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Background: Targeted therapy is now the standard of care in driver-oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver-oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver-oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear., Methods: Using the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed., Results: In total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28-1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33-1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19-4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25-0.91, P = 0.025)., Conclusion: ICI plus chemotherapy improves treatment efficacy in rare driver-oncogene-positive NSCLC., (© 2024. The Author(s).)

Isolation of tumor-specific T cells and their antigen receptors (TCRs) from malignant pleural effusions (MPE) may facilitate the development of TCR-transduced adoptive cellular immunotherapy products for advanced lung cancer patients. However, the characteristics and markers of tumor-specific T-cells in MPE are largely undefined. To this end, to establish the phenotypes and antigen specificities of CD8 + T cells, we performed single-cell RNA and TCR sequencing of samples from three advanced lung cancer patients. Dimensionality reduction on a total of 4,983 CD8 + T cells revealed 10 clusters including naïve, memory, and exhausted phenotypes. We focused particularly on exhausted T cell clusters and tested their TCR reactivity against neoantigens predicted from autologous cancer cell lines. Four different TCRs specific for the same neoantigen and one orphan TCR specific for the autologous cell line were identified from one of the patients. Differential gene expression analysis in tumor-specific T cells relative to the other T cells identified CXCL13 , as a candidate gene expressed by tumor-specific T cells. In addition to expressing CXCL13 , tumor-specific T cells were present in a higher proportion of T cells co-expressing PDCD1 (PD-1)/ TNFRSF9 (4-1BB). Furthermore, flow cytometric analyses in advanced lung cancer patients with MPE documented that those with high PD-1/4-1BB expression have a better prognosis in the subset of 57 adenocarcinoma patients ( p  = .039). These data suggest that PD-1/4-1BB co-expression might identify tumor-specific CD8 + T cells in MPE, which are associated with patients' prognosis. (233 words)., Competing Interests: This study was partly funded by NEC Corporation., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: Determining whether patients' unrealistic expectations of chemotherapy as a cure were associated with their perception of the disclosure of incurability., Methods: This prospective study included consecutive patients with pretreated non-small cell lung cancer from four study sites. Patients and their oncologists were asked whether they perceived the disclosure of cancer incurability. Patients were also asked if they thought that chemotherapy was curative. We followed up on whether the deceased patients received specialized palliative care 14 months after their last enrollment. Multiple regression analyses were conducted to examine the association between the expectation of chemotherapy as a cure and patient/oncologist-reported perceptions of the disclosure of incurability., Results: We analyzed 200 patients, 77 (38.5%) of whom had unrealistic expectations of a cure. Based on patients' perceptions, incurability was disclosed to 138 (69.0%) patients, and based on their oncologists' perceptions, incurability was disclosed to 185 (92.5%) patients (patient/oncologist agreements, κ = 0.19). Patients without a perception of the oncologist's disclosure of incurability-regardless of their oncologist's perception-were more likely to have unrealistic expectations of a cure than patients for whom both patient and oncologist perceptions were present. Patients who had unrealistic expectations of chemotherapy as a cure were shown to be significantly less likely to have received specialized palliative care, after adjusting for covariates (adjusted OR, 0.45; 95% CI, 0.23-0.91; p = .027)., Conclusion: Oncologists' disclosure of incurability was not fully recognized by patients, and expectations of chemotherapy as a cure were associated with patients' perception of the disclosure of incurability., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their study are limited to small-scale or case reports. Therefore, daily clinical practices often require a search for previous reports. In the last 20 years, several genetic rearrangements have been identified, such as MYB::NF1B rearrangements in adenoid cystic carcinoma, CRTC1::MAML2 rearrangements in mucoepidermoid carcinoma, EWSR1::ATF1 rearrangements in hyalinizing clear cell carcinoma and rearrangements of the EWSR1 locus or FUS (TLS) locus in myoepithelioma and myoepithelial carcinoma. These molecular alterations have been useful in diagnosing these tumors, although they have not yet been linked to molecularly targeted therapies. The morphologic, immunophenotypic, and molecular characteristics of these tumors are similar to those of their counterparts of extrapulmonary origin, so clinical and radiologic differential diagnosis is required to distinguish between primary and metastatic disease of other primary sites. However, these molecular alterations can be useful in differentiating them from other primary lung cancer histologic types. The management of these tumors requires broad knowledge of the latest diagnostics, surgery, radiotherapy, bronchoscopic interventions, chemotherapy, immunotherapy as well as therapeutic agents in development, including molecularly targeted agents. This review provides a comprehensive overview of the current diagnosis and treatment of pulmonary salivary gland tumors, with a focus on adenoid cystic carcinoma and mucoepidermoid carcinoma, which are the two most common subtypes., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: End-of-life discussions for patients