Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. METHODS: Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25-50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. RESULTS: Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). CONCLUSIONS: Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

Long contoured locking plate fixation of traumatic proximal humeral fractures with distal extension.

BACKGROUND: There is a paucity of data available with respect to outcome on long contoured locking plate fixation for proximal humerus fractures with distal fracture extension. METHODS: Thirty-four patients with traumatic proximal humerus fractures with distal extension underwent fixation with long contoured locking plates. Twenty-five patients (74%) were included in the study: one patient died, two patients had unrelated illnesses resulting in them being unable to complete follow-up assessment and six were lost to follow-up. Patients' case notes and radiographs were retrospectively reviewed, and patients were contacted to assess functional outcome using the Visual Analogue Scale (VAS) for pain, Disabilities of the Arm, Shoulder and Hand (DASH) score, Oxford Shoulder Score (OSS) and Stanmore Percentage of Normal Shoulder Assessment (SPONSA). RESULTS: Mean follow-up was 27 months (range 11 months to 60 months). Mean pain at final follow-up was 3.6 [95% confidence interval (CI) = 2.5 to 4.8] with only four patients having residual pain greater than 5 on the VAS scale. Mean DASH score was 41.2 (95% CI = 32.0 to 50.4), mean OSS was 29.1 (95% CI = 24.3 to 33.9) and mean SPONSA was 63.9% (95% CI = 50.8 to 77.2). There was one wound infection. Three patients had non-unions that required bone grafting and revision internal fixation. CONCLUSIONS: We feel long contoured locking plates represent a useful treatment option for complex proximal humerus fractures.