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Biomedical subjects

Hans E Grossniklaus

Publications and source records attributed to Hans E Grossniklaus.

At least 19 recordsLinked to original sources

Excimer laser exacerbation of Avellino corneal dystrophy.

We review the clinical, histopathological, and ultrastructural findings and DNA phenotyping of a patient with Avellino corneal dystrophy exacerbated by laser in situ keratomileusis. The findings are reported and interpreted in the context of a literature review. The case highlights the possible difficulty of recognizing subtle dystrophic findings, as well as the importance of avoiding refractive surgical intervention in patients with Avellino corneal dystrophy to avoid exacerbation of dystrophic deposits in the cornea and subsequent reduction in vision.

Adult↗

Angiostatin decreases cell migration and vascular endothelium growth factor (VEGF) to pigment epithelium derived factor (PEDF) RNA ratio in vitro and in a murine ocular melanoma model.

PURPOSE: Our previous experiments have shown that low dose angiostatin results in decreased hepatic micrometastasis in a mouse model of uveal melanoma. The purpose of these experiments is to evaluate the effect of angiostatin on in vitro migration of melanoma cells and to explore the in vivo mechanism of angiostatin in our model. METHODS: For in vitro studies, quantitative RT-PCR was used to detect VEGF and PEDF mRNA in mouse B16LS9 melanoma cells and Mel290 human uveal melanoma cells with or without supplemental 0.1 mug/ml murine or human recombinant angiostatin. A wound healing assay was used to measure cellular migration in these two groups of cells. For the in vivo mechanism, aliquots of tissue culture B16LS9 cells treated with or without 0.1 mug/ml murine angiostatin were heterotopically inoculated into the posterior compartments of the right eyes of C57BL/6 mice. Frozen hepatic tissue was prepared and stained with hematoxylin using an RNase-free technique. Hepatic micrometastatic uveal melanoma cells were obtained by laser capture microdissection (LCM). Levels of VEGF and PEDF mRNA were detected by real time RT-PCR in the hepatic micrometastases. RESULTS: After in vitro treatment of the cell lines with angiostatin, the ratio of VEGF/PEDF mRNA significantly decreased in the B16LS9 (0.88+/-0.11 [mean+/-standard deviation] versus 2.70+/-0.15 in the control group; p=0.00006) and Mel290 (0.12+/-0.02 versus 0.68+/-0.04 in the control group; p=0.00346). However, the absolute VEGF mRNA and PEDF mRNA did not significantly change (p>0.08 for both cell lines). The migration assay showed significantly decreased migration at 24 h and 48 h after angiostatin treatment for both B16LS9 (p<0.01) and Mel290 (p<0.01) cell lines. For the in vivo experiments, pretreatment with angiostatin resulted in a decreased VEGF/PEDF mRNA ratio in B16LS9 cells compared to controls (0.0274+/-0.0070 versus 0.1726+/-0.0313; p=0.0014). Additionally, there was significantly increased PEDF mRNA (2.14+/-0.12 versus 0.30+/-0.05 in the control group; p=0.00002) in the liver metastases after pretreatment with angiostatin. CONCLUSIONS: Angiostatin inhibits the migration of melanoma cells in vitro. Angiostatin significantly decreases the ratio of VEGF/PEDF mRNA level in vitro and in hepatic micrometastatic melanoma cells. Angiostatin increases PEDF mRNA in melanoma metastases.

Angiostatins↗

Ocular argyrosis after long-term self-application of eyelash tint.

PURPOSE: To report cases of ocular argyrosis that developed after long-term self-application of commercially available eyelash tint. DESIGN: Observational case series. METHODS: Case review, clinicopathologic analysis, and literature review. RESULTS: Three patients developed ocular argyrosis after the long-term self-application of Revlon Professional Roux Lash and Brow Tint (Colomer USA Corp, New York, New York, USA). Clinical evaluation revealed various degrees of silver deposition on the upper eyelid, lid margin, caruncle and conjunctiva, and diffuse Descemet's membrane deposits. In one case, histologic examination demonstrated silver deposition in the basement membrane and superficial substantia propria of the conjunctiva. CONCLUSIONS: Argyrosis can occur after long-term application of readily available eyelash tints, and the deposition of silver may be permanent. In certain circumstances, conjunctival argyrosis may simulate benign and malignant lesions, including conjunctival melanoma. These products should only be applied by trained cosmetologists.

