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Abstract Introduction Studies have shown the antitumor efficacy of immune checkpoint inhibitors (ICI) in patients with non‐small cell lung cancer (NSCLC) and brain metastases (BM). However, it is unclear whether the efficacy of ICI is similar between patients with and without BM. It is yet unclear whether the efficacy of ICI in patients with BM increases with higher levels of programmed cell death‐ligand 1 (PD‐L1) expression, as observed in patients without BM. Methods We compared the outcomes of ICI treatment between patients with and without BM using a cohort containing 1741 prospectively enrolled patients with lung cancer. We investigated whether there were differences in the outcomes of ICI based on PD‐L1 expression levels between these patients. Results We enrolled 240 patients with NSCLC with or without BM who were treated with ICI or both chemotherapy and ICI. There were no significant differences in overall survival (OS) between all patients with or without BM (p = 0.489). However, OS was significantly shorter in patients with BM than in those without in the PD‐L1 ≥ 50% group (16.5 M vs. 30.6 M, p = 0.003) but not in the PD‐L1 ≥ 1% or negative group. BM was an independent poor prognostic factor for OS (hazard ratio: [95% confidence interval], 2.045; [1.058–3.953], p = 0.033) in the PD‐L1 ≥ 50% group. Conclusion Our study indicated that the outcomes of patients with or without BM treated with ICI were not significantly different. The efficacy of ICI in patients with PD‐L1 expression ≥50% would be lower in patients with BM than in those without.

ABSTRACT Background Cancer‐associated thromboembolism has been thoroughly investigated in previous studies, and direct oral anticoagulants (DOACs) were established for the treatment and prevention of venous thromboembolism (VTE). However, the risks of cancer‐associated arterial thromboembolism (ATE) and the efficacy of DOACs remain unclear. Objectives To evaluate the risk factors and the clinical activity of edoxaban (EDO) for the prevention of ATE in patients with advanced lung cancer. Methods From the prospective Rising‐VTE/NEJ037 study which investigated VTE in newly diagnosed advanced lung cancer, we investigated the incidence rate and the risk factors of ATE as secondary endpoints. Results A total of 1008 patients were screened for VTE at study baseline and were followed up for 2 years. Excluding patients with a contraindication to DOACs, those with VTE were treated with EDO. ATE events were identified in 41 patients (4.1%). The most common location for ATE was cerebral infarction (N = 31, 75.6%), followed by myocardial infarction (N = 4, 9.8%). Multivariate analysis determined the incidence of VTE, D‐dimer, a comorbidity of atrial fibrillation, and four other factors as independent risk factors of ATE. For VTE (+) patients, the incidence rate of ATE was 15.9% for the EDO administration (+) patients, compared with 11.1% for the EDO administration (−) patients (p = 0.626). Conclusions The incidence rate of ATE was 4.1% over 2‐year follow‐up in advanced lung cancer patients. VTE was further identified as an independent risk factor for ATE, while intervention with DOACs was seen as less effective for the prevention of ATE in advanced lung cancer patients with VTE. Trial Registration This trial was registered in the Japan Registry of Clinical Trials (jRCTs061180025)

Abstract A 61‐year‐old man presented to our hospital with a chief complaint of chronic cough. He was diagnosed with lung squamous cell carcinoma at clinical stage cT2aN3M1a. He received chemotherapy up to the fourth line, but both the primary tumor and lymph node metastases increased in size. Nivolumab, administered as the fifth line, resulted in a complete response (CR) that continued for 2 years and 8 months. Treatment was stopped due to the appearance of common terminology criteria for adverse events grade 1 pneumonitis. He was followed up without treatment for 3 years and 8 months, but a left supraclavicular fossa lymph node metastasis appeared. Retreatment with nivolumab was initiated, and the patient achieved CR again. One year and 6 months after retreatment, CR was maintained with nivolumab. This case represents a rare instance in which nivolumab yielded a significant response after a prolonged immune checkpoint inhibitor (ICI)‐free interval. Our experience has shown that the long‐term response to ICIs may deteriorate in the future. Therefore, retreatment with ICIs may be effective when the initial therapy is successful.

Abstract Emphysema limits airflow and causes irreversible progression of chronic obstructive pulmonary disease (COPD). Strain differences must be considered when selecting mouse models of COPD, owing to disease complexity. We previously reported that a novel C57BL/6JJcl substrain, the Mayumi-Emphysema (ME) mouse, exhibits spontaneous emphysema; however, the other characteristics remain unknown. We aimed to characterize the lungs of ME mice and determine their experimental availability as a model. ME mice had a lower body weight than the control C57BL/6JJcl mice, with a median survival time of ~80 weeks. ME mice developed diffused emphysema with respiratory dysfunction from 8 to 26 weeks of age, but did not develop bronchial wall thickening. Proteomic analyses revealed five extracellular matrix-related clusters in downregulated lung proteins in ME mice. Moreover, EFEMP2/fibulin-4, an essential extracellular matrix protein, was the most downregulated protein in the lungs of ME mice. Murine and human EFEMP2 were detected in the pulmonary artery. Furthermore, patients with mild COPD showed decreased EFEMP2 levels in the pulmonary artery when compared to those without COPD. The ME mouse is a model of mild, accelerated aging with low-inflammatory emphysema and respiratory dysfunction that progresses with age and pulmonary EFEMP2 decrease, similar to that observed in patients with mild COPD.

Primary lung cancer with pulmonary alveolar proteinosis (PAP) is a rare condition. We present a case of a patient with primary lung cancer with PAP treated with an immune checkpoint inhibitor (ICI). A 62-year-old man was diagnosed with autoimmune PAP 8 years prior to current admission. Lung adenocarcinoma was found in his right lung, and platinum-based chemotherapy was administered, followed by atezolizumab. He experienced disease progression after atezolizumab treatment, whereas ICI-induced pneumonia or exacerbation of PAP did not occur. This indicates that ICI may be safely used in patients with primary lung cancer with PAP.

Abstract An 82‐year‐old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune‐related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine‐based immunosuppressant was effective against irAE hepatitis, therefore thiopurine‐based immunosuppressants may be effective against steroid‐refractory hepatitis.

Abstract Background Endocytoscopy (ECS) provides a magnification of approximately 450× for real‐time observation of lesion nuclei. Using ECS, we aimed to evaluate whether sufficient samples for diagnosis can be obtained during bronchoscopy. We also investigated whether ECS can enable two‐class diagnosis of malignant or non‐malignant transbronchial biopsy specimens in real‐time during bronchoscopy. Methods This was a single‐facility, prospective, observational, ex vivo study. Forty cases with localized peripheral pulmonary lesions underwent transbronchial biopsy with endobronchial ultrasonography using a guide sheath. Each biopsy specimen was immediately observed and evaluated endocytoscopically after the collection by the bronchoscopic procedure. Results Thirty‐seven cases were enrolled. The diagnostic accuracy achieved by ECS was 91.9% (34/37). The agreement rate between the endocytoscopic evaluation and pathological diagnosis of each specimen (170 specimens) was 65.3% (111/170). The median time required for endocytoscopic evaluation per specimen was 70 s. When we judged a specimen to be malignant a second time on ECS evaluations of five specimens in one case, pathologically malignant specimens were collected in 26 of 27 cases (96.3%). Conclusions ECS with methylene blue staining may aid in the two‐class diagnosis of malignant or non‐malignant transbronchial biopsy specimens during bronchoscopy. This may reduce the number of tissue biopsies.

