Complete DPYD genotyping combined with dihydropyrimidine dehydrogenase phenotyping to prevent fluoropyrimidine toxicity: A retrospective study.

INTRODUCTION: In April 2019, French authorities mandated dihydropyrimidine dehydrogenase (DPD) screening, specifically testing uracilemia, to mitigate the risk of toxicity associated with fluoropyrimidine-based chemotherapy. However, this subject is still of debate as there is no consensus on a standardized DPD deficiency screening test. We conducted a real-life retrospective study with the aim of assessing the impact of DPD screening on the occurrence of severe toxicity and exploring the potential benefits of complete genotyping using next-generation sequencing. METHODS: All adult patients consecutively treated with 5-fluorouracil (5-FU) or its oral prodrug at six cancer centers between March 2018 and February 2019 were considered for inclusion. Dihydropyrimidine dehydrogenase deficiency screening included gene encoding DPD (DPYD) genotyping using complete genome sequencing and DPD phenotyping (uracilemia or dihydrouracilemia/uracilemia ratio) or both tests. Associations between each DPD screening method and (i) severe (grade ≥3) early toxicity and (ii) fluoropyrimidine dose reduction in the second chemotherapy cycle were evaluated using multivariable logistic regression analysis. Furthermore, we assessed the concordance between DPD genotype and phenotype using Cohen's kappa. RESULTS: A total of 551 patients were included. Most patients were tested for DPD deficiency (86%) including DPYD genotyping only (6%), DPD phenotyping only (8%), or both (72%). Complete DPD deficiency was not detected in the study population. Severe early toxicity events were observed in 73 patients (13%), with two patients (0.30%) presenting grade 5 toxicity. Despite the numerically higher toxicity rate in untested patients, the occurrence of severe toxicity was not significantly associated with the DPD screening method (p = 0.69). Concordance between the DPD genotype and phenotype was weak (Cohen's kappa of 0.14). CONCLUSION: Due to insufficient numbers, our study was not able to demonstrate any added value of DPYD genotyping using complete genome sequencing to prevent 5-FU toxicity. The optimal strategy for DPD screening before fluoropyrimidine-based chemotherapy requires further clinical evaluation.

Long-Term Outcomes and Prognostic Factors of Patients with Metastatic Solid Tumors Admitted to the Intensive Care Unit.

INTRODUCTION: Admission of metastatic cancer patients to the intensive care unit (ICU) poses medical and ethical challenges in the absence of reliable prognostic tools to guide decision-making. MATERIAL AND METHODS: We retrospectively analyzed the medical charts of 129 consecutive patients with metastatic solid tumors admitted to the ICU between January and September 2014 and identified prognostic factors (PFs) using Cox models. RESULTS: The mean patient age at ICU admission was 58.9 years (range, 25-81 years; males, 51%). Performance status (PS) was 0-1 and 2-3 in 61% and 39% of the patients, respectively. The most prevalent cancers were lung cancer (20%), sarcoma (17%), and breast cancer (16%). ICU admission was attributable to the cancer itself (53%), cancer treatment toxicity (43%), and comorbidities (37%). The median overall survival (OS) after ICU admission was 2.6 months; 15% of the patients died during the ICU stay. Poor PFs for OS were PS >1 before ICU admission (p = 0.007) and ICU admission for the cancer itself (p < 10-3). After ICU discharge, 58% and 42% of the patients received systemic treatment within 12 months and showed good PS recovery, respectively. Multiple organ failure and a multidisciplinary decision to limit therapeutic efforts were poor PFs for reinitiation of systemic treatment (p = 0.2 and 0.006, respectively), and the latter was also a poor PF for PS recovery (p = 0.004). DISCUSSION: In the ICU, the OS of adult patients with solid tumors was similar to that of the noncancer population. For ICU admissions related to the cancer itself, the prognosis is poor.

Gastric Bypass But Not Sleeve Gastrectomy Increases Risk of Major Osteoporotic Fracture: French Population-Based Cohort Study.

The objective of this work was to investigate the risk of major osteoporotic fracture (MOF; hip, proximal humerus, wrist and distal forearm, and clinical spine) in bariatric surgery patients versus matched controls. Bariatric surgery is associated with an increase in fracture risk. However, it remains unclear whether the same degree of fracture risk is associated with sleeve gastrectomy, which has recently surpassed gastric bypass. Records from the French National Inpatient database were used from 2008 to 2018. Bariatric surgery patients, aged 40 to 65 years, with BMI ≥40 kg/m2 , hospitalized between January 1, 2010 and December 31, 2014, were matched to one control (1:1) by age, sex, Charlson comorbidity index, year of inclusion, and class of obesity (40 to 49.9 kg/m2 versus ≥50 kg/m2 ). We performed a Cox regression analysis to assess the association between the risk of any MOF and, respectively, (i) bariatric surgery (yes/no) and (ii) type of surgical procedure (gastric bypass, gastric banding, vertical banded gastroplasty, and sleeve gastrectomy) versus no surgery. A total of 81,984 patients were included in the study (40,992 in the bariatric surgery group, and 40,992 matched controls). There were 585 MOFs in the surgical group (2.30 cases per 1000 patient-year [PY]) and 416 MOFs in the matched controls (1.93 cases per 1000 PY). The risk of MOF was significantly higher in the surgical group (hazard ratio [HR] 1.22; 95% CI, 1.08-1.39). We observed an increase in risk of MOF for gastric bypass only (HR 1.70; 95% CI, 1.46-1.98) compared with the matched controls. In patients aged 40 to 65 years, gastric bypass but not sleeve gastrectomy or the other procedures increased risk of major osteoporotic fractures. © 2020 American Society for Bone and Mineral Research.