Aged↗

Clinicopathologic studies of eyes that were obtained postmortem from four patients who were enrolled in the submacular surgery trials: SST Report No. 16.

PURPOSE: To compare the fundus photographic and fluorescein angiographic features with the histologic findings in eyes from patients enrolled in the Submacular Surgery Trials (SST). DESIGN: Clinical trials with clinicopathologic correlation. METHODS: Eyes that were obtained postmortem from patients who participated in the donor program were processed at the SST Pathology Center and examined histologically; the macular regions were reconstructed topographically with two-dimensional cartography. Fundus photographic and fluorescein angiographic features were correlated with the histopathologic and two-dimensional cartographic findings. RESULTS: The eyes from two patients each from the SST Group N and B Trials were studied. The study eye of one patient that had been assigned randomly to observation contained a subretinal fibrovascular scar that corresponded to a histologic growth pattern of a thick, collagenized subretinal component combined with a subretinal pigment epithelium (subRPE) fibrovascular component. The study eye of the other patient who was assigned randomly to observation showed angiographic occult without classic choroidal neovascularization (CNV) that corresponded to subRPE CNV. The study eye of one patient who was assigned randomly to surgery showed an angiographic surgical defect without CNV and histologic retinal pigment epithelium (RPE)/photoreceptor atrophy that was associated with a thin layer of subRPE CNV. The study eye of the other patient who was assigned randomly to surgery showed an angiographic surgical defect with classic CNV that corresponded to histologic RPE/photoreceptor atrophy that was associated with subRPE fibrovascular tissue and subretinal CNV. Both surgical eyes contained linear breaks in Bruch's membrane that included chevron-shaped breaks. CONCLUSION: Four SST study eyes that were examined postmortem contained CNV. The angiographic patterns and histologic features of the CNV support previous correlations of surgically excised CNV.

Aged↗

Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma.

PURPOSE: To report four cases of optic nerve neuropathy in three children treated with periocular carboplatin injections for unilateral or bilateral intraocular retinoblastoma. DESIGN: Retrospective, observational case series. METHODS SETTING: University-based Ophthalmology Practice. STUDY POPULATION: Four eyes of three children with retinoblastoma enucleated after nonsuccessful multimodality treatment including periocular carboplatin injections. OBSERVATION PROCEDURES: The enucleated eyes were routinely processed and evaluated by light microscopy. A retrospective chart review of all four cases was performed. RESULTS: Three enucleated eyes (Reese-Ellsworth groups III and VB) were obtained from two children with bilateral multifocal retinoblastoma, and one eye (Reese-Ellsworth group IIB) was harvested from a child with unilateral retinoblastoma. All affected eyes underwent three to seven periocular carboplatin injections before enucleation. Additional treatment modalities included systemic chemotherapy, transpupillary thermotherapy, transscleral cryotherapy, and external beam radiotherapy. Histopathologic evaluation of the enucleated eyes revealed focal areas of ischemic necrosis or atrophy of the optic nerve along with dystrophic calcification and mild inflammation in the surrounding fibrovascular adipose tissue. CONCLUSIONS: Periocular injections of carboplatin may be a useful treatment approach in the management of patients with advanced intraocular retinoblastoma and may minimize systemic side-effects. However, ophthalmologists and pediatric oncologists should be aware of potential marked local complications with periocular carboplatin delivery, including ischemic optic neuropathy. Modifying the injection site/location (for example, subtenon space) or adding other delivery routes adjuncts (for example, fibrin sealant) deserves further study.

Antineoplastic Agents↗

Interface fluid syndrome in laser in situ keratomileusis after complicated trabeculectomy.

A 69-year-old man developed stromal edema and a pocket of fluid in the laser in situ keratomileusis (LASIK) interface wound in the left eye after acute endothelial cell loss from complicated trabeculectomy. He eventually required penetrating keratoplasty along with cataract surgery. Histologic examination of the corneal button showed an edematous 720 microm central residual stromal bed, a 54 microm empty space at the level of the central interface wound, and a 154 microm LASIK flap. The endothelial cell count was 0 to 2 cells per high-power field, corresponding to a cell density of 450 to 500 cells/mm(2). Four years after LASIK, the central interface wound was susceptible to forming a pocket of serous fluid after the corneal endothelial function was compromised.

