Nikolaos E. Bechrakis

Biopsy in indeterminate intraocular tumors

OBJECTIVEnTo describe an intraocular biopsy technique that allows accurate histopathologic diagnosis in cases of clinically unclassifiable uveal tumors.nnnDESIGNnRetrospective noncomparative consecutive interventional case series.nnnPARTICIPANTS/METHODSnIntraocular biopsies were performed by a vitreous cutter either by a two-port clear cornea approach in 11 patients with unclassifiable iris tumors or by a three-port pars plana vitrectomy in 23 patients with unclassifiable choroidal tumors. Specimens were formalin fixed and paraffin processed. Hematoxylin-eosin and periodic acid-Schiff stains were performed in all cases, with additional immunohistochemical stains using the alkaline phosphatase, antialkaline phosphatase method in cases that could not be conventionally classified.nnnMAIN OUTCOME MEASURESnClinical observation and histopathologic examination of intraocular biopsies.nnnRESULTSnIn 97% of cases (n = 33) a definite diagnosis could be established by the biopsy specimen. A melanoma could be diagnosed in 73% of cases (n = 8) of iris tumors and in 57% of cases (n = 13) of posterior intraocular tumors. Other diagnoses included nevus, metastasis, vasoproliferative tumor, hemorrhage, gliosis, and scleritis. Complications were encountered in four cases: a vitreous hemorrhage occurred twice, an inconclusive biopsy result, and an intraocular tumor spread occurred once, respectively. No increased tumor-related mortality was observed after a mean follow-up of 44 months.nnnCONCLUSIONSnIntraocular biopsy by a vitreous cutter allows the histopathologic examination of formalin-fixed paraffin-embedded tumor tissue. This increases the diagnostic accuracy, avoiding the risk of extraocular tumor spread seen with transscleral biopsy techniques.

Effects of granulocyte-macrophage colony-stimulating factor and foreign helper protein as immunologic adjuvants on the T-cell response to vaccination with tyrosinase peptides

Immunologic adjuvants are used to augment the immunogenicity of MHC class I–restricted peptide vaccines, but this effect has rarely been systematically evaluated in a clinical trial. We have investigated, in a phase I study, whether addition of the 2 adjuvants GM‐CSF and KLH can enhance the T‐cell response to MHC class I peptide vaccines. Forty‐three high‐risk melanoma patients who were clinically free of disease received 6 vaccinations with MHC class I–restricted tyrosinase peptides alone, with either GM‐CSF or KLH or with a combination of both adjuvants. The primary end point was induction of tyrosinase‐specific T cells, and serial T‐cell monitoring was performed in unstimulated peripheral blood samples before and after the second, fourth and sixth vaccinations by ELISPOT assay. Tyrosinase‐specific IFN‐γ‐producing T cells were detected as early as 2 weeks after the second vaccination in 5 of 9 patients vaccinated with tyrosinase peptides in combination with GM‐CSF and KLH but not in any patient vaccinated with tyrosinase peptides without adjuvants or in combination with either adjuvant alone. After 6 vaccinations, tyrosinase‐specific T cells were found in patients immunized with peptides either without adjuvants (3 of 9 patients) or in combination with the single adjuvant GM‐CSF (4 of 9 patients) but not with KLH (0 of 10 patients). Our results suggest that addition of either GM‐CSF or KLH as a single adjuvant has little impact on the immunogenicity of tyrosinase peptides. The combined application of GM‐CSF and KLH was associated with early induction of T‐cell responses.

Intraocular metastases: differential diagnosis from uveal melanomas with high-resolution MRI using a surface coil

Magnetic resonance imaging with dedicated surface coils plays a pivotal role in differential diagnosis and staging of intraocular tumors. The purpose of this study was to establish MRI criteria for the differential diagnosis of uveal melanomas and intraocular metastases. In a prospective study 44 eyes in 36 patients with intraocular metastases and 200 patients with uveal 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. The MR signal intensities typically expected for metastases (slightly hyperintense on non-contrast T1-weighted images and hypointense on T2-weighted images compared to the vitreous body) were seen in only 23.1%. The typical melanoma signal of either moderate or strong hyperintensity on T1-weighted images and hypointensity on T2-weighted images was seen in 69.4% of the proven melanomas. Contrast enhancement was observed in both metastases and melanomas. Morphological differences between metastases and melanomas were detected in tumor size, shape, position, frequency of retinal detachment, and homogeneity of the tumor. Differentiation between intraocular metastases and uveal melanoma is limited by overlap of signal intensities. Some improvement is achieved with morphologic criteria.

