Jacqueline Emrich

Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: A phase II trial☆

Twenty-five patients with primary presentation of malignant astrocytoma, astrocytoma with anaplastic foci, and glioblastoma multiforme were treated with surgical resection and definitive radiation therapy followed by intravenous or intra-arterial administration of Iodine-125 labeled monoclonal antibody-425, which binds specifically to human epidermal growth factor receptor. The patients presented with primary untreated disease, positive contrast enhanced computed tomography scans of the brain, and compatible clinical symptoms. In this Phase II clinical trial, the patients had surgical debulking or biopsy followed by definitively administered external beam radiation therapy and one or multiple doses (35 to 90 mCi per infusion) of radiolabeled antibody. The total cumulative doses ranged from 40 to 224 mCi. The administrations of the radiolabeled antibody were performed in most cases 4-6 weeks following completion of the primary surgery and radiation therapy. Ten patients had astrocytoma with anaplastic foci and 15 had glioblastoma multiforme. No significant life-threatening toxicities were observed during this trial. At 1 year 60% of the patients with astrocytoma with anaplastic foci or glioblastoma multiforme are alive. The median survival for both groups was 15.6 months.

A Phase II study of anti–epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme

OBJECT This single-institution Phase II study tests the efficacy of adjuvant radioimmunotherapy with (125)I-labeled anti-epidermal growth factor receptor 425 murine monoclonal antibody ((125)I-mAb 425) in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS A total of 192 patients with GBM were treated with (125)I-mAb 425 over a course of 3 weekly intravenous injections of 1.8 GBq following surgery and radiation therapy. The primary end point was overall survival, and the secondary end point was toxicity. Additional subgroup analyses were performed comparing treatment with (125)I-mAb 425 (RIT, 132 patients), (125)I-mAb 425 and temozolomide (TMZ+RIT, 60 patients), and a historical control group (CTL, 81 patients). RESULTS The median age was 53 years (range 19-78 years), and the median Karnofsky Performance Scale score was 80 (range 60-100). The percentage of patients who underwent debulking surgery was 77.6% and that of those receiving temozolomide was 31.3%. The overall median survival was 15.7 months (95% CI 13.6-17.8 months). The 1- and 2-year survivals were 62.5 and 25.5%, respectively. For subgroups RIT and TMZ+RIT, the median survivals were 14.5 and 20.2 months, respectively. No Grade 3 or 4 toxicity was seen with the administration of (125)I-mAb 425. The CTL patients lacked Karnofsky Performance Scale scores, had poorer survival, were older, and were less likely to receive radiation therapy. On multivariate analysis, the hazard ratios for RIT versus CTL, TMZ+RIT versus CTL, and TMZ+RIT versus RIT were 0.49 (p < 0.001), 0.30 (p < 0.001), and 0.62 (p = 0.008), respectively. CONCLUSIONS In this large Phase II study of 192 patients with GBM treated with anti-epidermal growth factor receptor (125)I-mAb 425 radioimmunotherapy, survival was 15.7 months, and treatment was safe and well tolerated.

Radioiodinated (I-125) monoclonal antibody 425 in the treatment of high grade glioma patients: ten-year synopsis of a novel treatment.

The present report is the follow-up of patients enrolled in a phase II clinical trial using 125I-MAb 425 as an adjuvant treatment for high grade gliomas. Patient median survivals support published data from an earlier preliminary report. From January 29, 1987 to January 25, 1997, 180 patients diagnosed with astrocytoma with anaplastic foci (AAF) and glioblastoma multiforme (GBM) were treated as outpatients with an average of three weekly intravenous or intraarterial injections of radiolabeled MAb 425. The mean dose was 140 mCi (5.2 GBq). Only one patient who received a single dose of more than 60 mCi (2.2 GBq) experienced acute toxicity. Patients received prior surgery and radiation therapy, with and without chemotherapy. Overall median survival for patients with GBM and AAF was 13.4 and 50.9 months, respectively, with Karnofsky Performance Status (KPS) ranging from 40 to 100 and age ranging from 11 to 75 years. Prognostic factors (KPS and age) correlated positively with increased survival, with KPS the most important determinant of median survival. Data analysis was performed on patients followed 5 years or longer. We conclude that the administration of 125I-MAb 425 with intensive medical management demonstrates a significant increase in median survival and should be considered a therapeutic regimen for the management of patients with high grade gliomas.