Aged↗

Combined immunologic and anti-angiogenic therapy reduces hepatic micrometastases in a murine ocular melanoma model.

PURPOSE: To evaluate the combined effect of neoadjuvant intracameral interferon alpha -2b and adjuvant low-dose angiostatin in reducing the number of hepatic micrometastases in a murine model of ocular melanoma. METHODS: The posterior compartments of the right eyes of C57BL6 mice were inoculated with 5 x 10(5) cells/2.5 microl of cells from the Queens, B16F10, or B16LS9 melanoma cell lines. The right eyes were enucleated at 7 days, and the mice were sacrificed at 28 days postinoculation, respectively. Hepatic micrometastases were counted. There were four treatment groups (n = 15 each) for each cell line as follows: group 1, intraperitoneal injections of 20 KIU interferon alpha -2b for 4 days prior to enucleation; group 2, intramuscular injections of 100 microl 0.1 microg/microl murine angiostatin every day for 14 days starting on day 1 after enucleation; group 3, treatment of group 1 and group 2 combined; group 4, intraperitoneal and intramuscular injections of equal volumes of phosphate-buffered saline (PBS) (control group). RESULTS: Results showed decreased micrometastases for groups 1 through 3 compared with group 4, with the greatest reduction in group 3 (p < 0.006). CONCLUSIONS: This study suggests that combined neoadjuvant interferon alpha -2b and adjuvant low-dose angiostatin therapy act synergistically to decrease hepatic micrometastases in a murine ocular melanoma model.

Angiogenesis Inhibitors↗

Avellino corneal dystrophy exacerbated after LASIK: scanning electron microscopic findings.

PURPOSE: To evaluate the ultrastructure of the cornea of Avellino corneal dystrophy (ACD) exacerbated by LASIK. METHODS: Three ACD patients with exacerbation of granular corneal deposits after LASIK underwent surgical removal of the corneal flap. The corneal flap was processed for scanning electron microscopy (SEM). RESULTS: SEM of all patients showed abnormal granular clusters in the fibrils of the corneal flap. CONCLUSION: Laser in situ keratomileusis induces corneal collagen abnormalities and adhesions of granular material in ACD patients.

Adult↗

Keratan sulfate and chondroitin/dermatan sulfate in maximally recovered hypocellular stromal interface scars of postmortem human LASIK corneas.

PURPOSE: To analyze the amounts and distributions of nonsulfated and sulfated keratan sulfate (KS) and chondroitin/dermatan sulfate (CS/DS) disaccharides in the interface wound of human postmortem LASIK corneas in comparison with normal control corneas. METHODS: Corneal stromal tissue samples from central and paracentral hypocellular primitive stromal interface scars of human LASIK corneas and from similar regions of normal control corneas were collected by laser capture microdissection (LCM) and subsequently were digested with specific glycosidase enzymes. Digests were directly analyzed by electrospray ionization tandem mass spectrometry (ESI-MS/MS). RESULTS: Concentrations of both monosulfated GlcNAc(6S)-beta-1,3-Gal (MSD2) and disulfated Gal (6S)-beta-1,4-GlcNAc(6S) (DSD) KS disaccharides from the LASIK interface scars were significantly lower than in normal control corneal stromas. No significant difference was found for the concentration of nonsulfated (NSD) KS disaccharides in LASIK interface scars compared with normal controls. The concentration of DeltaUA-beta-1,3-GalNAc(6S) (Deltadi-6S) CS/DS disaccharides from the LASIK interface scar was significantly higher than normal corneal stroma, whereas concentrations of DeltaUA-beta-1,3-GalNAc(4S) (Deltadi-4S) and nonsulfated Deltadi-0S CS/DS disaccharides demonstrated no significant differences from normal corneas. CONCLUSIONS: The profiles of KS and CS/DS disaccharides in LASIK interface scars are significantly different from those in normal cornea stromal tissue, as revealed by LCM and ESI-MS/MS.

Chondroitin Sulfates↗

Histologic, ultrastructural, and immunofluorescent evaluation of human laser-assisted in situ keratomileusis corneal wounds.

