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OBJECTIVES: Aneurysm number (An) is a novel prediction tool utilizing parameters of pulsatility index (PI) and aneurysm geometry. An has been shown to have the potential to differentiate intracranial aneurysm (IA) rupture status. The objective of this study is to investigate the feasibility and accuracy of An for IA rupture status prediction using Australian based clinical data. METHODS: A retrospective study was conducted across three tertiary referral hospitals between November 2017 and November 2020 and all saccular IAs with known rupture status were included. Two sets of An values were calculated based on two sets of PI values previously reported in the literature. RESULTS: Five hundred and four IA cases were included in this study. The results demonstrated no significant difference between ruptured and unruptured status when using An ≥1 as the discriminator. Further analysis showed no strong correlation between An and IA subtypes. The area under the curve (AUC) indicated poor performance in predicting rupture status (AUC1 = 0.55 and AUC2 = 0.56). CONCLUSIONS: This study does not support An ≥1 as a reliable parameter to predict the rupture status of IAs based on a retrospective cohort. Although the concept of An is supported by hemodynamic aneurysm theory, further research is needed before it can be applied in the clinical setting. ADVANCES IN KNOWLEDGE: This study demonstrates that the novel prediction tool, An, proposed in 2020 is not reliable and that further research of this hemodynamic model is needed before it can be incorporated into the prediction of IA rupture status.
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Aneurisma Roto , Aneurisma Intracraniano , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/fisiopatologia , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/fisiopatologia , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos de Viabilidade , Fluxo Pulsátil , Adulto , Angiografia Cerebral/métodos , Valor Preditivo dos Testes , AustráliaRESUMO
BACKGROUND: Up to 50% of antibiotic prescriptions for upper respiratory infections (URIs) are inappropriate. Clinical decision support (CDS) systems to mitigate unnecessary antibiotic prescriptions have been implemented into electronic health records, but their use by providers has been limited. OBJECTIVE: As a delegation protocol, we adapted a validated electronic health record-integrated clinical prediction rule (iCPR) CDS-based intervention for registered nurses (RNs), consisting of triage to identify patients with low-acuity URI followed by CDS-guided RN visits. It was implemented in February 2022 as a randomized controlled stepped-wedge trial in 43 primary and urgent care practices within 4 academic health systems in New York, Wisconsin, and Utah. While issues were pragmatically addressed as they arose, a systematic assessment of the barriers to implementation is needed to better understand and address these barriers. METHODS: We performed a retrospective case study, collecting quantitative and qualitative data regarding clinical workflows and triage-template use from expert interviews, study surveys, routine check-ins with practice personnel, and chart reviews over the first year of implementation of the iCPR intervention. Guided by the updated CFIR (Consolidated Framework for Implementation Research), we characterized the initial barriers to implementing a URI iCPR intervention for RNs in ambulatory care. CFIR constructs were coded as missing, neutral, weak, or strong implementation factors. RESULTS: Barriers were identified within all implementation domains. The strongest barriers were found in the outer setting, with those factors trickling down to impact the inner setting. Local conditions driven by COVID-19 served as one of the strongest barriers, impacting attitudes among practice staff and ultimately contributing to a work infrastructure characterized by staff changes, RN shortages and turnover, and competing responsibilities. Policies and laws regarding scope of practice of RNs varied by state and institutional application of those laws, with some allowing more clinical autonomy for RNs. This necessitated different study procedures at each study site to meet practice requirements, increasing innovation complexity. Similarly, institutional policies led to varying levels of compatibility with existing triage, rooming, and documentation workflows. These workflow conflicts were compounded by limited available resources, as well as an implementation climate of optional participation, few participation incentives, and thus low relative priority compared to other clinical duties. CONCLUSIONS: Both between and within health care systems, significant variability existed in workflows for patient intake and triage. Even in a relatively straightforward clinical workflow, workflow and cultural differences appreciably impacted intervention adoption. Takeaways from this study can be applied to other RN delegation protocol implementations of new and innovative CDS tools within existing workflows to support integration and improve uptake. When implementing a system-wide clinical care intervention, considerations must be made for variability in culture and workflows at the state, health system, practice, and individual levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04255303; https://clinicaltrials.gov/ct2/show/NCT04255303.
