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1.
J Natl Compr Canc Netw ; 21(10): 1050-1057.e13, 2023 10.
Article in English | MEDLINE | ID: mdl-37856197

ABSTRACT

BACKGROUND: More than 50% of patients with lung cancer are admitted to the hospital while receiving treatment, which is a burden to patients and the healthcare system. This study characterizes the risk factors and outcomes of patients with lung cancer who were admitted to the hospital. METHODS: A multidisciplinary oncology care team conducted a retrospective medical record review of patients with lung cancer admitted in 2018. Demographics, disease and admission characteristics, and end-of-life care utilization were recorded. Following a multidisciplinary consensus review process, admissions were determined to be either "avoidable" or "unavoidable." Generalized estimating equation logistic regression models assessed risks and outcomes associated with avoidable admissions. RESULTS: In all, 319 admissions for 188 patients with a median age of 66 years (IQR, 59-74 years) were included. Cancer-related symptoms accounted for 65% of hospitalizations. Common causes of unavoidable hospitalizations were unexpected disease progression causing symptoms, chronic obstructive pulmonary disease exacerbation, and infection. Of the 47 hospitalizations identified as avoidable (15%), the median overall survival was 1.6 months compared with 9.7 months (hazard ratio, 2.07; 95% CI, 1.34-3.19; P<.001) for unavoidable hospitalizations. Significant reasons for avoidable admissions included cancer-related pain (P=.02), hypervolemia (P=.03), patient desire to initiate hospice services (P=.01), and errors in medication reconciliation or distribution (P<.001). Errors in medication management caused 26% of the avoidable hospitalizations. Of admissions in patients receiving immunotherapy (n=102) or targeted therapy (n=44), 9% were due to adverse effects of treatment. Patients receiving immunotherapy and targeted therapy were at similar risk of avoidable hospitalizations compared with patients not receiving treatment (P=.3 and P=.1, respectively). CONCLUSIONS: We found that 15% of hospitalizations among patients with lung cancer were potentially avoidable. Uncontrolled symptoms, delayed implementation of end-of-life care, and errors in medication reconciliation were associated with avoidable inpatient admissions. Symptom management tools, palliative care integration, and medication reconciliations may mitigate hospitalization risk.


Subject(s)
Lung Neoplasms , Humans , Middle Aged , Aged , Lung Neoplasms/epidemiology , Lung Neoplasms/therapy , Retrospective Studies , Hospitalization , Palliative Care , Hospitals
2.
Front Health Serv ; 3: 1209720, 2023.
Article in English | MEDLINE | ID: mdl-37674596

ABSTRACT

Introduction: To assess healthcare professionals' perceptions of rural barriers and facilitators of lung cancer screening program implementation in a Veterans Health Administration (VHA) setting through a series of one-on-one interviews with healthcare team members. Methods: Based on measures developed using Reach Effectiveness Adoption Implementation Maintenance (RE-AIM), we conducted a cross-sectional qualitative study consisting of one-on-one semi-structured telephone interviews with VHA healthcare team members at 10 Veterans Affairs medical centers (VAMCs) between December 2020 and September 2021. An iterative inductive and deductive approach was used for qualitative analysis of interview data, resulting in the development of a conceptual model to depict rural barriers and facilitators of lung cancer screening program implementation. Results: A total of 30 interviews were completed among staff, providers, and lung cancer screening program directors and a conceptual model of rural barriers and facilitators of lung cancer screening program implementation was developed. Major themes were categorized within institutional and patient environments. Within the institutional environment, participants identified systems-level (patient communication, resource availability, workload), provider-level (attitudes and beliefs, knowledge, skills and capabilities), and external (regional and national networks, incentives) barriers to and facilitators of lung cancer screening program implementation. Within the patient environment, participants revealed patient-level (modifiable vulnerabilities) barriers and facilitators as well as ecological modifiers (community) that influence screening behavior. Discussion: Understanding rural barriers to and facilitators of lung cancer screening program implementation as perceived by healthcare team members points to opportunities and approaches for improving lung cancer screening reach, implementation and effectiveness in VHA rural settings.

4.
Cancer Discov ; 5(11): 1155-63, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26286086

ABSTRACT

UNLABELLED: Oncogenic EGFR mutations are found in 10% to 35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKI). In analyzing the tumor from a 33-year-old male never-smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18-25 kinase domain duplication (EGFR-KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR-KDD-transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI afatinib. The patient eventually progressed, at which time resequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target. SIGNIFICANCE: We identified oncogenic and drug-sensitive EGFR-KDD that is recurrent in lung, brain, and soft-tissue cancers and documented that a patient with metastatic lung adenocarcinoma harboring the EGFR-KDD derived significant antitumor response from treatment with the EGFR inhibitor afatinib. Findings from these studies will be immediately translatable, as there are already several approved EGFR inhibitors in clinical use.


