Noriaki Sunaga

EGFR ‐mutant lung cancer represents a major subtype of non‐small cell lung cancer in Asia, with particularly high prevalence in never‐smokers, women, and patients with adenocarcinoma histology. Although this clinicopathologic enrichment has been recognized for more than two decades, the mechanisms underlying the excess frequency of EGFR ‐mutant disease in Asian populations remain only partially understood. Accumulating evidence suggests a multifactorial basis involving host genetic susceptibility and diversity, endogenous mutational processes and exogenous exposures such as ambient particulate matter. In particular, recent genomic and experimental studies support a tumour‐promotion framework in which inflammatory microenvironmental cues may facilitate the outgrowth of pre‐existing oncogenic clones, while mutational signatures provide genomic footprints of these processes. In parallel, the treatment landscape for EGFR ‐mutant non‐small cell lung cancer has evolved substantially with successive generations of EGFR tyrosine kinase inhibitors (EGFR‐TKIs), leading to marked improvements in survival. However, acquired resistance remains inevitable in most patients with advanced disease and is driven by both genetic and non‐genetic mechanisms, including secondary EGFR alterations, bypass pathway activation, TP53 ‐associated genomic instability, adaptive mutagenesis, and drug‐tolerant persister states. These insights have provided a strong rationale for combination strategies beyond EGFR‐TKI monotherapy. In this review, we summarize current understanding of the epidemiology and biological basis of EGFR ‐mutant lung cancer in Asia and discuss the preclinical rationale and emerging clinical evidence supporting combination approaches with chemotherapy, anti‐angiogenic agents, and EGFR/MET‐directed therapies.

Organic solvents contained in oil and waterproofing sprays, along with glycerin and propylene glycol found in e‐cigarettes, have been reported to trigger exogenous lipoid pneumonia. We report a 30‐year‐old male who developed lipoid pneumonia following exposure to paraffin‐based oil spray, waterproofing spray, and subsequent e‐cigarette use. Initial evaluation suggested occupational asthma due to elevated IgE and fractional exhaled nitric oxide levels, but inhaled corticosteroid therapy was ineffective. Chest computed tomography eventually revealed diffuse ground‐glass opacities, and bronchoalveolar lavage fluid analysis demonstrated lipid‐laden macrophages, confirming the diagnosis. Component analysis indicated that e‐cigarette vapor containing glycerin and propylene glycol was the primary trigger, whereas occupational exposures contributed minimally. The patient was managed with observation without steroid therapy, and symptoms resolved over 4 months with lifestyle modifications, including cessation of e‐cigarette use. This case highlights the combined impact of occupational and lifestyle factors in exogenous lipoid pneumonia and emphasizes the importance of assessing inhaled substances, workplace environment, and e‐cigarette use to determine the cause and guide exposure control.

Dupilumab is an effective biologic therapy for severe asthma; however, its safety and efficacy in women undergoing infertility treatment remain uncertain. A woman in her late 30s with severe asthma and eosinophilic chronic rhinosinusitis underwent assisted reproductive technology while receiving dupilumab. The medication was discontinued upon confirmation of pregnancy. Asthma control improved significantly with dupilumab. The patient conceived successfully and delivered a healthy infant. Dupilumab may be a viable treatment option for women with severe asthma undergoing fertility treatment, though additional safety data are needed to support its use during conception and pregnancy.

Histologic transformation from non‐small cell to small cell lung cancer (SCLC) is a resistance mechanism to immune checkpoint inhibitors. We report herein a case of lung adenocarcinoma who developed liver and brain metastases during adjuvant atezolizumab therapy. The patient underwent a craniotomy to resect a brain metastasis, which was pathologically diagnosed as SCLC. He subsequently received platinum‐based chemotherapy with durvalumab, resulting in sustained regression of the liver metastases. This case demonstrates a metastatic brain tumor‐acquired resistance to atezolizumab through histologic transformation from adenocarcinoma to SCLC. Therefore, rebiopsy is needed if recurrent disease appears during immune checkpoint inhibitor treatment in patients with non‐small cell lung cancer.

