Successful treatment of intraocularly invasive conjunctival squamous cell carcinoma with proton beam therapy.
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Aged, 80 and over↗
Biomedical subjects
Joan M O'Brien
Publications and source records attributed to Joan M O'Brien.
Estimates of ocular and visual retention following treatment of extra-large uveal melanomas by proton beam radiotherapy.
OBJECTIVE: To assess outcomes of proton beam radiotherapy for the treatment of extra-large uveal melanomas in patients specifically referred to the University of California, San Francisco, for ocular conservation therapy. Series patients uniformly refused enucleation both at an outside institution and again as a treatment option after extensive discussion at the University of California, San Francisco. DESIGN: In a retrospective, nonrandomized cohort study, 21 patients with extra-large choroidal or ciliochoroidal melanomas measuring at least 10 mm in maximum thickness or 20 mm in maximum basal diameter or tumors located within 3 mm of the optic nerve measuring at least 8 mm in maximum thickness or 16 mm in maximum basal diameter met inclusion criteria. Main outcome measures were frequency of (1) anterior segment complications (lash loss, keratopathy, cataract, and neovascular glaucoma), (2) posterior segment complications (vitreous hemorrhage, radiation retinopathy, and radiation papillopathy), (3) treatment failure (tumor growth, enucleation, or metastases), and (4) final visual acuity. RESULTS: Median follow-up was 28 months. Mean age at treatment was 58.3 years. The frequencies of hypertension and diabetes mellitus were 14.3% and 9.5%, respectively. Mean tumor thickness and mean basal diameter were 8.6 mm and 18.7 mm, respectively. Lash loss occurred in 52.4%; dry eye, in 23.8%; cataract, in 28.6%; neovascular glaucoma, in 38.1% (100% in patients with diabetes mellitus); radiation retinopathy, in 9.5%; and radiation papillopathy, in 9.5%. No patient developed radiation-associated scleral necrosis or vitreous hemorrhage. The 2-year Kaplan-Meier estimate of local tumor growth after treatment was 33%, and the rate of distant metastasis was 10%. Visual acuity of 20/200 or better was preserved in 25% of patients, including 4 patients (19%) who experienced an average of 4 lines of Snellen visual acuity improvement. Development of neovascular glaucoma was associated with tumors in close proximity to the optic nerve (P = .04), while cataract (P = .03) and lash loss (P = .02) occurred with more anteriorly located tumors. Proton beam radiotherapy provided a 67% probability of local control and 90% probability of clinically discernible metastases-free survival at 24 months after treatment. CONCLUSION: Proton beam radiotherapy is an ocular-conserving option that may be considered for the treatment of extra-large uveal melanoma in carefully selected patients.
Adult↗
Desmoplastic small round cell tumor: a potentially lethal neoplasm manifesting in the orbit with associated visual symptoms.
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Adult↗
Pathology and genetics of primary central nervous system and intraocular lymphoma.
Ongoing studies based on gene expression profile analysis using microarrays have provided preliminary evidence for significant molecular distinctions between primary central nervous system lymphoma (PCNSL) and nodal lymphomas of the large B-cell type. The application of array-based comparative genomic hybridization techniques attempts to identify genomic distinctions between PCNSL and nodal lymphomas and to identify the molecular markers that relate to prognosis. It is possible that insights gained from these studies will facilitate the development of targeted therapies, which address the fundamental genetic mutations that drive PCNSL and intraocular lymphoma growth.
Central Nervous System Neoplasms↗
Retinoblastoma: animal models.
Employment of animal models in basic research has significantly advanced the understanding of fundamental processes underlying tumorigenesis in retinoblastoma, including elucidating the complex role of pRb and other related protein products in cell cycle regulation, apoptosis, DNA damage responses, and terminal differentiation. The evolution of therapy for retinoblastoma has also been facilitated through translational research using in vivo models, including xenograft and genetically engineered systems. In retinoblastoma, these models provide a valuable preclinical context for testing the efficacy and safety of conventional chemotherapy, radiotherapy, or novel agents on tumor growth, tissue invasion, and metastasis.
Animals↗
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↗
Retinoblastoma and hypochondroplasia: a case report of two germline mutations arising simultaneously.