with advanced cancer are internationally recommended to ensure consistency of end-of-life care with patients' values. This study examined the elements of end-of-life discussions associated with end-of-life care., Materials and Methods: We performed a prospective observational study among consecutive patients with pretreated non-small cell lung cancer after the failure of first-line chemotherapy. We asked oncologists whether they had ever discussed "prognosis," "do not attempt resuscitation," "hospice," and "preferred place of death" with a patient at baseline. The quality of life (QOL) and depressive symptoms of patients were assessed using validated questionnaires at baseline and 3 months later. The end-of-life care that patients received was investigated using medical records. Oncologists' compassion and caregivers' preferences for hospice care were also assessed using questionnaires. Multiple regression analyses were conducted to examine the association between elements of end-of-life discussions and patient-reported outcomes as well as actual end-of-life care., Results: We obtained 200 valid responses at baseline, 147 valid responses 3 months later, and 145 data points for medical care at the end-of-life stage. No element of the end-of-life discussion between the patient and their oncologist was significantly associated with patients' reported outcomes or actual end-of-life care. In addition, oncologists' compassion was significantly associated with improvement in both comprehensive QOL and depressive symptoms, and caregivers' preferences for hospice care and high educational level were significantly associated with hospice death., Conclusion: Oncologist-patient alliances and caregivers' involvement in end-of-life discussions may be influential in achieving optimal end-of-life care., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The Cockcroft-Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non-small-cell lung cancer remain unknown., Methods: We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin-pemetrexed. Glomerular filtration rate values in Calvert's formula were back-calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups., Results: Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression-free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76-1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65-1.17; p = 0.363), with higher grade 3-4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20-0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23-0.82; p = 0.010)., Conclusions: Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Although patients with advanced cancer often have poor prognostic awareness, the most effective communication approach for improving prognostic awareness is unclear. In addition, the association between prognostic awareness and preferences for future medical treatment remains unexplored., Materials and Methods: We performed a prospective observational study of consecutive patients with advanced or post-operative recurrent non-small cell lung cancer whose disease had progressed after first-line chemotherapy, and their caregivers. We evaluated patterns of clinical discussions about incurability, prognostic awareness, and preference for future medical treatment at baseline and 3 months later., Results: We obtained 200 valid responses to the questionnaires at baseline and 147 valid responses 3 months later. In addition, 180 caregivers returned valid responses. A total of 54% of patients and 51% of caregivers had accurate awareness at baseline, and 52% of patients had accurate awareness 3 months later. Multiple logistic regression analysis revealed that patients who were informed about incurability in recent and past discussions were significantly more likely to have accurate awareness 3 months later, compared with those who were only informed recently (adjusted odds ratio 5.08; 95% CI, 1.31-19.78; P = .019). Accurate awareness at 3 months was significantly negatively associated with preference for life-prolonging treatment at 3 months after adjusting for covariates (adjusted odds ratio 0.39; 95% CI, 0.17-0.90; P = .028)., Conclusion: Patients with advanced cancer who had both recent and past discussions about incurability with their oncologists have more accurate prognostic awareness. Improving prognostic awareness could reduce the preference for life-prolonging treatment., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation., Methods: We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer., Results: One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect., Conclusions: The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Post-bronchoscopy pneumonia can affect the prognosis of lung cancer patients. This prospective study examined the efficacy of prophylactic antibiotics for lung cancer patients at high-risk of post-bronchoscopy pneumonia, determined by our prediction score, using three risk factors: age 70 years or older, current smoking, and central tumors visualized on CT., Methods: Patients with lung cancer who underwent diagnostic bronchoscopy between June 2018 and March 2020 with a score of 2 points or higher were enrolled. Sulbactam/ampicillin was administered intravenously within one hour prior to bronchoscopy, followed by oral clavulanate/amoxicillin for three days. We used the data of lung cancer patients who underwent diagnostic bronchoscopy between April 2012 and July 2014 and exhibited a score of 2 or higher as the historical control., Results: Post-bronchoscopy pneumonia occurred in none of the 24 patients in the prophylaxis group and in 17 of 144 patients in the control group, with no significant difference in the incidence of pneumonia between the two groups., Conclusions: Antibiotic prophylaxis can be effective and safe for the patients high-risk of post-bronchoscopy pneumonia. A multicenter prospective study to examine the effects of prophylactic antibiotics in high-risk patients is feasible with a modest number of participants.