Abstract Endobronchial ultrasonography with a guide sheath (EBUS-GS) improves the accuracy of bronchoscopy. The possibility of differentiating benign from malignant lesions based on EBUS findings may be useful in making the correct diagnosis. The convolutional neural network (CNN) model investigated whether benign or malignant (lung cancer) lesions could be predicted based on EBUS findings. This was an observational, single-center cohort study. Using medical records, patients were divided into benign and malignant groups. We acquired EBUS data for 213 participants. A total of 2,421,360 images were extracted from the learning dataset. We trained and externally validated a CNN algorithm to predict benign or malignant lung lesions. Test was performed using 26,674 images. The dataset was interpreted by four bronchoscopists. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the CNN model for distinguishing benign and malignant lesions were 83.4%, 95.3%, 53.6%, 83.8%, and 82.0%, respectively. For the four bronchoscopists, the accuracy rate was 68.4%, sensitivity was 80%, specificity was 39.6%, PPV was 76.8%, and NPV was 44.2%. The developed EBUS-computer-aided diagnosis system is expected to read EBUS findings that are difficult for clinicians to judge with precision and help differentiate between benign lesions and lung cancers.

Abstract Management of cancer-associated venous thromboembolism (VTE) is essential in treatment selection and cancer prognosis. However, to date, there is no method to assess the risk of VTE specifically associated with advanced lung cancer. Our aim was to create a new risk assessment scoring system that can predict the concomitant or incidence of VTE in advanced lung cancer. We used the dataset of 1008 patients with lung cancer in the Rising-VTE/NEJ037 study, of which 100 (9.9%) developed VTE. The items extracted in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2, and diastolic blood pressure. This model had a maximum score of 8 points, with ≥ 5 points indicating a high risk of VTE. This simple risk-assessment model for VTE complications with advanced lung cancer could help identify cases that required monitoring for VTE.

Abstract An 83‐year‐old woman with RET fusion‐positive advanced lung adenocarcinoma was administered selpercatinib 320 mg/day. Despite the shrinking of the tumour, fever, fatigue, and anorexia developed on day 17. Selpercatinib administration was interrupted. On day 21, elevated blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. On day 28, AST and ALT levels increased to demonstrate Grade 4 in CTCAE Ver.5. The patient received a glycyrrhizin‐compounding agent and steroid treatment, and AST and ALT levels gradually decreased. On day 63, selpercatinib 160 mg/day was restarted after improvement of the hepatic disorder. Since then, selpercatinib was continued without any severe adverse events. Selpercatinib is a reasonable treatment option for RET fusion‐positive advanced non‐small cell lung cancer even in older patients. However, old age may be a risk factor for adverse events including hepatic disorders. For safe treatment in such patients, careful follow‐up is required.

The patient, a 62-year-old woman, complained chiefly of cough. We planned chemoradiotherapy for squamous nonsmall cell lung cancer. A single dose of 2-Gy irradiation and no anticancer agent administration exacerbated the airway stenosis with severe respiratory failure. Urgent tracheal intubation was performed, and a tracheal stent was implanted under extracorporeal membrane oxygenation (ECMO). Because her performance status (PS) worsened from 1 to 2, we administered radiotherapy. The tumor size decreased. There was no recurrence for the next 3 months, and her PS improved to 1. Emergency tracheal intubation and tracheal stent placement under ECMO can be effective for exacerbated airway obstruction after radiotherapy.

Abstract A light blue line (LBL) was observed along the edge of a lesion using narrow band imaging under saline injection during bronchoscopy in an 82‐year‐old patient with a lobulated mass on the left B4. The histopathological diagnosis was hamartoma with ciliated bronchial epithelium, and we speculated that LBL appeared around the ciliated bronchial epithelium.

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors. Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation. Results: Data were available for 1008 patients. The median age was 70 years (range: 30–94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group. Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate. Trial registration: jRCTs061180025.

Abstract Due to the emergence of immune checkpoint inhibitors, the abscopal effect has gained more attention. We report a case of extracranial abscopal effect after whole‐brain irradiation therapy due to brain metastasis. After the initial abscopal effect was confirmed, a second abscopal effect was confirmed following radiation therapy for bone metastases. This case confirms the reproducibility of the abscopal effect. Moreover, the abscopal effect was not observed in metastatic lesions with low immunogenicity, even in the same patient.

Abstract Introduction Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. Methods We constructed an umbrella‐type lung cancer patient registry (CS‐Lung‐003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS‐Lung‐003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. Discussion We successfully launched the umbrella‐type CS‐Lung‐003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. Key points CS‐Lung‐003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.

