Are polypharmacy side effects predicted by public data still valid in real-world data?

Background and Objective: Although interest in predicting drug-drug interactions is growing, many predictions are not verified by real-world data. This study aimed to confirm whether predicted polypharmacy side effects using public data also occur in data from actual patients. Methods: We utilized a deep learning-based polypharmacy side effects prediction model to identify cefpodoxime-chlorpheniramine-lung edema combination with a high prediction score and a significant patient population. The retrospective study analyzed patients over 18 years old who were admitted to the Asan medical center between January 2000 and December 2020 and took cefpodoxime or chlorpheniramine orally. The three groups, cefpodoxime-treated, chlorpheniramine-treated, and cefpodoxime & chlorpheniramine-treated were compared using inverse probability of treatment weighting (IPTW) to balance them. Differences between the three groups were analyzed using the Kaplan-Meier method and Cox proportional hazards model. Results: The study population comprised 54,043 patients with a history of taking cefpodoxime, 203,897 patients with a history of taking chlorpheniramine, and 1,628 patients with a history of taking cefpodoxime and chlorpheniramine simultaneously. After adjustment, the 1-year cumulative incidence of lung edema in the patient group that took cefpodoxime and chlorpheniramine simultaneously was significantly higher than in the patient groups that took cefpodoxime or chlorpheniramine only (p=0.001). Patients taking cefpodoxime and chlorpheniramine together had an increased risk of lung edema compared to those taking cefpodoxime alone [hazard ratio (HR) 2.10, 95% CI 1.26-3.52, p<0.005] and those taking chlorpheniramine alone, which also increased the risk of lung edema (HR 1.64, 95% CI 0.99-2.69, p=0.05). Conclusions: Validation of polypharmacy side effect predictions with real-world data can aid patient and clinician decision-making before conducting randomized controlled trials. Simultaneous use of cefpodoxime and chlorpheniramine was associated with a higher long-term risk of lung edema compared to the use of cefpodoxime or chlorpheniramine alone.

Association of metabolic health and obesity with coronary heart disease in adult cancer survivors.

BACKGROUND: The metabolically healthy obese (MHO) phenotype is associated with an increased risk of coronary heart disease (CHD) in the general population. However, association of metabolic health and obesity phenotypes with CHD risk in adult cancer survivors remains unclear. We aimed to investigate the associations between different metabolic health and obesity phenotypes with incident CHD in adult cancer survivors. METHODS: We used National Health Insurance Service (NHIS) to identify a cohort of 173,951 adult cancer survivors aged more than 20 years free of cardiovascular complications. Metabolically healthy nonobese (MHN), MHO, metabolically unhealthy nonobese (MUN), metabolically unhealthy obese (MUO) phenotypes were created using as at least three out of five metabolic health criteria along with obesity (body mass index ≥ 25.0 kg/m2). We used Cox proportional hazards model to assess CHD risk in each metabolic health and obesity phenotypes. RESULTS: During 1,376,050 person-years of follow-up, adult cancer survivors with MHO phenotype had a significantly higher risk of CHD (hazard ratio [HR] = 1.52; 95% confidence intervals [CI]: 1.41 to 1.65) as compared to those without obesity and metabolic abnormalities. MUN (HR = 1.81; 95% CI: 1.59 to 2.06) and MUO (HR = 1.92; 95% CI: 1.72 to 2.15) phenotypes were also associated with an increased risk of CHD among adult cancer survivors. CONCLUSIONS: Adult cancer survivors with MHO phenotype had a higher risk of CHD than those who are MHN. Metabolic health status and obesity were jointly associated with CHD risk in adult cancer survivors.

Increased risk of ischemic stroke associated with elevated gamma-glutamyl transferase level in adult cancer survivors: a population-based cohort study.

