J-TAIL-2: A Prospective, Observational Study of Atezolizumab Combined With Carboplatin and Etoposide in Patients With Extensive-Stage SCLC in Japan.

Introduction: On the basis of the IMpower133 trial, atezolizumab plus carboplatin and etoposide (CE) is approved as first-line treatment for extensive-stage (ES)-SCLC. The J-TAIL-2 study evaluated atezolizumab plus CE in routine clinical practice settings.

Methods: J-TAIL-2 was a prospective, multicenter observational study in Japan.

Inhibition of non-homologous end joining mitigates paclitaxel resistance resulting from mitotic slippage in non-small cell lung cancer.

Mitotic slippage, which enables cancer cells to bypass cell death by transitioning from mitosis to the G1 phase without undergoing normal cytokinesis, is one likely mechanism of paclitaxel (PTX) resistance. DNA double-strand breaks (DSBs) in the G1 phase are mainly repaired through non-homologous end joining (NHEJ). Therefore, inhibiting NHEJ could augment the PTX-induced cytotoxicity by impeding the repair of PTX-induced DSBs during the G1 phase following mitotic slippage.

Gefitinib-induced Myositis: A Novel Case Report.

Chemotherapy-induced myositis is a severe adverse event caused by chemotherapeutic agents such as immune checkpoint inhibitors (ICIs) or cytotoxic agents. We experienced a patient with gefitinib-induced myositis with symptoms of muscle cramps and stiffness in the limbs, and reported the treatment process. A 70-year-old woman received four courses of carboplatin (CBDCA)+pemetrexed (PEM)+gefitinib (intravenous CBDCA area under the curve (AUC) 5 and PEM 500 mg/m, every 3 weeks, and oral gefitinib 250 mg daily), for epidermal growth factor receptor (EGFR) mutation-positive stage IV lung cancer treatment; followed by seven courses of PEM+gefitinib, and continued gefitinib monotherapy thereafter.

Risk of bleeding associated with transbronchial biopsy using flexible bronchoscopy in patients with echocardiographic or chest CT evidence of pulmonary hypertension.

Background: Endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) facilitates the diagnosis of various respiratory diseases. The safety of performing EBUS-guided TBB in patients with a finding of pulmonary hypertension (PH) is controversial. Little is known about the relationship between the risk of bleeding associated with EBUS-guided TBB in the presence of PH suspected on echocardiography or chest CT.

Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

Introduction: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures.

Phase II study of carboplatin-paclitaxel alone or with bevacizumab in advanced sarcomatoid carcinoma of the lung: HOT1201/NEJ024.

Objectives: Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid carcinomas (PSCs). There is, thus, a crucial need to develop novel treatment strategies for this rare tumor.

Patients And Methods: Chemotherapy-naïve patients with histologically confirmed PSCs were assigned to receive either carboplatin/paclitaxel alone (CP) or with bevacizumab (CPB) followed by bevacizumab maintenance.

Elevated serum CYFRA 21-1 level as a diagnostic marker for thymic carcinoma.

Background: No useful tumor markers have been identified for the diagnosis of thymic carcinomas. Serum cytokeratin 19 fragment, measured using the CYFRA 21-1 immunoassay, is used as a tumor marker for squamous cell carcinomas in various malignant tumors. Here, we evaluated the value of CYFRA 21-1 in diagnosing thymic carcinoma.

Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).

Background: A cisplatin plus irinotecan (CPT-11) regimen is used for patients with extensive disease small cell lung cancer (ED-SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open-label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED-SCLC who responded to induction therapy.

A case of radio-insensitive SMARCA4-deficient thoracic undifferentiated carcinoma with severe right heart failure.

SMARCA4-deficient thoracic sarcomatoid tumors were characterized by inactivating mutations of SMARCA4 and often found in the chest of young and middle-aged males with a smoking history. Recently, SMARCA4-deficient thoracic sarcomatoid tumors were reported to represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. The main complication of this tumor is compression of the respiratory tract and/or blood vessels.

Nivolumab-induced immune thrombocytopenia in a patient with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor. Nivolumab showed durable antitumor effect in patients with recurrent MPM and was approved for those patients in Japan in 2018. Immune related adverse event (irAE) is occurred in various organs and is suggestive to be related to better outcome of nivolumab.

Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer.

Purpose: We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells.

Methods: Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines.

A prospective phase II study of carboplatin and nab-paclitaxel in patients with advanced non-small cell lung cancer and concomitant interstitial lung disease (HOT1302).

Objectives: Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD.

Patients And Methods: The enrolled patients had treatment-naïve, advanced NSCLC with ILD.

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC.

Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition.

Bromodomain and extraterminal domain inhibition synergizes with WEE1-inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer.

Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry.

DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail.

Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell-fate decisions and is tumor-suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear.

Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma.

Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma.

Successful Application of Edoxaban in the Treatment of Venous Thromboembolism Recurrence in a Patient with Non-small Cell Lung Cancer after Tumor Shrinkage.

This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed.

The predictive value of endobronchial ultrasonography with a guide sheath in the diagnosis of the histologic subtypes of lung cancer.

Background: Recent studies have shown differential response to chemotherapy among the subtypes of non-small cell lung carcinoma (NSCLC). Therefore, to accurately differentiate between the types of lung cancer is of paramount importance. Transbronchial biopsy using endobronchial ultrasonography with a guide sheath (EBUS-GS) is a promising method for the diagnosis of NSCLC.

Combined antitumor effect of γ-secretase inhibitor and ABT-737 in Notch-expressing non-small cell lung cancer.

Background: Inhibition of Notch by γ-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis.

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer.

Unlabelled: As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma.

Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition.

Non-small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT.

Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells.

Purpose: Non-small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 in mutant EGFR signaling is not known.

Experimental Design: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity.