Real-World Efficacy and Safety of Durvalumab Administration Following Chemoradiotherapy in Elderly Patients With Unresectable Locally Advanced Nonsmall Cell Lung Cancer: A Multicenter, Retrospective Study.

BACKGROUND: The PACIFIC trial established durvalumab administration after chemoradiotherapy as the standard of care for unresectable locally advanced nonsmall cell lung cancer (LA-NSCLC). However, the efficacy and safety of durvalumab in elderly patients aged 75 years or above remains unclear. This study aimed to investigate the real-world efficacy and safety of durvalumab for LA-NSCLC, with a specific focus on elderly patients. PATIENTS AND METHODS: We reviewed 214 patients who received durvalumab out of 278 patients with unresectable LA-NSCLC who underwent chemoradiotherapy at 7 institutions between July 2018 and March 2022. Propensity score matching (PSM) analysis was performed to evaluate the efficacy of durvalumab in elderly patients. RESULTS: The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates were 42.2% (95% confidence interval [CI], 34.7%-49.5%) and 77.1% (95% CI, 70.1-82.7%), respectively. Grade ≥ 3 immune-related adverse events (irAEs) occurred in 8.2% of patients. PSM analysis revealed that OS was significantly shorter in elderly patients (≥ 75 years) than in younger patients (< 75 years) (hazard ratio [HR]; 95% CI, 1.39-8.99; P = .008), whereas PFS did not differ significantly between the 2 groups (HR: 1.50, 95% CI, 0.84-2.68, P = .169). The frequency of irAEs did not differ between these groups. CONCLUSIONS: The real-world efficacy and safety of durvalumab administration following chemoradiotherapy for LA-NSCLC coincided with the PACIFIC trial's findings. Disease control achieved with this protocol did not differ significantly between elderly and younger patients but had acceptable tolerability, demonstrating its benefit even in elderly LA-NSCLC patients aged 75 years or above.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Metastasis to hypopharynx from epidermotropic metastatic malignant melanoma.

Previous reports proposed the concept and criteria of epidermotropic metastatic malignant melanoma (EMMM): (a) dermal involvement equal to or broader than the epidermal involvement, (b) atypical melanocytes within the dermis, (c) thinning of the epidermis, (d) widening of the papillary dermis with an epithelial collarette, and (e) vascular invasion of atypical melanocytes. However, it remains unclear whether EMMM also involves the mucosal epithelium. In this case, the patient was diagnosed with EMMM based on the histopathological findings of the patient's multiple skin lesions and clinical course. The patient also developed metastasis to the hypopharynx. Although histopathological findings of the lesion suggested the possibility of melanoma in situ, as the lesion included atypical melanocytes in the mucosal epithelium, the clinical course supported the diagnosis of hypopharyngeal metastasis from EMMM. This case suggests that EMMM may have epitheliotropic features not only in the skin but also in the mucosa.

Negative impact of ratio of the microvascular area to tumor area on the response to EGFR-TKI in non-small cell lung cancer with an EGFR mutation.

Background: The clinical impact of tumor microvessels on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC) is unclear. Thus, the aim of this study was to investigate whether a tumor microenvironment, abundant in microvessels, affects EGFR-TKI efficacy in patients with NSCLC and EGFR mutations. Methods: We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFR mutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital from January 2010 to February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The ratio of microvascular area to tumor area (RMV), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of RMV on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. Results: The median PFS in the high RMV group (≥0.058) was significantly shorter than that in the low RMV group [<0.058; 296 days, 95% confidence interval (CI): 217-374 vs. 918 days, 95% CI: 279-1,556, P=0.002]. Multivariate analysis revealed that high RMV was an independent negative predictor of PFS (hazard ratio, 3.21; 95% CI: 1.18-8.76, P=0.022). Conclusions: High RMV may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

Utility of Covered Self-Expanding Metal Stents for Biliary Drainage during Neoadjuvant Chemotherapy in Patients with Borderline Resectable Pancreatic Cancer.

OBJECTIVES: We aimed to compare the utility of covered self-expanding metal stents (CSEMSs) with that of plastic stents (PSs) for biliary drainage during neoadjuvant chemotherapy in patients with borderline resectable pancreatic cancer. METHODS: Forty patients with borderline resectable pancreatic cancer underwent biliary stenting during neoadjuvant chemotherapy at Hiroshima University Hospital. PSs and CSEMSs were placed in 19 and 21 patients, respectively. Two gemcitabine-based regimens for chemotherapy were used. Treatment outcomes and postoperative complications were compared between both groups. RESULTS: The incidence of recurrent biliary obstruction was significantly lower in the CSEMS group (0% vs. 47.4%, p < 0.001), and the median time to recurrent biliary obstruction in the PS group was 47 days. There was no difference in the incidence of other complications such as non-occlusive cholangitis, pancreatitis, and cholecystitis between the two groups. Delays in the chemotherapy schedule due to stent-related complications were significantly frequent in the PS group (52.6% vs. 4.8%, p = 0.001). There was no significant difference in the incidence of postoperative complications between the two groups. CONCLUSIONS: CSEMSs may be the best choice for safely performing neoadjuvant chemotherapy for several months in patients with borderline resectable pancreatic cancer with bile duct stricture.

