Subconjunctival carboplatin in retinoblastoma: impact of tumor burden and dose schedule.

OBJECTIVE: To evaluate the impact of tumor burden and chemotherapy dose scheduling on the response to subconjunctival carboplatin treatment in a murine transgenic retinoblastoma model. METHODS: Eighty simian virus 40 T antigen-positive mice were treated at age 5 or 10 weeks. Six control animals received placebo treatment. Twenty-four 5-week-old mice received 6 subconjunctival carboplatin injections at doses of 30 to 300 microg delivered at 72-hour intervals. Fifty 10-week-old mice received either 6 or 12 subconjunctival carboplatin injections at doses of 30 to 300 microg delivered at 72-hour intervals. All eyes were obtained at age 16 weeks for histopathologic examination. Eyes were graded as positive if any tumor was present. RESULTS: All simian virus 40 T antigen-positive control eyes contained large tumor foci throughout the retina. Subconjunctival carboplatin injections controlled tumors in a dose-dependent manner. Tumor control was observed in 50% of treated eyes at 138.3 microg for the 10-week-old 6-injection group, 94.3 microg for the 5-week-old 6-injection group, and 85.9 microg for the 10-week-old 12-injection group. CONCLUSION: Increased tumor burden requires an increase in subconjunctival carboplatin dose scheduling to maintain local tumor control in this murine model of retinoblastoma. CLINICAL RELEVANCE: This study documents the efficacy of subconjunctival carboplatin in the treatment of an animal model of retinoblastoma. These data establish a framework for further human clinical trials. Arch Ophthalmol. 2000;118:1549-1554

Design of a magnetically integrated microporous implant.

OBJECTIVE: To determine the orbital tolerance of a microporous implant fitted with an integrated stainless steel post and the enhanced motility associated with magnetic coupling of the prosthetic and the implant in a rabbit model. METHODS: Six New Zealand white rabbits underwent primary enucleation with implantation of a 12-mm microporous polyethylene implant with a 2 x 3-mm stainless steel post embedded flush with the anterior surface. At 1 month, the rabbits were fitted with an external prosthesis containing two 1-mm circular rare earth dental magnets embedded at 0. 5 mm off the midline (right and left of center at the horizon). Magnetic coupling forces were determined with a hanging block technique. RESULTS: No evidence of toxicity was observed in association with this integrated ocular implant. Magnetic coupling forces were noted maximally at 0.47 N. Clinical grading of motility documented enhancement in lateral excursion when compared with nonintegrated controls. CONCLUSION: Magnetically integrated microporous implants achieve excellent enhancement of motility without evidence of complications in this rabbit model. CLINICAL RELEVANCE: This study establishes a framework for the clinical evaluation of a magnetically integrated implant that may enhance prosthetic motility without requiring direct mechanical coupling of the implant to the prosthesis. Arch Ophthalmol. 2000;118:1259-1262

In vitro efficacy of carboplatin and hyperthermia in a murine retinoblastoma cell line.

PURPOSE: To determine the cell-killing activity of varying doses of carboplatin, graded hyperthermia, and the combination of carboplatin and hyperthermia in the treatment of a transgenic murine retinoblastoma cell line. METHODS: Replicate cell wells (more than six wells per dose point) from an established transgenic murine retinoblastoma cell line (Rb-6) were exposed to a single application of hyperthermia for 15, 30, 60, and 120 minutes at temperatures of 37 degrees C (control), 40 degrees C, and 43 degrees C. Carboplatin dose response treatment was studied at doses of 2000, 1000, 500, 400, 300, 200, 100, and 50 ng per well. Combined treatment studies used these carboplatin dosages with each of the graded hyperthermia exposure temperatures at each exposure time. At 24 hours, all wells were pulsed with 3H-thymidine for 24 hours, washed three times, harvested, and counted. Raw counts (3H-thymidine) were fitted to a linear regression model to calculate the lethal dose for 50% (LD50) of cells. RESULTS: The LD50 for carboplatin exposure at 37 degrees C occurred at 542 ng. The LD50 for hyperthermia at 40 degrees C occurred at 90 minutes and at 43 degrees C it occurred at 62 minutes. Combined hyperthermia and carboplatin exposure yielded a synergistic interaction with an LD50 of 327 ng at 43 degrees C for 30 minutes. Determination of a thermal enhancement ratio yielded an enhancement range of 1.1 to 25.8. CONCLUSIONS: The synergistic cytocidal interaction of heat and carboplatin in a transgenic murine retinoblastoma cell line has been established in this study. The increased thermal enhancement ratio documents the potential utility of combined treatment applications in reducing treatment levels of single-modality therapy, potentially allowing for a decrease in treatment-related morbidity.

Subconjunctival carboplatin therapy and cryotherapy in the treatment of transgenic murine retinoblastoma.

OBJECTIVES: To determine the efficacy and dose response of subconjunctival carboplatin with and without cryotherapy in the treatment of murine transgenic hereditary retinoblastoma. METHODS: Fifty-one 5-week-old transgenic BLH SV-40 (Charles Rivers Laboratories, Boston, Mass) T-antigen-positive mice with retinoblastoma were administered 6 subconjunctival injections of carboplatin in 1 eye at drug doses of 10, 15, 20, 25, 62.5, 125, and 250 microg. Six control eyes received 6 subconjunctival injections of balanced salt solution. Fourteen of the 51 subconjunctivally treated eyes received a single application of transconjunctival cryotherapy immediately prior to each carboplatin injection. Six control eyes received 6 single applications of transconjunctival cryotherapy using the above schedule but did not receive carboplatin. All experimental and control eyes were obtained at 16 weeks of age for histopathologic examination. RESULTS: A dose-dependent inhibition of intraocular tumor growth by subconjunctivally delivered carboplatin was observed in these transgenic retinoblastoma mice. Tumor development was inhibited in 50% of the mouse eyes at doses of 180 microg. In animals treated with cryotherapy alone, no tumor control was noted (0 of 6). In animals treated with subconjunctival carboplatin coupled with cryotherapy, a tumor control dose of 417 microg was found. No evidence of histopathologic treatment toxicity was noted. CONCLUSIONS: Subconjunctival delivery of carboplatin in serial doses effectively inhibits intraocular tumor growth in a dose-dependent fashion in a transgenic murine retinoblastoma model. Cryotherapy does not increase tumor control in this murine retinoblastoma model.

