Nationwide data from comprehensive genomic profiling assays for detecting driver oncogenes in non-small cell lung cancer.

Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment.

AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells.

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

Prospective Observational Study of Ramucirumab Plus Docetaxel After Combined Chemoimmunotherapy in Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. PATIENTS AND METHODS: This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. RESULTS: Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. CONCLUSION: Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.

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.

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.

A case of adult multisystem Langerhans histiocytosis successfully treated by smoking cessation and radiotherapy for bone lesion.

An adult patient was diagnosed with multisystem Langerhans cell histiocytosis with lung and bone lesions. Her lung lesions improved after smoking cessation. Radiotherapy was performed for the bone lesions. Follow-up assessment at 2 years after diagnosis showed no recurrence. Our case shows that remission is possible even without systemic treatment.

A Real-World Analysis of Immune Checkpoint Inhibitor-Based Therapy After Osimertinib Treatment in Patients With EGFR-Mutant NSCLC.

Introduction: The use of immune checkpoint inhibitors (ICIs) with chemotherapy has increased the survival of patients with advanced NSCLC. Nevertheless, the efficacy of ICI treatment for NSCLC with EGFR mutations is limited. Previous studies have not evaluated the efficacy of ICI treatment after osimertinib treatment in real-world settings. Methods: This study performed a retrospective analysis of the association between clinical characteristics and ICI efficacy in patients with EGFR-mutant NSCLC treated with ICIs after osimertinib treatment at 12 institutions in Japan from March 2016 to March 2021. Results: Among 80 patients with EGFR-mutant lung cancer, 42 received ICI monotherapy and 38 received chemoimmunotherapy. In the chemoimmunotherapy group, the progression-free survival (PFS) was significantly longer in the group that exhibited PFS more than 10 months with osimertinib than in the group that exhibited PFS less than or equal to 10 months with osimertinib (8.4 mo versus 3.8 mo, p = 0.026). Nevertheless, there was no significant difference in PFS in the ICI monotherapy group (1.7 mo versus 1.5 mo, p = 0.45). Regardless of the EGFR mutation subtype, PFS of osimertinib treatment was a predictor of the PFS of chemoimmunotherapy (exon 19 deletion mutation: p = 0.03 and exon 21 L858R mutation: p = 0.001). Conclusions: The PFS of osimertinib might be a predictor of PFS of chemoimmunotherapy in patients with EGFR-mutant NSCLC. Further clinical investigations on the predictors of efficacy of administering ICIs after osimertinib treatment are required.

Interstitial Lung Disease Associated with Agaricus blazei Murill in a Patient with Pancreatic Ductal Adenocarcinoma Receiving Gemcitabine-Based Therapy.

A male in his sixties with locally advanced pancreatic ductal adenocarcinoma (PDAC) was administered gemcitabine plus nab-paclitaxel therapy. Computed tomography (CT) scans after five courses revealed nonspecific interstitial pneumonitis in addition to PDAC aggravation. No evidence of respiratory infection was detected, and his condition was stable and asymptomatic at diagnosis. Sputum test and interferon-gamma release assay revealed no evidence of tuberculosis. Through careful history taking, the patient was found to be taking dietary supplementation with Agaricus blazei Murill extract for approximately 1 month. Drug-induced lymphocyte stimulation tests for gemcitabine and nab-paclitaxel were negative, whereas those for Agaricus blazei Murill were positive. CT scans after withdrawal showed improved pneumonitis. These findings suggest a possibility that the dietary supplementation may lead to drug-induced interstitial lung disease (ILD). This patient indicates that pertinent diagnostic interviews are essential for the identification of drug-induced ILD.

Accelerated Discovery of Potent Bioactive anti-TNFα Aptamers by Microbead-Assisted Capillary Electrophoresis (MACE)-SELEX.

Dysregulation of tumor necrosis factor-α (TNFα), a pro-inflammatory cytokine, causes several diseases, making it an important therapeutic target. Here, we identified a novel DNA aptamer against human TNFα using in vitro selection, which included a high exclusion pressure process against non-binding and weak binders through microbead-assisted capillary electrophoresis (MACE) in only three rounds. Among the 15 most enriched aptamers, Apt14 exhibited the highest inhibitory activity for the interaction between TNFα and its cognate receptor in mouse L929 cells. For further improving the bioactivity of the aptamer, dimerization programed by hybridization was evaluated, resulting in the Apt14 dimer exhibited a twofold higher binding affinity and stronger inhibition compared to the monomer counterpart. Rapid identification of bioactive aptamers using MACE in combination with facile dimerization by hybridization accelerates the discovery of novel bioactive aptamers, paving the way toward replacing current monoclonal antibody therapy with the less expensive and non-immunogenic aptamer therapy.

Late-onset Pleural and Pericardial Effusion as Immune-related Adverse Events after 94 Cycles of Nivolumab.

A 67-year-old man with primary lung adenocarcinoma was hospitalized due to massive bilateral pleural effusion and pericardial effusion after 94 cycles of nivolumab therapy. We were unable to identify the cause of these effusions using blood tests, cytology tests, or bacterial culture of pleural effusion and thoracoscopy. Finally, we administrated corticosteroids, which immediately improved the fluid accumulation. This case may support the introduction of corticosteroids for late-onset pleural and pericardial effusion during immune checkpoint inhibitor (ICI) treatment. However, the safety of rechallenge of ICIs after the improvement of fluid accumulation is controversial.

Serum N-terminal Pro-brain Natriuretic Peptide Level is Associated with the Development of Chronic Kidney Diseases in Patients with Type 2 Diabetes.

BACKGROUND AND OBJECTIVE: Previous studies revealed the association between serum Nterminal pro-brain natriuretic peptide (NT-proBNP) level and chronic kidney diseases (CKD) in general population. However, little is known about the association between serum NT-proBNP level and incident CKD in patients with type 2 diabetes. Thus, we investigated the impact of serum NT-proBNP level on incident CKD in patients with type 2 diabetes. METHOD: We enrolled 211 type 2 diabetic patients without CKD in this cohort study. CKD was diagnosed as estimated glomerular filtration rate <60 ml/min/1.73 m2. We divided the patients into three groups according to the tertiles of serum NT-proBNP level. Univariates and multivariate hazard ratios (HRs) for the incident CKD were calculated by Cox regression analyses. RESULTS: Over the median follow-up period of 7 years, 56 patients developed incident CKD. Log NTproBNP was positively associated with incident CKD (HR 3.70, 95%CI 1.72-8.18, p <0.001). Compared with the lowest level of serum NT-proBNP tertile (≤36 pg/mL), the highest level of serum NTproBNP tertile (≥84 pg/mL) showed increased risk of incident CKD after adjusting age, sex, body mass index, hemoglobin A1c, creatinine, smoking, usage of hypertension drug and urinary albumin excretion at baseline examination (adjusted HR2.37, 95% CI 1.09-5.48, p = 0.028). CONCLUSION: Serum NT-proBNP level is an independent biomarker for incident CKD in patients with type 2 diabetes.

Analysis of damage to underground railway structures in the Hyogoken - Nanbu earthquake

The damage caused to underground concrete railway structures by the Hyogoken-Nanbu earthquake has been investigated and the observations compared with the results of nonlinear frame analysis. The major damage was to cut-and-cover tunnels in and around three stations on the Kobe Express Railway. The first paper in this series covered the damage to Daikai Station. This paper now gives the results for two further locations- Sannomiya and Kamisawa Stations- where the damage was found to be caused by shear fracture of the center pillars induced by large shear deformations in the nearby ground. The numerical analysis backs up this conclusion.(AU)