The inciting factor for bradycardia in COVID-19 patients: a potential harm of steroid treatment.

Background: The coronavirus disease 2019 (COVID-19) is a condition caused by the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Although several papers have reported the presence bradycardia in patients with COVID-19, the pathophysiology behind this remains unclear. Therefore, we investigated the presence of bradycardia in patients with COVID-19. Methods: We conducted a retrospective cohort study in a total of 153 patients with COVID-19 and 90 patients with influenza who were hospitalized in our hospital from January 1, 2020 to December 31, 2021 and from January 1, 2014 to December 31, 2021, respectively. Data were collected from patient medical records, which included sex, age, duration of hospitalization, pneumonia complications, supplemental oxygen therapy, antiviral treatment, past history, and vital signs. Results: After adjustment, the incidence of bradycardia and steroid use in patients with COVID-19 were significantly higher than those in patients with influenza (P=0.007 and P<0.001, respectively). We then compared the detailed characteristics of patients with COVID-19 to evaluate risk factors for bradycardia. Multivariate logistic regression analysis revealed that steroid use was significantly related to bradycardia [P=0.031; odds ratio (OR): 3.67; 95% confidence interval (CI): 1.12-11.96]. Overall, results showed a higher incidence of bradycardia in patients with COVID-19 who received steroid treatment. Conclusions: Our results showed that steroid treatment in patients with COVID-19 may be associated with the incidence of bradycardia.

Clinical Characteristics and Pharmacokinetics Change of Long-Term Responders to Antiprogrammed Cell Death Protein 1 Inhibitor Among Patients With Advanced NSCLC.

Introduction: Immune checkpoint inhibitors (ICIs) induce long-term, durable responses in patients with advanced NSCLC. Nevertheless, these responses are limited to a few patients, and most responders have disease progression. The purpose of this study was to determine the differences in clinical factors and blood drug concentrations between long-term responders (LTRs) and non-LTRs. Methods: We retrospectively analyzed consecutive patients with advanced NSCLC who received antiprogrammed cell death protein 1 (PD-1) inhibitor monotherapy (nivolumab) from December 22, 2015, to May 31, 2017. Patients who obtained a clinical benefit for more than 6 months were referred to as "responders"; among these, individuals who had a durable response for more than 2 years were defined as "LTRs." Those with a clinical benefit for less than 2 years were defined as "non-LTRs." Results: A total of 212 patients received anti-PD-1 inhibitor monotherapy. The responders accounted for 35% (75 of 212) of the patients. Of these, 29 (39%) were LTRs and 46 (61%) were non-LTRs. The overall response rate and median tumor shrinkage in the LTR group were significantly higher than those in the non-LTR group (76% versus 35%, p < 0.0001, and 66% versus 16%, p < 0.001, respectively). The groups had no significant difference in PD-L1 expression and serum drug concentration at 3- and 6-month post-treatment initiation. Conclusions: Significant tumor shrinkage was associated with a long-term response to an anti-PD-1 inhibitor. Nevertheless, the PD-L1 expression level and pharmacokinetic profile of the inhibitor could not be used to predict the durable response among the responders.

Early change in the clearance of pembrolizumab reflects the survival and therapeutic response: A population pharmacokinetic analysis in real-world non-small cell lung cancer patients.

OBJECTIVES: The dosing pattern of pembrolizumab is based on population pharmacokinetic (Pop-PK) analysis of clinical trials. Data for Japanese patients or patient populations with poor conditions such as cachexia are scarce. In this study, we performed a Pop-PK analysis of Japanese non-small cell lung cancer patients and analyzed the relationship between exposure, treatment effect, and survival. MATERIALS AND METHODS: A total of 270 blood samples from 76 patients who received 200 mg pembrolizumab every 3 weeks between March 2017 and December 2018 were included. Blood concentrations of pembrolizumab were measured using mass spectrometry, and Pop-PK analysis was conducted using the Phoenix NLME software with a one-compartment model. RESULTS: The estimated median of clearance (CL) in this analysis population was 0.104 L/day, about half of the historical data for Western data. Overall, pembrolizumab CL decreased over time, with some populations showing increased CL early in the treatment and others showing decreased CL over time. When the time-varying CL was stratified by quartile, the group with decreasing CL showed significantly better treatment response and survival than the group with increasing CL, even though the group included more patients with cachexia. Detailed analysis suggested that the patient population that responded to pembrolizumab treatment had an improved general condition and reduced protein catabolism, further decreasing CL. CONCLUSION: In populations that benefit from pembrolizumab treatment, CL may be reduced early in their treatment, which may be a predictive and prognostic factor. However, further prospective validation of our findings is needed.