A 44-year-old man developed coronavirus disease 2019 (COVID-19) pneumonia during immunochemotherapy consisting of carboplatin, paclitaxel, and pembrolizumab for non-small cell lung cancer. Low-grade fever, followed by mild hypoxemia, and febrile neutropenia, were observed, and granulocyte colony-stimulating factor (G-CSF) was administered until the recovery of neutropenia, when he developed a high fever, severe hypoxemia, and hypotension accompanied by consolidation in the bilateral lungs. His conditions promptly improved after treatment including hydrocortisone and the primary and metastatic tumors remained regressed for 10 months without further treatment. Post-COVID-19 organizing pneumonia during cancer immunochemotherapy can be aggravated by immune-checkpoint inhibitors and G-CSF.

Background: Immune checkpoint inhibitor (ICI) therapy plus chemotherapy has become a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Pre-existing interstitial lung disease (ILD) is a risk factor for drug-induced pneumonitis caused by chemotherapy or ICI monotherapy. However, clinical data in patients with pre-existing ILD who received ICI therapy plus chemotherapy are limited. This study aimed to identify the risk factors for drug-induced pneumonitis in patients with NSCLC treated with ICIs plus chemotherapy., Methods: We retrospectively reviewed the medical records of 160 consecutive patients who were diagnosed with NSCLC and treated with ICIs plus chemotherapy at Aichi Cancer Center Hospital between December 2018 and November 2020. Patients with a prior history of ICI treatment or thoracic radiotherapy were excluded from the analysis., Results: Among 125 patients, pre-existing ILD was observed in 20 patients (16.0%). Drug-induced pneumonitis developed in 17 patients (13.6%), with a median time to onset of 19.3 weeks (range, 1.6-108.9 weeks). In multivariate logistic analysis, pre-existing ILD (odds ratio = 19.07, p = 0.0001) and PEM exposure (odds ratio = 5.67, p = 0.022) were identified as risk factors for the development of drug-induced pneumonitis., Conclusions: Pre-existing ILD and pemetrexed exposure are risk factors for drug-induced pneumonitis in patients with NSCLC., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: The purposes of this study are to clarify the details of the ALK tyrosine kinase inhibitor (TKI) resistance mechanism in rebiopsy cases and to predict novel resistance gene alterations using molecular dynamics simulation., Methods: A total of 21 patients with ALK-positive NSCLC who underwent a rebiopsy after ALK TKI failure were included in this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and rebiopsy tumor specimens., Results: Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs., Conclusions: The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

A 72-year-old man was treated with prednisolone and cyclosporine A for idiopathic pulmonary fibrosis. A nodule with a diameter of 19 mm was found in the right lung and diagnosed as lung squamous cell carcinoma. Anti-cancer treatments were not performed because of the presence of advanced interstitial pneumonia and chronic respiratory failure. Cyclosporine A was tapered to avoid suppression of anti-tumor immunity, and pirfenidone was initiated. Within 2 months, the tumor had shrunk to 10 mm in diameter and remained regressed for 9 months. This is the first report of a non-hematologic solid organ tumor responding to the discontinuation of immunosuppressants.

Objective: Malignant pleural effusions (MPEs) deteriorate the quality of life in patients with advanced stages of cancer. Although vascular endothelial growth factor (VEGF) is known to be a key factor for MPE formation, it is not fully clarified whether there are other components related to its appearance., Methods: Pleural effusion and serum samples were collected from patients with MPEs of non-small cell lung cancer. Cellular analysis of pleural effusion was performed using fluorescence flow cytometry. The concentrations of 12 cytokines, chemokines, and growth factors in MPEs and serum samples were analyzed using the cytometric bead array method., Results: Fifteen patients (median age: 70 years, 11 males) with non-small cell lung cancer (13 adenocarcinoma, 2 squamous cell carcinoma) were enrolled in this study. Concentrations of VEGF, interleukin (IL)-5, IL-6, IL-8, IL-12/IL-23p40, and C-C motif chemokine ligand (CCL) 2 were significantly higher in MPE than in serum. Pleural IL-5 levels correlated with malignant cell numbers in MPE. There was no factor related to the total amount of drained effusion or period of chest tube insertion., Conclusions: Production of six molecules were increased in the pleural cavity with MPE of non-small cell lung cancer. Complex interactions among these molecules may regulate MPE formation.

