The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

The incidence and prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of the lung related to methotrexate: A retrospective study.

BACKGROUND AND OBJECTIVE: Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are rare but well-known diseases that manifest during or after methotrexate (MTX) administration. Limited information is available on the clinical characteristics of OIIA-LPD of the lung because only a few cases have been reported. Thus, we aimed to assess the incidence and prognosis of patients with OIIA-LPD of the lung. METHODS: Patients with OIIA-LPD of the lung treated at our institution between January 2008 and July 2020 were retrospectively analysed. RESULTS: Among the 51 patients with OIIA-LPD, 16 (31.3%, 7 men, 9 women) had OIIA-LPD of the lung (median age, 69 [range, 63-82] years). Peripheral lesions were observed in 10 (62.5%), central lesions in two (12.5%), and both lesions in four (25.0%) patients. Nine of the 16 patients underwent bronchoscopic biopsy, seven were diagnosed (diagnostic yield, 77.8%) and, re-biopsy was performed in 2 patients. Eight (50.0%) patients had LPD and six (37.5%) had diffuse large B-cell lymphoma. In the 14 patients with confirmed treatment efficacy, the overall response rate to MTX withdrawal was 71.4%. However, chemotherapy was required in case of larger lesions (three patients). Death related to OIIA-LPD occurred in only one patient, and 11 of the 14 patients were alive during the study period (median follow-up time, 53.7 [range, 4.3-84.2] months). CONCLUSION: The incidence of OIIA-LPD of the lung is 31.3% and higher than that reported previously. The treatment effect of MTX withdrawal seems to be sufficient; however, in some cases, chemotherapy may be required from the beginning.

A case with multiple nodules and mucosal oedema of the trachea and both bronchi induced by IgG4-related disease.

BACKGROUND: IgG4-related disease is a systemic fibroinflammatory disease that is mainly seen in older men, and involves multiple organs, such as the pancreas and lungs. However, 75% of patients with IgG4-related lung disease are asymptomatic (if they are symptomatic, they mainly complain of nasal congestion, rhinorrhoea, chest pain, and cough) and are incidentally diagnosed through chest computed tomograph. Although, nodules in the airway and bronchial wall thickening are criteria for diagnosis, it is important that nodules have been reported in peripheral airways in several cases and rarely in the central airway. CASE PRESENTATION: A 74-year-old woman previously diagnosed with Mikulicz's disease presented with swelling of the eyelid margin on both sides and visual disturbances. Computed tomography revealed extensive multiple nodules and mucosal oedema of the trachea and both bronchi. On flexible bronchoscopy under local anaesthesia, extensive lesions were observed from the middle of the trachea to the carina, extending into both segmental bronchi. The nodules were continuous with the normal respiratory tract mucosa, and the surfaces were smooth with minimal neovascularisation. Due to the solid nature of the lesion, obtaining an adequate amount of specimen was challenging. Therefore, we used a 1.9 mm cryoprobe under intubation, resulting in minimal bleeding. Subsequently, the patient was diagnosed with IgG4-related lung disease. CONCLUSIONS: The present case is very rare because of the presence of multiple nodules, severe mucosal edema of the central airway and the absence of mediastinal lymphadenopathy, ground glass nodules, and lung masses. Therefore, it is important to consider differential diagnoses. Thus, we emphasise the importance of endobronchial cryobiopsy for obtaining an adequate number of tissue specimens in such cases to establish a definitive pathological diagnosis.

Endobronchial ultrasound-guided transbronchial mediastinal cryobiopsy: a narrative review.

Background and Objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive, safe, and well-established method for diagnosing and staging lung cancer and other conditions associated with mediastinal lymphadenopathy. Efforts have been made to enhance the material adequacy of EBUS-TBNA, including the recent introduction of EBUS-guided transbronchial mediastinal cryobiopsy (EBUS-TMC). This advancement facilitates the acquisition of larger and better-preserved tissue samples from the mediastinum. We evaluated the diagnostic accuracy and safety of EBUS-TMC in the diagnosis of malignant lesions and its effectiveness in relation to benign conditions, such as tuberculosis and sarcoidosis. Methods: We searched the PubMed® database for relevant English articles published up to July 1, 2023. Subsequently, we conducted a comprehensive bibliographic analysis with a particular emphasis on diagnostic yield, safety profile, and procedural technicalities. Key Content and Findings: Our narrative review, comprising seven publications, emphasizes the significance of EBUS-TMC as an effective technique for obtaining diagnostic tissue in malignant and benign conditions while maintaining an excellent safety profile. Furthermore, its capability for obtaining larger tissue samples facilitates molecular and immunological analysis in non-small cell lung cancer. Conclusions: EBUS-TMC exhibits significant efficacy with regard to obtaining diagnostic tissue in malignant and benign conditions. However, further studies are needed to evaluate uncertainties regarding the selection of suitable cases and technical intricacies.

Risk Factors for Desaturation in Anesthetic Management During Airway Stenting.