Adult cancer survivors may have an increased risk of developing ischemic stroke, potentially influenced by cancer treatment-related factors and shared risk factors with stroke. However, the association between gamma-glutamyl transferase (GGT) levels and the risk of ischemic stroke in this population remains understudied. Therefore, our study aimed to examine the relationship between GGT levels and the risk of ischemic stroke using a population-based cohort of adult cancer survivors. A population-based cohort of adult cancer survivors was derived from the National Health Insurance Service-Health Screening Cohort between 2003 and 2005 who survived after diagnosis of primary cancer and participated in the biennial national health screening program between 2009 and 2010. Cox proportional hazards model adjusted for sociodemographic factors, health status and behavior, and clinical characteristics was used to investigate the association between GGT level and ischemic stroke in adult cancer survivors. Among 3095 adult cancer survivors, 80 (2.58%) incident cases of ischemic stroke occurred over a mean follow-up of 8.2 years. Compared to the lowest GGT quartile, the hazard ratios (HRs) for ischemic stroke were 1.56 (95% CI 0.75-3.26), 2.36 (95% CI 1.12-4.99), and 2.40 (95% CI 1.05-5.46) for the second, third, and fourth sex-specific quartiles, respectively (Ptrend = 0.013). No significant effect modification was observed by sex, insurance premium, and alcohol consumption. High GGT level is associated with an increased risk of ischemic stroke in adult cancer survivors independent of sex, insurance premium, and alcohol consumption.

A protocol of a single arm, prospective, open-label, multicenter, phase II study of ramucirumab and erlotinib in treatment-naïve non-small cell lung cancer patients with EGFR mutation and brain metastases (SPIRAL-BRAIN study).

Background: The combination of erlotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) antibody, is one of the most effective treatments for patients with non-small cell lung cancer (NSCLC) and EGFR mutation. However, little is known about the safety and efficacy of this combination treatment for patients with brain metastases. Methods: This single arm, prospective, open-label, multicenter, phase II study will recruit 32 NSCLC patients with EGFR mutation (except for T790M mutation) and brain metastases (asymptomatic or mild symptoms). Patients will be treated with erlotinib at a dose of 150 mg/body once daily and ramucirumab at a dose of 10 mg/kg once every 2 weeks. The primary endpoint is intracranial overall response rate (iORR) and the secondary endpoints are intracranial disease control rate, intracranial progression-free survival (iPFS), extracranial ORR, extracranial PFS, ORR, overall PFS, overall survival (OS), and safety. The planned number of enrollments was calculated based on a one-sample binomial test (normal approximation) with a two-sided α level of 5% and 80% power, assuming that the expected iORR is 65% and the iORR threshold is 40%. Discussion: A prospective study to confirm the safety and efficacy of the combined erlotinib plus ramucirumab treatment for NSCLC patients with EGFR mutation and brain metastases is ongoing. Trial Registration: Japan Registry of Clinical Trials, jRCTs051220059.

A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01.

BACKGROUND: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. METHODS: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). RESULTS: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. CONCLUSIONS: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized, double-blind, active-controlled, multicenter phase 3 trial.

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are -19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and -11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.

Analysis of Tumor Heterogeneity Through AXL Activation in Primary Resistance to EGFR Tyrosine Kinase Inhibitors.

Introduction: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. Methods: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. Results: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. Conclusions: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

Rationale and design of phase II clinical trial of dual inhibition with ramucirumab and erlotinib in EGFR exon 19 deletion-positive treatment-naïve non-small cell lung cancer with high PD-L1 expression (SPIRAL-3D study).

