Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, with a uniformly poor prognosis. The tumor microenvironment is composed of both supportive cellular substrates and exogenous factors. We hypothesize that exogenous factors secreted by brain tumor initiating cells (BTICs) could predispose normal neural precursor cells (NPCs) to transformation. When NPCs are grown in GBM-conditioned media, and designated as "tumor-conditioned NPCs" (tcNPCs), they become highly proliferative and exhibit increased stem cell self-renewal, or the unique ability of stem cells to asymmetrically generate another stem cell and a daughter cell. tcNPCs also show an increased transcript level of stem cell markers such as CD133 and ALDH and growth factor receptors such as VEGFR1, VEGFR2, EGFR and PDGFRα. Media analysis by ELISA of GBM-conditioned media reveals an elevated secretion of growth factors such as EGF, VEGF and PDGF-AA when compared to normal neural stem cell-conditioned media. We also demonstrate that tcNPCs require prolonged or continuous exposure to the GBM secretome in vitro to retain GBM BTIC characteristics. Our in vivo studies reveal that tcNPCs are unable to form tumors, confirming that irreversible transformation events may require sustained or prolonged presence of the GBM secretome. Analysis of GBM-conditioned media by mass spectrometry reveals the presence of secreted proteins Chitinase-3-like 1 (CHI3L1) and H2A histone family member H2AX. Collectively, our data suggest that GBM-secreted factors are capable of transiently altering normal NPCs, although for retention of the transformed phenotype, sustained or prolonged secretome exposure or additional transformation events are likely necessary.

Background/Purpose Although much has been written about the medical learning environment, the patient, who is the focus of care, is rarely the focus in this literature. The purpose of this study was to explore the role of the patient as an active participant with agency in the medical learning environment from the standpoint of the learner, the attending physician, and most importantly, the patient. We hoped to gain insights into the mechanisms that can reinforce professional values such as patient‐centred and respectful behaviours in a patient‐present learning environment. Methods We conducted this study in an ambulatory internal medicine clinic using ‘patient‐present’ clinic visits. All case presentations occurred in examination rooms with the patient. We invited participants (attending physicians, undergraduate and postgraduate learners, patients and family members) to participate in semistructured interviews after each clinic visit to explore the impact of the patient‐present learning environment. We recruited 34 participants in the study; 10 attending physicians, 12 learners, 10 patients and 2 family members. We analysed the data deductively using a conceptual framework of agency. Summary/Results We identified three major insights: (1) Patients felt engaged and valued opportunities to be heard; (2) Attending physicians and learners reported a more respectful learning environment and a positive though challenging teaching and learning experience; and (3) A hidden curriculum emerged in a performance‐based view of professional behaviour. Conclusions Patient‐present teaching engaged patients and enhanced their agency by recasting the patient as the central focus within the healthcare encounter. We identified a tension between performing and learning. This study adds new insights to the concept of patient centredness and professionalism from the perspectives of all participants in the medical teaching and learning environment.

Introduction: In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations. Patients and Methods: This retrospective review evaluated patients in British Columbia, Canada with mCRC and RAS testing performed between 1 January 2016 and 31 December 2018. Sequencing information from The Cancer Genome Analysis (TCGA) was also obtained and analysed. Results: Age at diagnosis, sex, anatomic location and stage at diagnosis did not differ by RAS mutation type. Progression free survival on first chemotherapy for patients with metastatic KRAS G12C tumours was 11 months. Median overall survival did not differ by RAS mutation type but was worse for both KRAS G12C (27 months) and non-G12C alterations (29 months) than wildtype (43 months) ( p = 0.01). Within the TCGA, there was no differential gene expression between KRAS G12C and other RAS mutations. However, eight genes with copy number differences between the G12C and non-G12C RAS mutant groups were identified after adjusting for multiple comparisons ( FITM2, PDRG1, POFUT1, ERGIC3, EDEM2, PIGU, MANBAL and PXMP4). We also noted that other RAS mutant mCRCs had a higher tumour mutation burden than those with KRAS G12C mutations (median 3.05 vs 2.06 muts/Mb, p = 4.2e–3) and that KRAS G12C/other RAS had differing consensus molecular subtype distribution from wildtype colorectal cancer (CRC) ( p < 0.0001) but not each other ( p = 0.14). Conclusion: KRAS G12C tumours have similar clinical presentation to other RAS mutant tumours, however, are associated with differential copy number alterations.

