Wolfgang Sauerwein

Risk Factors for Metastases in Patents with Retinoblastoma

The study is based upon a review of data from 583 consecutive patients with retinoblastoma over the years 1956 to 1986. Mean follow-up was 8 years, and median was 5.5 years. In 41 patients, metastases developed within 5 years. The influence of clinical and histopathologic risk factors on the occurrence of metastases was first analyzed by univariate tests. Significant variables were then reevaluated using the Cox proportional hazards method. Four factors were found to be independently associated with the development of metastases: optic nerve invasion with and without involvement of the resection line, choroidal invasion and enucleation of an affected eye more than 120 days after initial diagnosis. The 5-year metastatic risks associated with these factors were 67%, 13%, 8%, and 4%, respectively. The relative risk estimate, calculated from the Cox model, was used for a score classification with groups of low, medium, and high metastatic risk. The 5-year incidence of metastases was 4%, 43%, and 68%, respectively.

Long term results after low dose ocular irradiation for choroidal haemangiomas

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

Boron analysis and boron imaging in biological materials for Boron Neutron Capture Therapy (BNCT)

Boron Neutron Capture Therapy (BNCT) is based on the ability of the stable isotope 10B to capture neutrons, which leads to a nuclear reaction producing an alpha- and a 7Li-particle, both having a high biological effectiveness and a very short range in tissue, being limited to approximately one cell diameter. This opens the possibility for a highly selective cancer therapy. BNCT strongly depends on the selective uptake of 10B in tumor cells and on its distribution inside the cells. The chemical properties of boron and the need to discriminate different isotopes make the investigation of the concentration and distribution of 10B a challenging task. The most advanced techniques to measure and image boron are described, both invasive and non-invasive. The most promising approach for further investigation will be the complementary use of the different techniques to obtain the information that is mandatory for the future of this innovative treatment modality.

Uptake of two 10B-compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001).

Disseminated metastases of colorectal cancer in liver are incurable. The trial EORTC 11001 investigates whether autotransplantation after extracorporeal irradiation of the liver by boron neutron capture therapy (BNCT) might become a curative treatment option because of selective uptake of the compounds sodium mercaptoundecahydro‐closo‐dodecaborate (BSH) or L‐para‐boronophenylalanine (BPA). BSH (50 mg/kg bw) or BPA (100 mg/kg bw) were infused into patients who subsequently underwent resection of hepatic metastases. Blood and tissue samples were analyzed forthe 10B‐concentration with prompt gamma ray spectroscopy (PGRS). Three patients received BSH and 3 received BPA. Adverse effects from the boron carriers did not occur. For BSH, the highest 10B‐concentration was observed in liver (31.5 ± 2.7 μg/g) followed by blood (24.8 ± 4.7 μg/g) and tumor (23.2 ± 2.1 μg/g) with a mean 10B‐concentration ratio metastasis/liver of 0.72 ± 0.07. For BPA, the highest 10B‐concentration was measured in metastases (12.1 ± 2.2 μg/g) followed by liver (8.5 ± 0.5 μg/g) and blood (5.8 ± 0.8 μg/g). As BPA is transported actively into cells, viable, metabolically active cells accumulate exclusively this compound. Consequently, a model is proposed to adjust the values measured by PGRS for the proportion of viable cells to express the relevant 10B‐concentration in the tumor cells, revealing a 10B‐concentration ratio metastasis/liver of 6.8 ± 1.7. In conclusion, BSH is not suitable as 10B‐carrier in liver metastases as the 10B‐concentration in liver was higher compared to metastasis. BPA accumulates in hepatic metastases to an extent that allows for extracorporeal irradiation of the liver with BNCT.

Boron Neutron Capture Therapy for Glioblastoma Multiforme

Aim: Glioblastoma multiforme (GBM) is an incurable disease that can only be managed in a palliative way. The GBM accounts for approximately half of all newly diagnosed primary brain tumors with an incidence of 2–3 cases per 100,000 people each year. Surgery and radiation are the standard options for palliation, and whether there is a place for chemotherapy is still discussed. Boron neutron capture therapy (BNCT) is a promising and possibly curative method of treating GBM. The purpose of this article is to provide an updated review on the current management and future possibilities of treating GBM with BNCT.Method: Use was made of computerized searches and of checking cross-references of articles and book chapters.Results: The principle of BNCT uses the high ability of 10B to capture thermal neutrons and to disintegrate immediately into a He nucleus (α-particle) and a Li nucleus. To reach a sufficient concentration of 10B in the malignant cells compared to the surrounding healthy tissue, 10B-carriers must be highly tumor-selective. At present, the 10B carriers boronophenylalanine (BPA) and sodium borocaptate (BSH) are used in clinical trials to perform BNCT.Conclusion: The BNCT is a promising and possibly curative method of treating GBM, but at present this procedure is far from perfect. Because of the lack of selectivity of the boron carriers, it appears so far that radiation toxicity limits the radiation dose, so that tumor damage is modest. Current investigations and developments are aimed at targeting the boron carriers to the tumor, in order to limit the damage to the healthy, surrounding tissue.

Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial.