Airway stenting involves a stent being inserted into a stenotic site in the airway. In patients with airway stenosis, the airway is the surgical field; therefore, anesthetic management is challenging, and avoiding hypoxia is important. Limited information is available on the anesthetic management of airway stenting. Risk factors for oxygen desaturation during airway stenting remain unknown. The present study was conducted to retrospectively examine patients who underwent airway stenting during a specific period and identify risk factors associated with oxygen desaturation. We performed univariate and multivariate analyses. The main evaluation items in a multivariate analysis were risk factors for desaturation (SpO2 ≤ 90%). Body mass index, preoperative orthopnea, the stenotic site of the airway, and severity of stenosis were selected for clinical usefulness. We analyzed 302 patients who underwent airway stenting at our hospital between July 2011 and June 2014 under general anesthesia with controlled ventilation. Total intravenous anesthesia with propofol target-controlled infusion and remifentanil was performed. Clinical data were extracted from electronic anesthetic records. The incidence of desaturation (SpO2 ≤ 90%) was 18.5% (56 out of 302 cases). Preoperative orthopnea (OR, 3.06)and stenosis distal to the bronchus (OR, 3.31) were identified as risk factors for desaturation in a multivariate analysis. We herein identified risk factors for desaturation during airway stenting. Anesthetic plans need to be carefully considered for patients with these risk factors.

Talc slurry pleurodesis in patients with secondary intractable pneumothorax: A phase 2 study.

BACKGROUND: Secondary pneumothorax, which occurs most commonly in the elderly, is caused by underlying diseases. Cardiac dysfunction and other organ inefficiencies may render surgical repair impossible. Such non-operative and poor-risk cases are targets for pleurodesis, which involves the instillation of chemicals or irritants to the thoracic cavity through injection, bronchoscopic bronchial occlusion, or other procedures. Sterile graded talc has been used for pleurodesis mainly in Europe and the United States; however, only a few studies and case series investigating this topic have been published. This study evaluates the efficacy and safety of talc slurry pleurodesis. METHODS: Patients with inoperable secondary intractable pneumothorax, who were not candidates for surgical repair, were recruited. Four grams of sterilized talc was suspended in 50 mL of physiological saline and injected through a tube into the pleural cavity. Additional 50 mL of saline was subsequently injected through the same channel to clean the residual saline in the injection tube. Another additional talc instillation was allowed to control persistent air leakage. The primary endpoint was the proportion of drainage tube removal within 30 days after talc pleurodesis. RESULTS: Thirty-one patients were included in this study. In 23 out of 28 patients, the drainage tube could be removed within 30 days of talc instillation (82.1 %, 95 % CI = 63.1-93.9), exceeding the threshold of 36.0 % (p < 0.0001). The most common event was pain (11/28 patients, 39.3 %). CONCLUSIONS: Talc slurry pleurodesis is effective for intractable secondary pneumothorax, with minor side effects.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined. Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Liquid biopsy detects genomic drivers in NSCLC without EGFR mutations by single-plex testing: WJOG13620L.

BACKGROUND: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing. METHODS: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes. RESULTS: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days). CONCLUSION: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing.

Endobronchial ultrasound with a guide sheath during bronchoscopy for peripheral pulmonary lesions.

INTRODUCTION: Radial probe endobronchial ultrasound (rEBUS) improves the diagnostic yield of peripheral pulmonary lesions (PPLs). A notable methodological limitation of rEBUS is that it does not provide real-time images during transbronchial biopsy (TBB) procedures. To overcome this limitation, a guide sheath (GS) method was developed. AREAS COVERED: This review covers the procedures and complications of rEBUS-guided TBB with a GS (EGS method). We also present the data from key randomized controlled trials (RCTs) of the EGS method and summarize the usefulness of combining the EGS method with various techniques. Finally, we discuss in which situations EGS should be used. EXPERT OPINION: A large RCT showed that the diagnostic yield of the EGS method for PPLs was significantly higher than that of rEBUS-guided TBB without a GS (non-GS method). However, since the EGS and non-GS methods each have their own advantages and disadvantages, they should be considered complementary and used flexibly in different cases. In some cases, a combination of the two may be an option. The appropriate combination of EGS with various techniques may enhance the diagnostic yield of PPLs and help prevent complications. The choice should be based on the location and texture of the target lesion, as well as operator skill, resource availability, safety, and accuracy.

Efficacy and safety of second-line therapy of docetaxel plus ramucirumab after first-line platinum-based chemotherapy plus immune checkpoint inhibitors in non-small cell lung cancer (SCORPION): a multicenter, open-label, single-arm, phase 2 trial.

Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and ß error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed. Interpretation: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options. Funding: Eli Lilly Japan K.K.

Transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration for diagnostic and staging purposes: a narrative review.