PURPOSE: To report a rare case of a patient with two germline mutations arising de novo resulting in bilateral retinoblastoma and hypochondroplasia. DESIGN: A brief review about retinoblastoma and hypochondroplasia; a case report with genetic mutational analysis results. CASE REPORT: We report a patient manifesting the clinical features of both bilateral retinoblastoma and hypochondroplasia. Genetic analysis revealed two germline mutations, a seven base-pair deletion in exon 12 (G70313-703129del) in one allele of the retinoblastoma gene (RB1) and the N540K (C1620C > A) mutation in one allele of the fibroblast growth factor 3 (FGFR3) gene, a frequent mutation in hypochondroplasia. Neither parent has a personal or family history of cancer or ocular tumors. Only the patient's mother is short in stature, and her genetic analysis revealed no FGFR3 mutations. CONCLUSIONS: Although the probability of both germline mutations occurring in a single individual is exceedingly low, the etiology and mechanism are unknown in this patient. To the best of our knowledge, this is the first report of two clinically distinct heritable germline mutations arising de novo in an individual.
Female↗
3D MRI-based tumor delineation of ocular melanoma and its comparison with conventional techniques.
The aim of this study is to (1) compare the delineation of the tumor volume for ocular melanoma on high-resolution three-dimensional (3D) T2-weighted fast spin echo magnetic resonance imaging (MRI) images with conventional techniques of A- and B-scan ultrasound, transcleral illumination, and placement of tantalum markers around tumor base and (2) to evaluate whether the surgically placed marker ring tumor delineation can be replaced by 3D MRI based tumor delineation. High-resolution 3D T2-weighted fast spin echo (3D FSE) MRI scans were obtained for 60 consecutive ocular melanoma patients using a 1.5 T MRI (GE Medical Systems, Milwaukee, WI), in a standard head coil. These patients were subsequently treated with proton beam therapy at the UC Davis Cyclotron, Davis, CA. The tumor was delineated by placement of tantalum rings (radio-opaque markers) around the tumor periphery as defined by pupillary transillumination during surgery. A point light source, placed against the sclera, was also used to confirm ring agreement with indirect ophthalmoscopy. When necessary, intraoperative ultrasound was also performed. The patients were planned using EYEPLAN software and the tumor volumes were obtained. For analysis, the tumors were divided into four categories based on tumor height and basal diameter. In order to assess the impact of high-resolution 3D T2 FSE MRI, the tumor volumes were outlined on the MRI scans by two independent observers and the tumor volumes calculated for each patient. Six (10%) of 60 patients had tumors, which were not visible on 3D MRI images. These six patients had tumors with tumor heights < or = 3 mm. A small intraobserver variation with a mean of (-0.22 +/- 4)% was seen in tumor volumes delineated by 3D T2 FSE MR images. The ratio of tumor volumes measured on MRI to EYEPLAN for the largest to the smallest tumor volumes varied between 0.993 and 1.02 for 54 patients. The tumor volumes measured directly on 3D T2 FSE MRI ranged from 4.03 to 0.075 cm3. with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.
Adolescent↗
Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells.
PURPOSE: Although the clinical efficacy of cyclosporin A (CSA) in retinoblastoma (RB) has been attributed to multidrug resistance reversal activity, the authors hypothesized that CSA is also directly toxic to RB cells through inhibition of calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling. METHODS: Antiproliferative effects of CSA, PSC-833 (a CSA analogue that does not inhibit CN), and FK506 (a CN inhibitor structurally unrelated to CSA) were evaluated in Y79 and Weri-RB1 cells by WST-1 assay. Apoptosis induction by CSA and PSC-833 was measured by detection of caspase 3/7 activity and by flow cytometry, using annexin-V and 7-AAD stains. Expression of CN was assayed in RB cells by immunocytochemistry. Expression of NFAT, a CN-dependent transcription factor family, and FK506 binding protein 12/12.6 (FKBP12/12.6), effectors of CN inhibition by FK506, was assayed in RB cells by Western blot analysis. NFAT activity was assayed in CSA-treated and -untreated Y79 cells transfected with an NFAT-sensitive reporter gene. RESULTS: CSA induced dose-dependent antiproliferative and proapoptotic effects at clinically achievable levels in Y79 and Weri-RB1 cells. PSC-833 induced antiproliferative effects only at nonphysiologic concentrations with minimal associated apoptosis. FK506 induced minimal antiproliferative effects in RB cell lines, probably due to trace or absent FKBP12/12.6 expression. RB cell lines expressed CN-alpha, CN-beta, NFATc1, and NFATc3. CSA treatment also potently inhibited NFAT-mediated reporter gene transcription. CONCLUSIONS: These results demonstrate functional integrity of the CN/NFAT signaling cascade in RB cells and suggest that CSA is cytotoxic to RB cells through inhibition of this pathway and consequent apoptosis induction.
