma

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.

Therapeutische Optionen in der Behandlung des malignen Melanoms der Bindehaut

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.

METASTATIC ADENOCARCINOMA OF THE PROSTATE TO THE CHOROID WITH LOSS OF VISUAL ACUITY AS A PRESENTING SYMPTOM

Choroidal metastasis is the most common intraocular malignancy. In more than 80% of all cases breast or lung cancer is the primary tumor.2.3 Choroidal metastasis is rare in prostate cancer. In most patients the first sign is loss of visual acuity, eventually leading to blindness2 Symptomatic disease may be treated effectively with radiotherapy, while breast and lung cancer may be treated with radiotherapy and/or chemotherapy.3.4 To our knowledge we report on the first patient in the urological literature in whom symptomatic choroidal metastasis was associated with prostate cancer.

Family Screening in Patients with Retinal Angiomatosis

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.