Patient: Female, 16-year-old Final Diagnosis: Fusobacterium necrophorum infection Symptoms: Chest pain center dot dyspnea center dot high fever Clinical Procedure: - Specialty: Infectious Diseases Objective: Rare disease Background: Most Fusobacterium necrophorum infections originate in the head and neck region. Infections originating from sites other than the head and neck are rare but are more common in older than in younger adults and have a higher mortality rate than that of infections originating from the head and neck region. Case Report: We present the case of a previously healthy 16-year-old female patient who developed bacteremia and pleural effusions with a burn ulcer on the lower leg but had no abnormality in the head and neck region. She sustained a second-degree burn injury on the left shin that remained untreated for several weeks, resulting in the development of Fusobacterium necrophorum bacteremia. She was admitted after developing fever, chest pain, and dyspnea. Blood culture revealed Fusobacterium necrophorum, but no abnormality was noted in the head and neck region, and a second-degree burn was observed on the left shin. She had bilateral pleural effusions assumed to result from a burn ulcer and was intravenously treated with tazobactam/piperacillin and therapeutic thoracentesis. She responded to therapy and made a full recovery. Conclusions: While the origin of the Fusobacterium necrophorum infection in the burn ulcer could not be detected, this case report suggests that burn ulcers are a potential source of systemic Fusobacterium necrophorum infection and highlights the importance of early medical and surgical treatment and antimicrobial therapy.

Background: Regional lymph node recurrence after radical surgery for non‐small cell lung cancer (NSCLC) is an oligo‐recurrent disease; however, no treatment strategy has been established. In the present study we aimed to determine the clinical outcomes of postoperative regional lymph node recurrence and identify prognostic predictors in the era of molecular‐targeted therapy.Methods: We retrospectively analyzed data on clinical characteristics and outcomes of patients with regional lymph node recurrence after surgery who underwent treatment for NSCLC between 2002 and 2022.Results: A total of 53 patients were included in this study. The median time between surgery and detection of recurrence was 1.21 years. Radiotherapy (RT) alone and chemoradiotherapy (CRT) were performed in 38 and six patients, respectively. Driver gene alterations were detected in eight patients (EGFR: 6, ROS1:1, and BRAF: 1) and programmed death‐ligand 1 (PD‐L1) expression was examined in 22 patients after 2016. Median progression‐free survival (PFS) and overall survival (OS) after lymph node recurrences were 1.32 and 4.34 years, respectively. Multiple lymph node recurrence was an independent prognostic factor for PFS, whereas driver gene alteration was the only prognostic factor for OS. There was no significant difference in the OS between patients stratified according to the initial treatment modality for lymph node recurrence.Conclusion: Our results suggest that the number of tumor recurrences may correlate with PFS, while detection of driver gene alterations could guide decision‐making for the appropriate molecular‐targeted therapy to achieve longer OS.

Epidermal growth factor (EGF) signaling regulates multiple cellular processes and plays an essential role in tumorigenesis. Epiregulin (EREG), a member of the EGF family, binds to the epidermal growth factor receptor (EGFR) and ErbB4, and it stimulates EGFR-related downstream pathways. Increasing evidence indicates that both the aberrant expression and oncogenic function of EREG play pivotal roles in tumor development in many human cancers, including non-small cell lung cancer (NSCLC). EREG overexpression is induced by activating mutations in the EGFR, KRAS, and BRAF and contributes to the aggressive phenotypes of NSCLC with oncogenic drivers. Recent studies have elucidated the roles of EREG in a tumor microenvironment, including the epithelial–mesenchymal transition, angiogenesis, immune evasion, and resistance to anticancer therapy. In this review, we summarized the current understanding of EREG as an oncogene and discussed its oncogenic role in lung tumorigenesis and therapeutic resistance.

Background: Molecular abnormalities in the Wnt/β‐catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine‐rich repeat‐containing G protein‐coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon β‐catenin knockdown in non‐small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes.Methods: LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT‐PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments.Results: LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1‐mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild‐type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6‐related pathways and genes associated with cancer development and stemness properties.Conclusions: Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/β‐catenin signaling in lung cancer.