Abstract Background In Japan, approximately half of all lung cancer patients are aged > 75 years, and the proportion of older patients is increasing. In older patients, it is necessary to consider comorbidities and concomitant drug use to ensure optimal cancer treatment; however, geriatric assessment (GA) is not widely performed. We plan to conduct a study (ENSURE-GA) of GA in older lung cancer patients to determine whether GA with intervention improves patient satisfaction with their treatment. Methods The study will be a phase III comparative clinical trial with a cluster-randomized design, and it will be conducted at 81 sites distributed throughout Japan. Approximately 1000 lung cancer patients aged ≥ 75 years will be enrolled in the study. All participants will undergo a standardized GA before starting treatment (using an iPad). At the intervention sites, the GA results and intervention method recommended on the basis of the GA results will be returned as an instant report to guide the physician’s choice of intervention. At the control sites, the physician will decide on interventions based on standard practice. All participants will complete a patient satisfaction survey before treatment initiation (after the GA) and 3 months later. Discussion The purpose of the ENSURE-GA study is to evaluate whether GA with interventions improves patient satisfaction with treatment outcomes. The study may lead to the increased use of GA and improved treatment of cancer in older adults. The results will also be used to prepare guidelines for treating older cancer patients and will provide a foundation for the development of a standardized geriatric oncology system. Trial registration The study has been registered in the University Hospital Medical Information Network database (no. UMIN000037590). The registration date is August 4, 2019, and the protocol version is 2.0. ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000042853 .)

Abstract Background Multiple synchronous ground glass nodules (GGNs) are known to be malignant, however, they tend to progress slowly. Multiple synchronous lesions in the same patient which show different characteristics must be treated individually. Methods This was a retrospective review of 34 lung adenocarcinoma patients with multiple synchronous GGNs in an Asian population. One hundred twenty-seven single lung adenocarcinoma patients were included for comparison purposes. The follow-up period was 5 years for all patients. Results The 5-year overall survival (OS) patients with multiple lesions did not differ from that of the patients with single lesions to a statistically significant extent (Single: 81.8% vs. Multiple: 88.2%, P = 0.3602). Dominant tumors (DTs) with a ground glass component and consolidation were divided into three categories based on the consolidation-to-tumor ratio on radiological imaging. No significant differences were observed among the three DT categories. Twenty-four patients had unresected GGNs, while a progression of the unresected GGN occurred in 10 of these cases. The OS and disease-free survival (DFS) curves of patients with and without GGN progression did not differ to a statistically significant extent (OS: 80% vs. 92.9%, P = 0.3870; DFS: 80% vs. 100%, P = 0.0977). Conclusions The outcomes were best predicted by the stage of the DT. After surgery patients require a careful follow-up because unresected GGNs may show progression. At the same time, the increase in residual lesions and the appearance of new GGNs were not related to OS. The management of such patients should be determined according to the DT with the worst prognosis.

The single nucleotide polymorphisms of COX-2 gene, also known as PTGS2, which encodes a pro-inflammatory factor cyclooxygenase-2, alter the risk of developing multiple tumors, but these findings are not consistent for lung cancer. We previously reported that the homozygous COX-2 –1195A genotype is associated with an increased risk for chronic obstructive pulmonary disease (COPD) in Japanese individuals. COPD is a significant risk factor for lung cancer due to genetic susceptibility to cigarette smoke. In this study, we investigated the association between COX-2 –1195G/A polymorphism and lung cancer susceptibility in the Japanese population. We evaluated the genotype distribution of COX-2 –1195G/A using a polymerase chain reaction-restriction fragment length polymorphism assay for 330 newly diagnosed patients with lung cancer and 162 healthy controls. Our results show that no relationship exists between the COX-2 –1195G/A polymorphism and the risk of developing lung cancer. However, compared to the control group, the homozygous COX-2 –1195A genotype increased the risk for lung squamous cell carcinoma (odds ratio = 2.902; 95% confidence interval, 1.171–7.195; p = 0.021), whereas no association is observed with the risk for adenocarcinoma. In addition, Kaplan-Meier analysis shows that the genotype distribution of homozygous COX-2 –1195A does not correlate with the overall survival of patients with lung squamous cell carcinoma. Thus, we conclude that the homozygous COX-2 –1195A genotype confers an increased risk for lung squamous cell carcinoma in Japanese individuals and could be used as a predictive factor for early detection of lung squamous cell carcinoma.