Plaque Radiotherapy for Juxtapapillary Choroidal Melanoma: Tumor Control in 650 Consecutive Cases

PURPOSE To evaluate treatment of juxtapapillary choroidal melanoma with plaque radiotherapy and to investigate the role of supplemental transpupillary thermotherapy (TTT). DESIGN Retrospective, comparative case series. PARTICIPANTS We included 650 consecutive eyes with juxtapapillary choroidal melanoma within 1 mm of the optic disc. METHODS Eyes with juxtapapillary choroidal melanoma receiving plaque radiotherapy over a 31-year period from October 1974 to November 2005 were included in the study. The TTT and no TTT groups were analyzed separately and compared. MAIN OUTCOME MEASURES Local tumor control, metastasis, and tumor-related mortality. RESULTS The median basal tumor diameter was 10 mm (range, 1.5-21) and median thickness was 3.5 mm (range, 0.5-14.8). In 481 eyes (74%), the tumor was directly adjacent to the optic disc and in 169 eyes (26%) the posterior tumor margin was between 0.1 and 1.0 mm from the optic disc. The circumpapillary extent of the tumor was <4 clock-hours in 321 eyes (50%), 4-8 clock-hours in 250 eyes (38%), and >8 clock-hours in 79 eyes (12%). Plaque radiotherapy using iodine-125 in 616 eyes (95%), cobalt-60 in 19 eyes (3%), iridium-192 in 12 eyes (2%), and ruthenium-106 in 3 eyes (<1%) delivered a median radiation dose of 8000 cGy (range, 3600-15 500) to the tumor apex and adjunctive TTT was used in 307 eyes (56%). Kaplan-Meier estimates for tumor recurrence, metastasis, and death were 14%, 11%, and 4% at 5 years and 21%, 24%, and 9% at 10 years, respectively. Eyes treated with additional TTT showed slight (statistically nonsignificant) reduction in recurrence and metastasis. Using multivariable analysis, factors predictive of tumor recurrence included foveolar tumor requiring TTT (hazard ratio, 5.07; P<0.001) and greater tumor thickness (hazard ratio, 1.29 per mm increase; P<0.001). Factors predictive of metastasis included greater tumor base (hazard ratio, 1.21 per mm increase; P<0.001) and increasing intraocular pressure (hazard ratio, 1.11 per mmHg increase; P = 0.020). CONCLUSIONS Plaque radiotherapy for juxtapapillary melanoma provides local tumor control in approximately 80% of eyes at 10 years. In subjects who received TTT, there was slight but nonsignificant improved local tumor control and lower metastatic rate.

Irradiation Toxic Effects During Intra-arterial Chemotherapy for Retinoblastoma: Should We Be Concerned?

OBJECTIVE To evaluate irradiation toxic effects from fluoroscopy during intra-arterial chemotherapy for retinoblastoma. DESIGN Prospective trial. PARTICIPANTS Eight patients treated with intra-arterial chemotherapy. MAIN OUTCOME MEASURES Irradiation toxic effects in vital organs. RESULTS The mean patient age was 29 months (range, 10-74 months) and 63% were male. The mean irradiation dose to the skin of the affected eye was 0.19173 Gy, to the contralateral eye was 0.03533 Gy, to the chest wall was 0.00296 Gy, and to the abdominal wall was 0.00104 Gy. The estimated irradiation dose to the lens in the treatment eye was 0.16 Gy, which, in accumulated doses, could be cataractogenic. The estimated irradiation dose from a single fluoroscopy session to other organs, including the brain (0.05560 Gy), thyroid (0.00192 Gy), bone marrow (0.00059 Gy), and gonads (0.00015 Gy), was far lower than the minimal toxic level. CONCLUSIONS Careful use of fluoroscopy during intra-arterial chemotherapy with limited irradiation exposure is advised. Accumulated irradiation toxic effects following multiple sessions of intra-arterial chemotherapy could be cataractogenic and possibly carcinogenic, especially in irradiation-sensitive patients with retinoblastoma.

Histone H1 suppresses tumor growth of leukemia cells in vitro, ex vivo and in an animal model suggesting extracellular functions of histones.