Klinische Charakteristika der Aderhautmetastasierung

ZusammenfassungHintergrundDie Aderhautmetastase ist der häufigste maligne intraokulare Tumor. Ziel dieser Untersuchung ist die Charakterisierung des klinischen Erscheinungsbildes, der zugrunde liegenden Tumorerkrankung sowie des differenzialdiagnostischen Vorgehens bei Aderhautmetastasierung (AM).Patienten und MethodeEs wurden 71 konsekutive Patienten mit AM ausgewertet. Besondere Beachtung fanden die okulären Symptome, das ophthalmoskopische und sonographische Erscheinungsbild der AM sowie die Charakterisierung der zugrunde liegenden Tumorerkrankung. Bei allen Patienten erfolgte ein vollständiges Screening (CT Kopf, Thorax und Abdomen; Knochenszintigraphie) zur Primärtumorsuche bzw. bei bereits bekanntem Primärtumor zur Suche nach weiteren Organmetastasen.ErgebnisseEine symptomatische AM zeigten 95% der Patienten, bei 5% handelte es sich um einen Zufallsbefund. Bei 60% der Patienten bestand eine solitäre AM, bei 40% multiple AM (2–14). Bei Erstvorstellung war bei 18% der Patienten (n=13) keine Tumorerkrankung bekannt. Bei 12 dieser Patienten konnte ein Bronchialkarzinom diagnostiziert werden. Insgesamt bestand bei 53% der Patienten ein Mammakarzinom, bei 26% ein Bronchialkarzinom, bei je 3% ein Nieren- oder Darmkarzinom, ein Aderhautmelanom oder ein kutanes Melanom, sowie bei einzelnen Patienten ein Zervix-, Ovarial-, Thymus- oder Prostatakarzinom sowie in einem Fall ein unbekannter Primärtumor. Weitere Fernmetastasen zeigten 96% der Patienten. Beim Bronchialkarzinom trat die AM im Mittel 9xa0Monate, beim Mammakarzinom 68xa0Monate nach Diagnose der Tumorerkrankung auf. Bei 58% der Patienten mit Bronchialkarzinom war die AM die Erstmanifestation der Grunderkrankung, beim Mammakarzinom bei 28% das erste Zeichen der Metastasierung.SchlussfolgerungAderhautmetastasen finden sich fast nur bei einer generalisierten Tumorerkrankung. Beim Mammakarzinom treten sie typischerweise Jahre nach Diagnose auf und können das erste Zeichen einer Generalisierung sein. Beim Bronchialkarzinom kann die Aderhautmetastase das erste klinische Zeichen der Erkrankung sein.AbstractBackgroundChoroidal 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 designRetrospective observational case series.Patients and methodsA 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.ResultsOf 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.ConclusionsChoroidal 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.

Photodynamic therapy with verteporfin for uveal melanoma

ZusammenfassungHintergrundZiel dieser Studie ist es, zu untersuchen, ob mittels einer photodynamischen Therapie (PDT) mit Verteporfin eine Tumorzellnekrose beim humanen Aderhautmelanom induziert werden kann.MethodeBei 4 Augen mit einem nicht bulbuserhaltend therapierbaren malignen Melanom der Aderhaut wurde 2–3xa0Tage vor der geplanten Enukleation das Melanom mit einer PDT behandelt. Die Bulbi wurden histologisch untersucht.ErgebnisseBei einer Lichtdosis ≥100xa0J/cm2 konnten bei 2 weniger stark pigmentierten Tumoren nach der PDT Effekte im Tumorgewebe bis 2,5xa0mm Tiefe gefunden werden. Histologisch zeigten sich Gefäßverschlüsse und Thrombosen in den Tumorgefäßen. Bei starker Pigmentierung konnte keine Tumorzellnekrose induziert werden.SchlussfolgerungIn Abhängigkeit von den Behandlungsparametern und dem Pigmentierungsgrad des Tumors lässt sich mit der PDT mit Verteporfin eine Nekrose im humanen Aderhautmelanom erzeugen. Evtl. kann die PDT mit angepassten Parametern als adjuvante Therapie bei der Behandlung von wenig pigmentierten okulären Malignomen eingesetzt werden.AbstractBackgroundThe aim of this study was to evaluate whether photodynamic therapy (PDT) with verteporfin is able to induce tumor cell necrosis in human uveal melanomas.MethodsOn four eyes with an uveal melanoma, PDT with verteporfin was performed on the tumor 2–3xa0days before planned enucleation. The eyes were evaluated histologically.ResultsIn two melanomas with only mild pigmentation some effects after PDT were detected on tumor tissue in a depth up to 2,5xa0mm at light doses ≥100xa0J/cm2. 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.ConclusionDepending 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.