Abstract A 69‐year‐old woman with rheumatoid arthritis, using immunosuppressants, including etanercept—a tumour necrosis factor (TNF)‐α antagonist—was referred to our hospital with fever and fatigue. Chest computed tomography revealed cavities in the left upper lobe. As Mycobacterium intracellulare infection was diagnosed, all immunosuppressants were discontinued, and treatment with anti‐nontuberculous Mycobacterium drugs was initiated. However, her condition worsened paradoxically. We diagnosed immune reconstitution inflammatory syndrome (IRIS) resulting from the discontinuation of the TNF‐α antagonist. Her condition improved with prednisolone treatment. IRIS is generally observed during HIV treatment, but a good understanding of immunosuppressant‐related non‐HIV IRIS is needed.

IntroductionMore older adults die from lung cancer worldwide than breast, prostate, and colorectal cancers combined. Current lung cancer treatments may prolong life, but can also cause considerable treatment-related toxicity.ObjectiveThis study is a secondary analysis of a cluster-randomized clinical trial which evaluated whether providing a geriatric assessment (GA) summary and GA-guided management recommendations can improve grade 3-5 toxicity among older adults with advanced lung cancer.MethodsWe analyzed participants aged ≥70 years(y) with stage III & IV (advanced) lung cancer and ≥1 GA domain impairment starting a new cancer treatment with high-risk of toxicity within the National Cancer Institute’s Community Oncology Research Program. Community practices were randomized to the intervention arm (oncologists received GA summary & recommendations) versus usual care (UC: no summary or recommendations given). The primary outcome was grade 3-5 toxicity through 3 months post-treatment initiation. Secondary outcomes included 6-month (mo) and 1-year overall survival (OS), treatment modifications, and unplanned hospitalizations. Outcomes were analyzed using generalized linear mixed and Cox proportional hazards models with practice site as a random effect. Trial Registration: NCT02054741.Results & ConclusionAmong 180 participants with advanced lung cancer, the mean age was 76.3y (SD 5.1), 39.4% were female and 82.2% had stage IV disease. The proportion of patients who experienced grade 3-5 toxicity was significantly lower in the intervention arm vs UC (53.1% vs 71.6%, P=0.01). More participants in the intervention arm received lower intensity treatment at cycle 1 (56.3% vs 35.3%; P

In recent years, the combination of platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) has become the standard treatment for patients with lung cancer. Hepatitis is one of the common toxicities following ICI/chemotherapy. When drug-induced hepatitis occurs, the suspected drug must be discontinued. Since it may be difficult to determine the exact drug causing the hepatitis, liver biopsy may help identify this. We report the case of a patient diagnosed with immune-related adverse event hepatitis from liver biopsy and clinical course.A 45-year-old man with lung adenocarcinoma (stage IV, cT4N3M1c) negative for driver gene mutation was treated with carboplatin (CBDCA), pemetrexed (PEM), and pembrolizumab. Elevated blood aspartate aminotransferase and alanine aminotransferase levels after chemotherapy indicated hepatitis induced by cytotoxic anticancer agents and ICIs. As autoimmune hepatitis was also suspected, liver biopsy was performed and the findings suggested ICI-induced hepatitis. Pembrolizumab was discontinued and CBDCA/PEM was resumed, following which, the primary lesion shrank. When drug-induced hepatitis is suspected, clinicians should actively perform liver biopsy to confirm the diagnosis, so that appropriate therapeutic regimen can be administered.