Background/PurposeAlthough much has been written about the medical learning environment, the patient, who is the focus of care, has often been excluded from this discourse. The purpose of this study was to explore the role of the patient as an active participant with agency in an authentic medical learning environment from the standpoint of the learner, the attending physician, and most importantly, the patient. We hoped to gain insights into the mechanisms that can reinforce professional values such as patient-centred and respectful behaviours in patient-present learning environments.MethodsThis study took place in an internal medicine ambulatory clinic using a "patient-present” clinic visit approach. We conducted all case presentations in examination rooms with the patient. We invited participants (attending physicians, undergraduate and postgraduate learners, patients and family members) to participate in semi-structured interviews after each clinic visit to explore the impact of the patient-present learning environment. We recruited 34 participants in the study; 10 attending physicians, 12 learners, 10 patients and 2 family members. We analyzed the data deductively using a conceptual framework of agency.Summary/ResultsWe identified three major insights: 1. Patients were engaged and valued opportunities to be heard; 2. Attending physicians and learners reported that presenting cases with patients present challenged normal teaching practices, and they differed on whether it supported a more inclusive health care environment; and 3. A hidden curriculum emerged in a performance-based view of professional behaviour.ConclusionsPatient-present teaching engaged patients and enhanced their agency by recasting the patient as the central focus within the healthcare encounter. We identified a tension between performing and learning. This study adds new insights to the concept of patient centredness and professionalism from the perspectives of all participants in the medical teaching and learning environment.

3125 Background: MAP2K1 (MEK1) mutations are potentially actionable driver mutations in cancer. MAP2K1 mutations can be classified into 3 classes according to molecular characteristics. The efficacy of MAPK inhibitors (MAPKi) for the treatment of MAP2K1 mutant tumors is not well understood. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors, and to evaluate the relationship between MAP2K1 mutation class and clinical activity of MAPKi in patients with MAP2K1 mutant metastatic solid tumors. Methods: We interrogated AACR GENIE (v13) to identify all tumors with Class 1/2/3 MAP2K1 mutant solid tumors. We performed a systematic review and meta-analysis of individual patient data from patients with MAP2K1 mutant cancer published between 2010-22. Key inclusion criteria were: MAP2K1 mutation, solid tumor, metastatic disease, treatment with MAPKi and available treatment response data. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall response rate (RR) and duration of response (DOR). Chi-squared and Log-Rank tests were used to evaluate statistical significance of differences between groups. Results: MAP2K1 driver mutations were present in 917/167,423 (0.5%) tumors in the AACR GENIE dataset. MAP2K1 mutants were most commonly identified in melanoma, colorectal (CRC) and non-small cell lung cancer (NSCLC). In solid tumors, Class 2 mutations were the most prevalent (n=310, 63%) followed by Class 1 (n=119, 24%) and Class 3 (n=66, 13%). Co-occurring MAPK pathway activating mutations (KRAS, NRAS, HRAS, NF1, BRAF, RAF1, or EGFR) were significantly more likely (P<0.0001) to occur in Class 1 (82.3%), versus Class 2 (30.9%) or Class 3 (10.6%) MAP2K1 mutant tumors. We identified 55 patients with MAP2K1 mutant tumors who received MAPKi (n=16/30/6/3 for Class 1/2/3/unclassified, respectively). Of these, (n=22, 18, 12, 3) had melanoma, CRC, NSCLC, or other cancers, respectively. Patients were treated with BRAFi (n=12), MEKi (n=24), BRAF+MEKi (n=2), ERKi (n=1) or EGFRi (n=16). Co-occurring MAPK pathway mutations were present in 51% of tumors. In the entire cohort, the RR was 24% and median PFS was 3.3 months. The RR did not differ according to mutation class, cancer type or MAPKi regimen. However, patients with Class 2 mutations experienced longer PFS (4.0 months) and DOR (23.8 months) compared to patients with Class 1, 3 or unclassified MAP2K1 mutations (PFS 3.0 months, P=0.035; DOR 4.2 months, P=0.04). Conclusions: Class 2 MAP2K1 mutations are RAF-regulated oncogenic mutations with a relatively low incidence of co-occurring MAPK pathway activating mutations. Some patients with Class 2 MAP2K1 mutations may derive durable therapeutic benefit from MAPKi. Prospective clinical studies with MAPK inhibitors are warranted in patients with MAP2K1-mutated metastatic cancer.