Lessons Learned. Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short‐term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin‐associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient‐reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring “at least rarely” after cycle 1, prior to objective high‐frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long‐term toxicity are needed.Background.Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole.Materials and Methods.Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6–19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle.Results.Pantoprazole had no impact on decrements in hearing threshold at 4–8 kHz, post‐treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died.Conclusion.Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N‐acetyl‐ß‐glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.

Methotrexate (MTX) is an antimetabolite, widely used in the practice of pediatric oncology. It plays a major role, along with other drugs, in the treatment of children with acute lymphoblastic leukemia, B-cell lymphomas, and osteogenic sarcomas. In these diseases, MTX is used in high doses (HD), ranging from 5 g/m 2 to 12 g/m 2 . MTX exerts its antineoplastic effect by inhibiting activity of dihydrofolate reductase, an enzyme that plays a central role in the metabolism of folic acid. The main side effects of HDMTX are mucositis and renal and hepatic damage. Allergic reactions to HDMTX have been reported rarely, especially in children [1]. Our successful management of this problem might therefore be instructive.Our patient was a 16-year-old boy previously in excellent health who had an osteogenic sarcoma of the right proximal tibia with multiple metastases to bones, bone marrow, brain, and lung. There was no previous history of allergic reactions to drugs or a history of allergic diseases in the patient or his first-degree relatives. The child was started on three courses of HDMTX (12 g/m 2 ) for 4 hr weekly. He developed an urticarial rash on his trunk and lower extremities approximately 30 min after beginning the first dose of MTX. The drug was stopped and the child was given diphenylhydramine intravenously (0.5 mg/kg). The rash disappeared approximately 20 min after the antihistamine was given, and MTX was resumed. Its infusion this time was uneventful, and no other symptoms or signs of anaphylactic reaction were seen.Before starting MTX, the child was given 5% glucose solution and ondansetron (Zofran) for the first time. Subsequent doses of MTX were given with a premedication of diphenyldramine IV and were not accompanied by any signs of allergic reaction.

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e22013 Background: HDMTX AKI delays MTX excretion and increases the risk for severe systemic toxicity. MTX is thought to crystalize in renal tubules at urine [MTX] above the solubility limit, leading to AKI. Methods: Pharmacokinetic simulations of plasma and urine [MTX] at varying infusion durations (IDs) for 12 g/m2 MTX dose identified 12 h as the shortest duration with urine [MTX] below the solubility limit at pH 7.5. Using a randomized crossover design, we compared 4h and 12h IDs in patients with osteosarcoma treated with 12 g/m2 MTX. Urine AKI biomarkers (NAG, NGAL, KIM-1), urinalysis, and estimated glomerular filtration rate (GFR) were endpoints. [MTX] was measured in plasma using a commercial fluorescence polarization assay and in urine by HPLC. Results: Twelve patients, age 12.8 (5.6-19) y, received 12 g/m2 HDMTX over 4 h (40 infusions) and 12 h (35 infusions). At baseline (BL), GFR was 120 (100-175) mL/min/1.73m2; Median (range) NAG [21(5-64) U/gCr] and NGAL [11(0.7-325) µg/gCr] were normal and KIM-1 [0.9(0.4-6.3) µg/gCr] was elevated. Urine pH was maintained > 7 for all infusions. Proteinuria occurred during 93% of infusions. Table 1 compares 4h and 12h IDs. One patient had HDMTX AKI during a 12 h ID (data excluded from Table); end of infusion (EOI) [MTX] was 930 µM in plasma and 38 mM in urine. By 24h after the start of the HDMTX infusion, serum creatinine (sCr) was 1.4 mg/dL (3.5x BL), cystatin C was 1.0 (1.4x BL); NAG, NGAL and Kim-1 increased by > 350%. At 40h, plasma [MTX] was 40 µM; glucarpidase was administered. Plasma [MTX] < 0.1 µM was achieved at 310 h. Recovery to BL occurred at 20 d for sCr and 40 d for cystatin C. Conclusions: Transient proteinuria, increase in KIM-1 and NAG indicate acute proximal renal tubular damage in all HDMTX infusions regardless of ID. EOI urine [MTX] after 4 h or 12 h IDs did not exceed the solubility limit, including the patient with clinical HDMTX AKI. These results suggest that MTX crystallization in urine may not be the primary mechanism of HDMTX AKI. Clinical trial information: NCT01848457. [Table: see text]