Endocytoscopy enables real-time observation of lesions at ultra-magnification. In the gastrointestinal and respiratory fields, endocytoscopic images are similar to hematoxylin-eosin-stained images. This study aimed to compare the nuclear features of pulmonary lesions in endocytoscopic and hematoxylin-eosin-stained images. We performed an endocytoscopy to observe resected specimens of normal lung tissue and lesions. Nuclear features were extracted using ImageJ. We analyzed five nuclear features: nuclear number per area, mean nucleus area, median circularity, coefficient of variation of roundness, and median Voronoi area. We conducted dimensionality reduction analyses for these features, followed by assessments of the inter-observer agreement among two pathologists and two pulmonologists to evaluate endocytoscopic videos. We analyzed the nuclear features of hematoxylin-eosin-stained and endocytoscopic images from 40 and 33 cases, respectively. Endocytoscopic and hematoxylin-eosin-stained images displayed a similar tendency for each feature, despite there being no correlation. Conversely, the dimensionality reduction analyses demonstrated similar distributions of normal lung and malignant clusters in both images, thus differentiating between the clusters. The diagnostic accuracy of the pathologists was 58.3% and 52.8% (κ-value 0.38, fair), and that of the pulmonologists was 50% and 47.2% (κ-value 0.33, fair). The five nuclear features of pulmonary lesions were similar in the endocytoscopic and hematoxylin-eosin-stained images.

Abstract Background Protein tyrosine kinase 2 (PTK2) expression has been reported in various types of human epithelial cancers including lung cancer; however, the role of PTK2 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has not been elucidated. We previously reported that pemetrexed-resistant NSCLC cell line PC-9/PEM also acquired EGFR-TKI resistance with constitutive Akt activation, but we could not find a therapeutic target. Methods Cell viability in EGFR-mutant NSCLC cell lines was measured by the WST-8 assay. Phosphorylation antibody array assay for receptor tyrosine kinases was performed in PC-9 and PC-9/PEM cell lines. We evaluated the efficacy of EGFR and PTK2 co-inhibition in EGFR-TKI-resistant NSCLC in vitro. Oral defactinib and osimertinib were administered in mice bearing subcutaneous xenografts to evaluate the efficacy of the treatment combination in vivo. Both the PTK2 phosphorylation and the treatment combination efficacy were evaluated in erlotinib-resistant EGFR-mutant NSCLC cell lines. Results PTK2 was hyperphosphorylated in PC-9/PEM. Defactinib (PTK2 inhibitor) and PD173074 (FGFR inhibitor) inhibited PTK2 phosphorylation. Combination of PTK2 inhibitor and EGFR-TKI inhibited Akt and induced apoptosis in PC-9/PEM. The combination treatment showed improved in vivo therapeutic efficacy compared to the single-agent treatments. Furthermore, erlotinib-resistant NSCLC cell lines showed PTK2 hyperphosphorylation. PTK2 inhibition in the PTK2 hyperphosphorylated erlotinib-resistant cell lines also recovered EGFR-TKI sensitivity. Conclusion PTK2 hyperphosphorylation occurs in various EGFR-TKI-resistant NSCLCs. Combination of PTK2 inhibitor and EGFR-TKI (defactinib and osimertinib) recovered EGFR-TKI sensitivity in the EGFR-TKI-resistant NSCLC. Our study result suggests that this combination therapy may be a viable option to overcome EGFR-TKI resistance in NSCLC.

Abstract A 28‐year‐old man had a cavitary lesion in the upper right lobe with a tree‐in‐bud appearance on chest computed tomography (CT). Diagnostic bronchoscopy was performed. An ultrathin bronchoscope in the right B2aiiβxyy reached the cavity. We filled the cavity with saline under direct bronchoscopic visualization. We suspected a blood vessel was present in the cavity wall based on narrow‐band imaging. Bronchial lavage of the cavity was performed. Next, endobronchial ultrasonography (EBUS) using a guide sheath was performed with a thin bronchoscope. EBUS showed a pulsating blood vessel in the cavity wall. Bronchial lavage collected with ultrathin and thin bronchoscopy revealed Mycobacterium kansasii. Observation of vessels in the wall of a cavitary lesion with ultrathin bronchoscopy and EBUS may be useful for avoiding severe bleeding associated with biopsy of a cavitary lesion.