Correlation between body mass index and efficacy of anti-PD-1 inhibitor in patients with non-small cell lung cancer.

BACKGROUND: High body mass index (BMI) has been reported to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC), but the association between BMI and efficacy of anti-PD-1 inhibitors remains controversial. The present study investigated this association in patients with advanced NSCLC. METHODS: We retrospectively reviewed patients with advanced NSCLC who received PD-1 inhibitors at the National Cancer Center Hospital between January 2016 and December 2018. The efficacy of PD-1 inhibitors (progression-free survival [PFS], overall survival [OS], and response rate) was compared between overweight (BMI ≥25 kg/m2) and non-overweight (BMI <25 kg/m2) groups. Cohort 1 included patients with high PD-L1 expression who were treated with pembrolizumab as first-line therapy; Cohort 2 included patients treated with nivolumab/pembrolizumab as second- or later-line treatment. RESULTS: A total of 324 patients were included in this study and the median BMI (IQR) was 21.4 (19.5-23.6) kg/m2. Of the 324 patients, 279 (86.1%) and 45 (13.9%) were in the non-overweight and overweight groups, respectively. No significant differences in objective response rate (ORR), PFS, or OS were found between overweight and non-overweight patients overall (n = 324; overweight vs. non-overweight: ORR, 28.9% vs. 31.9%, respectively [p = 0.68]; PFS, 7.6 vs. 5.8 months, respectively [p = 0.43]; and OS, 17.6 vs. 15.3 months, respectively [p = 0.90]), or between overweight and non-overweight patients in Cohorts 1 and 2. CONCLUSIONS: No significant differences in the efficacy of PD-1 inhibitors were observed between overweight and non-overweight patients.

Prognostic significance of cachexia in advanced non-small cell lung cancer patients treated with pembrolizumab.

BACKGROUND: Cancer cachexia is a multifactorial syndrome characterized by weight loss leading to immune dysfunction that is commonly observed in patients with advanced non-small cell lung cancer (NSCLC). We examined the impact of cachexia on the prognosis of patients with advanced NSCLC receiving pembrolizumab and evaluated whether the pathogenesis of cancer cachexia affects the clinical outcome. PATIENTS AND METHODS: Consecutive patients with advanced NSCLC treated with pembrolizumab were retrospectively enrolled in the study. Serum levels of pro-inflammatory cytokines and appetite-related hormones, which are related to the pathogenesis of cancer cachexia, were analyzed. Cancer cachexia was defined as (1) a body weight loss > 5% over the past 6 months, or (2) a body weight loss > 2% in patients with a body mass index < 20 kg/m2. RESULTS: A total of 133 patients were enrolled. Patients with cachexia accounted for 35.3%. No significant difference in the objective response rate was seen between the cachexia and non-cachexia group (29.8% vs. 34.9%, P = 0.550), but the median progression-free survival (PFS) and overall survival (OS) periods were significantly shorter in the cachexia group than in the non-cachexia group (PFS: 4.2 months vs. 7.1 months, P = 0.04, and OS: 10.0 months vs. 26.6 months, P = 0.03). The serum TNF-alpha, IL-1 alpha, IL-8, IL-10, and leptin levels were significantly associated with the presence of cachexia, but not with the PFS or OS. CONCLUSION: The presence of cachexia was significantly associated with poor prognosis in advanced NSCLC patients receiving pembrolizumab, not with the response to pembrolizumab.

Comparative Study on the Efficacy and Exposure of Molecular Target Agents in Non-small Cell Lung Cancer PDX Models with Driver Genetic Alterations.

Patient-derived xenografts (PDX) can adequately reflect clinical drug efficacy. However, the methods for evaluating drug efficacy are not fully established. We selected five non-small cell lung cancer (NSCLC) PDXs with genetic alterations from established PDXs and the corresponding molecular targeted therapy was administered orally for 21 consecutive days. Genetic analysis, measurement of drug concentrations in blood and tumors using LC/MS-MS, and analysis of drug distribution in tumors using matrix-assisted laser desorption/ionization mass spectrometry were performed. Fifteen (20%) PDXs were established using samples collected from 76 patients with NSCLC with genetic alterations. The genetic alterations observed in original patients were largely maintained in PDXs. We compared the drug efficacy in original patients and PDX models; the efficacies against certain PDXs correlated with the clinical effects, while those against the others did not. We determined blood and intratumor concentrations in the PDX model, but both concentrations were low, and no evident correlation with the drug efficacy could be observed. The intratumoral spatial distribution of the drugs was both homogeneous and heterogeneous for each drug, and the distribution was independent of the expression of the target protein. The evaluation of drug efficacy in PDXs enabled partial reproduction of the therapeutic effect in original patients. A more detailed analysis of systemic and intratumoral pharmacokinetics may help clarify the mode of action of drugs. Further development of evaluation methods and indices to improve the prediction accuracy of clinical efficacy is warranted.