Background: Osimertinib is a standard treatment option for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, osimertinib monotherapy yields poor clinical outcomes in some patients, necessitating the development of novel treatment strategies. In addition, several studies have suggested that high programmed cell death-ligand 1 (PD-L1) expression is associated with poor progression-free survival (PFS) for osimertinib monotherapy in patients with advanced NSCLC harboring EGFR mutations. Objective: To evaluate the clinical efficacy of erlotinib plus ramucirumab for EGFR exon 19 deletion-positive treatment-naïve NSCLC with high PD-L1 expression. Design: A single-arm, prospective, open-label, phase II study. Methods and Analysis: Patients with treatment-naïve EGFR exon 19 deletion-positive NSCLC with high PD-L1 expression and a performance status of 0-2 will receive combination therapy with erlotinib plus ramucirumab until evidence of disease progression or development of unacceptable toxicity. High PD-L1 expression is defined as a tumor proportion score of 50% or higher, as determined by PD-L1 immunohistochemistry 22C3 pharmDx testing. The Kaplan-Meier method and the Brookmeyer and Crowley method with the arcsine square-root transformation will be used with PFS as the primary endpoint. The secondary endpoints include overall response rate, disease control rate, overall survival, and safety. A total of 25 patients will be enrolled. Ethics: The study has been approved by the Clinical Research Review Board, Kyoto Prefectural University of Medicine, Kyoto, Japan, and written informed consent will be obtained from all patients. Discussion: To the best of our knowledge, this is the first clinical trial to focus on PD-L1 expression in EGFR mutation-positive NSCLC. If the primary end point is met, combination therapy with erlotinib and ramucirumab could become a potential treatment option for this clinical population. Trial Registration: This trial was registered with the Japan Registry for Clinical Trials on 12 January 2023 (jRCTs 051220149).

Prospective Observational Study Evaluating the Prognostic Value of the G8 Screening Tool for Extensive-Stage Small Cell Lung Cancer Patients Who Received Programmed Death-Ligand 1 Inhibitor plus Platinum-Etoposide Chemotherapy.

BACKGROUND: Programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy is used as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), regardless of age. OBJECTIVE: We examined the role of the Geriatric 8 (G8) screening tool for evaluating treatment outcomes in patients with ES-SCLC treated with PD-L1 inhibitor plus platinum-etoposide chemotherapy as first-line therapy. PATIENTS AND METHODS: Between September 2019 and October 2021, we prospectively evaluated patients with ES-SCLC treated with immunochemotherapy at ten institutions in Japan. The G8 score was assessed before treatment initiation. RESULTS: We evaluated 44 patients with ES-SCLC. Patients with G8 score > 11 had longer overall survival (OS) than those with G8 score ≤ 11 (not reached versus 8.3 months; log-rank test, p = 0.005). In univariate and multivariate analyses, G8 score > 11 [hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.15-0.75; p = 0.008 and HR 0.34; 95% CI 0.14-0.82; p = 0.02, respectively) and performance status (PS) of 2 (HR 5.42; 95% CI 2.08-14.2; p < 0.001 and HR 6.94; 95% CI 2.25-21.4; p < 0.001, respectively) were independent prognostic factors for OS. Among patients with good PS (0 or 1), the OS in patients with G8 score > 11 was significantly longer than that in patients with G8 score ≤ 11 (not reached versus 12.3 months; log-rank test, p = 0.02). CONCLUSIONS: G8 score evaluation before treatment initiation was useful as a prognostic factor for ES-SCLC patients who received PD-L1 inhibitors and platinum-etoposide chemotherapy, even with good PS.

Association of dietary sodium intake with impaired fasting glucose in adult cancer survivors: A population-based cross-sectional study.

BACKGROUND: Dietary sodium intake is a crucial lifestyle factor that should be assessed in adult cancer survivors due to their increased risk of adverse health outcomes compared to the general population. However, its with impaired fasting glucose (IFG) in adult cancer survivors remains unclear. This study aimed to investigate the association of dietary sodium intake categorized by the American Heart Association (AHA) recommendation with IFG in the community-dwelling adult cancer survivors. METHODS: A total of 1,052 adult cancer survivors without diabetes were identified from the sixth and seventh Korea National Health and Nutrition Examination Survey (KNHANES), 2013-2018. Data on dietary sodium intake was categorized as <1,500 mg/day, 1,500-2,999 mg/day, 2,300-3,999 mg/day, and ≥4,000 mg/day according to the AHA recommendation. A multiple logistic regression model adjusted for demographic, lifestyle, and health status was used to compute odds ratios (OR) and 95% confidence intervals (95% CI) for IFG according to dietary sodium intake categories. RESULTS: After adjusting for confounding variables identified in the KNHANES, the adjusted OR among the adult cancer survivors who consumed 1,500-2,999 mg/day, 2,300-3,999 mg/day, and ≥4,000 mg/day of dietary sodium were 1.16 (95% CI: 0.25-5.27), 1.93 (95% CI: 0.40-9.37), and 2.67 (95% CI: 0.59-12.18), respectively, as compared to those who consumed <1,500 mg/day (P value for trend = 0.036). CONCLUSION: Among community-dwelling adult cancer survivors, high dietary sodium intake was marginally associated with increased odds of IFG. Well-designed cohort studies or randomized clinical trials are needed to establish more epidemiologic evidence on this association in adult cancer survivors.