Interstitial Lung Disease in Adulthood Associated with Surfactant Protein C Gene Mutation in a Patient with a History of Lipoid Pneumonia in Infancy.

Mutations in the surfactant protein C gene (SFTPC) are responsible for hereditary interstitial lung disease (ILD), which is a rare disease. We herein report a patient with a clinical history of endogenous lipoid pneumonia in infancy who developed diffuse progressive pulmonary fibrosis in adulthood associated with SFTPC mutations. A surgical lung biopsy and genetic sequencing revealed fibrotic interstitial pneumonia and two SFTPC mutations (c.215G>A and c.578C>A). Based on these findings, we diagnosed the series of lung diseases as sporadic ILD caused by SFTPC mutations. Physicians should suggest genetic sequencing in patients with early-onset ILD.

Primary lung sebaceous carcinoma successfully treated with radiotherapy and pembrolizumab: A case report.

Sebaceous carcinoma is a rare cutaneous malignant tumor, usually occurring on the eyelids, head, neck, and trunk. There have been few reports about sebaceous carcinoma with primary lung cancer, for which optimal therapy has not yet been established. A 70-year-old man presented with a mass in the left iliac bone and tumor of the lower left lung. The morphological characteristics of the iliac bone biopsy pathology and immunostaining results showed sebaceous gland differentiation. After systemic examination, we diagnosed a primary lung sebaceous carcinoma with intrapulmonary and bone metastases. PD-L1 was positive in 1%-24% of tumor cells, and microsatellites were stable. We detected protein kinase B (AKT1) mutations using the Oncomine Dx target test. Palliative radiotherapy (RT) of a total of 45 Gy was provided in 15 fractions to the left iliac region, which resulted in a 25% reduction in the tumor size. Subsequently, four courses of first-line pembrolizumab led to a 30% reduction in the total tumor count. RT and pembrolizumab may be treatment options for certain rare primary sebaceous carcinomas of the lungs. A synergistic effect from RT and subsequent administration of immune checkpoint inhibitors may have contributed to tumor reduction.

Combination bezafibrate and nivolumab treatment of patients with advanced non-small cell lung cancer.

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I-IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Clinical impact of SUVmax of interstitial lesions in lung cancer patients with interstitial lung disease who underwent pulmonary resection.

Background: Acute exacerbation of interstitial lung disease often causes fatal respiratory deterioration in lung cancer patients with interstitial lung disease. Here, we examined whether the maximum standardized uptake value of a contralateral interstitial lesion was a predictive factor of acute exacerbation of interstitial lung disease within 30 days postoperatively in lung cancer patients with interstitial lung disease who underwent pulmonary resection. Methods: Overall, 117 consecutive lung cancer patients with interstitial lung disease who underwent pulmonary resection between August 2010 and April 2019 at the Kumamoto University Hospital were retrospectively analysed for the association between the maximum standardized uptake value of the contralateral interstitial lesions and interstitial lung disease parameters. Results: The median maximum standardized uptake value of contralateral interstitial lesions was 1.61, which was regarded as the cut-off point predictive of the incidence of acute exacerbation of interstitial lung disease. Eight patients developed postoperative acute exacerbation of interstitial lung disease. There was no significant association between the maximum standardized uptake value of the contralateral interstitial lesions and postoperative acute exacerbation of interstitial lung disease. The maximum standardized uptake value was weakly but significantly associated with lactate dehydrogenase levels (r=0.211, P=0.022), Krebs von den Lungen-6 (r=0.208, P=0.028), and % diffusing capacity for carbon monoxide (r=-0.290, P=0.002). Moreover, seven patients developed acute exacerbation of the interstitial lung disease during the clinical course after 30 postoperative days, and the incidence rate of acute exacerbation of interstitial lung disease was significantly higher in the high maximum standardized uptake value group (≥1.61) than in the low maximum standardised uptake value group (<1.61) (12.7% vs. 0%, P=0.002, Gray's test). Conclusions: Maximum standardized uptake value was not a predictor of postoperative acute exacerbation of interstitial lung disease in lung cancer patients with interstitial lung disease after pulmonary resection, but could be a predictive tool of an association with interstitial lung disease severity and activity markers.

Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors.

Oral microbiota is associated with human diseases including cancer. Emerging evidence suggests that proton pump inhibitors (PPIs), which allow the oral microbiome to translocate into the gut, negatively influence the efficacy of immune checkpoint blockade (ICB) in cancer patients. However, currently there is no effective treatment that restores the decreased efficacy. To address this issue, we retrospectively evaluated 118 advanced or recurrent non-small cell lung cancer (NSCLC) patients treated with ICB and analyzed 80 fecal samples of patients with lung cancer by 16S metagenomic sequencing. Clostridium butyricum therapy using C. butyricum MIYAIRI 588 (CBM588), a live biotherapeutic bacterial strain, was shown to improve the ICB efficacy in lung cancer. Thus, we investigated how CBM588 affects the efficacy of ICB and the gut microbiota of lung cancer patients undergoing PPI treatment. We found that PPI treatment significantly decreased the efficacy of ICB in NSCLC patients, however, CBM588 significantly restored the diminished efficacy of ICB and improved survival. In addition, CBM588 prolonged overall survival in patients receiving PPIs and antibiotics together. The fecal analysis revealed that PPI users had higher abundance of harmful oral-related pathobionts and lower abundance of beneficial gut bacteria for immunotherapy. In contrast, patients who received CBM588 had lesser relative abundance of potentially harmful oral-related bacteria in the gut. Our research suggests that manipulating commensal microbiota by CBM588 may improve the therapeutic efficacy of ICB in cancer patients receiving PPIs, highlighting the potential of oral-related microbiota in the gut as a new therapeutic target for cancer immunotherapy.

Implementation of 99mTc-GSA SPECT Image-guided Inverse Planning into Palliative Radiotherapy for Diffuse Liver Metastases: A Novel Approach.

BACKGROUND/AIM: This is a report of the first clinical implementation of 99mTc-labeled diethylene triamine pentaacetate-galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) image-guided inverse planning into palliative radiotherapy (RT) for diffuse liver metastases. CASE REPORT: A 48-year-old man developed chemo-refractory diffuse liver metastases from thymic carcinoma characterized by abdominal pain and distension. Palliative RT was performed with a total dose of 20 Gy in five fractions using double arc volumetric modulated arc therapy to reduce the dose to functional liver defined by 99mTc-GSA SPECT images. His symptoms were immediately relieved after RT and did not experience radiation-induced liver disease. Both Functional Assessment of Cancer Therapy (FACT)-G and FACT-Hep total scores improved after 2 weeks of RT initiation and did not become worse than baseline scores. CONCLUSION: The 99mTc-GSA SPECT image-guided palliative RT is an effective and safe treatment for patients with diffuse liver metastases.

Clinical impact of cerebral infarction in patients with non-small cell lung cancer.

BACKGROUND: Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC. METHODS: We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis. RESULTS: Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P < 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors. CONCLUSION: Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.

Optimal indication of endoscopic retrograde pancreatography-based cytology in the preoperative pathological diagnosis of pancreatic ductal adenocarcinoma.

BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is extremely useful for pathological diagnosis of pancreatic ductal adenocarcinoma (PDAC); however, puncturing is difficult in some cases, and there is a risk of needle tract seeding. This study evaluated the indications for endoscopic retrograde pancreatography-based (ERP)-based cytology for the preoperative diagnosis of PDAC. METHODS: This study included 267 patients with PDAC who underwent preoperative ERP. The diagnostic performance of ERP-based cytology for PDAC was evaluated based on the sample collection method (pancreatic juice cytology [PJC] during ERP, brush cytology, PJC via endoscopic nasopancreatic drainage [ENPD] catheter), lesion site (pancreatic head, body/tail), and lesion size (≤10 mm, 10-20 mm, >20 mm), and compared with the diagnostic performance of EUS-FNA. RESULTS: The overall sensitivity of ERP-based cytology was 54.9%; sensitivity by the sampling method was 34.7% for PJC during ERP, 65.8% for brush cytology, and 30.8% for PJC via an ENPD catheter. The sensitivity of EUS-FNA was 85.3%. Brush cytology and PJC via an ENPD catheter were performed more often in pancreatic body/tail lesions than in head lesions (P = 0.016 and P < 0.001, respectively), and the overall sensitivity of ERP-based cytology was better for body/tail lesions (63.2% vs. 49.0%, P = 0.025). The sensitivities of ERP-based cytology and EUS-FNA in diagnosing PDAC ≤10 mm were 92.3% and 33.3%, respectively. Post-ERP pancreatitis was observed in 22 patients (8.2%) and significantly less common with ENPD catheters (P = 0.002). CONCLUSIONS: ERP-based cytology may be considered the first choice for pathological diagnosis of PDAC ≤10 mm and in the pancreatic body/tail.