OBJECTIVE: To evaluate human corneas after laser-assisted in situ keratomileusis at different postoperative intervals. METHODS: Thirty-eight postmortem corneas from 20 patients with postoperative intervals from 2 months to 6.5 years after laser-assisted in situ keratomileusis surgery were collected from eye banks. The corneas were trisected and processed for conventional histologic analysis, transmission electron microscopy, and immunofluorescence. RESULTS: Light microscopy and transmission electron microscopy showed focal undulations in Bowman layer, focal epithelial hypertrophic modifications, and a variably thick (range, 0.4-16.4-mum) lamellar stromal interface scar in all specimens. The flap wound margin, which was adjacent to the epithelium, healed by producing an approximately 8-mum-thick hypercellular fibrotic stromal scar, whereas the central and paracentral wound regions healed differently because a thinner (approximately 5-mum) hypocellular primitive stromal scar was present in all the corneas examined. Immunofluorescence identified increased type 3 collagen and myofibroblasts in the hypercellular fibrotic scar regions and decreased or absent levels of all corneal stromal components other than type 1 collagen in the hypocellular primitive scar regions. CONCLUSIONS: After laser-assisted in situ keratomileusis surgery, the keratocyte-mediated production of a variably thick lamellar corneal stromal scar occurs, resulting in 2 regional types of scarring. The hypercellular fibrotic scar at the wound margin is usually visible clinically and functions to hold the flap in place, while the more central hypocellular primitive scar is not visible clinically and allows easy lifting of the flap postoperatively.

Actins↗

Histopathologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions: submacular surgery trials report no. 7.

OBJECTIVES: To identify the histologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions from patients enrolled in the Submacular Surgery Trials and to compare them with clinical data. METHODS: Surgically excised subfoveal choroidal neovascular lesions from patients enrolled in the Submacular Surgery Trials group N trial (lesion predominantly choroidal neovascularization [CNV] with evidence of classic CNV from age-related macular degeneration), group B trial (lesion predominantly hemorrhagic from age-related macular degeneration), and group H trial (idiopathic subfoveal CNV or subfoveal CNV from ocular histoplasmosis syndrome) between October 1, 1999, and September 1, 2001, were submitted to the pathology center. The lesion growth pattern (subretinal pigment epithelial [sub-RPE], subretinal, combined, or indeterminate) and the cellular and extracellular constituents were classified independently. Demographic, clinical, and fluorescein angiographic characteristics of patients, eyes, and lesions, respectively, were compared with the pathologic features. RESULTS: Of 269 patients assigned to surgery during the 24 months that pathologic specimens were collected, surgical specimens from study eyes of 199 were submitted to the pathology center. Of the 199 routine histologic specimens processed, 144 (72%) were classified as CNV, 51 (26%) as fibrocellular tissue, and 4 (2%) as hemorrhage. The median specimen size was smaller in group H (932 x 208 mum) than in groups N (1980 x 325 mum) and B (1800 x 395 mum). The CNV growth pattern was determined in 91 (46%) of 199 specimens. Of 159 group N and group B lesions, 76 (48%) had an indeterminate growth pattern, 28 (18%) had a sub-RPE growth pattern, and 33 (21%) had sub-RPE and subretinal growth patterns. Of 40 group H lesions, 32 (80%) had an indeterminate growth pattern, 7 (18%) had a subretinal growth pattern, and 1 (2%) had a combined sub-RPE and subretinal pattern. Based on electron microscopy, the most common cellular lesion components were RPE, macrophages, erythrocytes, fibrocytes, and vascular endothelium; the most common extracellular components were 24-nm collagen and fibrin. Basal laminar and linear deposits were found in 80% (40/50) and 16% (8/49) of group N specimens, 66% (43/65) and 5% (3/65) of group B specimens, and 8% (2/26) and 0% (0/26) of group H specimens, respectively. CONCLUSIONS: Most surgically excised subfoveal specimens had evidence of CNV or tissue associated with CNV. The constituents in CNV were consistent with granulation tissue proliferation. The presence of basal deposits in surgically excised specimens suggested a clinical diagnosis of age-related macular degeneration, even when blood was the predominant component of the lesion. Correlation of growth patterns above or below the RPE with fluorescein angiographic patterns of classic or occult CNV was limited because most specimens had insufficient material to determine these patterns.

Aged↗

Retinal neovascularization associated with retinoblastoma.

PURPOSE: To report retinal neovascularization associated with retinoblastoma in a 14-month-old infant. DESIGN: Observational case report. METHODS: Review of clinical and pathologic findings. RESULTS: A large frond of retinal neovascularization was present posterior to the lens in the right eye, which also contained a retinoblastoma. CONCLUSIONS: Retinal neovascularization is an unusual association with retinoblastoma.

Eye Enucleation↗

Long-term histopathologic findings in human corneal wounds after refractive surgical procedures.

OBJECTIVE: To describe the human corneal histopathology after laser in situ keratomileusis, photorefractive keratectomy, astigmatic keratoplasty, clear corneal refractive lens surgery, conductive keratoplasty, and intrastromal corneal ring segment placement. DESIGN: Retrospective histopathologic study and selected literature review. METHODS: Ninety-four postmortem corneas from 49 patients and 10 corneal button specimens from 6 patients with previous refractive surgery were collected from eye banks and refractive surgeons in North America. This observational case series evaluated the pathologic findings in the wounds of these corneas in the context of previous studies. RESULTS: Three histopathologic types of corneal wound-healing responses were present in corneas after refractive surgery. The first was an epithelial cell modification that reestablished a smooth anterior corneal surface through basal epithelial cell hypertrophy, by epithelial hyperplasia, or both. The second was the production of a hypercellular fibrotic stromal scar, and the third was the production of a hypocellular primitive stromal scar. Although only the hypercellular fibrotic stromal scar could be identified on gross examination, all three wound responses were identified with light, electron, and immunofluorescence microscopy. Confocal microscopy also identified these three processes but with less detail and resolution. CONCLUSION: Understanding the locations, clinical appearance, and functional attributes of these wound-healing responses will help guide evolving techniques or adjunctive treatments.

Cornea↗

Histopathologic examination of conjunctival tophi in gouty arthritis.

PURPOSE: To report a case of conjunctival tophi in a 59-year-old woman with gouty arthritis. DESIGN: Observational case report. METHODS: A 59-year-old woman with a 25-year history of severe gouty arthritis presented with bilateral chalky white conjunctival deposits. Conjunctival biopsies were obtained, and light and electron microscopy studies were performed. RESULTS: Light microscopy confirmed multiple gouty tophi. Transmission electron microscopy revealed intracytoplasmic crystalline deposits within histiocytes. Extracellular aggregates of the crystalline deposits were enclosed by membranous material. CONCLUSIONS: Conjunctival crystals may aid in identifying undiagnosed patients. In addition to conjunctival tophi, patients may also have uveitis, corneal crystals, and band keratopathy.

Arthritis, Gouty↗

Conjunctival granulomas caused by synthetic fibers: report of two cases and review of literature.

PURPOSE: We sought to demonstrate the histopathologic and ultrastructural features of conjunctival foreign body granulomas because of synthetic fibers and to compare them to other cases published in the literature. METHODS: A 2- and a 7-year-old girl were referred for the surgical removal of slow-growing unilateral inferior conjunctival masses with a lack of primary trauma or surgery. In this report, we describe the light and electron microscopic findings of the 2 cases and review the literature of similar cases using the Medline database. RESULTS: Histopathologic and ultrastructural examination of both specimens revealed a granulomatous inflammatory cell response, including histiocytes and multinucleated foreign body giant cells around acellular, uniform sized, oval to round birefringent fibers with manufacturing artifacts. Thirteen other patients with conjunctival synthetic fiber granulomas were identified from the literature. CONCLUSIONS: On the basis of the findings in our cases and the review of literature, it appears that conjunctival synthetic fiber granulomas are not a rare entity but are not recognized frequently by ophthalmologists. The most reliable clinical sign to suggest this diagnosis is the presence of a unilateral inferior conjunctival mass in a child or adolescent. Histopathologic and ultrastructural evaluation appears to be the only way to specifically diagnose this condition with certainty.

Child↗

Ex vivo confocal microscopy of human LASIK corneas with histologic and ultrastructural correlation.

