Citations

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed > 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

2017 Background: Response Assessment in Neuro-Oncology (RANO) criteria for high-grade and low-grade glioma (HGG and LGG) were developed to improve reliability of response assessment in glioma trials. Several limitations of the original RANO criteria have been reported. Methods: To address limitations of the original RANO criteria, a large cohort of patients with newly diagnosed and recurrent glioblastoma were evaluated comparing RANO-HGG with modified RANO (mRANO) and immunotherapy RANO (iRANO) criteria to inform the following proposed updates (RANO 2.0). Results: Based on the 2021 WHO classification of glioma, we recommend a single common set of criteria for all gliomas regardless of WHO grade and IDH mutational status. These criteria will be used for all trials regardless of the treatment modalities being evaluated. In newly diagnosed glioblastoma, the post-radiotherapy MRI, usually obtained approximately 4 weeks after completion of radiotherapy, rather than the post-surgical MRI as proposed in original RANO criteria, will be used as the baseline for comparison of subsequent scans. Since the incidence of pseudoprogression is high in the first 3 months following radiotherapy, confirmation of progression during this period with a repeat MRI (in 4-8 weeks) will be required for determining radiographic progression of disease (PD) if the patient is clinically stable. However, confirmation scans are not mandatory after this period nor for recurrent tumors since these scans do not appear to improve reliability in determining progression. For agents with a high likelihood of producing pseudoprogression such as viral therapies and some other immunotherapies, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement will remain the 2-dimensional maximum cross-sectional area of tumor as the simplest method, but where resources are available, volumetric measurements are an option. For IDH wild-type tumors with contrast enhancement, non-enhancing tumor will no longer be evaluated with the possible exception of patients receiving antiangiogenic therapies. However, in tumors with a significant non-enhancing component, both the contrast enhancing and non-enhancing components will be evaluated as target lesions. Conclusions: We hope that these and other proposed changes by the RANO working group will improve response assessment in glioma clinical trials and help the development of more effective therapy for patients.

Abstract Introduction To enter a profession is to take on a new identity. Professional identity formation can be difficult, with medical learners struggling to adopt professional norms. The role of ideology in medical socialisation may offer insight into these tensions experienced by medical learners. Ideology is the system of ideas and representations that dominates the minds of individuals or social groups and calls individuals into certain ways of being and acting in the world. In this study, we use the concept of ideology to explore residents' experiences with identity struggle during residency. Methods We conducted a qualitative exploration of residents in three specialties at three academic institutions in the United States. Participants engaged in a 1.5‐hour session involving a rich picture drawing and one‐on‐one interview. Interview transcripts were coded and analysed iteratively, with developing themes compared concurrently to newly collected data. We met regularly to develop a theoretical framework to explain findings. Results We identified three ways that ideology contributed to residents' identity struggle. First was the intensity of work and perceived expectations of perfectionism. Second were tensions between the developing professional identity and pre‐existing personal identities. Many residents perceived messages regarding the subjugation of personal identities, including the feeling that being more than physicians was impossible. Third were instances where the imagined professional identity clashed with the reality of medical practice. Many residents described how their ideals misaligned with normative professional ideals, constraining their ability to align their practice and ideals. Conclusion This study uncovers an ideology that shapes residents' developing professional identity—an ideology that creates struggle as it calls them in impossible, competing or even contradictory ways. As we uncover the hidden ideology of medicine, learners, educators and institutions can play a meaningful role in supporting identity development in medical learners through dismantling and rebuilding its damaging elements.

AbstractWe tested the hypothesis that post‐COVID‐19 adults (PC) would have impaired cutaneous nitric oxide (NO)‐mediated vasodilation compared to controls (CON). We performed a cross‐sectional study including 10 (10 F/0 M, 69 ± 7 years) CON and 7 (2 F/5 M, 66 ± 8 years) PC (223 ± 154 days post‐diagnosis). COVID‐19 symptoms severity (survey) was assessed (0–100 scale for 18 common symptoms). NO‐dependent cutaneous vasodilation was induced by a standardized 42°C local heating protocol and quantified via perfusion of 15 mM NG‐nitro‐L‐arginine methyl ester during the plateau of the heating response (intradermal microdialysis). Red blood cell flux was measured with laser‐Doppler flowmetry. Cutaneous vascular conductance (CVC = flux/mm Hg) was presented as a percentage of maximum (28 mM sodium nitroprusside +43°C). All data are means ± SD. The local heating plateau (CON: 71 ± 23% CVCmax vs. PC: 81 ± 16% CVCmax, p = 0.77) and NO‐dependent vasodilation (CON: 56 ± 23% vs. PC: 60 ± 22%, p = 0.77) were not different between groups. In the PC group neither time since diagnosis nor peak symptom severity (46 ± 18 AU) correlated with NO‐dependent vasodilation (r < 0.01, p = 0.99 and r = 0.42, p = 0.35, respectively). In conclusion, middle‐aged and older adults who have had COVID‐19 did not have impaired NO‐dependent cutaneous vasodilation. Additionally, in this cohort of PC, neither time since diagnosis nor symptomology were related to microvascular function.