Background and Objective: Transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) is a feasible and well-tolerated modality that is increasingly used to diagnose intrathoracic lesions. This narrative review summarizes the current application of EUS-B-FNA for diagnosing lung cancer, thoracic sarcoidosis, and metastases from extrathoracic malignancies. Methods: A comprehensive and systematic online literature search via Medline/PubMed for the period January 2005 to December 2022 was conducted for articles published using the keywords "EUS-B-FNA", "endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA)", "endoscopic ultrasound fine-needle aspiration (EUS-FNA)", "lung cancer", "staging", and "sarcoidosis". Key Content and Findings: Recent data prove the efficacy and safety of EUS-B-FNA for providing complete lung cancer staging, when combined with EBUS-TBNA, and in the evaluation of para-esophageal lesions. EUS-B-FNA allows access to inferior mediastinal lymph nodes and para-esophageal masses that are not accessible by EBUS-TBNA. Additional advantages of using EUS-B-FNA include significantly lower doses of anesthetics and sedatives, a shorter procedural time, fewer incidents of oxygen desaturation due to a poor respiratory reserve, significantly less cough, and higher operator satisfaction. Moreover, this procedure can be performed sequentially in the same setting with EBUS-TBNA by one operator. Other benefits include a lower cost, a single setting, and scope use. Conclusions: As EUS-B-FNA and EBUS-TBNA have complementary access to the mediastinum, the diagnostic yield of EUS-B-FNA combined with EBUS-TBNA is higher than that of endosonographic techniques alone in the diagnostic workup of intrathoracic lesions.

Ultrathin bronchoscopy for diagnosing peripheral pulmonary lesions.

Bronchoscopes are continuously improving. Increasingly, thinner bronchoscopes with larger working channels and better imaging quality are becoming available for clinical use. Concurrently, useful ancillary devices have been developed, such as radial probe endobronchial ultrasound (rEBUS) and navigation devices. Randomized studies have demonstrated the diagnostic superiority of ultrathin bronchoscopy over thin bronchoscopy under rEBUS and virtual bronchoscopic navigation guidance for small, peripheral pulmonary lesions. Furthermore, biopsy needles and cryoprobes have been miniaturized and adapted to the working channel of the new ultrathin bronchoscopes. Multi-modality and multi-instrumental ultrathin bronchoscopy using such new technologies has facilitated high diagnostic yields.

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE).

INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

Mucous Gland Adenoma of the Lung: A Neoplastic Counterpart of Mucinous Bronchial Glands.

Mucous gland adenoma (MGA) is a rare benign tumor that usually arises in the proximal airway and consists of mucus-secreting cells resembling bronchial glands. Here, we report 2 cases of MGAs and describe their morphologic, immunohistochemical, and molecular profiles in comparison with 19 pulmonary tumors of 5 other histologic types with mucinous cells (invasive mucinous adenocarcinoma, mucoepidermoid carcinoma, mixed squamous cell and glandular papilloma, bronchiolar adenoma/ciliated muconodular papillary tumor, and sialadenoma papilliferum). Two MGAs were found in 1 male patient and 1 female patient, located in the bronchus and trachea, respectively. One MGA was examined by RNA sequencing, and no putative driver mutations (including BRAF, KRAS, and AKT1 mutations) or gene fusions were identified. In another case of MGA, V600E mutations of BRAF and E17K mutations of AKT1 were not detected by allele-specific real-time PCR or digital PCR, respectively. However, a gene expression analysis revealed that the MGA presented a specific RNA expression profile with multiple genes enriched in the salivary gland. The gene expression of NKX3.1 was significantly higher in the MGA case in comparison to normal control lungs (P < .001). We then examined NKX3.1 immunohistochemistry for 2 MGAs and 19 tumors of 5 other histologic types. NKX3.1 was positive in MGA (2/2, 100%), whereas all constituent cells, including mucinous cells, were negative for NKX3.1 in other histologic types (0%, 0/19). In normal lung tissue, NKX3.1 was positive for mucinous acinar cells of the bronchial glands. In conclusion, the gene expression profile, taken together with the histologic similarity between MGA and bronchial glands, and the preferred location of the tumors (proximal airways with submucosal glands) suggest that MGA is a neoplastic counterpart of mucinous bronchial glands. NKX3.1 immunohistochemistry can be a sensitive and specific ancillary marker that distinguishes MGA from other histologic mimics.

A phase II study (WJOG12819L) to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is an established standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, of such patients who have received prior treatment with a first- or second-generation EGFR TKI, only approximately half are eligible for osimertinib therapy because its indication as second-line treatment and beyond is limited to metastatic NSCLC that is positive for the T790M resistance mutation of the EGFR gene. This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. METHODS: We conducted a phase II study to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. The primary end point was response rate (assessed by a central imaging reviewer). RESULTS: From August 2020 to February 2021, 55 patients from 15 institutions were enrolled in the study. The overall response for primary analysis was achieved in 16 patients (29.1 %; 95 % CI, 17.6-42.9), which exceeded the threshold response rate necessary for analysis. Stable disease was found in 16 patients (29.1 %), and progressive disease, in 18 (32.7 %). The median length of progression-free survival (PFS) was 4.07 months (95 % CI 2.10-4.30), and the rate of 12-month PFS was 17.3 %. CONCLUSIONS: Osimertinib demonstrated modest antitumor activity against progressive EGFR T790M-negative disease.

Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study).

BACKGROUND: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. METHODS: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences. RESULTS: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. CONCLUSIONS: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.).