Apoptosis↗
Rapid identification of germline mutations in retinoblastoma by protein truncation testing.
OBJECTIVE: To demonstrate the utility of protein truncation testing (PTT) for rapid detection and sequencing of germline mutations in the retinoblastoma tumor suppressor gene (RB1). METHODS: We performed PTT, a technique based on the in vitro synthesis of protein from amplified RNA, on 27 probands from 27 kindreds with hereditary retinoblastoma. In 4 kindreds, PTT was also performed on 1 additional affected relative. Ten unrelated patients without retinoblastoma were included as negative control subjects. All PTT-detected mutations were further analyzed by focused sequencing of genomic DNA. When no mutation was detected by PTT, we performed exon-by-exon sequencing, as well as cytogenetic analysis by Giemsa-trypsin-Giemsa banding and by fluorescent in situ hybridization for RB1. The results of proband testing were used for direct genetic testing by polymerase chain reaction and sequencing in 11 relatives from 7 of the 27 kindreds. RESULTS: Of the probands tested, 19 (70%) of 27 tested positive for germline mutations by PTT. In 1 kindred, the proband had negative PTT results but an additional affected relative had positive PTT results. Focused DNA sequencing of 1 patient with positive PTT results from each of the 20 kindreds with positive PTT results revealed truncating mutations in 19 kindreds. Four demonstrated frameshift deletions, 6 had splice site mutations, and 9 showed nonsense mutations. Further analysis by genomic exon-by-exon sequencing and karyotype analysis of the 8 probands who tested negative for germline mutations by PTT revealed 1 splice site mutation, 2 missense mutations, and 1 chromosomal deletion. Focused sequencing based on positive PTT results was successfully used to confirm shared truncating mutations in additional affected family members in 2 kindreds. Using a multitiered approach to genetic testing, 23 (85%) of 27 kindreds had mutations identified and those detected by PTT received a positive result in as few as 7 days. In control subjects, PTT produced no false-positive results. CONCLUSIONS: Protein truncation testing is an effective, rapid single-modality screen for germline mutations in patients with retinoblastoma. When used as an initial screen, PTT can increase the yield of additional testing modalities, such as sequencing and chromosomal analysis, providing a timely and cost-effective approach for the diagnosis of heritable germline mutations in patients with retinoblastoma.Clinical Relevance The clinical application of PTT in retinoblastoma will improve detection of germline retinoblastoma mutations, which will supply critical information for prognosis, treatment planning, follow-up care, and genetic counseling.
DNA Mutational Analysis↗
External beam radiation "salvage" therapy in transgenic murine retinoblastoma.
OBJECTIVE: To determine the efficacy of low-dose "salvage" external beam radiation therapy (EBRT) following failed subconjunctival carboplatin chemotherapy in a murine model of heritable retinoblastoma. METHODS: Eighty-four eyes from 8-week-old, simian virus 40, T-antigen-positive mice were treated with 6 serial subconjunctival carboplatin injections (100 microg/25 microL). At 12 weeks of age, 64 eyes received EBRT for a total dose of 480 (4.8 Gy), 1200 (12.0 Gy), 1560 (15.6 Gy), or 3000 (30.0 Gy) rad. Twenty eyes received no additional therapy following subconjunctival carboplatin injections. Ten eyes received a total dose EBRT of only 3000 rad. Eight eyes received subconjuctival injections of only an isotonic sodium chloride solution. Ten eyes served as untreated controls. MAIN OUTCOME MEASURES: Eyes were enucleated at 20 weeks to assess the presence of tumor on histopathological examination. RESULTS: Salvage therapy using low-dose EBRT was able to reestablish tumor control in a dose-dependent manner. Increasing the EBRT dose to 3000 rad resulted in 100% tumor control. The dose-dependent curves were significantly different between the treatment groups-EBRT alone vs salvage EBRT after receiving subconjunctival carboplatin injections (P<.001). CONCLUSION: Low-dose hyperfractionated salvage EBRT following failed primary subconjunctival carboplatin chemotherapy is efficacious in the treatment of retinoblastoma in this animal model. Clinical Relevance Salvage EBRT using a reduced total radiation dose could be associated with a radiation-related treatment enhancement in pediatric retinoblastoma.
Animals↗
Geographic disparities in diagnostic screening for metastatic uveal melanoma.
PURPOSE: To evaluate current practice patterns in diagnostic screening for asymptomatic metastatic uveal melanoma. DESIGN: Survey. PARTICIPANTS: Ocular oncologists practicing in North America (United States, Canada) and Europe. METHODS: Questionnaire sent to specialists participating in the Collaborative Ocular Melanoma Study (COMS) or listed in the Ophthalmic Oncology Task Force of the European Organization for Research and Treatment of Cancer. MAIN OUTCOME MEASURES: Methods used to screen patients with uveal melanoma for asymptomatic metastasis at initial presentation and follow-up. RESULTS: Thirty-six of 43 (84%) North American (COMS) specialists and 57 of 103 (55%) European specialists responded to the survey. At presentation, 6 of 36 (17%) North American specialists, versus 54 of 57 (95%) European specialists, performed at least one type of liver imaging study (computed tomography, magnetic resonance imaging, ultrasonography, or nuclear medicine) (P<0.0001). On follow-up, only 1 of 36 (3%) North American specialists, versus 45 of 57 (79%) European specialists, obtained a liver imaging study (P<0.0001). Thirty-six of 36 (100%) North American specialists, versus 49 of 57 (86%) European specialists, ordered chest x-rays at presentation (P<0.02). This disparity was greater at the time of follow-up, when 28 of 36 (78%) North American specialists, versus 28 of 57 (49%) European specialists, ordered chest x-rays (P<0.01). Similar proportions of specialists in North America and Europe obtained a physical examination and liver function tests at the time of presentation and on subsequent follow-up examination. CONCLUSIONS: Significant differences exist between ocular oncologists in North America and Europe in the use of techniques to screen for metastatic uveal melanoma. North American COMS centers rely primarily upon liver function tests and chest x-rays. The majority of European centers use liver ultrasonography at initial diagnosis and continue to do so every 6 months. Cost-effective screening protocols for patients with uveal melanoma should be designed and implemented uniformly among ocular oncologists.
Europe↗
High-resolution 3D T2-weighted fast spin echo: new applications in the orbit.
Recent developments have made available for ophthalmologic MR imaging a very high-resolution 3D fast spin echo T2 (3D FSE T2) sequence, which runs in a standard head coil. A modification of this technique, 3D FSEz T2, uses a zero-filled slice interpolation method during post-processing to further improve spatial resolution. We describe the technique and share our early clinical observations in patients with ocular masses. Briefly, the additional information from the 3D FSEz T2 resulted in a change in diagnosis from the conventional imaging series in 11 of (41%) 27 studies, usually through the identification of previously treated retinoblastoma lesions. The new sequence significantly increased diagnostic confidence in six (38%) of the remaining 16 cases, usually through better anatomical detail and lesion conspicuity, and did not change interpretation in 10 cases. Such an approach improves diagnostic confidence and may eliminate the need for a dedicated surface coil examination.
Fourier Analysis↗
Hyperfractionated external beam radiation therapy in the treatment of murine transgenic retinoblastoma.