Abstract Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrolment and treatment monitoring in Alzheimer’s disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer’s disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analysing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, amyloid-β42/40, glial fibrillary acidic protein or neurofilament light chain. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% versus 68%; P = 0.001). A machine learning approach incorporating plasma biomarkers, demographics and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set) and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity, which could non-invasively enhance the interpretation of blood-based AD biomarker profiles in the population.

Background: The purpose of this study was to validate the Foot and Ankle Outcome Score (FAOS) for osteochondral lesions of the talus (OLTs). We hypothesize that the FAOS will meet all 4 psychometric criteria for validity in this patient population. Methods: From 2008 to 2014, a total of 208 patients with OLTs were included in the construct validity portion of the study. All patients completed FAOS and 12-Item Short-Form Health Survey (SF-12) scores. Twenty additional patients were prospectively recruited and were asked to complete questionnaires to determine the relevance of each of the FAOS questions as it related to their OLT. Forty-four patients completed the FAOS 1 month after the first FAOS to assess reliability via Spearman correlation coefficient. Responsiveness of the FAOS was assessed with 54 patients who had both preoperative and postoperative FAOS scores via Student paired t test with significance determined as P < .05. In total, 229 unique patients were included in this study. Results: Statistically significant associations were found between all FAOS and SF-12 subscales ( P < .01). The FAOS symptoms subscale demonstrated the lowest correlation with the SF-12 physical health domains. No floor or ceiling effects were identified. Weak correlations were calculated between the 5 FAOS subscales and the SF-12 mental component summary score. All FAOS domains met the threshold for acceptable content validity (score > 2.0). All FAOS subscales demonstrated acceptable test-retest reliability, with ICC values ranging from 0.81 (ADL) to 0.92 (Pain). Conclusion: This study demonstrates the acceptable yet moderate construct and content validity, reliability, and responsiveness of the FAOS for patients with OLTs of the ankle joint. We endorse the use of the FAOS in evaluating ankle OLTs in both the research and clinical setting and consider it a useful patient-reported, self-administered instrument following surgical intervention. Level of Evidence: Level IV, retrospective case study.

Abstract Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface–associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.

Study Design This retrospective cohort study utilized the National Inpatient Sample (NIS) database for the years 2016–2018. Incidences of street fighting were identified using the corresponding ICD-10 codes. Objective To determine whether alcohol use (measured by blood alcohol content (BAC)) in patients sustaining maxillofacial trauma from hand-to-hand fighting influence hospitalization outcomes. Methods The primary predictor variable was BAC stratified into six categories of increasing magnitude. The primary outcome variable was mean length of hospital stay (days). The secondary outcome variable was total hospital charges (US dollars). Results Our final sample consisted of 3038 craniomaxillofacial fractures. Each additional year in age added +$545 in hospital charges ( P < .01). Non-elective admissions added $14 210 in hospital charges ( P < .05). Patients admitted in 2018 experienced approximately $7537 more in hospital charges ( P < .01). Le Fort fractures (+$61 921; P < .01), mandible fractures (+$13 227, P < .01), and skull base fractures (+$22 170; P < .05) were all independently associated with increased hospital charges. Skull base fractures added +7.6 days to the hospital stay ( P < .01) and each additional year in patient age added +.1 days to the length of the hospital stay ( P < .01). Conclusions BAC levels did not increase length of stay or hospitalization charges. Le Fort fractures, mandible fractures, and skull base fracture each independently increased hospital charges. This reflects the necessary care (ie, ICU) and treatment (ie, ORIF) of such fractures. Older adults and elderly patients are associated with increased length of stay and hospital charges—they are likely to struggle in navigating the healthcare system and face socioeconomic barriers to discharge.