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PURPOSE: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR engineered NSCLC cell lines and PXD models support a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. RESULTS: These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be re-sensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alteration, and in these double mutant models capivasertib and osimertinib combination elicits an improved anti-tumor effect versus osimertinib alone. CONCLUSIONS: Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC that have a sub-optimal response, or develop resistance, to osimertinib through PIK3CA/AKT/PTEN alterations.
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Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Overprescribing of antibiotics for acute respiratory infections (ARIs) remains a major issue in outpatient settings. Use of clinical prediction rules (CPRs) can reduce inappropriate antibiotic prescribing but they remain underutilized by physicians and advanced practice providers. A registered nurse (RN)-led model of an electronic health record-integrated CPR (iCPR) for low-acuity ARIs may be an effective alternative to address the barriers to a physician-driven model. METHODS: Following qualitative usability testing, we will conduct a stepped-wedge practice-level cluster randomized controlled trial (RCT) examining the effect of iCPR-guided RN care for low acuity patients with ARI. The primary hypothesis to be tested is: Implementation of RN-led iCPR tools will reduce antibiotic prescribing across diverse primary care settings. Specifically, this study aims to: (1) determine the impact of iCPRs on rapid strep test and chest x-ray ordering and antibiotic prescribing rates when used by RNs; (2) examine resource use patterns and cost-effectiveness of RN visits across diverse clinical settings; (3) determine the impact of iCPR-guided care on patient satisfaction; and (4) ascertain the effect of the intervention on RN and physician burnout. DISCUSSION: This study represents an innovative approach to using an iCPR model led by RNs and specifically designed to address inappropriate antibiotic prescribing. This study has the potential to provide guidance on the effectiveness of delegating care of low-acuity patients with ARIs to RNs to increase use of iCPRs and reduce antibiotic overprescribing for ARIs in outpatient settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255303, Registered February 5 2020, https://clinicaltrials.gov/ct2/show/NCT04255303 .
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Sistemas de Apoio a Decisões Clínicas , Infecções Respiratórias , Humanos , Antibacterianos/uso terapêutico , Papel do Profissional de Enfermagem , Infecções Respiratórias/tratamento farmacológico , Registros Eletrônicos de Saúde , Padrões de Prática Médica , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. METHODS: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. RESULTS: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. CONCLUSIONS: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.
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Neoplasias , Proteínas Serina-Treonina Quinases , Humanos , Animais , Camundongos , Proteínas Serina-Treonina Quinases/genética , Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular , Linhagem Celular Tumoral , RNA Mensageiro , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas de Ciclo Celular/genéticaRESUMO
BACKGROUND: Prescription medication labels are often constructed in a manner which hinders safe and appropriate use of medicines. The United States Pharmacopeia released voluntary standards to revise medication labels in an effort to support patients' understanding and improve medication use. OBJECTIVE: To examine the impact of label changes on medication adherence before and after pharmacy implementation of the United States Pharmacopeia patient-centered prescription medication label standards. METHODS: This study used a retrospective pre-post cohort design. Prescription fill claims data were obtained from a community health plan serving Medicaid patients for 1 independent community pharmacy organization across 8 retail pharmacy sites. We calculated medication possession ratios (MPR) and proportion of days covered (PDC) for medications used for contraception, asthma, hypertension, and depression from 15 months before to 13 months after implementation of the label changes. RESULTS: Findings showed significant increases in mean MPR for asthma controller (increased by 0.111 [t = 0.290, P<0.0001]), antihypertensives (increased by 0.062 [t = 0.146, P < 0.0002]), and contraceptives medications (increased 0.133 [t = 0.209, P < 0.0001]) from preintervention to postintervention periods. Results also revealed increases in mean PDC for asthma controllers (increased by 0.193 [t = 0.267, P < 0.0001]), antihypertensives (increased by 0.067 [t = 0.175, P = 0.049]), and contraceptives (increased by 0.111 [t = 0.208, P < 0.0119]) from preintervention to postintervention periods. CONCLUSION: We report an association between a change to more patient-centered prescription medication labels and increased medication adherence based on MPR and PDC among Medicaid recipients.
