WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• High dose methotrexate (HD MTX) is generally well tolerated, although unpredictable acute toxicities occur frequently.• Low overall toxicity in paediatric patients and increased liver toxicity in adults has been reported, but there are no reports addressing the relationship between acute liver toxicity and gender in patients treated with HD MTX. • Previous studies in animals suggested involvement of the 7-hydroxy-methotrexate metabolite in acute liver toxicity, but this has not been investigated in humans and the aetiology of acute liver toxicity remains unclear. WHAT THIS STUDY ADDS• Survival has increased dramatically over the past decades for patients with malignancies such as osteosarcoma and since these patients are frequently children or adolescents at the time of high dose methotrexate, identification of risk factors for toxicity increases the possibility for tailoring treatment.• Our study presents a detailed analysis of acute toxicity, folate concentrations and pharmacokinetics of both methotrexate and its major extracellular metabolite 7-hydroxy-methotrexate and identifies several factors that are highly correlated with acute liver toxicity. AIMSTo investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy. METHODSMTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration-time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not. RESULTSS-and ER-folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER-folate pretreatment concentrations were higher among males (median 610 nmol l , 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7-OH-MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALATmax) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7-OH-MTX concentrations (P < 0.001), the latter being the main factor influencing ALATmax. CONCLUSIONOur results suggest that 7-OH-MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected.

Osteosarcoma patients are commonly treated with high doses of methotrexate (MTX). MTX is an analog of folate, which is essential for DNA synthesis. Genetic polymorphism at single nucleotide can be indicative to the prognostic outcome in patients. Germ-line variants in candidate genes, coding for enzymes active in the metabolism of MTX, were studied in 62 osteosarcoma patients. Patients harboring the GG genotype in reduced folate carrier 1 (RFC1) rs1051266 had significantly better survival in comparison with patients having the AA genotype (P=0.046). These patients also had a lower frequency of metastasis (15%, P=0.029). Also patients homozygous for the G allele of rs1053129 in the dihydrofolate reductase (DHFR) gene were more likely to have a metastasis (45%, P= 0.005), and the methylenetetetrahydrofolate reductase (MTHFR) 677C allele was associated with higher degree of liver toxicity (88%, P=0.007). The study suggests that germ-line variants in the MTX metabolic pathway are associated with survival and side effects in patients treated with MTX.

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Liver and cardiac uptakes of bone-seeking agents have been described in amyloidosis, and for the heart, after myocardial infarction. We have ruled out any possible contamination by interfering radiopharmaceuticals and cannot find any reason for these findings. Eleven patients with amyloidosis seem one of several hypotheses that is highly improbable.

We aimed to use DECAS to estimate the long-term effectiveness of colonoscopy screening and perform a between-model comparison.Methods: We used DECAS to simulate a cohort of averaged-risk individuals from age of 20 to 90 for three scenarios: (1) no screening; (2) one colonoscopy screening at age of 55; (3) two colonoscopies at age of 55 and 65. We assumed the adenoma pathway accounted for 85% of the CRC development and the serrated pathway the other 15%, as well as 100% uptake of screening and surveillance colonoscopy for positive precancerous findings. Outcomes were reductions in CRC cumulative incidence and mortality in the two screening scenarios compared to no screening. We compared the results with incidence reductions estimated from another German CRC Markov model by Brenner et al. Results:The base case DECAS predicted relative risks of 25-year (age of 55 to 80 years) CRC cumulative incidence at approximately 0.3 and 0.2 for once colonoscopy and twice colonoscopies, respectively. The relative risks of mortality were approximately 0.3 and 0.25 for the two strategies, respectively. The trend in incidence reduction was comparable to those resulting from Brenner et al.'s model. Additional sensitivity analyses on the proportions of CRC developing from adenoma and serrated pathways were performed. Conclusions:We confirmed the long-term colonoscopy screening effectiveness by modeling with DECAS, with the implications overall consistent with another German modeling study. We will further apply DECAS to perform economic evaluations on various CRC screening strategies and policies.Legal entity responsible for the study: The authors.