How Sensitive Are Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Squamous Cell Carcinoma of the Lung Harboring EGFR Gene–Sensitive Mutations?

Introduction:Epidermal growth factor receptor (EGFR) mutations are found mostly in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations.Methods:Between April 2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry.Results:Thirty-three of 249 patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval [CI], 8.7%–49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7–5.8 months) and 14.6 months (95% CI, 2.9–undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1.Conclusions:Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but also clinical factors and pathologic findings should be taken into consideration

Prognostic impact of clinical factors for immune checkpoint inhibitor with or without chemotherapy in older patients with non-small cell lung cancer and PD-L1 TPS ≥ 50%

IntroductionThe proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO.MethodsWe retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching.ResultsOf the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group.ConclusionsECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%

副腎クリーゼ発症者における慢性副腎機能不全の診断とその予後：過去起点コホート研究

京都大学0048新制・課程博士博士(医学)甲第22352号医博第4593号新制||医||1042(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 稲垣 暢也, 教授 森田 智視, 教授 柳田 素子学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Clinical characteristics of adrenal crisis in adult population with and without predisposing chronic adrenal insufficiency: a retrospective cohort study

Abstract Background Adrenal crisis (AC) occurs in various clinical conditions but previous epidemiological studies in AC are limited to chronic adrenal insufficiency (AI) and sepsis. The aim of this study was to investigate characteristics of AC patients, including predisposing diseases and to describe candidate risk factors for AC such as comorbidities and glucocorticoid (GC) therapy. Methods We conducted a retrospective cohort study using a claims database on 7.4 million patients from 145 acute care hospitals between January 1, 2003 and April 30, 2014. We identified AC patients who met the following criteria: 1) disease name with ICD-10 corresponded with AI; 2) therapeutic GC administration (hydrocortisone equivalent dose ≥100 mg/day); 3) admission; and 4) age ≥18 years. Results We identified 504 patients with AC (median age, 71 years; interquartile range, 59 to 80; 50.6% male). As predisposing conditions, primary AI and central AI accounted for 23 (4.6%) and 136 patients (27.0%), respectively. In the remaining AC patients (68.5%), comorbidities such as cancer, autoimmune diseases, and renal failure were frequent. The most frequent indication for hospitalization was AC (16.3%), followed by pituitary disease (14.7%), cancer (14.7%), AI-related clinical symptoms (11.5%), and infection (11.1%). Admission under oral GC treatment was reported in 104 patients (20.6%). Twenty-six patients were admitted within 14 days after GC cessation (5.2%). Conclusions These findings present an overview of patients with AC in general practice settings, clarifying that predisposing factors for AC were complicated and that patients other than those with chronic AI were older and had more comorbid conditions than those with primary and central AI

Újszülöttkori ultrahangvizsgálatok

Disease lists corresponding with adrenal insufficiency and number of patients. Table S2. Demographic and clinical characteristics at admission of patients receiving excessive GC administration (hydrocortisone equivalent dose >1000 mg/day). Table S3. Disease lists corresponding with risk factors for primary AI. Table S4. Diseases corresponding with risk factors of central AI. Table S5. Codes for pituitary disease, adrenal tumor and adrenal insufficiency (AI)-related symptoms as an indication for hospital admission. Table S6. Diseases corresponding with comorbidities. Table S7. Drugs that interact with glucocorticoids. Table S8. Comparison of glucocorticoid preparations. Table S9. Clinical characteristics in “Others” category at admission according to prior admission within 1 year before AC. Table S10. Clinical characteristics in “Others” category at admission with or without hospitalization under GC medication. Table S11. Clinical characteristics in “Others” category at admission according to hospitalization within 30 days after GC cessation. (DOCX 46 kb

Additional file 1: Table S1. of Clinical characteristics of adrenal crisis in adult population with and without predisposing chronic adrenal insufficiency: a retrospective cohort study

Disease lists corresponding with adrenal insufficiency and number of patients. Table S2. Demographic and clinical characteristics at admission of patients receiving excessive GC administration (hydrocortisone equivalent dose >1000 mg/day). Table S3. Disease lists corresponding with risk factors for primary AI. Table S4. Diseases corresponding with risk factors of central AI. Table S5. Codes for pituitary disease, adrenal tumor and adrenal insufficiency (AI)-related symptoms as an indication for hospital admission. Table S6. Diseases corresponding with comorbidities. Table S7. Drugs that interact with glucocorticoids. Table S8. Comparison of glucocorticoid preparations. Table S9. Clinical characteristics in “Others” category at admission according to prior admission within 1 year before AC. Table S10. Clinical characteristics in “Others” category at admission with or without hospitalization under GC medication. Table S11. Clinical characteristics in “Others” category at admission according to hospitalization within 30 days after GC cessation. (DOCX 46 kb

Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review

The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer

Asthma Controller Medications for Children in Japan

Background. Treatment and management strategies for asthma in children are generally consistent internationally, but prescription of antiasthma drugs differs among countries. The objective of this study was to examine the prescribing patterns of antiasthma drugs, particularly controller medications, in children. Methods. A retrospective cohort study was performed in children with asthma using an administrative claims database in Japan. Results . A total of 1149 preschool-age and 3226 school-age children were identified. Leukotriene receptor antagonists were prescribed for about 80% of the children. Long-acting β-agonists were prescribed for 87.6% and 59.6% of preschool-age and school-age children, respectively, whereas prescriptions of inhaled corticosteroids had lower rates of 8.2% and 16.5%, respectively. In an examination of prescriptions at 1-month intervals, a relatively high number of children were prescribed bronchodilators without anti-inflammatory agents. Conclusion . Our findings suggest that asthma care for children in Japan can be improved through changes in drug prescriptions

Rationale and design of phase II clinical trial of dual inhibition with ramucirumab and erlotinib in 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)