Prevalence, Treatment Patterns, and Outcomes of Individuals with EGFR Positive Metastatic Non-Small Cell Lung Cancer in a Canadian Real-World Setting: A Comparison of Exon 19 Deletion, L858R, and Exon 20 Insertion EGFR Mutation Carriers.

Real-world evidence surrounding EGFR positive NSCLC patients in Canada is limited. Administrative databases in Alberta, Canada were used to evaluate EGFR testing and mutation prevalence in de novo metastatic NSCLC, as well as the characteristics, treatment patterns, and outcomes of individuals with Exon 19, L858R and Exon20ins mutations. Between 2013-2019, 2974 individuals underwent EGFR testing, of which 451 (15.2%) were EGFR positive. Among EGFR positive individuals, 221 (49.0%) had an Exon 19 mutation, 159 (35.3%) had an L858R mutation, and 18 (4%) had an Exon20ins mutation. The proportion of individuals who initiated 1L systemic therapy was 89.1% for Exon19, 85.5% for L858R, and 72.2% for Exon20ins carriers. The primary front-line systemic therapy was gefitinib or afatinib monotherapy for individuals with Exon 19 (93.4%) and L858R (94.1%) mutations versus platinum combination therapy for individuals with Exon20ins mutations (61.5%). The Exon20ins cohort had worse median overall survival from initiation of 1L systemic therapy (10.5 months [95% CI: 8.0-not estimable]) than the Exon19 (20.6 months [95% CI: 18.4-24.9]), and L858R cohorts (19.1 months [95% CI: 14.5-23.1]). These findings highlight that Exon20ins mutations represent a rare subset of NSCLC in which treatment options are limited and survival outcomes are worse relative to individuals with more common types of EGFR mutations.

Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis.

Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2ß disrupts acinar morphogenesis and promotes cell proliferation and invasion in MCF-10A cells. By characterizing the targets of these oncogenic splicing factors, we identify shared spliced isoforms associated with well-established cancer hallmarks. Finally, we demonstrate that TRA2ß is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival.

Photoacoustic thermal flowmetry with a single light source.

We report a photoacoustic thermal flowmetry based on optical-resolution photoacoustic microscopy (OR-PAM) using a single laser source for both thermal tagging and photoacoustic excitation. When an optically absorbing medium is flowing across the optical focal zone of OR-PAM, a small volume of the medium within the optical focus is repeatedly illuminated and heated by a train of laser pulses with a high repetition rate. The average temperature of the heated volume at each laser pulse is indicated by the photoacoustic signal excited by the same laser pulse due to the well-established linear relationship between the Grueneisen coefficient and the local temperature. The thermal dynamics of the heated medium volume, which are closely related to the flow speed, can therefore be measured from the time course of the detected photoacoustic signals. Here, we have developed a lumped mathematical model to describe the time course of the photoacoustic signals as a function of the medium's flow speed. We conclude that the rising time constant of the photoacoustic signals is linearly dependent on the flow speed. Thus, the flow speed can be quantified by fitting the measured photoacoustic signals using the derived mathematical model. We first performed proof-of-concept experiments using defibrinated bovine blood flowing in a plastic tube. The experiment results have demonstrated that the proposed method has high accuracy (∼±6%) and a wide range of measurable flow speeds. We further validated the method by measuring the blood flow speeds of the microvasculature in a mouse ear in vivo.