OBJECTIVE: To perform confocal microscopy on postmortem human LASIK corneas and correlate these findings to histologic and ultrastructure evaluations. DESIGN: Prospective, consecutive, observational case series. PARTICIPANTS: Ninety postmortem LASIK corneas (47 patients) were evaluated for histopathology, of which 22 consecutive corneas (12 patients) were also evaluated by confocal microscopy. Six normal corneas (3 patients) served as controls. METHODS: This observational case series involving 22 corneas from 12 patients with postoperative intervals from 1 month to 6.5 years after LASIK surgery were collected. The corneas were mounted in an artificial anterior chamber and perfused with balanced salt solution before confocal microscopy was performed on the center of the cornea. The corneas were then bisected and processed for light and transmission electron microscopy. RESULTS: Confocal microscopy, along with histologic and ultrastructural correlations, demonstrated that the most prevalent alterations in the centers of LASIK corneas were a slightly thickened epithelium caused by focal basal epithelial cell hypertrophic modifications, random undulations in Bowman's layer over the flap surface, and a variably thick hypocellular primitive stromal interface scar. By using confocal microscopy, the interface wound was easily identified in 100% of the cases because numerous brightly reflective interface particles were always present in the hypocellular primitive stromal scar. These particles were found primarily to consist of organic cellular constituents, some of which were transient in nature. CONCLUSION: After LASIK, active stromal wound healing in the central cornea results in the production of a hypocellular primitive stromal scar, whereas secondary tissue adjustments seem to cause the Bowman's layer undulations and the subsequent epithelial cell modifications. Most of the interface particles revealed by confocal microscopy in the region of the stromal scar are organic in nature and presumably innocuous to the cornea.

Adult↗

Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma.

PURPOSE: To evaluate the efficacy of subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. DESIGN: Experimental study using LHbeta-Tag transgenic mice in a randomized controlled trial. PARTICIPANTS AND CONTROLS: Thirty-three 10-week-old LHbeta-Tag transgenic mice: 22 carboplatin-treated animals and 11 control animals. METHODS: Three groups of 11 mice were treated with a single, 30 microl injection of fibrin sealant in the subconjunctival space of 1 eye; the opposite eye was left untreated as an internal control. Group 1 (low-dose group) received 37.5 mg/ml calculated concentration of carboplatin in fibrin sealant (0.66 mg measured total dose). Group 2 (high-dose group) received 75 mg/ml calculated concentration of carboplatin in fibrin sealant (1.23 mg measured total dose). Group 3 (control group) received fibrin sealant only. Mice were killed on day 22 after treatment. Eyes were serially sectioned, and retinal tumor burden was quantified by histopathologic analysis. For statistical analysis of treatment effects, eyes were divided into 6 groups: low-dose group, sealant-treated eyes; low-dose group, untreated eyes; high-dose group, sealant-treated eyes; high-dose group, untreated eyes; control group, sealant-treated eyes; and control group, untreated eyes. MAIN OUTCOME MEASURES: Main outcome measure was mean tumor burden per level per eye in each experimental group. RESULTS: The best therapeutic results were obtained in eyes treated with low-dose carboplatin in fibrin sealant, where no histopathologic evidence of toxicity was observed, and 6 of 11 eyes had zero tumor burden. Tumor burden in the remaining 5 eyes in this group was minimal (4 eyes) or moderate (1 eye) compared with mean control values. Mean tumor burden in this group was significantly smaller than mean tumor burden in untreated eyes from the same mice (P<0.004), sealant-treated eyes in the control group (P<0.004), and untreated eyes in the control group (P<0.002). Although a similar reduction in mean tumor burden was observed in eyes treated with high-dose carboplatin in fibrin sealant, 5 of 10 eyes analyzed in this group also demonstrated histopathologic evidence of severe toxicity. CONCLUSIONS: Subconjunctival carboplatin in fibrin sealant is effective in the treatment of transgenic murine retinoblastoma. A single injection of low-dose carboplatin in fibrin sealant was sufficient to induce complete or near-complete intraocular tumor regression in 10 of 11 eyes (91%), with no associated histologic evidence of toxicity. These results suggest that subconjunctival carboplatin in fibrin sealant provides sustained release and could have clinical use in the treatment of intraocular retinoblastoma.

Animals↗