Paraspinal radiation recall myositis after gemcitabine for pancreatic adenocarcinoma

Radiation recall (RR) is a chemotherapy-induced reaction that leads to inflammation and necrosis in previously irradiated tissue. Gemcitabine is a cytidine analogue that is often used in conjunction with nab-paclitaxel in the treatment of pancreatic cancer. Herein, we present a case of a 56-year-old woman with stage III pancreatic adenocarcinoma diagnosed with gemcitabine-induced RR when she presented with lower back pain and new rim-enhancing collections within the right and left paraspinal musculature 5 months after radiation therapy to the pancreas. A PubMed search was performed for ‘Radiation Recall Myositis’ and a complete literature review performed. This case and review of the literature of published cases of RR myositis highlight the clinical course and presentation of RR myositis. This review highlights the importance of considering RR in the differential diagnosis when patients who are undergoing chemotherapy and radiation present with inflammatory changes in previously irradiated areas.

Gender Is A Major Determinant of Cytidine Analogue Metabolism and May Contribute to Differences in Treatment Outcomes

Abstract 1434 Cytidine analogues are mainstays in hematologic malignancy therapy. One documented limitation of therapy is interindividual variability in cytidine analogue pharmacokinetics that compromises predictability, safety and efficacy. Causes of interindividual variability include single nucleotide polymorphisms (SNPs) in cytidine metabolizing enzymes, particularly cytidine deaminase (CDA): the CDA SNP A79C (rs2072671) is present in >70% of Caucasians and decreases CDA enzyme activity. Gender is another known genetic determinant of cytidine analogue clinical activity, although the pathway is unknown (Dimopoulou et al, Ann Oncol 2004). With high dose cytarabine therapy, CDA may be saturated, dampening the clinical impact of CDA SNPs. However, the recently approved cytidine analogues 5-azacytidine and decitabine are used as single agents at relatively low doses, and interindividual variability could have greater clinical significance, since drug levels may be close to minimum thresholds required for efficacy. To evaluate this possibility, the impact of A79C and gender on treatment outcomes was examined in a cohort of patients with myelodysplastic syndrome (MDS, n=127) and acute myeloid leukemia (AML, n=74) classified by WHO criteria, initiated on treatment between 1/2002 and 12/2007, with IRB approved tissue-banked bone marrow samples available for analysis for the A79C SNP by sequencing and SNP array, and with verifiable follow-up and survival annotation. Other variables analyzed were those known to have major prognostic importance in patients with MDS and AML (bone marrow myeloblast percentage, karyotype, age). Patients were analyzed in three treatment groups: (i) did not receive cytidine analogues (n=35), (ii) treated with cytarabine (n=76), (iii) treated with 5-azacytidine or decitabine (n=90). In all three treatment groups, heterozygosity or homozygosity for A79C was not associated with significant differences in overall survival (OS). Similarly, there was no significant difference in overall survival in females versus males who were treated with cytarabine or who did not receive cytidine analogues. However, in the 5-azacytidine/decitabine treatment group, females had significantly longer overall survival than males (median 1033 v 563 days, Log Rank p=0.014). In multivariate analysis incorporating age, karyotype, bone marrow blast percentage and A79C, only age, gender and karyotype were significantly (Cox Proportional Hazards p<0.01) associated with survival, with the hazard ratio for female gender 0.356 (95%CI 0.165–0.766). An important caveat is that MDS in females has a less aggressive natural history (Nosslinger et al, Ann Oncol 2010), therefore, it is possible that gender differences in cytidine analogue metabolism do not underlie the difference in overall survival. Nonetheless, in AML myeloblasts (GSE15434) and normal liver tissue (measured by microarray), CDA mRNA expression in females was significantly lower than in males (Wilcoxon test p=0.005 and p=0.025 respectively). To measure functional CDA activity, uridine conversion from cytidine by plasma was measured by uHPLC (Dionex). As expected, there was a significant 2-fold decrease in mean enzyme activity in individuals homozygous for the A79C variant (CC, n=32) compared to individuals homozygous for the ancestral allele (AA, n=32, t-test p=0.02). However, the decrease in mean enzyme activity in females (n=48) compared to males (n=48) was even greater (3-fold, t-test p<0.001). In an analysis of decitabine pharmacokinetics after administration of oral decitabine 1 mg/kg to female (n=18) and male (n=18) adult mice, plasma levels of decitabine measured by LCMSMS were consistently higher in females at all time-points (1.169-4.375 fold at the different time points, paired t-test p=0.001). In conclusion, decreased cytidine analogue conversion to uridine counterparts in females, most likely from differences in CDA expression, could be relevant to gender differences in treatment outcomes with 5-azacytidine or decitabine. Disclosures: No relevant conflicts of interest to declare.

Cellular Pharmacology of D-d4FC, a Nucleoside Analogue Active against Drug-Resistant HIV

The backbone of effective highly active antiretroviral therapy regimens for the treatment of HIV infections currently contains at least two nucleosides. Among the features that influence the potency of each component of a regimen and the overall efficacy of the combination are the cellular uptake and bioconversion of nucleoside analogues to their active triphosphate form, and the extent of possible interactions in these steps that might occur when more than one nucleoside is used in a regimen. D-d4FC (Reverset™), a new cytidine analogue with the ability to inhibit many nucleoside-resistant viral variants, was examined for these parameters. In phytohemaglutinin-stimulated human peripheral blood mononuclear cells, D-d4FC was taken up in a rapid (8 h to 50% maximal value), saturable (plateau above 10 μM parent nucleoside concentration) process, resulting in levels of D-d4FC triphosphate that should provide potent antiviral activity against a variety of virus genotypes. Based on measurement of antiviral effects in cell culture, additive and in some cases, synergistic interactions were observed with protease inhibitors, non-nucleoside reverse transcriptase inhibitors or other nucleosides, including cytidine analogues.