Immune checkpoint inhibitors (ICIs) have dramatically changed the strategy used to treat patients with non-small-cell lung cancer (NSCLC); however, the vast majority of patients eventually develop progressive disease (PD) and acquire resistance to ICIs. Some patients experience oligoprogressive disease. Few retrospective studies have evaluated clinical efficacy in patients with oligometastatic progression who received local therapy after ICI treatment. We conducted a retrospective analysis of advanced NSCLC patients who received PD-1 inhibitor monotherapy with nivolumab or pembrolizumab to evaluate the effects of ICIs on the patterns of progression and the efficacy of local therapy for oligoprogressive disease. Of the 307 patients treated with ICIs, 148 were evaluated in our study; 42 were treated with pembrolizumab, and 106 were treated with nivolumab. Thirty-eight patients showed oligoprogression. Male sex, a lack of driver mutations, and smoking history were significantly correlated with the risk of oligoprogression. Primary lesions were most frequently detected at oligoprogression sites (15 patients), and 6 patients experienced abdominal lymph node (LN) oligoprogression. Four patients showed evidence of new abdominal LN oligometastases. There was no significant difference in overall survival (OS) between the local therapy group and the switch therapy group (reached vs. not reached, P = .456). We summarized clinical data on the response of oligoprogressive NSCLC to ICI therapy. The results may help to elucidate the causes of ICI resistance and indicate that the use of local therapy as the initial treatment in this setting is feasible treatment option., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: RNA-based sequencing is considered ideal for detecting pathogenic fusion-genes compared to DNA-based assays and provides valuable information about the relative expression of driver genes. However, RNA from formalin-fixed paraffin-embedded tissue has issues with both quantity and quality, making RNA-based sequencing difficult in clinical practice. Analyzing stamp-derived RNA with next-generation sequencing (NGS) can address the above-mentioned obstacles. In this study, we validated the analytical specifications and clinical performance of our custom panel for RNA-based assays on the Ion Torrent platform., Methods: To evaluate our custom RNA lung panel, we first examined the gene sequences of RNA derived from 35 NSCLC tissues with diverse backgrounds by conventional methods and NGS. Next, we moved to the clinical phase, where clinical samples (all stamp-derived RNA) were used to examine variants. In the clinical phase we conducted an NGS analysis while simultaneously applying conventional approaches to assess the feasibility and validity of the panel in clinical practice., Results: In the prerun phase, all of the variants confirmed with conventional methods were detected by NGS. In the clinical phase, a total of 80 patients were enrolled and 80 tumor specimens were sequenced from February 2018 to December 2018. There were 66 cases in which the RNA concentration was too low to be measured, but sequencing was successful in the vast majority of cases. The concordance between NGS and conventional methods was 95.0%., Conclusions: RNA extraction using stamp specimens and panel sequencing by NGS were considered applicable in clinical settings., Key Points: Significant findings of the study Next-generation sequencing using RNA from stamp specimens was able to detect driver gene changes in non-small cell lung cancer including fusion genes with the same accuracy as conventional methods. What this study adds Using RNA from stamp specimens obtained from biopsy increases the number of candidate cases for RNA sequencing in clinical settings., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