Phacoemulsification following treatment of choroidal melanoma

Abstractu2002Background: 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.

Jod-125-Brachytherapie und transsklerale Tumorresektion bei großen uvealen Melanomen

ZusammenfassungHintergrund. Die Behandlung großer uvealer Melanome stellt in Anbetracht der häufig auftretenden Spätkomplikationen eine besondere therapeutische Herausforderung dar. Zweck dieser Studie war der Vergleich der funktionellen Ergebnisse und der Komplikationsraten bei Patienten mit großen uvealen Melanomen, die entweder mittels einer Jod-125-Brachytherapie oder mittels einer transskleralen Tumorresektion behandelt wurden.nPatienten und Methoden. Von einem Gesamtkollektiv von 211 Patienten mit uvealen Melanomen, deren Prominenz größer als 7,5 mm war, wurden 135 Patienten mit ähnlichen Tumorcharakteristika selektiert. Mittels einer Jod-125-Brachytherapie wurden 87 Patienten behandelt, und 48 Patienten erhielten eine transsklerale Resektion. Die mittlere Nachbeobachtungszeit betrug 26 Monate.nErgebnisse. 58% der Patienten, bei denen eine transsklerale Tumorresektion durchgeführt wurde, und 15%, bei denen eine Jod-125-Brachytherapie durchgeführt wurde, behielten in einer Nachbeobachtungszeit von 28 Monaten einen Visus =0,1. Nach Jod-125-Brachytherapie besteht eine 6fach höhere Rate an Sekundärglaukomen im Vergleich zur transskleralen Resektion. Die sekundäre Enukleations- und Mortalitätsrate war in beiden Gruppen gleich.nSchlussfolgerung. Die transsklerale Tumorresektion ermöglicht Patienten mit großen uvealen Melanomen im Vergleich zur Jod-Brachytherapie einen besseren langfristigen Visuserhalt.AbstractBackground. 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.nPatients 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.nResults. After transscleral resection 58% of the patients and after 125Iodine -brachytherapy 15% of the patients retained a visual acuity of ≥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.nConclusion. Patients with large melanomas eligible for transscleral local resection have a better visual function than those treated by 125Iodine brachytherapy.

[Tamoxifen retinopathy: a case series of clinical and functional data].

BACKGROUNDnTamoxifen is used in the treatment of selected patients with breast carcinoma. Rarely, it has been shown to cause ocular toxic effects including crystalline retinopathy.nnnMETHODSnRetrospective 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.nnnRESULTSnSeven 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.nnnCONCLUSIONSnMost 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.ZusammenfassungHintergrundTamoxifen wird in der adjuvanten Therapie bei der Behandlung des Mammakarzinoms eingesetzt. In seltenen Fällen können Sehstörungen unter Tamoxifen-Therapie beobachtet werden.Patienten und MethodeRetrospektive Auswertung von klinischen und funktionellen (Visus, Gesichtsfeld, Farbensehen) Befunden bei einer Fallserie von 8xa0Patientinnen unter Tamoxifen-Therapie mit Einschluss einer elektrophysiologischen Untersuchung.ErgebnisseSieben der 8xa0Patientinnen gaben Sehstörungen an. Bei einer Patientin zeigten sich kristalline Ablagerungen in der Hornhaut und Makula. Drei Patientinnen wiesen Veränderungen im Ganzfeld- und multifokalen Elektroretinogramm auf, 2xa0Patientinnen zeigten lediglich ein pathologisches multifokales Elektroretinogramm. In 6 Fällen wurde ein desaturierter Panel-D-15-Farbsehtest durchgeführt, der bei 5xa0Patientinnen mäßige Verwechselungen offenbarte.SchlussfolgerungDie Mehrzahl der sehbeeinträchtigten Tamoxifen-Patientinnen zeigte elektrophysiologische Veränderungen, insbesondere im multifokalen Elektroretinogramm, wobei sich ein morphologisches Korrelat häufig nicht sicher nachweisen ließ. Bei unklaren Sehstörungen unter Tamoxifen-Einnahme empfiehlt sich daher eine elektrophysiologische Abklärung.AbstractBackgroundTamoxifen is used in the treatment of selected patients with breast carcinoma. Rarely, it has been shown to cause ocular toxic effects including crystalline retinopathy.MethodsRetrospective 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.ResultsSeven 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 panelxa0D-15 colour vision test; five of these showed some disorders.ConclusionsMost 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.