Pembrolizumab-induced Focal Pancreatitis Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration.

A 69-year-old man with advanced non-small-cell lung cancer was treated with pembrolizumab for 4 months. Three months after pembrolizumab was discontinued, computed tomography showed enlargement of the pancreatic head, with hypoattenuating areas in the pancreatic head to body. On endoscopic ultrasonography, the entire pancreatic parenchyma was hypoechoic. Endoscopic retrograde cholangiopancreatography showed narrowing of the main pancreatic duct at the pancreatic head. Endoscopic ultrasound-guided fine-needle aspiration showed inflammatory cell infiltration in the stroma but no neoplastic lesions. CD8-positve T cells were dominant over CD4-positive T cells in the infiltrating lymphocytes, and the patient was diagnosed with pembrolizumab-induced pancreatitis.

Pharmacokinetic and pharmacogenomic analysis of low-dose afatinib treatment in elderly patients with EGFR mutation-positive non-small cell lung cancer.

PURPOSE: An increasing number of advanced non-small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly patients are scarce. We conducted a prospective multicentre, single-arm, and open-label phase II trial for low-dose afatinib (30 mg/day) use in elderly patients with NSCLC with EGFR mutation to assess quality-of-life (QOL) and pharmacokinetic (PK)/pharmacogenomic (PGx) parameters. PATIENTS AND METHODS: The primary end-point was the objective response rate (ORR), and the planned number of registered cases was 35, with a threshold ORR of 50%, an expected ORR of 75%, α of 0.05, and ß of 0.1. Secondary end-points were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (Css) and at the occurrence of clinically significant AEs. RESULTS: The median age of the patients was 79 years. The ORR was 80.0% and the disease control rate was 91.4%. The median PFS and OS were 15.6 and 29.5 months, respectively. Four patients discontinued because of AEs. Treatment-related death was not observed. No significant change in QOL was observed at baseline and after 4, 8, and 12 weeks. Css was comparable with those in previous reports and was significantly higher in patients with grade 3 AEs. Direct correlations between afatinib treatment and PGx profiles were not observed. CONCLUSIONS: An afatinib starting dose of 30 mg/day could be an effective and safe treatment option for elderly patients.

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy.

The effect of radiotherapy during immunotherapy on immune-related adverse events (irAEs) is not fully understood. We herein report a 74-year-old woman diagnosed with lung adenocarcinoma with programmed death ligand 1 expression ≥50% and treated with pembrolizumab. She developed fatal immune thrombocytopenia associated with pembrolizumab immediately following radiotherapy. A flow cytometry analysis of peripheral blood detected an increased expression of programmed death-1 (PD-1) and Ki-67 in CD4+ and CD8+ T cells after radiotherapy, compared with pre-irradiation measurements. This case suggests that radiotherapy may evoke irAEs during treatment with anti-PD-1 antibodies, which physicians should consider when using radiotherapy in patients treated with these drugs.

Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).

TGFß Signaling Activated by Cancer-Associated Fibroblasts Determines the Histological Signature of Lung Adenocarcinoma.

Invasive lung adenocarcinoma (LADC) can be classified histologically as lepidic, acinar, papillary, micropapillary, or solid. Most LADC tumors manifest several of these histological subtypes, with heterogeneity being related to therapeutic resistance. We report here that in immunodeficient mice, human LADC cells form tumors with distinct histological features, MUC5AC-expressing solid-type or cytokeratin 7 (CK7)-expressing acinar-type tumors, depending on the site of development, and that a solid-to-acinar transition (SAT) could be induced by the tumor microenvironment. The TGFß-Smad signaling pathway was activated in both tumor and stromal cells of acinar-type tumors. Immortalized cancer-associated fibroblasts (CAF) derived from acinar-type tumors induced SAT in 3D cocultures with LADC cells. Exogenous TGFß1 or overexpression of an active form of TGFß1 increased CK7 expression and reduced MUC5AC expression in LADC cells, and knockdown of Tgfb1 mRNA in CAFs attenuated SAT induction. RNA-sequencing analysis suggested that angiogenesis and neutrophil recruitment are associated with SAT in vivo. Our data indicate that CAF-mediated paracrine TGFß signaling induces remodeling of tumor tissue and determines the histological pattern of LADC, thereby contributing to tumor heterogeneity. SIGNIFICANCE: CAFs secrete TGFß to induce a solid-to-acinar transition in lung cancer cells, demonstrating how the tumor microenvironment influences histological patterns and tumor heterogeneity in lung adenocarcinoma.