Subject(s)
Antineoplastic Agents/therapeutic use , ErbB Receptors/genetics , Gene Duplication , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Interaction Domains and Motifs/genetics , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adult , Afatinib , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , Gene Frequency , Humans , Lung Neoplasms/diagnosis , Male , Models, Molecular , Molecular Targeted Therapy , Mutation , Neoplasm Staging , Protein Conformation , Protein Kinase Inhibitors/pharmacology , Protein Multimerization , Quinazolines/pharmacology , Tomography, X-Ray Computed , Treatment Outcome
5.
J Biol Chem ; 281(32): 22674-83, 2006 Aug 11.
Article in English | MEDLINE | ID: mdl-16772289

ABSTRACT

The response of mammalian cells to Sn1 DNA methylators depends on functional MutSalpha and MutLalpha. Cells deficient in either of these activities are resistant to the cytotoxic effects of this class of chemotherapeutic drug. Because killing by Sn1 methylators has been attributed to O6-methylguanine (MeG), we have constructed nicked circular heteroduplexes that contain a single MeG-T mispair, and we have examined processing of these molecules by mismatch repair in nuclear extracts of human cells. Excision provoked by MeG-T is restricted to the incised heteroduplex strand, leading to removal of the MeG when it resides on this strand. However, when the MeG is located on the continuous strand, the heteroduplex is irreparable. MeG-T-dependent repair DNA synthesis is observed on both reparable and irreparable 3' and 5' heteroduplexes as judged by [32P]dAMP incorporation. Labeling with [alpha-32P]dATP followed by a cold dATP chase has demonstrated that newly synthesized DNA on irreparable molecules is subject to re-excision in a reaction that is MutLalpha-dependent, an effect attributable to the presence of MeG on the template strand. Processing of the irreparable 3' heteroduplex is also associated with incision of the discontinuous strand of a few percent of molecules near the thymidylate of the MeG-T base pair. These results provide the first direct evidence for mismatch repair-mediated iterative processing of DNA methylator damage, an effect that may be relevant to damage signaling events triggered by this class of chemotherapeutic agent.


Subject(s)
Base Pair Mismatch , DNA Repair , Adenosine Triphosphate/chemistry , Base Sequence , Cell Nucleus/metabolism , DNA Methylation , DNA Repair Enzymes , Guanine/analogs & derivatives , Guanine/chemistry , HeLa Cells , Humans , Molecular Sequence Data , MutL Proteins , MutS DNA Mismatch-Binding Protein/metabolism , Neoplasm Proteins/metabolism , Nucleic Acid Heteroduplexes/chemistry
6.
J Biol Chem ; 280(6): 4264-9, 2005 Feb 11.
Article in English | MEDLINE | ID: mdl-15561716

ABSTRACT

Activation of phospholipase C-dependent inositol polyphosphate signaling pathways generates distinct messengers derived from inositol 1,4,5-trisphosphate that control gene expression and mRNA export. Here we report the regulation of telomere length by production of a diphosphorylinositol tetrakisphosphate, PP-IP4, synthesized by the KCS1 gene product. Loss of PP-IP4 production results in lengthening of telomeres, whereas overproduction leads to their shortening. This effect requires the presence of Tel1, the yeast homologue of ATM, the protein mutated in the human disease ataxia telangiectasia. Our data provide in vivo evidence of a regulatory link between inositol polyphosphate signaling and the checkpoint kinase family and describe a third nuclear process modulated by phospholipase C activation.


Subject(s)
Inositol Phosphates/metabolism , Saccharomyces cerevisiae Proteins/physiology , Signal Transduction , Telomere/ultrastructure , Ataxia Telangiectasia Mutated Proteins , Biological Transport , Blotting, Southern , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Enzyme Activation , Gene Expression Regulation , Genetic Complementation Test , Hydrolysis , Models, Biological , Mutation , Open Reading Frames , Phosphorylation , Phosphotransferases (Phosphate Group Acceptor) , Plasmids/metabolism , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/biosynthesis , Time Factors , Tumor Suppressor Proteins/metabolism , Type C Phospholipases/chemistry , Type C Phospholipases/metabolism
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