Purpose: The uptake of the boron compound Na2B12H10-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial ‘Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility’ (protocol 11961).Methods and Materials: The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100 mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9 mg BSH/kg BW. The toxicity due to BSH was evaluated.Results: The average boron concentration in the tumor was 19.9±9.1 ppm (1 standard deviation (SD)) in the high dose group and 9.8±3.3 ppm in the low dose group, the tumor/blood ratios were 0.6±0.2 and 0.9±0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2±0.02 and 0.4±0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed.Conclusion: BSH proved to be safe for clinical application at a dose of 100 mg BSH/kg infused and at a dose rate of 1 mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.

Positive Interaction Between Light Iris Color and Ultraviolet Radiation in Relation to the Risk of Uveal Melanoma: A Case-Control Study

PURPOSE To examine the association among phenotypic characteristics, chronic and intermittent ultraviolet (UV) radiation, and the risk of uveal melanoma. DESIGN Case-control study. PARTICIPANTS Overall, between September of 2002 and March of 2005, 1677 eligible subjects (age range: 20-74 years, living in Germany) participated. Interviews were conducted with 459 incident uveal melanoma cases (response proportion 94%), 827 population controls (55%), 180 ophthalmologist controls (52%), and 187 sibling controls (57%). METHODS Data on phenotypic characteristics and chronic and intermittent UV radiation exposure were obtained from a self-administered postal questionnaire and computer-assisted telephone interview. We used conditional logistic regression to estimate odds ratios adjusting for the matching factors. Furthermore, we studied the presence of synergy (super additive of risk or relative excess risk due to interaction) between light iris color and several UV radiation exposures. MAIN OUTCOME MEASURES Hair color at age 20 years, eye color, untanned skin color, ability to tan, propensity to burn on exposure, freckling, occupational sun exposure, artificial UV radiation, burns to the eyes. RESULTS In all 3 control groups, fair skin color, freckling as a child, nevi on the upper arms, burns to the eyes, use of sunlamps, and ever worked outside for 4 or more hours per day were positively associated with uveal melanoma. The association with eye color was apparent only in population controls (odds ratio = 1.9; 95% confidence interval [CI], 1.4-5.2), resulting in a relative excess risk due to interaction of 0.9 (95% CI, -0.6-2.3) for light iris color and more than 5 eye burns (UV-related keratitis) and 0.6 (95% CI, -0.3 to 1.5) for light iris color and eye protection. CONCLUSIONS Our interaction analyses suggest that there is an etiologic synergism between light iris color and the exposure of UV radiation. People with light iris color may have an especially increased risk for uveal melanoma if they are exposed to UV radiation. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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

Aim: To investigate the safety and efficacy of β ray brachytherapy in treatment of vasoproliferative tumours of the retina (VTR). Methods: 35 consecutive patients with symptomatic VTR were treated with a ruthenium-106 (106Ru) 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: β ray brachytherapy with 1106Ru plaques was able to control the activity of VTR and retain vision. Cases with secondary glaucoma before treatment had a very poor prognosis.

New and recurrent tumor foci following local treatment as well as external beam radiation in eyes of patients with hereditary retinoblastoma.

The study is based on a retrospective analysis of data from 200 patients with hereditary retinoblastoma. Apart from four unilateral cases with a positive family history all patients had bilateral disease; 229 appeared suitable for conservative treatment while 167 eyes had to be enucleated. Primary local treatment was performed in 102 eyes, while 127 eyes received primary external beam radiation using a linear accelerator. Follow-up was adjusted by life tables, with 75% of the patients being observed longer than 2 years. Using life-table statistics new and recurrent tumors were found in 41 of all patients and in 95% of these cases they were noted within 26 months after initiation of therapy. Among eyes treated with primary external beam radiation new and recurrent tumors were observed significantly less frequently when 50 Gy (22% compared with 49% after 40 Gy) and a highly accurate beam alignment technique (22% compared with 48% after alignment to the outer bony canthus) were applied. The incidence of recurrent tumors following primary local treatment did not differ significantly with regard to the application of either photo-or cryocoagulation (28% vs 33%), while no recurrence was observed among tumors that were suitable for primary treatment using ruthenium or cobalt plaques.

LONG-TERM TREATMENT EFFECTS IN PATIENTS WITH BILATERAL RETINOBLASTOMA : OCULAR AND MID-FACIAL FINDINGS

A total of 99 patients with bilateral retinoblastoma who had been treated between 1965 and 1982 were reexamined in April 1988 to study the late effects of treatment. Their median age at the follow-up visit in 1988 was 16 years (range, 6–27 years), and the median follow-up was 15 years (range, 6–26 years). All patients underwent a full eye examination, morphometric measurements of the mid-face and genetic counselling. Each eye or orbit and the corresponding side of the patients mid-face were evaluated separately, resulting in 198 data sets from 99 individuals. Subjects were divided into four treatment groups according to whether photo- and cryocoagulation, enucleation, radiation therapy or various combinations thereof were used. In all, 81 eyes had a visual acuity of >0.4 (in 23 of these, however, only with low-vision aids). Within a dose range of 36–51 Gy, the location of the tumor (36%) or cataract (15%) were the main factors responsible for poor visual acuity, whereas radiation retinopathy and/or optic neuropathy occurred in only three cases. Cataracts were more frequently observed following orthovoltage as compared with megavoltage therapy (P=0.012). A total of 72 eyes had been enucleated and had not received radiation therapy at any time. Cosmetic results (as measured by several parameters) in these cases were significantly better then those in 28 subjects who underwent combined radiation therapy and enucleation. As defined by various subjective as well as objective findings, mid-facial hypoplasia occurred significantly more often following orthovoltage as compared with megavoltage therapy.