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia. METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples. RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43). CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

Early Tumor Shrinkage as a Predictor of Favorable Treatment Outcomes in Patients With Extensive-Stage SCLC Who Received Programmed Cell Death-Ligand 1 Inhibitor Plus Platinum-Etoposide Chemotherapy: A Prospective Observational Study.

Introduction: In recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports evaluating ETS in ES-SCLC. Therefore, this study aimed to evaluate the role of ETS in the clinical outcomes of patients with ES-SCLC receiving chemoimmunotherapy. Methods: We prospectively identified 46 patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy at 10 institutions in Japan between September 2019 and October 2021. Of them, 35 patients were selected for analyses. Results: The responders (progression-free survival [PFS] ≥ 6.0 mo) had significantly greater tumor shrinkage at the first evaluation than the nonresponders (PFS < 6.0 mo) (65.0% versus 53.7%, p = 0.03). We defined the cutoff value for ETS as a 57% change from the baseline on the basis of the receiver operating characteristic results to determine the optimal tumor shrinkage rate at the first evaluation for identifying responders. The patients with ES-SCLC who achieved ETS had longer PFS and overall survival than those who did not achieve ETS (5.6 versus 4.0 mo, log-rank test p = 0.001 and 15.0 versus 8.3 mo, log-rank test p = 0.02). In the multivariate analyses, ETS was significantly associated with PFS and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.12-0.63, p = 0.002 and hazard ratio = 0.34, 95% confidence interval: 0.13-0.85, p = 0.02). Conclusions: Our prospective observational study indicated that ETS was related to favorable clinical outcomes for patients with ES-SCLC receiving PD-L1 inhibitor plus platinum-etoposide chemotherapy.

TTF-1 Expression and Clinical Outcomes of Combined Chemoimmunotherapy in Patients With Advanced Lung Adenocarcinoma: A Prospective Observational Study.

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1-positive groups than in TTF-1-negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1-positive groups than in TTF-1-negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1-positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.

Explanatory Power and Prognostic Implications of Factors Associated with Troponin Elevation in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: We investigated the impact of comorbidity burden on troponin elevation, with separate consideration of neurological conditions, in patients with acute ischemic stroke (AIS). METHODS: This prospective, observational cohort study consecutively enrolled patients with AIS for 2 years. Serum cardiac troponin I was repeatedly measured, and disease-related biomarkers were collected for diagnosis of preassigned comorbidities, including atrial fibrillation (AF), ischemic heart disease (IHD), myocardial hypertrophy (MH), heart failure (HF), renal insufficiency (RI), and active cancer. The severity of neurological deficits and insular cortical ischemic lesions were assessed as neurological conditions. Adjusted associations between these factors and troponin elevation were determined using a multivariate ordinal logistic regression model and area under the receiver operating characteristic curve (AUC). Cox proportional hazards model was used to determine the prognostic significance of comorbidity beyond neurological conditions. RESULTS: Among 1,092 patients (66.5±12.4 years, 63.3% male), 145 (13.3%) and 335 (30.7%) had elevated (≥0.040 ng/mL) and minimally-elevated (0.040-0.010 ng/mL) troponin, respectively. In the adjusted analysis, AF, MH, HF, RI, active cancer, and neurological deficits were associated with troponin elevation. The multivariate model with six comorbidities and two neurological conditions exhibited an AUC of 0.729 (95% confidence interval [CI], 0.698-0.759). In Cox regression, AF, IHD, and HF were associated with adverse cardio-cerebrovascular events, whereas HF and active cancer were associated with mortality. CONCLUSION: Troponin elevation in patients with AIS can be explained by the burden of comorbidities in combination with neurological status, which explains the prognostic significance of troponin assay.