Smoking History Predicts High Presence of TILs and Efficacy of PD-1 Blockade in PD-L1 Expression-negative Non-small Cell Lung Cancer Patients.

BACKGROUND/AIM: Programmed death-ligand 1 (PD-L1) expression on tumor cells is a predictive biomarker of programmed cell death 1 (PD-1) blockade therapy. This study sought to clarify predictors of the efficacy of nivolumab in non-small cell lung cancer (NSCLC) patients with PD-L1 expression-negative tumors. PATIENTS AND METHODS: We retrospectively reviewed the records of advanced NSCLC patients between January 2016 and April 2019, and investigated the predictive marker of nivolumab including the status of CD8+ tumor infiltrating lymphocytes (TILs). RESULTS: A total of 70 NSCLC patients were included. Overall response rate (ORR) and progression-free survival (PFS) were better in patients with a heavy smoking history (smoking index: SI≥600) than in those without (SI<600) [ORR: 20.6% vs. 2.8%, (p=0.02), and PFS: 2.4 months vs. 1.8 months, (p=0.04)]. A high density of CD8+ TILs was significantly associated with a heavy smoking history (p=0.04). Conlusion: Heavy smoking history (SI≥600), which was correlated with a large number of CD8+ TILs, could be a predictor of the efficacy of nivolumab in NSCLC patients with PD-L1 expression-negative tumors.

Clinical outcomes of pembrolizumab therapy in advanced-NSCLC patients with poor performance status (≥3) and high PD-L1 expression (TPS ≥50%): A case series.

Pembrolizumab is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression tumor proportion score (TPS) ≥50%. The benefit of pembrolizumab in patients with advanced NSCLC and poor performance status (PS ≥3) is limited, even when the tumor is PD-L1-expression-positive. We retrospectively reviewed a total of four NSCLC cases with high PD-L1 expression (TPS ≥50%) and poor PS. The only patient with very high PD-L1 expression (TPS 100%) responded to pembrolizumab, but none of the three patients with high PD-L1 expression (50%-80%) responded to pembrolizumab. In conclusion, pembrolizumab can serve as a treatment option for patients with poor PS, if PD-L1 expression TPS is 100%.

Eltrombopag olamine for refractory immune-related thrombocytopenia induced by pembrolizumab in a non-small cell lung cancer patient.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have shown antitumor activity against a wide variety of malignancies. ICI-induced immune-related thrombocytopenia is a rare immune-related adverse event (irAE). Little is known about the treatment of refractory immune-related thrombocytopenia in non-small cell lung cancer (NSCLC) patients treated with pembrolizumab. RESULTS: We report the case of a patient with advanced NSCLC complicated by pembrolizumab-induced refractory immune-related thrombocytopenia who showed remarkable improvement in the thrombocytopenia in response to eltrombopag olamine treatment. CONCLUSION: Eltrombopag olamine can be a viable treatment option for refractory pembrolizumab-induced immune-related thrombocytopenia in an NSCLC patient.

Loxoprofen-induced interstitial pneumonia: a case report.

BACKGROUND: Loxoprofen is a nonsteroidal anti-inflammatory drug used in the treatment of many diseases. However, there are no case reports about loxoprofen-induced pneumonia. We have encountered a rare case of loxoprofen-induced pneumonia. CASE PRESENTATION: We report the case of a 71-year-old Japanese woman who was initially treated with loxoprofen for fever. She was admitted to our hospital because of worsening of her symptoms, including fever and dyspnea. Her symptoms improved after treatment with ceftriaxone. Seven days after admission, she again developed high fever. She was again treated with loxoprofen and levofloxacin. However, acute respiratory failure developed after initiation of loxoprofen treatment. Chest computed tomography showed peribronchovascular consolidation. She was diagnosed with loxoprofen-induced pneumonia for which she was administered steroids. After treatment, her dyspnea and radiological findings improved. CONCLUSIONS: The findings in this case report reveal an association between treatment with a nonsteroidal anti-inflammatory drug and pneumonia. This rare case was diagnosed after accidental retreatment with loxoprofen. This is the first report of loxoprofen-induced pneumonia.