Can ChatGPT Answer Patient Questions Regarding Total Knee Arthroplasty?

The internet has introduced many resources frequently accessed by patients prior to orthopaedic visits. Recently, Chat Generative Pre-Trained Transformer, an artificial intelligence-based chat application, has become publicly and freely available. The interface uses deep learning technology to mimic human interaction and provide convincing answers to questions posed by users. With its rapidly expanding usership, it is reasonable to assume that patients will soon use this technology for preoperative education. Therefore, we sought to determine the accuracy of answers to frequently asked questions (FAQs) pertaining to total knee arthroplasty (TKA).Ten FAQs were posed to the chatbot during a single online interaction with no follow-up questions or repetition. All 10 FAQs were analyzed for accuracy using an evidence-based approach. Answers were then rated as "excellent response not requiring clarification," "satisfactory requiring minimal clarification," satisfactory requiring moderate clarification," or "unsatisfactory requiring substantial clarification."Of the 10 answers given by the chatbot, none received an "unsatisfactory" rating with the majority either requiring minimal (5) or moderate (4) clarification. While many answers required nuanced clarification, overall, answers tended to be unbiased and evidence-based, even when presented with controversial subjects.The chatbot does an excellent job of providing basic, evidence-based answers to patient FAQs prior to TKA. These data were presented in a manner that will be easily comprehendible by most patients and may serve as a useful clinical adjunct in the future.

Study Groups and POSNA: A Review of Podium Presentations From 2006 to 2020.

BACKGROUND: Study groups are multicenter collaborations aimed at improving orthopaedic decision-making through higher-powered, more generalizable studies. New research is disseminated through peer-reviewed literature and academic meetings, including the Pediatric Orthopaedic Society of North America (POSNA) annual meeting, which brings together academic and medical professionals in pediatric orthopaedics. The goal of this study was to identify patterns in podium presentations (PP) at the POSNA annual meeting resulting from multicenter study groups during a 15-year period. METHODS: A total of 2065 PP from the 2006 to 2020 POSNA annual meetings were identified. The abstracts of each PP were reviewed to determine if they resulted from a multicenter study group and for characteristics including subspecialty focus. PP from 2006 to 2018 were further reviewed for publication in academic journals. Pearson correlation was used to assess change in the number of PP resulting from study groups overtime. Univariate analysis was used to compare characteristics of PP based on study group involvement (significance P<0.05). RESULTS: The proportion of PP resulting from study groups increased from 2.2% (n=2) in 2006 to 9.4% in 2020 (n=16) (R2=0.519, P=0.002). Of the PP resulting from study groups, 52.9% focused on spine, 26.5% on hip, 2.9% on sports, and 2.0% on trauma. This is compared with a distribution of 16.7% (P<0.001) spine, 15.9% (P=0.005) hip, 9.5% (P=0.026) sports, and 14.6% (P<0.001) trauma focus of PP not from study groups. There was no difference in publication rate of PP resulting from study groups compared with those that were not (69.1% vs. 66.2%, P=0.621). CONCLUSIONS: In the 15-year period from 2006 to 2020, there was a nearly 5-fold increase in the proportion of POSNA PP resulting from study groups. Spine surgery is disproportionately supported by study groups, suggesting that there is an opportunity to establish new study groups across the breadth of pediatric orthopaedics. LEVEL OF EVIDENCE: Level V.

Teaching what matters: Integrating health equity education into the core surgery clerkship.

BACKGROUND: Significant disparities in surgical outcomes exist. It is imperative to prepare future doctors to eliminate disparities. Our team of senior medical students developed a surgical clerkship module examining equity in prostate cancer. Student attitudes before and after a facilitated teaching session were assessed. METHODS: A surgical equity pilot module was integrated into the core surgical clerkship starting in July 2020. This module was composed of (1) asynchronous preparatory material and (2) a synchronous interactive case discussion regarding disparities in prostate cancer. Discussion sessions were facilitated by upper-level medical students. Participants answered optional anonymous Likert-style and open-ended survey questions before and after the session. Pre- and post-responses were compared. RESULTS: One hundred and sixteen students completed the module between July 2020 and January 2021. Pre- and post-survey response rates were 66% and 29%, respectively. At baseline, almost all students (95%) agreed knowledge of disparities would make them a better physician. However, the majority (95%) described their general knowledge of surgical disparities as "nonexistent," "poor," or "average." Most students did not have a framework for assessing causes of surgical disparities (86%) and were not aware of interventions for reducing disparities (90%). After intervention, the majority rated their knowledge of surgical disparities as "good" or "excellent" (71%; P < .001). Most students indicated they had a framework 79%; P < .001) and were aware of effective interventions (62%; P < .001). CONCLUSION: We demonstrated a successful pilot of an equity-focused clerkship module. Student attitudes after a single session reflected significant improvement in knowledge of causes and interventions related to surgical disparities. Equity-focused teaching can be incorporated into the surgical clerkship.