BRAF mutations are rare driver mutations in non-small cell lung cancer (NSCLC), accounting for 1%-2% of the driver mutations, and the mutation spectrum has a wide range in contrast to other tumors. While V600E is a dominant mutation in melanoma, more than half of the mutations in NSCLCs are non-V600E. However, treatment with dabrafenib plus trametinib targets the BRAF V600E mutation exclusively. Therefore, distinguishing between V600E and non-V600E mutations is crucial for biomarker testing in NSCLC in order to determine treatment of choice. Immunohistochemistry (IHC) using the BRAF V600E mutation-specific antibody is clinically used in melanoma patients, but little is known about its application in NSCLC, particularly with regard to the assay performance for non-V600E mutations. In the present study, we examined 117 tumors with BRAF mutations, including 30 with non-V600E mutations, using BRAF mutation-specific IHC. None of the tumors with non-V600E mutations, including two compound mutations, showed a positive reaction. Furthermore, all V600E mutations were positive except for one case with combined BRAF V600E and K601_W604 deletion. Our findings confirmed that the BRAF V600E mutation-specific IHC is specific without any cross-reactions to non-V600E mutations, suggesting that this assay can be a useful screening tool in clinical practice., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: We examined whether fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) performed before chemotherapy could predict the onset of acute exacerbation of interstitial lung disease (AE-ILD) in patients with lung cancer and ILD treated with chemotherapy., Methods: Thirty-three patients with lung cancer and ILD who underwent 18 F-FDG PET/CT and were treated with chemotherapy at Kumamoto University Hospital between April 2006 and March 2018 were retrospectively analyzed. The maximum standardized uptake value (SUV max ) of interstitial lesions was measured to quantify the background ILD activity. A prediction model of AE-ILD was developed using logistic regression analyses for the SUV max , and receiver operating characteristic (ROC) curve analyses were conducted., Results: Among the 33 patients, 7 experienced AE-ILD. The SUV max of contralateral interstitial lesions was significantly higher in patients with vs. without AE-ILD (median SUV max : 2.220 vs. 1.795, P = 0.025). Univariable logistic regression analyses showed that the SUV max of contralateral interstitial lesions trended towards being significantly associated with the onset of AE-ILD [odds ratio: 8.683, 95% confidence interval (CI) 0.88-85.83, P = 0.064]. The area under the ROC curve of the SUV max for predicting AE-ILD was 0.780 (95% CI 0.579-0.982, P = 0.025). The optimal cut-off value for SUV max was 2.005, with sensitivity and specificity values of 0.857 and 0.769, respectively., Conclusions: The SUV max of contralateral interstitial lesions in 18 F-FDG PET/CT images might be useful for predicting the onset of AE-ILD in patients with lung cancer and ILD treated with chemotherapy.

Aims: Anaplastic lymphoma kinase (ALK) immunohistochemistry has shifted from being a screening tool to being a sole determinant for ALK-targeted therapy. Recent articles have referred to small-cell lung cancer (SCLC) transformation as a resistance mechanism after ALK inhibitor treatments, but few reports have addressed ALK expression in treatment-naive SCLC in a comprehensive manner. Therefore, we examined ALK expression and the mechanisms in treatment-naive SCLCs., Methods and Results: We examined ALK expression in a consecutive series of SCLC tumours, and the expression mechanism was analysed regarding gene rearrangement, copy number changes, and point mutations. We also examined whether SCLC with ALK expression can be suppressed by crizotinib treatment in vitro. Immunohistochemical results revealed that ALK was expressed in 16 of 142 (11.3%) SCLCs. The expression was focal and less intense, which is in contrast to strong and uniform expression in adenocarcinoma with ALK rearrangement. Two combined SCLCs showed a positive reaction restricted to the SCLC component. None of the known genetic alterations, including rearrangement, amplification, copy number gain, or point mutations, were associated with ALK expression. A SCLC cell line, SKLC2, which expressed ALK without known genetic alterations, was not inhibited by a practically achievable serum concentration of crizotinib., Conclusions: Anaplastic lymphoma kinase immunohistochemistry for treatment-naive SCLCs should not be used as a predictive biomarker for ALK inhibitor therapy, because the positive reactions were due to intrinsic expression of normal ALK transcript., (© 2019 John Wiley & Sons Ltd.)

