Osteogenesis imperfecta and primary open angle glaucoma: genotypic analysis of a new phenotypic association.

PURPOSE: Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by bone fragility. Ocular findings include blue sclera, low ocular rigidity, and thin corneal thickness. However, there are no documented cases linking OI and primary open angle glaucoma (POAG). In this report, we describe three individuals, one isolated case and two from a multiplex family, with OI type I and POAG. METHODS: Available family members with OI and POAG had a complete eye examination, including visual acuity, intraocular pressure (IOP), pachymetry, slit-lamp exam, dilated fundus exam, and visual fields. DNA from blood samples was sequenced and screened for mutations in COL1A1/2 and myocilin (MYOC). RESULTS: All subjects had OI type I. Findings of POAG included elevated IOP, normal gonioscopy, and glaucomatous optic disc cupping and visual field loss. POAG cosegregated with OI in the multiplex family. The multiplex family had a single nucleotide insertion (c.540_541insC) in COL1A1 resulting in a frameshift mutation and a premature termination codon. The sporadic case had a COL1A1 splice acceptor site mutation (c.2452-2A>T or IVS36-2A>T) predicted to result in a premature termination codon due to intron inclusion or a cryptic splice site. None of the glaucoma cases had mutations or sequence changes in MYOC. CONCLUSIONS: We identified two novel mutations in COL1A1 in individuals with OI type I and POAG. Thus, some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.

Cumulative cisplatin dose is not associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma treated with cisplatin based adjuvant chemotherapy: report from the Children's Oncology Group.

BACKGROUND: Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin-containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with newly diagnosed average-risk medulloblastoma. PROCEDURE: CCD data were reviewed for 363 patients in a prospective study evaluating patients between 3 and 21 years with a newly diagnosed average-risk medulloblastoma and treated with craniospinal radiation and post-radiation cisplatin based adjuvant chemotherapy. RESULTS: Eight-year event-free survival (EFS) and overall survival (OS) estimates were 78.2 ± 2.6% and 83.9 ± 2.4%, respectively. Only 73 patients received the protocol specified CCD of 600 mg/m(2), primarily due to mandated cisplatin toxicity-related dose reductions. The median CCD given to those without relapse or death on treatment was 487.5 mg/m(2). CCD, as a time-dependent covariate, was not associated with EFS (P = 0.54) or OS (P = 0.11). The 343 patients who completed chemotherapy failure-free were categorized into four groups according to CCD (n = 10; 75-150 mg/m(2)), (n = 26; 151-300 mg/m(2)), (n = 113; 301-450 mg/m(2)), and (n = 194; 451-600 mg/m(2)). There were no statistically significant differences in distributions of EFS (P = 0.53) or OS (P = 0.49) among these four groups. CONCLUSION: CCD is not associated with EFS or OS suggesting that lower doses of cisplatin may be incorporated into future medulloblastoma trials, thereby limiting its toxicity profile without affecting survival. If ototoxicity is encountered, more stringent cisplatin dose modification/cessation rules seem warranted.

Phthisis after endoscopic cyclophotocoagulation.

A 47-year-old man was treated with one session of endoscopic cyclophotocoagulation for uncontrolled, elevated intraocular pressure. Before treatment, the eye was quiet and uninflamed. Pretreatment visual acuity was 4/200 and the intraocular pressure was 24 mm Hg. Treatment was applied to the ciliary processes for nearly 360 degrees. During the postoperative follow-up, the patient developed eye pain and persistent ocular inflammation. This ultimately led to phthisical changes evident 5 months postoperatively, when visual acuity was 1/200 and the intraocular pressure was 7 mm Hg. Eighteen months after endoscopic cyclophotocoagulation, visual acuity was light perception and intraocular pressure was less than 1 mm Hg. Phthisis is among the complications that may result after treatment with endoscopic cyclophotocoagulation.

Detection of the bcl-2 t(14;18) translocation and proto-oncogene expression in primary intraocular lymphoma.

PURPOSE: Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells. METHODS: Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis. RESULTS: Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger. CONCLUSIONS: PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lymphomas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profiling, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease.

Primary testicular and intraocular lymphomas: two case reports and a review of the literature.

Testicular lymphoma is a rare neoplasm of the testis that is most commonly seen in older patients. It metastasizes preferentially to extranodal sites, including the skin, central nervous system, Waldeyer ring, contralateral testis, and lung. Two case reports of patients with a history of testicular lymphoma who developed involvement of the vitreous and retina are presented. These are interesting cases as the testis, central nervous system, and eye are all immune privileged organs, which may account for occurrence of disease in these sites. Histopathologic examination of diagnostic vitrectomy specimens from both cases showed atypical lymphoid cells with immunoglobulin heavy chain (IgH) gene rearrangements, consistent with the diagnosis of intraocular B-cell lymphoma. The results of a literature review of all reports of ocular involvement with testicular lymphoma are discussed. Patients with testicular lymphoma are at risk for relapse, particularly in the central nervous system. Clinicians should be suspicious for intraocular lymphoma in patients with a history of testicular lymphoma who present with vitritis or retinal lesions.

Management of primary intraocular lymphoma.

Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma (PCNSL) in which malignant lymphoid cells invade the retina, vitreous body, or optic nerve head. It is usually a large B-cell non-Hodgkin's lymphoma. PIOL typically presents as a vitritis that is unresponsive to corticosteroid therapy. Diagnosis of PIOL requires pathologic confirmation of malignant cells in specimens of the cerebrospinal fluid, vitreous, or chorioretinal biopsies. The optimal therapy for PIOL has yet to be determined. It is generally believed that PIOL should be treated with a combination of systemic chemotherapy, including high-dose methotrexate and radiotherapy. However, several new developments for PIOL with central nervous system involvement have been reported, including intrathecal therapy and autologous stem-cell transplantation. In addition, intravitreal methotrexate has been successful in the treatment of isolated recurrent ocular disease. This article provides an overview of treatment modalities for initial, recurrent, and relapsed PIOL.

Intraocular lymphoma: update on diagnosis and management.

BACKGROUND: Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma (PCNSL) in which lymphoma cells initially invade the retina, vitreous, or optic nerve head, with or without concomitant CNS involvement. The incidence of this previously rare condition has increased dramatically. Given its nonspecific presentation and aggressive course, PIOL provides a diagnostic and therapeutic challenge. METHODS: We review the current strategies for diagnosis and treatment of PIOL and present our own experience with PIOL. RESULTS: Recent developments in the diagnosis of PIOL include immunohistochemistry, flow cytometry, cytokine evaluation, and molecular analysis. However, definitive diagnosis still requires harvesting of tissue for histopathology. Optimal treatment for PIOL remains unclear. Initial therapeutic regimens should include methotrexate-based chemotherapy and radiotherapy to the brain and eye. In addition, promising results have been seen with intravitreal methotrexate and autologous stem cell transplantation for recurrent and refractory disease. CONCLUSIONS: Efforts to further determine the immunophenotype and molecular characteristics of PIOL will continue to assist in the diagnosis of PIOL. Future studies are required to determine the role of radiotherapy and optimal local and systemic chemotherapeutic regimens.