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-ß signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.

Unplanned ICU Admission Is Associated With Worse Clinical Outcomes in Geriatric Trauma Patients.

BACKGROUND: Geriatric trauma patients who require an unplanned ICU admission (UIA) may experience worse outcomes. As such, the American College of Surgeons initiated the Trauma Quality Improvement Program which tracks UIA as a quality benchmark. We sought to determine the overall rate and impact of UIA in our geriatric trauma population and to identify predictive risk factors. METHODS: All geriatric trauma patients (≥65) admitted to an urban, level I trauma center from January 2012 to June 2018 were identified. A retrospectively collected administrative database was queried for demographics, comorbidities, injury characteristics, and outcomes. UIA were identified and medical records were queried. Univariate analysis followed by binary logistic regression analysis were performed (P < 0.05 = significant). RESULTS: Of the 2923 geriatric patients identified, 95 (3.3%) patients experienced UIA, most commonly secondary to respiratory (34.7%) and cardiac (22.1%) events. Patients with UIA were older (81 versus 78, P = 0.04), and had higher injury severity score (10 versus 9, P < 0.01) and Charlson comorbidity indices (5 versus 4, P = 0.02). On logistic regression, age (OR 1.027, P = 0.04) and injury severity score (OR 1.032, P < 0.01) were predictive of unplanned ICU admission. Of the UIA, 69.4% were readmissions, or "bounce backs". Patients initially admitted to the ICU had 2.5 increased odds of requiring UIA. Patients with UIA experienced longer hospital stays (15 versus 5, P < 0.01), more days in the ICU (6 versus 1, P < 0.01), and higher rates of mortality (11.6% versus 5.0%, P = 0.02). CONCLUSIONS: Despite relatively low injury severity, geriatric trauma patients requiring UIA have a significant increase in morbidity and mortality. Those initially admitted to the ICU are at especially high risk for UIA, suggesting the benefit of strategies to provide an extra layer of care post-ICU.

Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR.

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.

Extracellular vesicle-mediated phenotype switching in malignant and non-malignant colon cells.

BACKGROUND: Extracellular vesicles (EVs) are secreted from many cells, carrying cargoes including proteins and nucleic acids. Research has shown that EVs play a role in a variety of biological processes including immunity, bone formation and recently they have been implicated in promotion of a metastatic phenotype. METHODS: EVs were isolated from HCT116 colon cancer cells, 1459 non-malignant colon fibroblast cells, and tumor and normal colon tissue from a patient sample. Co-cultures were performed with 1459 cells and malignant vesicles, as well as HCT116 cells and non-malignant vesicles. Malignant phenotype was measured using soft agar colony formation assay. Co-cultures were also analyzed for protein levels using mass spectrometry. The importance of 14-3-3 zeta/delta in transfer of malignant phenotype was explored using siRNA. Additionally, luciferase reporter assay was used to measure the transcriptional activity of NF-κB. RESULTS: This study demonstrates the ability of EVs derived from malignant colon cancer cell line and malignant patient tissue to induce the malignant phenotype in non-malignant colon cells. Similarly, EVs derived from non-malignant colon cell lines and normal patient tissue reversed the malignant phenotype of HCT116 cells. Cells expressing an EV-induced malignant phenotype showed increased transcriptional activity of NF-κB which was inhibited by the NF--κB inhibitor, BAY117082. We also demonstrate that knock down of 14-3-3 zeta/delta reduced anchorage-independent growth of HCT116 cells and 1459 cells co-cultured with HCT derived EVs. CONCLUSIONS: Evidence of EV-mediated induction of malignant phenotype, and reversal of malignant phenotype, provides rational basis for further study of the role of EVs in tumorigenesis. Identification of 14-3-3 zeta/delta as up-regulated in malignancy suggests its potential as a putative drug target for the treatment of colorectal cancer.

The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies.

PURPOSE: A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described. EXPERIMENTAL DESIGN: To study acquired resistance to third-generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses. RESULTS: Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs. CONCLUSIONS: Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments.

Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.

UNLABELLED: Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required. SIGNIFICANCE: This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms.

RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.