Peripheral central catheter insertion in low eGFR patients: Retrospective single institution study.

PURPOSE: To identify the rate of Peripherally Inserted Central Catheter (PICC) placement in patients with chronic kidney disease (CKD), stage 3B or higher (glomerular filtration rate (eGFR) <45 mL/min/1.73 m2). MATERIAL AND METHODS: A retrospective study of 2825 adult patients (male 51.2%, female 48.8%) who had a PICC insertion from January 2017 to December 2019. The data collected includes gender, eGFR value at the date of insertion, accessed vein and side, ongoing or subsequent dialysis within 1 year, and death within 1 year of the insertion date. The study excluded pediatric patients, patients with missing eGFR values prior to the procedure and follow-up information. RESULT: PICC insertion was done in patients with eGFR⩽45 mL/min/1.73 m2 in 26.7% (724/2709) of the sample. Ongoing dialysis was documented in 10.2% (198/1946) and subsequent dialysis in 6.5% of the patients within the year after insertion. The overall death rate for the year post PICC insertion was 38.7% (1094/2825), which was significantly higher in low eGFR patients (413/724, 57%) compared to patients with eGFR>45 mL/min/1.73 m2 (632/1985, 31.8%) (p-value < 0.0001, odds ratio 2.84 (95% confidence interval 2.38-3.38)). The rate of dialysis initiated in the year post PICC insertion was 5.9% (98/1657). This was significantly higher in patients with a low eGFR and not previously dialyzed (59/310, 19%) compared to patients with eGFR>45 who required dialysis in the year post insertion (39/1347, 2.9%) (p < 0.0001, odds ratio 7.88 (95% confidence interval 5.14-12.07)). CONCLUSION: PICC insertion in patients with CKD is practiced frequently. Rigorous strategies should be implemented to improve adherence to clinical practice guidelines and reduce unnecessary insertions and preserve veins for when an AVF may be required.

Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer.

PURPOSE: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib. EXPERIMENTAL DESIGN: Biopsies from patients with ROS1 + NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing. RESULTS: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%). CONCLUSIONS: ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.