Purified histone H1 exerts growth inhibition of leukemia cells independent of lineage, stage, and maturation. At 200 micrograms/ml, H1 proved cytotoxic in 19 of 21 of the tested leukemia-derived cell lines and for 11 of 16 of the fresh tumor samples from leukemia patients. In all cases, normal peripheral blood mononuclear cells and bone marrow cells remained unaffected. Multicellular spheroids from the Burkitts lymphoma cell line IM-9 were growth arrested at 500 micrograms H1/ml. The clonogenic growth of the Burkitts lymphoma cell line Daudi was arrested at 160 micrograms H1/ml. Synthetic H1-peptides as well as peptides and proteins with biochemical properties similar to H1 had no inhibitory growth effect at equimolar concentrations. Furthermore, 250 micrograms H1 injected into a Burkitts lymphoma (Daudi), xenotransplanted into nude mice, arrested tumor growth. As shown by electron microscopy and flow cytometry, incubation of leukemia cells with H1 resulted in severe plasma membrane damage and ultimately cytolysis. This report characterizes a 33-kd protein that binds H1 and is responsible for the cell death via destruction of the cell membrane integrity. New extranuclear functions of histones are presented.

Iris Melanoma Management with Iodine-125 Plaque Radiotherapy in 144 Patients: Impact of Melanoma-Related Glaucoma on Outcomes

PURPOSE To evaluate the outcomes of iris melanoma managed with plaque radiotherapy on the basis of the initial presence or absence of glaucoma. DESIGN Retrospective, comparative case series. PARTICIPANTS A total of 144 patients. INTERVENTION Custom-designed iodine-125 plaque radiotherapy delivering planned 8000 cGy to melanoma apex using transcorneal application. MAIN OUTCOME MEASURES Tumor control and treatment-related complications. RESULTS Of 144 patients with iris melanoma, glaucoma was present at the initial visit in 58 (40%). Causes of elevated intraocular pressure included angle infiltration by melanoma in 50 patients (86%), angle neovascularization in 4 patients (7%), and hyphema in 4 patients (7%). At presentation, the eyes displaying iris melanoma with glaucoma (vs. without glaucoma) were statistically more likely to display angle tumor (66% vs. 43%), with minimal thickness (1.9 vs. 2.9 mm), and melanoma seeding in iris stroma (7 vs. 3 clock hours) and angle (5 vs. 2 clock hours). Plaque radiotherapy was performed in all cases. Kaplan-Meier estimates at 7 years post-treatment revealed no statistical differences in outcomes of local recurrence (14% vs. 15%), enucleation (14% vs. 11%), or metastasis (2% vs. 0%) comparing eyes with and without glaucoma. Of the entire group, multivariate analysis for factors predictive of recurrence included partial (vs. complete) anterior segment irradiation and postradiotherapy glaucoma. Factors related to enucleation included diabetes mellitus, poor initial visual acuity, higher radiation dose to tumor apex, and tumor recurrence. There were no factors predictive of metastasis. CONCLUSIONS Iodine-125 plaque radiotherapy provides adequate tumor control for iris melanoma with a low metastatic potential of 1% at 7 years. Iris melanoma with secondary glaucoma showed a statistically significant greater likelihood of flat tumor with iris and angle seeding and no difference in outcomes compared with eyes without glaucoma. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Plaque radiotherapy for juxtapapillary choroidal melanoma overhanging the optic disc in 141 consecutive patients.

OBJECTIVE To evaluate tumor control with plaque radiotherapy for juxtapapillary choroidal melanoma that overhangs the optic disc. METHODS Retrospective medical record review of 141 consecutive patients with data on complications of treatment, final visual acuity, visual loss, enucleation, tumor recurrence, metastasis, and death. RESULTS The median patient age was 61 years. Presenting symptoms included reduced visual acuity in 72 eyes (51%), photopsia in 14 (10%), and visual field defect in 18 (13%); 35 patients (25%) were asymptomatic. The median tumor basal diameter was 11 mm and the median thickness was 5.2 mm. The tumor overhung 50% or less of the disc in 88 eyes (62%) and more than 50% of the disc in 53 eyes (38%). In 19 cases (13%), the tumor overhung the entire disc. All patients were treated with plaque radiotherapy, using a notched design in 126 eyes (89%) and a round design in 14 eyes (10%), with iodine 125 in 132 eyes (94%) and cobalt 60 in 9 eyes (6%). The median radiation dose to the tumor apex was 8500 cGy. Adjuvant transpupillary thermotherapy was used in 54 eyes (39%). During a mean follow-up of 56 months, complications included nonproliferative retinopathy in 61 eyes (51%), proliferative retinopathy in 26 (22%), maculopathy in 44 (37%), papillopathy in 57 (48%), neovascular glaucoma in 23 (19%), and vitreous hemorrhage in 48 (40%). A final visual acuity of 20/200 or worse was measured in 72 eyes (77%), and visual loss of more than 5 Snellen lines occurred in 59 eyes (63%). Enucleation was necessary in 27 eyes (23%). Tumor recurrence was found in 12 eyes (10%). Metastasis developed in 15 patients (13%) and death in 4 cases (3%). CONCLUSIONS Using plaque radiotherapy for choroidal melanoma overhanging the optic disc, local tumor control was achieved in 90% of cases. Tumor and radiation effects led to poor visual acuity in 77% of eyes. The metastatic rate was 13% and the mortality rate was 3%.

