Cobalt toxic optic neuropathy and retinopathy: Case report and review of the literature.

PURPOSE: We detail a case of cobalt toxicity with visual and systemic complications, review the pathogenic process for the optic neuropathy and retinopathy, and discuss the controversy of metallic hip prosthesis. OBSERVATIONS: A 59-year-old female with a history of multiple left hip arthroplasties presented to our clinic with bilateral visual loss. The year prior, she had failure of the hip implant necessitating revision surgery with placement of a chrome-cobalt head. A few months after surgery, she began experiencing blurred and "white, spotty" vision in both eyes in addition to hypothyroidism, cardiomyopathy and neuropathy. The possibility of the patient's symptoms being due to cobalt toxicity from her hip prosthesis was proposed and she was found to have a serum cobalt level >1000 µg/L (normal 0-0.9 ng/mL). Visual acuity was 20/600 in the right and 20/800 in the left eye. There was bilateral temporal optic disc pallor. Goldmann visual field testing demonstrated bilateral central scotomas, optical coherence tomography (OCT) showed severe ganglion cell layer-inner plexiform layer (GCLIPL) thinning and multifocal electroretinography (mfERG) demonstrated decreased amplitudes in both eyes. She underwent a total hip revision arthroplasty with extensive debridement of "black sludge" found within a pseudocapsule. Four days after surgery, cobalt serum levels had significantly decreased to 378 ng/mL. One month after surgery, she had significant improvement in visual acuity (20/150 right eye, 20/250 left eye), Goldmann visual field testing, and mfERG. OCT showed retinal nerve fiber thinning and persistent GCLIPL thinning in both eyes. CONCLUSIONS AND IMPORTANCE: Excessive cobalt levels can result in systemic toxicity leading to visual changes, peripheral neuropathy, hearing loss, cognitive deficits, cardiomyopathy and hypothyroidism. In recent years it has become apparent that cobalt toxicity can be associated with metal-on-metal total hip arthroplasty, or the grinding effects of retained ceramic particles from a fractured ceramic head on a cobalt-chromium femoral head prosthesis.

Treatment-related adverse events associated with a modified UK ALLR3 induction chemotherapy backbone for childhood relapsed/refractory acute lymphoblastic leukemia.

BACKGROUND: The UK ALLR3 (R3) regimen has been adopted to treat pediatric relapsed acute lymphoblastic leukemia (ALL) by many centers in the United States and has become a preferred therapeutic backbone for testing novel agents in clinical trials. A detailed toxicity profile of this platform has not previously been reported. The toxicity and response rates for its use beyond first relapse are unknown. PROCEDURES: We performed a multi-institutional, retrospective study including children with relapsed ALL treated with the R3 reinduction chemotherapy backbone block 1 across five pediatric centers. Data were extracted from medical records and analyzed. RESULTS: Fifty-nine patients were included in the study, including 16 patients with ≥2nd relapse. Ninety-seven percent of patients experienced at least one Grade ≥3 nonhematologic adverse event (AE). Grade 3 or higher infection was reported in 90% of patients. Other nonhematologic Grade ≥3 AEs included electrolyte abnormalities, elevation in hepatic enzymes, and pain. Eighty-five percent of patients achieved a complete remission (CR). There were no significant differences in the incidence of AEs, CR rate, and rate of minimal residual disease negativity between patients with 1st or ≥2nd relapse. CONCLUSION: Our study confirmed that R3 block 1 is a highly active reinduction regimen in childhood relapsed ALL. However, it was associated with a high incidence of severe toxicities, particularly infection. The toxicity profiled in our report should be used to inform optimal supportive care and future clinical trial design with the R3 backbone, particularly when new agents are combined with this regimen.

Initial characterization of a dually radiolabeled peptide for simultaneous monitoring of protein targets and enzymatic activity.

OBJECTIVE: The goal of this study was to develop dually radiolabeled peptides for simultaneous imaging of cancer cell localization by targeting the α(v)ß(3) integrin and their pathophysiology by targeting the activity of the proteolytic enzyme MMP2, involved in the metastatic process. METHODS: A hybrid peptide c(RGDfE)K(DOTA)PLGVRY containing an RGD motif for binding to the α(v)ß(3)integrin, a metal chelator (DOTA) for radiolabeling with [(64)Cu], and the MMP2 substrate cleavage sequence PLGVRY with terminal tyrosine for labeling with [(123)I] was synthesized, labeled with [(64)Cu] and [(123)I], and evaluated in vitro as a potential imaging agent. RESULTS: The peptide was synthesized and labeled with [(64)Cu] and [(123)I] with 300 and 40 µCi/µg (542 and 72.2 mCi/µmol) specific activities, respectively, and radiochemical purity of >98%. c(RGDfE)K(DOTA)PLGVRY demonstrated high affinity for α(v)ß(3) integrins (Kd=83.4+13.2 nM) in both substrate competition and cell binding assays. c(RGDfE)K(DOTA)PLGVRY peptide, but not the scrambled version, c(RGDfE)K(DOTA)GRPLVY was specifically cleaved by MMP2. CONCLUSIONS: These results demonstrate the feasibility of developing dually radiolabeled peptides for the simultaneous imaging of cancer cells and their pathophysiologic activity.