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Asma , Farmácias , Medicamentos sob Prescrição , Estados Unidos , Humanos , Anti-Hipertensivos/uso terapêutico , Estudos Retrospectivos , Adesão à Medicação , Medicamentos sob Prescrição/uso terapêutico , Asma/tratamento farmacológico , Prescrições , Assistência Centrada no PacienteRESUMO
Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.
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Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we investigate BRAFV600E amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that BRAF amplifications acquired de novo are the primary cause of resistance. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2; however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation, including TIPIN, PLK2 and PLK3, remain at low abundance. This suggests that DNA replication following escape from G1 arrest in drug is more error prone and provides a potential explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that escape from G1 arrest in drug promotes de novo BRAF amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through de novo gene amplification and can be suppressed by impeding cell cycle entry in drug.
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BACKGROUND: Aneurysmal subarachnoid hemorrhage is a cause of profound morbidity and mortality. Its effects extend beyond functional neurological status to neurocognitive and psychological functioning. Endovascular treatment is becoming more prevalent after increasing evidence for its safety and efficacy; however, there is a relative paucity of evidence specific to neurocognitive status after treatment. OBJECTIVE: To assess and compare neuropsychological outcomes after the treatment of ruptured and unruptured intracranial aneurysms. METHODS: A systematic review of the literature was conducted searching for articles assessing the neuropsychological and cognitive outcomes after the treatment of ruptured and unruptured intracranial aneurysms. Inclusion criteria were English language, publication between January 2000 and October 2020, and discussion of neuropsychological outcomes in adequate detail. Outcomes were categorized into 8 domains: 5 Neurocognitive (Language, Executive Function, Complex Attention, Memory and Learning, and Perceptual motor function), Intelligence Quotient, Affect, and Quality of Life. RESULTS: Twenty-four articles were included comprising 2236 patients (924 surgical clipping, 1095 endovascular coiling, and 217 controls). These studies reported that most tests revealed no significant difference [n = 356/421 (84.56%)] between treatment modalities. More studies reported significantly superior test scores in the fields of language, executive function, and memory and learning after coiling [n = 53/421 tests (12.59%)] compared with clipping [n = 12/421 tests (2.85%)]. CONCLUSION: The current available data and published studies demonstrate a trend toward improved neurocognitive and psychological outcomes after endovascular treatment. Although these findings should be considered when deciding on the optimal treatment method for each patient, drawing definitive conclusions is difficult because of heterogeneity between patients and studies.
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Aneurisma Roto , Procedimentos Endovasculares , Aneurisma Intracraniano , Hemorragia Subaracnóidea , Humanos , Aneurisma Intracraniano/cirurgia , Aneurisma Intracraniano/psicologia , Qualidade de Vida , Procedimentos Endovasculares/métodos , Hemorragia Subaracnóidea/cirurgia , Função Executiva , Resultado do Tratamento , Aneurisma Roto/cirurgiaRESUMO
Approximately 15% of all cancer patients harbor mutated KRAS. Direct inhibitors of KRAS have now been generated and are beginning to make progress through clinical trials. These include a suite of inhibitors targeting the KRASG12C mutation commonly found in lung cancer. We investigated emergent resistance to representative examples of different classes of Ras targeted therapies. They all exhibited rapid reactivation of Ras signaling within days of exposure and adaptive responses continued to change over long-term treatment schedules. Whilst the gene signatures were distinct for each inhibitor, they commonly involved up-regulation of upstream nodes promoting mutant and wild-type Ras activation. Experiments to reverse resistance unfortunately revealed frequent desensitization to members of a panel of anti-cancer therapeutics, suggesting that salvage approaches are unlikely to be feasible. Instead, we identified triple inhibitor combinations that resulted in more durable responses to KRAS inhibitors and that may benefit from further pre-clinical evaluation.
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Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de SinaisRESUMO
BACKGROUND: Two major studies, The International Subarachnoid Aneurysm Trial and the Barrow Ruptured Aneurysm Trial, compare the long-term outcomes of clipping and coiling. Although these demonstrated coiling's initial benefits, rebleeding and retreatment rates as well as converging patient outcomes sparked controversy regarding its durability. This article will critically examine the available evidence for and against clipping and coiling of intracranial aneurysms. Critics of endovascular treatment state that the initial benefit seen with endovascular coiling decreases over the duration of follow-up and eventually functional outcomes of both treatment modalities are similar. Combined with the increased rate of retreatment and rebleeding, these trials reveal that coiling is not as durable and not as effective as a long-term treatment compared to clipping. Also, due to the cost of devices following endovascular treatment and prolonged hospitalization following clipping, the financial burden has been considered controversial. SUMMARY/KEY MESSAGES: Short-term outcomes reveal better morbidity and mortality outcomes following coiling. Despite the higher rates of retreatment and rebleeding with coiling, there was no significant change in functional outcomes following retreatment. Furthermore, examining more recent trials reveals a decreased rate of recurrence and rebleeding with improved technology and expertise. Functional outcomes deteriorate for both cohorts over time while recent results revealed improved long-term cognitive outcomes and levels of health-related quality of life after coiling in comparison to clipping. The expense of longer hospital stays following clipping must be balanced against the expense of endovascular devices in coiling.
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BACKGROUND: We sought to compare the safety profile of prepectoral breast reconstruction with total submuscular tissue expander reconstruction, previously our standard. Primary outcomes of interest in this retrospective cohort study were incidence of infection, hematoma, seroma, mastectomy flap necrosis, and reconstruction loss. METHODS: Total submuscular and prepectoral with acellular dermal matrix reconstructions consecutively performed by a single surgeon (P.D.S.) between January 1, 2016, and December 31, 2019, were compared. Demographic and clinical characteristics, as well as complications and complication types, were extracted for all patients. A t test was used to assess differences in continuous variables. Multivariate logistics regression was used to assess the association between type of reconstruction and complication rate. The statistical significance was set at 0.05 for all comparisons. RESULTS: A total of 133 patients (234 breasts) were included. There was a significantly greater incidence of infection (16.5% vs 5.5%, P < 0.01) in the prepectoral/acellular dermal matrix cohort. However, reconstructive loss was low in both cohorts (2.5% and 3.0%, P = 0.83). Adjusted odds ratio for complications in the prepectoral cohort was 2.26, but this was not statistically significant (adjusted P = 0.24). CONCLUSIONS: Prepectoral breast reconstruction shares an overall complication profile that is not greater than that of total submuscular reconstruction. It is associated with a greater risk of infection; however, the ability to salvage the reconstruction with early, aggressive intervention results in low rates of reconstructive loss, comparable with those of total submuscular reconstruction.
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Derme Acelular , Implantes de Mama , Neoplasias da Mama , Mamoplastia , Implantes de Mama/efeitos adversos , Neoplasias da Mama/complicações , Estudos de Coortes , Feminino , Humanos , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Mastectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Dispositivos para Expansão de Tecidos/efeitos adversosRESUMO
Resistance to EGFR inhibitors (EGFRi) presents a major obstacle in treating non-small cell lung cancer (NSCLC). One of the most exciting new ways to find potential resistance markers involves running functional genetic screens, such as CRISPR, followed by manual triage of significantly enriched genes. This triage process to identify 'high value' hits resulting from the CRISPR screen involves manual curation that requires specialized knowledge and can take even experts several months to comprehensively complete. To find key drivers of resistance faster we build a recommendation system on top of a heterogeneous biomedical knowledge graph integrating pre-clinical, clinical, and literature evidence. The recommender system ranks genes based on trade-offs between diverse types of evidence linking them to potential mechanisms of EGFRi resistance. This unbiased approach identifies 57 resistance markers from >3,000 genes, reducing hit identification time from months to minutes. In addition to reproducing known resistance markers, our method identifies previously unexplored resistance mechanisms that we prospectively validate.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Reconhecimento Automatizado de Padrão , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Purpose: To assess the feasibility and acceptability of a health literacy-psychosocial support intervention - ADHERE and explore changes in glycemic values and medication adherence. Patients and Methods: Thirty-one participants with hemoglobin A1c (HbA1c) ≥ 8% were randomly allocated to control (usual care) or intervention groups (receiving usual care plus a 6-session pharmacist-led intervention focusing on the modifiable psychosocial factors that may influence medication adherence). Feasibility metrics evaluated recruitment, retention, and intervention adherence. Questionnaires were administered to collect psychosocial factors and self-reported medication adherence at baseline, the end of the intervention, 3 months, and 6 months post intervention. HbA1c values were extracted from electronic medical records. Repeated measures analysis of variance was used to compare differences in mean outcomes between the control and intervention groups. To assess intervention acceptability, eleven individuals participated in semi-structured interviews about their intervention experiences. Qualitative content analysis was used for analyzing the interviews. Results: Thirty participants completed the study. Overall, the findings support the feasibility of the intervention. There were significant differences in HbA1c values. Participants in the intervention group had lower A1C (8.3 ± 1.4) than in the control group (9.2 ± 1.3) at the time of 6-month follow-up (p = 0.003). In addition, the participants in the intervention group showed improved HbA1c at 6-month follow-up (8.3 ± 1.4), compared to baseline (9.4 ± 1.5, p = 0.011) and after 6-session intervention (8.9 ± 1.6, p = 0.046). However, there were no significant differences in medication adherence between groups over time. Qualitative themes suggest participants liked the intervention and perceived the additional support from the pharmacist as beneficial. Conclusion: A pharmacist-led intervention to provide additional health literacy-psychosocial support may contribute to long-term improvements in HbA1c. Equipping pharmacists with patient-specific diabetes medication adherence information and building in additional follow-up support for patients may improve patient health outcomes.