Predictive value of p53 and AXL immunostaining for the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor-mutant non-small cell lung cancer.

BACKGROUND: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. METHODS: We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. RESULTS: A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). CONCLUSION: The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted.

Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer.

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

Comparison of the prognosis of symptomatic cerebral infarction and pulmonary embolism in patients with advanced non-small cell lung cancer.

BACKGROUND: Lung cancer patients face a high risk of thromboembolism (TE), which is considered to be a poor prognostic factor. However, the impact of symptomatic cerebral infarction (CI) and pulmonary embolism (PE) on the prognosis of advanced non-small cell lung cancer (NSCLC) patients is not fully understood. METHODS: We retrospectively identified 46 patients with advanced NSCLC who developed symptomatic CI or PE at five hospitals in Japan between January 2010 and December 2019. Prognosis and biomarker levels after incident CI and PE were investigated. RESULTS: Of the 46 patients, 36 developed symptomatic CI, and 10 developed symptomatic PE. The median follow-up duration after incident CI and PE was 18.2 months. Although the proportion of Common Terminology Criteria for Adverse Events grade 4 tended to be higher in patients with PE than in those with CI (30% vs. 11%, p = 0.16), the overall survival (OS) after incident TE tended to be worse in patients with CI than in those with PE (median 2.3 months vs. 9.1 months, log-rank test p = 0.17). Multivariate analysis showed that OS after CI was worse in patients with high D-dimer (DD) levels than in those with low DD levels at the time of incident CI (median 1.3 months vs. 8.3 months, log-rank p < 0.001). CONCLUSIONS: This retrospective study demonstrated that the prognosis of patients tended to be poorer after CI than after PE. The DD levels at the time of incident CI might be a promising predictor of clinical outcomes in advanced NSCLC patients who develop CI.

Relationship between sexual differences and cardiovascular risk factors in the prevalence of asymptomatic coronary disease.

BACKGROUND: This study investigated the sexual differences of coronary artery disease (CAD) prevalence and its association with cardiovascular risk factors in the asymptomatic population. METHODS: In total 6434 asymptomatic participants without known CAD (1740 women and 4694 men) underwent coronary computed tomography angiography (CCTA). The prevalence of significant CAD (diameter stenosis ≥50%) and other CCTA findings were compared by sex, and its influence on CAD was investigated in groups stratified by the number of cardiovascular risk factors, including age (>55 years), hypertension, diabetes, dyslipidemia, and current smoking. RESULTS: The prevalence of current smokers, hypertension, and diabetes were higher in men than women. The mean coronary artery calcium score was 13.1 ± 58.4 for women and 51.1 ± 158.2 for men; the coronary atherosclerosis burden indices were significantly higher in men than women. Significant CAD was identified in 65 women (3.7%) and 429 men (9.1%), showing a significant association (adjusted odds ratio [OR] 2.38, P < 0.001). The relatively higher risk for significant CAD in men was observed in patients with fewer risk factors, and the risk difference was not significant in patients with many risk factors (adjusted ORs: 7.69, 3.37, 1.71, 1.31, and 0.88 in patients with 0, 1, 2, 3, and 4-5 risk factors, respectively). The association between sex and risk factor groups was significant (P < 0.001). CONCLUSIONS: In the asymptomatic population, a significantly higher CAD prevalence was noted in men than women. However, women with a high number of cardiovascular risk factors showed a CAD prevalence similar to that of men.

Combination bezafibrate and nivolumab treatment of patients with advanced non-small cell lung cancer.

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.