Ischemia as a potential etiologic factor in idiopathic unilateral sudden sensorineural hearing loss: Analysis of posterior circulation arteries.
Kim Chulho,Sohn Jong-Hee,Jang Min Uk,Hong Sung-Kwang,Lee Joong-Seob,Kim Hyung-Jong,Choi Hui-Chul,Lee Jun Ho
Hearing research
The association between idiopathic sudden sensorineural hearing loss (ISSNHL) and the radiologic characteristics of the vertebrobasilar artery is unclear. We hypothesized that the degree and direction of vertebrobasilar artery curvature in the posterior circulation contribute to the occurrence of ISSNHL. We consecutively enrolled patients diagnosed with unilateral ISSNHL in two tertiary hospitals. Magnetic resonance images were performed in all patients to exclude specific causes of ISSNHL, such as vestibular schwannoma, chronic mastoiditis, and anterior inferior cerebellar artery infarct. We measured the following parameters of posterior circulation: vertebral and basilar artery diameter, the degree of basilar artery curvature (modified smoker criteria), and vertebral artery dominance. Pure tone audiometries were performed at admission and again 1 week and 3 months later. A total of 121 ISSNHL patients (mean age, 46.0 ± 17.3 years; 48.8% male) were included in these analyses. The proportion of patients with the left side hearing loss was larger than the proportion with the right side hearing loss (left, 57.9%; right, 42.1%). The majority of patients were characterized by a left dominant vertebral artery and right-sided basilar artery curvature. The direction of the basilar artery curvature was significantly associated with hearing loss lateralization (p = 0.036). Age and sex matched multivariable analyses revealed the absence of diabetes and right-sided basilar artery curvature as significant predictors for left sided hearing loss. There was no statistical difference between atherosclerotic cardiovascular risk score (high versus low) and hearing outcomes at 3 months. In ISSNHL, the laterality of hearing loss was inversely associated with the direction of basilar artery curvature. Our results, therefore, indicate the importance of vascular assessment when evaluating ISSNHL.
10.1016/j.heares.2015.09.003
Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial.
Nature medicine
Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .
10.1038/s41591-023-02554-7
Complication Rates and Downstream Medical Costs Associated With Invasive Diagnostic Procedures for Lung Abnormalities in the Community Setting.
Huo Jinhai,Xu Ying,Sheu Tommy,Volk Robert J,Shih Ya-Chen Tina
JAMA internal medicine
Importance:The Centers for Medicare & Medicaid Services added lung cancer screening with low-dose computed tomography (LDCT) as a Medicare preventive service benefit in 2015 following findings from the National Lung Screening Trial (NLST) that showed a 16% reduction in lung cancer mortality associated with LDCT. A challenge in developing and promoting a national lung cancer screening program is the high false-positive rate of LDCT because abnormal findings from thoracic imaging often trigger subsequent invasive diagnostic procedures and could lead to postprocedural complications. Objective:To determine the complication rates and downstream medical costs associated with invasive diagnostic procedures performed for identification of lung abnormalities in the community setting. Design, Setting, and Participants:A retrospective cohort study of non-protocol-driven community practices captured in MarketScan Commercial Claims & Encounters and Medicare supplemental databases was conducted. A nationally representative sample of 344 510 patients aged 55 to 77 years who underwent invasive diagnostic procedures between 2008 and 2013 was included. Main Outcomes and Measures:One-year complication rates were calculated for 4 groups of invasive diagnostic procedures. The complication rates and costs were further stratified by age group. Results:Of the 344 510 individuals aged 55 to 77 years included in the study, 174 702 comprised the study group (109 363 [62.6%] women) and 169 808 served as the control group (106 007 [62.4%] women). The estimated complication rate was 22.2% (95% CI, 21.7%-22.7%) for individuals in the young age group and 23.8% (95% CI, 23.0%-24.6%) for those in the Medicare group; the rates were approximately twice as high as those reported in the NLST (9.8% and 8.5%, respectively). The mean incremental complication costs were $6320 (95% CI, $5863-$6777) for minor complications to $56 845 (95% CI, $47 953-$65 737) for major complications. Conclusions and Relevance:The rates of complications after invasive diagnostic procedures were higher than the rates reported in clinical trials. Physicians and patients should be aware of the potential risks of subsequent adverse events and their high downstream costs in the shared decision-making process.
10.1001/jamainternmed.2018.6277
Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival.
Kellish Patrick,Shabashvili Daniil,Rahman Masmudur M,Nawab Akbar,Guijarro Maria V,Zhang Min,Cao Chunxia,Moussatche Nissin,Boyle Theresa,Antonia Scott,Reinhard Mary,Hartzell Connor,Jantz Michael,Mehta Hiren J,McFadden Grant,Kaye Frederic J,Zajac-Kaye Maria
The Journal of clinical investigation
Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and modest response rates to immune checkpoint inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety of intrapulmonary MYXV delivery with efficient tumor-specific viral replication and cytotoxicity associated with induction of immune cell infiltration. We observed increased SCLC survival following intrapulmonary MYXV that was enhanced by combined low-dose cisplatin. We also tested intratumoral MYXV delivery and observed immune cell infiltration associated with tumor necrosis and growth inhibition in syngeneic murine allograft tumors. Freshly collected primary human SCLC tumor cells were permissive to MYXV and intratumoral delivery into patient-derived xenografts resulted in extensive tumor necrosis. We confirmed MYXV cytotoxicity in classic and variant SCLC subtypes as well as cisplatin-resistant cells. Data from 26 SCLC human patients showed negligible immune cell infiltration, supporting testing MYXV as an ablative and immune-enhancing therapy.
10.1172/JCI121323
Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.
Garassino Marina Chiara,Cho Byoung-Chul,Kim Joo-Hang,Mazières Julien,Vansteenkiste Johan,Lena Hervé,Corral Jaime Jesus,Gray Jhanelle E,Powderly John,Chouaid Christos,Bidoli Paolo,Wheatley-Price Paul,Park Keunchil,Soo Ross A,Huang Yifan,Wadsworth Catherine,Dennis Phillip A,Rizvi Naiyer A,
The Lancet. Oncology
BACKGROUND:Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. METHODS:ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. FINDINGS:Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines. INTERPRETATION:In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted. FUNDING:AstraZeneca.
10.1016/S1470-2045(18)30144-X
Lung Cancer Risk Prediction Model Incorporating Lung Function: Development and Validation in the UK Biobank Prospective Cohort Study.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Purpose Several lung cancer risk prediction models have been developed, but none to date have assessed the predictive ability of lung function in a population-based cohort. We sought to develop and internally validate a model incorporating lung function using data from the UK Biobank prospective cohort study. Methods This analysis included 502,321 participants without a previous diagnosis of lung cancer, predominantly between 40 and 70 years of age. We used flexible parametric survival models to estimate the 2-year probability of lung cancer, accounting for the competing risk of death. Models included predictors previously shown to be associated with lung cancer risk, including sex, variables related to smoking history and nicotine addiction, medical history, family history of lung cancer, and lung function (forced expiratory volume in 1 second [FEV1]). Results During accumulated follow-up of 1,469,518 person-years, there were 738 lung cancer diagnoses. A model incorporating all predictors had excellent discrimination (concordance (c)-statistic [95% CI] = 0.85 [0.82 to 0.87]). Internal validation suggested that the model will discriminate well when applied to new data (optimism-corrected c-statistic = 0.84). The full model, including FEV1, also had modestly superior discriminatory power than one that was designed solely on the basis of questionnaire variables (c-statistic = 0.84 [0.82 to 0.86]; optimism-corrected c-statistic = 0.83; p = 3.4 × 10). The full model had better discrimination than standard lung cancer screening eligibility criteria (c-statistic = 0.66 [0.64 to 0.69]). Conclusion A risk prediction model that includes lung function has strong predictive ability, which could improve eligibility criteria for lung cancer screening programs.
10.1200/JCO.2016.69.2467
Derepression of co-silenced tumor suppressor genes by nanoparticle-loaded circular ssDNA reduces tumor malignancy.
Meng Jing,Chen Shuang,Han Jing-Xia,Tan Qiang,Wang Xiao-Rui,Wang Hong-Zhi,Zhong Wei-Long,Qin Yuan,Qiao Kai-Liang,Zhang Chao,Gao Wan-Feng,Lei Yue-Yang,Liu Hui-Juan,Liu Yan-Rong,Zhou Hong-Gang,Sun Tao,Yang Cheng
Science translational medicine
The co-silencing of multiple tumor suppressor genes can lead to escalated malignancy in cancer cells. Given the limited efficacy of anticancer therapies targeting single tumor suppressor genes, we developed small circular single-stranded DNA (CSSD) that can up-regulate the expression of co-silenced tumor suppressor genes by sequestering microRNAs (miRNAs) that negatively regulate these genes. We found that cancer patients with low tumor expression of the tumor suppressor genes , , and had shortened survival times. The up-regulation of these genes upon transfection of artificial CSSD-9 inhibited tumor proliferation and metastasis and promoted apoptosis in vitro as well as in ex vivo and patient-derived xenograft models. In addition, CSSD is more stable and effective than current miRNA inhibitors, and transfecting CSSDs via nanoparticles substantially improved delivery efficiency. The use of a single CSSD can promote the inhibition of multiple tumor suppressor genes. This study provides evidence for the possibility of using CSSDs as therapeutic miRNA inhibitors to target the co-silencing of multiple tumor suppressor genes.
10.1126/scitranslmed.aao6321
Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer.
Nature immunology
Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (T cells), such as CD103, and CTLs from CD103 tumors displayed features of enhanced cytotoxicity. A greater density of T cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the 'molecular fingerprint' of tumor-infiltrating CTLs and identify potentially new targets for immunotherapy.
10.1038/ni.3775