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e14019 Background: Severe dihydropyrimidine dehydrogenase (DPD) deficiency can be lethal in 0.5-3.0% of patients receiving fluoropyrimidines. Unfortunately, there is no routine test in medical practice to identify high-risk patients. Here, we evaluated the use of plasma and saliva uracil (U) to dihydrouracil (UH2) metabolic ratio and DPYD genotyping, as a means to identify patients with DPD deficiency and fluoropyrimidine toxicity. In addition, we report on a functional test using UH2/U metabolic ratio in dried saliva spots (DSS). Methods: Prior to fluoropyrimidine therapy, plasma and saliva samples were obtained from 60 patients with GI cancer. U and UH2 levels were measured by LC-MS/MS in plasma and saliva. Patients were also genotyped for DPYD (*7/*2A/*13/Y186C). WHO grading were used to report treatment toxicity. Results: In 21 patients (35%) toxicity was documented. For those, no variant allele carrier for DPYD was identified. The UH2/U metabolic ratios were 0.1-26.7 in plasma and 0.1-24.0 in saliva, with a higher correlation with toxicity grade in saliva as compared to plasma (rs 0.52 vs 0.28). Median metabolic ratios were lower in patients with severe toxicity as compared to those with no toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P < 0.01). A cut-off of 1.16 for the salivary UH2/U ratio was set (AUC 0.84) with 86% sensitivity and 77% specificity for the identification of grade 3-4 toxicity. A plasma cut-off of 4.0 (AUC 0.75) revealed a 71% sensitivity and 76% specificity. Moreover, saliva of 21 patients were applied to filter paper to obtain DSS and sent to the laboratory by regular mail. U and UH2 were stable in DSS stored at 45°C up to 7 days. In this set of patients, grade 3-4 toxicity was documented in 3/21 cases (14%), all three cases had metabolic ratios below 1.16 in DSS, confirming our prior results. Conclusions: DPYD genotyping failed to identify severe DPD deficiency, but the UH2/U metabolic ratios in saliva showed enough sensitivity and specificity to deserve further evaluation. DSS samples allowed medical oncologists working at distant sites to send us samples by post, with results available within a week. This test is being validated in a larger sample population.

ResumoO osteoblastoma é uma doença benigna geralmente tratada com ressecção completa com intenção curativa e é responsável por 14% dos tumores ósseos benignos. Uma apresentação mais incomum refere-se a uma rápida apresentação em massa conhecida como osteoblastoma agressivo. Relatamos o caso de um jovem com inchaço cervical devido a uma massa progressiva no lado direito do pescoço com 3 meses de evolução. A biópsia incisional demonstrou osteoblastoma grau 3. Tentou-se uma ressecção cirúrgica radical, mas a ressecção completa não foi viável por causa da invasão cervical de C3 sem envolvimento espinal. Apesar da falta de dados robustos, a radioterapia modulada de intensidade foi realizada na região cervical ipsilateral em uma dose de 50 Gy em 25 frações até novembro de 2013. O paciente está sendo seguido regularmente sem evidências de recorrência desde então. O tratamento até agora bem-sucedido destaca a importância de uma abordagem multidisciplinar para o tratamento de pacientes com osteoblastoma agressivo.