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Treatment with anti-PD-1 and anti-PD-L1 therapies has shown durable clinical benefit in non-small cell lung cancer (NSCLC). However, patients with NSCLC with epidermal growth factor receptor (EGFR) mutations do not respond as well to treatment as patients without an EGFR mutation. We show that EGFR-mutated NSCLC expressed higher levels of CD73 compared with EGFR WT tumors and that CD73 expression was regulated by EGFR signaling. EGFR-mutated cell lines were significantly more resistant to T cell killing compared with WT cell lines through suppression of T cell proliferation and function. In a xenograft mouse model of EGFR-mutated NSCLC, neither anti-PD-L1 nor anti-CD73 antibody alone inhibited tumor growth compared with the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth, increased the number of tumor-infiltrating CD8+ T cells, and enhanced IFN-γ and TNF-α production of these T cells. Consistently, there were increases in gene expression that corresponded to inflammation and T cell function in tumors treated with the combination of anti-PD-L1 and anti-CD73. Together, these results further support the combination of anti-CD73 and anti-PD-L1 therapies in treating EGFR-mutated NSCLC, while suggesting that increased T cell activity may play a role in response to therapy.
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5'-Nucleotidase , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Mutação , Animais , Feminino , Humanos , Camundongos , 5'-Nucleotidase/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , DNA de Neoplasias/genética , Quimioterapia Combinada , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos SCID , Neoplasias Experimentais , Transdução de SinaisRESUMO
Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) with proven clinical efficacy; however, acquired resistance presents an obstacle to curing EGFR-driven disease. Recent studies have shown that drug-tolerant persister cells (DTP) have a distinct transcriptional profile that may confer specific vulnerabilities. By definition these cells avoid apoptosis, yet little is known about how their survival is regulated. We found that paradoxically, the proapoptotic gene BIM was upregulated in osimertinib DTPs, and cotreatment with BH3 mimetics could trigger DTP cell death. Furthermore, cIAP proteins, antiapoptotic members of the extrinsic pathway, were significantly elevated in DTPs. cIAP antagonists could block DTP formation as an up-front combination, and could eliminate preformed DTPs. Critically, when treated at the time of maximal osimertinib response, cIAP or MCL1 inhibitor treatment could significantly attenuate the regrowth of EGFRm cell line mouse xenografts. Finally, we show that apoptosis can be maximized in cell lines with acquired osimertinib resistance by combining BH3 or SMAC mimetics with agents that target the resistance driver in these models. Taken together, these data suggest novel therapeutic strategies at the point of minimal residual disease or full osimertinib resistance for patients in this critical area of unmet need. Significance: These studies uncover strategies to use targeted agents that activate apoptosis in non-small cell lung cancer cells that survive initial EGFR TKI treatment.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptores ErbB/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Preparações FarmacêuticasRESUMO
The clinical efficacy of epidermal growth factor receptor (EGFR)targeted therapy in EGFR-mutant nonsmall cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitorresistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.
Assuntos
Receptores ErbB , Neoplasias Pulmonares , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.