Radiation therapy and ferromagnetic hyperthermia in the treatment of murine transgenic retinoblastoma.

BACKGROUND: Combined modality therapy for childhood retinoblastoma holds the potential of decreasing treatment-related morbidity while maintaining excellent tumor control rates. OBJECTIVE: To evaluate the efficacy of external beam radiation therapy (EBRT), ferromagnetic hyperthermia (FMH), and the combination of both modalities in the control of ocular tumors in a transgenic murine model of retinoblastoma. METHODS: One hundred sixty-six mouse eyes from 4-week-old animals transgenically positive for simian virus 40 large T antigen were treated with a total dose of 10, 15, 20, 30, 40, 45, or 50 Gy of EBRT in 5-Gy fractions twice daily, with 48 degrees C or 54 degrees C FMH for 20 minutes, or with combined EBRT at 10 or 30 Gy and 48 degrees C or 54 degrees C FMH for 20 minutes. Serial histologic sections, obtained 8 weeks after treatment, were examined for the presence of tumor. RESULTS: The tumor control dose for 50% of eyes (TCD50) treated with EBRT occurred at 27.6 Gy. Ferromagnetic hyperthermia at 48 degrees C cured 30% (6/20) of eyes, while 54 degrees C FMH resulted in a 100% (20/20) cure rate. Combined treatment with 48 degrees C FMH and EBRT exhibited a TCD50 at 3.3 Gy. The thermal enhancement ratio was 8.4. Ferromagnetic hyperthermia at 54 degrees C exhibited tumor cure in all animals, but 25% of eyes were lost owing to secondary treatment complications. CONCLUSIONS: This represents the first documentation of tumor control via EBRT, ocular FMH, and a combination of these treatment modalities in this murine transgenic retinoblastoma model. The extent of treatment synergy in this model suggests that combined treatment application may allow a reduction in total ocular and periocular radiation dose while maintaining excellent local tumor control.

Local carboplatin and radiation therapy in the treatment of murine transgenic retinoblastoma.

BACKGROUND: Combined modality therapy in the treatment of retinoblastoma may decrease treatment-related morbidity and second tumor-associated mortality, while maintaining excellent tumor control rates. OBJECTIVE: To evaluate tumor control and potential synergy between intravitreally delivered carboplatin and external beam radiation therapy (EBRT), using a transgenic murine model of spontaneous heritable retinoblastoma. METHODS: Sixty-six mouse eyes from 4-week-old transgenic mice positive for the simian virus 40 large T antigen were evaluated. Thirty-three mice were treated with 5 intravitreal injections of carboplatin (ranging from 0.1-4.0 micrograms) combined with concurrent bilateral EBRT (ranging from 10-30 Gy) delivered in twice daily 5-Gy fractions. All eyes were followed up for treatment complications. Twelve weeks following final treatment, all eyes were enucleated, serial histologic sections obtained, and the eyes examined for the presence of retinoblastoma. RESULTS: No eye treated with 0.1 microgram of carboplatin and EBRT exhibited tumor control. Three (75%) of 4 mice receiving 1.0 microgram of carboplatin combined with 10-Gy EBRT had complete tumor control. Four (100%) of 4 mice receiving 1.0 microgram of carboplatin combined with 30-Gy EBRT had complete tumor control. Nine (100%) of 9 mice receiving 4.0 micrograms of carboplatin in combination with EBRT had complete tumor control. The chemotherapeutic enhancement ratio ranged from 1.07 to 3.24. CONCLUSIONS: Combined administration of intravitreal carboplatin and EBRT enhances local tumor control in murine retinoblastoma. Combining these treatment modalities may allow tumor control in selected patients with retinoblastoma while decreasing treatment-related morbidity and the mutagenic risks associated with radiation and systemic chemotherapy.

Local carboplatin therapy in transgenic murine retinoblastoma.

PURPOSE: To determine the efficacy and toxicity associated with intraocular delivery of carboplatin in the treatment of murine transgenic hereditary retinoblastoma. METHODS: Forty-eight transgenic BLH-SV40 Tag retinoblastoma mice were administered five intravitreal injections of carboplatin in one eye. After 12 weeks, the eyes were examined histopathologically to evaluate tumor burden. Twelve rabbits were administered intravitreal injections of carboplatin in one eye, after which they underwent serial electroretinography. All experimental and control eyes were obtained for histopathology and electron microscopy. RESULTS: A dose-dependent inhibition of intraocular tumor growth by carboplatin was observed in transgenic retinoblastoma mice. Tumor development was inhibited in 50% of the mouse eyes at doses of 1.4 micrograms. In rabbits, retinal toxicity resulted when intravitreal injections of carboplatin were administered at doses of 10 micrograms or higher. CONCLUSIONS: Local delivery of carboplatin in serial doses effectively inhibits intraocular tumor growth in a dose-dependent manner in transgenic murine retinoblastoma.