Summary: Background: The NEJ026 Phase 3 study demonstrated that erlotinib and bevacizumab (BE)-treated NSCLC patients with EGFR mutations had significantly better progression-free survival (PFS) than those treated with erlotinib alone (E). This study included a prospective analysis of the relationship between the mutational status of EGFR in plasma circulating tumor DNA (ctDNA) and the efficacy of TKI monotherapy or combination therapy. We describe these results herein. Methods: Plasma samples were collected from patients enrolled in NEJ026 at the start of treatment (P0), 6 weeks after the start of treatment (P1), and upon confirmation of progressive disease (P2). Plasma ctDNA was analyzed using a modified PNA-LNA PCR clamp method. PFS and OS according to EGFR status at the time of plasma collection were evaluated. Findings: Plasma activating EGFR mutation (aEGFR) at P0 was detected in 68% of cases; patients without plasma aEGFR had longer PFS. The frequency of T790M mutation at P2 was similar in both arms: 8 (19.0%) in BE and 11 (20.8%) in E. Based on the aEGFR profiles, PFS was evaluated among three groups: type A [P0(-), P1(-)], type B [P0(+), P1(-)], and type C [P0(+), P1(+)]. This revealed that BE was more efficacious than E, and that BE was associated with improved PFS in all types. Interpretation: Pre-treatment plasma aEGFR status have a potential of early predictor of response of TKI efficacy. Monitoring plasma aEGFR mutation will contribute to selection and continuation of treatment with BE or E. Funding: Chugai Pharmaceutical.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and the development of EGFR tyrosine kinase inhibitors (TKIs) have led to a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). EGFR mutation-positive NSCLC is common in East Asia, and approximately 50% of adenocarcinomas harbor EGFR mutations. Undoubtedly, EGFR-TKIs, with their promising efficacy, are the mainstay of primary therapy. However, even if tumor shrinkage is achieved, most patients become resistant to EGFR-TKIs and relapse; hence, EGFR-TKIs do not achieve a radical cure. The problem of the development of resistance to targeted drugs has been a persistent challenge. After the role of EGFR T790M mutation in acquired drug resistance was reported, osimertinib, a third-generation irreversible EGFR-TKI, was designed to overcome the resistance conferred by T790M mutation. In addition, some studies have reported the mechanism of drug resistance caused by mutations other than the T790M mutation and strategies to overcome them. Elucidating the mechanism underlying drug resistance development and combining therapeutic approaches are expected to further improve NSCLC prognosis.

Pulmonary nodular lymphoid hyperplasia (PNLH) involves proliferative lymphatic tissues and is reportedly associated with inflammatory disease or autoimmune disorders. Herein, we describe a case of PNLH with difficult diagnosis because of antibiotics therapy‐induced reduction in the abnormal tumour shadow. An 86‐year‐old man was admitted for persistent cough and bloody sputum. Computed tomography (CT) revealed a mass in the right middle lobe, which got smaller on treatment with tosufloxacin for pneumonia. Unexpectedly, the tumour shadow remained one month later. Positron emission tomography depicted fluorodeoxyglucose uptake at the site. Although lung cancer was suspected, the mass was non‐diagnostic on transbronchial and CT‐guided biopsies. He was eventually diagnosed with PNLH on post‐surgical histological analysis of the lung mass. Neutrophil accumulation and bacterial lumps were present, indicating Actinomyces infection in the pulmonary alveolus, suggesting that PNLH was associated with pneumonia. Histopathological examination helped identify the aetiology of this rare case of PNLH.

A 60‐year‐old woman developed a pulmonary abscess due to broncholithiasis. It was treated by bronchoscopic broncholithectomy after antibiotic administration. Broncholithiasis is a rare disease and various treatment options are available, which include bronchoscopic broncholithectomy and surgery. Bronchoscopic broncholithectomy has proved to be more useful because it can be used to easily extract the broncholith by using a balloon and haemostasis can be obtained at the same time.