Where is the superiority of proton radiation for ocular tumours

Most ocular tumours today are treated by different modalities preserving the eye, varying from radiotherapy to surgical excision. Important goals of all treatment options are effective tumour destruction and preservation of vision in the eye harbouring a tumour. Large studies with extensive follow-up have taught us in recent years that patient survival in the case of uveal melanoma, the most common primary malignancy of the eye, is independent of the treatment option chosen by the ophthalmic oncologist. We know, however, that each of the existing techniques has its limits and that we have to anticipate drawbacks if we do not respect them. The main limiting factors in the treatment of intraocular tumours are tumour size and location within the eye. By trying to retain eyes that harbour tumours with increasing size and location near structures critical for visual function, a rising incidence of treatment-related complications, such as radiation optic neuropathy and retinopathy, secondary glaucoma and retinal detachment, is observed. Direct comparison of the different treatment modalities in order to evaluate the intrinsic complication potential of each of them is extremely difficult, due to the selection bias of the treated tumours and the a priori allocation to one or the other therapeutic modality by the physician. Comparisons are sparse in the literature and have validity only if they are based on matched groups with tumours that have similar features [1, 2, 3]. When evaluating radiotherapy techniques in ophthalmology, one must consider the different physical properties of the isotopes or charged particles used to treat ocular tumours. Brachytherapy was introduced in ophthalmology by Stallard, who used cobalt-60 plaques, but isotope selection has changed towards ruthenium106 and iodine-125 plaques in recent decades. The latter two isotopes have better dose distributions and allow safer radiation protection. Gragoudas, Constable and co-workers started in 1975 to treat uveal melanomas with proton beam radiotherapy, which has since expanded to a number of centres worldwide that treat a large proportion of all ophthalmic tumour patients [8]. The theoretical advantages of proton beam irradiation are based on the physical properties Graefe’s Arch Clin Exp Ophthalmol (2002) 240:513–514

Aderhautmelanom Adjuvante Therapie bei Hochrisikopatienten und neue Therapieansätze im metastasierten Stadium

ZusammenfassungDie Behandlungsmodalität des primären Aderhautmelanoms hat bisher keinen direkten Einfluss auf die Überlebensprognose des Patienten. Durch die Identifizierung signifikanter Prognoseparameter bezüglich des Risikos, Metastasen eines Aderhautmelanoms zu entwickeln, werden neue Behandlungsstrategien erarbeitet mit dem Ziel, die Entstehung von Metastasen zu verhindern. Dabei spielt die Immuntherapie durch die Entwicklung geeigneter Impfstoffe gegen melanomspezifische Tumorantigene eine zunehmende Rolle. Beim bereits metastasierten Aderhautmelanom betrug bis dato die mittlere Überlebenszeit ca. 5 Monate. In der letzten Zeit konnte durch die intrahepatische Infusion von Fotemustin die mittlere Überlebenszeit auf 14 Monate bei selektierten Patienten verlängert werden. Neue Therapieprotokolle werden aufgrund von Chemosensitivitätsuntersuchungen aktuell erarbeitet. Des Weiteren werden immuntherapeutische Modalitäten auch in der Behandlung von Metastasen von Aderhautmelanomen untersucht.AbstractThe 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 infusions. 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.