Sp1 Facilitates DNA Double-Strand Break Repair through a Nontranscriptional Mechanism

ABSTRACT Sp1 is a ubiquitously expressed transcription factor that is phosphorylated by ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation and H2O2. Here, we show by indirect immunofluorescence that Sp1 phosphorylated on serine 101 (pSp1) localizes to ionizing radiation-induced foci with phosphorylated histone variant γH2Ax and members of the MRN (Mre11, Rad50, and Nbs1) complex. More precise analysis of occupancy of DNA double-strand breaks (DSBs) by chromatin immunoprecipitation (ChIP) shows that Sp1, like Nbs1, resides within 200 bp of DSBs. Using laser microirradiation of cells, we demonstrate that pSp1 is present at DNA DSBs by 7.5 min after induction of damage and remains at the break site for at least 8 h. Depletion of Sp1 inhibits repair of site-specific DNA breaks, and the N-terminal 182-amino-acid peptide, which contains targets of ATM kinase but lacks the zinc finger DNA binding domain, is phosphorylated, localizes to DSBs, and rescues the repair defect resulting from Sp1 depletion. Together, these data demonstrate that Sp1 is rapidly recruited to the region immediately adjacent to sites of DNA DSBs and is required for DSB repair, through a mechanism independent of its sequence-directed transcriptional effects.

Scleral necrosis after plaque radiotherapy of uveal melanoma: a case-control study.

PURPOSE To identify risk factors and outcome of scleral necrosis after plaque radiotherapy of uveal melanoma. DESIGN Case-control study. PARTICIPANTS A total of 73 cases with scleral necrosis and 73 controls without necrosis after plaque radiotherapy. Controls were matched for anteroposterior tumor epicenter and follow-up duration. INTERVENTION Plaque radiotherapy with iodine-125, cobalt-60, iridium-192, or ruthenium-106. MAIN OUTCOME MEASURES Scleral necrosis. RESULTS Of 5057 patients treated with plaque radiotherapy for uveal melanoma, 73 (1%) developed radiotherapy-induced scleral necrosis. Scleral necrosis occurred in <1% of patients (3/1140) when plaque radiotherapy was used for tumors <3 mm in thickness, 1% of patients (33/3155) with 3- to 8-mm tumor thickness, and 5% of patients (37/762) with >8-mm-thick tumors. On the basis of tumor location, scleral necrosis was detected after plaque radiotherapy of iris melanoma in 0% of patients (0/91), ciliary body melanoma in 29% of patients (67/235), and choroid melanoma in <1% of patients (6/4731). The mean time interval between plaque radiotherapy and scleral necrosis was 32 months (median, 23 months; range, 4-126 months). The mean basal dimension of scleral necrosis was 4 mm (median, 3 mm; range, 1-15 mm), equivalent to 29% of mean tumor base (median, 24%; range, 6%-100%) and 22% of mean plaque size (median, 19%; range, 5%-75%). Multivariate analysis of factors that predicted clinically evident scleral necrosis included ciliary body (P = 0.0001) and pars plana to ora serrata (P < 0.0001) locations of anterior tumor margin, tumor thickness ≥ 6 mm (P = 0.0001), and radiation dose ≥ 400 Gy to the outer sclera (P = 0.0455). Scleral necrosis remained stable in 48% of patients (35/73), increased in size/severity in 48% of patients (35/73), or progressed to scleral perforation in 4% of patients (3/73) over a mean follow-up of 79 months (median, 54 months; range, 5-351 months). Treatment of scleral necrosis included observation in 81% of patients (59/73), scleral patch graft in 14% of patients (10/73), and enucleation in 5% of patients (4/73). CONCLUSIONS Scleral necrosis after plaque radiotherapy of uveal melanoma was detected in 1% of cases. Factors predictive of scleral necrosis included increasing tumor thickness, ciliary body and peripheral choroidal location, and higher radiation dose to sclera. Most patients (81%) did not require treatment, and 4% evolved to full-thickness perforation. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.