OBJECTIVE: To determine the in vivo efficacy of hyperfractionated external beam radiation therapy (EBRT) in comparison with standard daily EBRT in a murine model of heritable retinoblastoma. METHODS: Two hundred twenty eyes from 6-week-old simian virus-40 large T-antigen--positive mice were treated with a total dose of EBRT ranging from 10-76 Gy (1000 to 7600 rad). One hundred ten eyes underwent EBRT administered in 2.0-Gy (200-rad) fractions once per day. Forty-two eyes received hyperfractionated EBRT administered in 1.2-Gy (120-rad) fractions twice per day, while 48 eyes received EBRT twice daily in fractions of 5.0 Gy (500 rad). Twenty eyes served as untreated controls. All eyes were obtained for histopathologic examination and graded positive if any tumor was present. RESULTS: A dose-dependent inhibition of ocular tumor was observed for EBRT in these transgenic retinoblastoma mice. The tumor control dose for 50% of eyes (TCD(50)) treated with 2.0 Gy fractions of EBRT was 45 Gy (4500 rad) when treatments were administered once daily. A significant increase in tumor control was observed when treatments were administered twice per day at fractions of 1.2 Gy, resulting in a TCD(50) of 33 Gy (3300 rad) (P =.003). A further increase in tumor control was observed when twice-daily EBRT was administered in 5.0 Gy fractions resulting in a TCD(50) of 28 Gy (2800 rad). CONCLUSIONS: Hyperfractionated EBRT safely and effectively controls intraocular retinoblastoma in this transgenic animal model. Use of hyperfractionation allows for a reduction in total radiation delivered dose, while shortening the total treatment time. CLINICAL RELEVANCE: This treatment approach may be applicable in the management of pediatric retinoblastoma by maintaining excellent tumor control, while reducing treatment-associated complications.
Animals↗
Three-dimensional high-resolution magnetic resonance imaging of ocular and orbital malignancies.
BACKGROUND: Ultrathin-section 3-dimensional fast spin-echo (3-D FSE) T2-weighted imaging is a new magnetic resonance imaging (MRI) technique that we used in the evaluation of ocular and orbital malignancies. We evaluated the usefulness of this new technique compared with conventional MRI. METHODS: Imaging data from 26 consecutive patients seen in the Ocular Oncology Unit at the University of California-San Francisco were retrospectively reviewed by physicians from the ocular oncology and neuroradiology units. For all patients, 3-D FSE T2-weighted images (27 scans) were compared with results of conventional MRI and correlated with results of computed tomography (CT), A- and B-scan ultrasonography, ultrasound biomicroscopy, clinical examinations, and histopathology, when available. RESULTS: The 3-D FSE T2-weighted imaging sequence resulted in an overall improvement in accuracy of imaging findings in 17 (63%) of our 27 cases compared with the standard MRI protocol. The increased resolution led to the radiographic detection of additional lesions in 11 (41%) of 27 cases and to an increase in confidence in radiographic diagnosis in 6 (22%) of the remaining cases. The improved resolution of the 3-D FSE T2-weighted sequence resulted in a change of disease management in 3 (60%) of the 5 patients with nonretinoblastoma lesions. One hundred percent of active retinoblastoma lesions could be detected by means of 3-D FSE and conventional imaging; however, inactive lesions were not always detected using conventional imaging. CONCLUSIONS: The 3-D FSE T2-weighted sequence offers superior resolution of intraocular and orbital structures compared with conventional MRI. It is particularly useful in the evaluation of intraocular tumors and the nerve-sheath complex. This new technique contributes significantly to improved diagnosis and management in patients with ocular and orbital malignancies.
Eye Neoplasms↗
Research: the track record justifies expanded support.
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Humans↗
Posterior pole tumor update.
This chapter focuses on the diagnosis and management of choroidal melanoma in light of recent findings from the COMS. Retinoblastoma is emphasized to describe recent trends in primary treatment away from EBRT and toward chemoreduction with local therapy. In addition, vascular and glial tumors of the retina and tumors of the retinal pigment epithelium are described because of the association between these lesions and systemic disease. Recent advances in treatment and genetic testing for these diseases are discussed. Finally, ocular metastasis, intraocular lymphoid tumors, and intraocular leukemia are included because of their importance in determining systemic treatment and prognosis. The chapter gives an overview of important posterior pole tumors and highlights recent developments in the management of each intraocular disease process.
Choroid Neoplasms↗
Masquerade syndromes: malignancies mimicking inflammation in the eye.
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Diagnosis, Differential↗