Objectives: Pneumonitis related to the use of anti-programmed death 1 (PD-1) antibodies is a common immune-related adverse event that can be life-threatening. However, the relationship between pulmonary fibrosis/emphysema and the incidence of anti-PD-1-related pneumonitis is unclear., Materials and Methods: We retrospectively reviewed data from 123 patients who were diagnosed with non-small-cell lung cancer and treated with anti-PD-1 antibodies (nivolumab or pembrolizumab) at the Aichi Cancer Center Hospital, Japan, between December 17, 2015, and November 30, 2017. Patients who previously received thoracic radiotherapy to the primary lesion, mediastinum, spinal, or rib metastases were excluded from the analysis. Fibrosis score (0-5) and emphysema score (0-4) on baseline chest computed tomography (CT) were determined by two diagnostic radiologists., Results: Eighteen patients (14.6%) experienced anti-PD-1-related pneumonitis, of which four (3.3%) were grade ≥3. The median onset time of pneumonitis after starting anti-PD-1 therapy was 60 days (range, 6-634 days). According to the analysis of fibrosis score, pneumonitis occurred in 13 (35.1%) of the 37 patients with a fibrosis score ≥1 and in 5 (5.8%) of 86 patients with a fibrosis score of 0. Univariate and multivariate logistic regression analysis revealed that fibrosis score ≥1 was the only risk factor for anti-PD-1-related pneumonitis (p = 0.0008)., Conclusion: Our results indicate that pre-existing pulmonary fibrosis significantly increases the risk of anti-PD-1-related pneumonitis. Further studies are needed to identify predictive factors of anti-PD-1-related pneumonitis in patients with fibrotic changes on CT findings., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/aim: The aim of this study was to evaluate the safety and efficacy of osimertinib for elderly patients, since the data remain limited., Patients and Methods: A total of 77 patients with advanced non-small cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation and treated with osimertinib were reviewed. Efficacy and safety indicators, such as EGFR-tyrosine kinase inhibitor (TKI)-related adverse events (AEs) and osimertinib-associated hematotoxicity, were evaluated in elderly patients (elderly group, EG; age, ≥75 years) by comparing them with younger patients (non-EG; aged <75 years). The frequency of AEs associated with osimertinib was compared with the initial EGFR-TKI treatment before osimertinib administration in the same patient cohort., Results: Of the total 77 patients, 18 (23%) were assigned to the EG, whereas 59 (77%) were assigned to the non-EG. There were no significant differences in overall response rate and progression-free survival between the two groups. Regarding the safety of osimertinib, the EG had significantly more grade ≥2 paronychia than the non-EG (16.6% vs. 1.6%, p=0.04). Additionally, the maximum grade of EGFR-TKI-related AEs associated with osimertinib in the EG was significantly lower than that of the initial EGFR-TKI treatment (p=0.03)., Conclusion: Osimertinib is a safe and effective treatment option for elderly patients with advanced NSCLC who harbor the EGFR mutation., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Competing Interests: None

Background: The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models., Methods: In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated., Results: Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2)., Conclusion: A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level., Clinical Trial Registration Id: ClinicalTrials.gov number, NCT01095302.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Emergence of the T790M point mutation in exon 20 of the epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of this study was to investigate the association between T790M mutation status and the progression patterns during EGFR-TKI treatment., Methods: We reviewed 181 patients with advanced non-small-cell lung cancer harboring EGFR mutation, who were evaluated for T790M mutation status after initial EGFR-TKI failure (gefitinib, erlotinib, or afatinib). We retrospectively investigated the patient characteristics, initial EGFR-TKI response, T790M mutation status, subsequent treatment after initial EGFR-TKIs, timing of re-biopsy, and progression patterns during the EGFR-TKI treatment., Results: After the resistance to the EGFR-TKIs, the T790M mutation was identified in 87 (48%) of 181 patients. Seventy-three (40%) patients had solitary lesion progression, and 108 (60%) had multiple lesion progression during the initial EGFR-TKI treatment. The prevalence of the T790M mutation was significantly greater in patients with solitary lesion progression than those with multiple lesion progression (58% vs. 24%; P < .0001). The overall response rate and progression-free survival on initial EGFR-TKIs were significantly better in patients who acquired T790M after failure of EGFR-TKIs than those without T790M (overall response rate, 80% vs. 60%; P = .0033 and progression-free survival, 11.4 vs. 9.3 months; P = .0050). The multivariate analysis showed that gender, initial EGFR-TKI response, and progression patterns were significantly associated with T790M mutation status., Discussion: The progression patterns during initial EGFR-TKIs and initial EGFR-TKI response are associated with the T790M mutation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Emergence of the T790M point mutation in exon 20 of epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). It remains unclear whether the efficacy of platinum-doublet chemotherapy is impacted by the presence of the T790M mutation. The aim of this study is to evaluate the efficacy of platinum-doublet chemotherapy after initial EGFR-TKI failure according to the EGFR T790M in patients with advanced EGFR-mutation-positive non-small cell lung cancer (NSCLC)., Patients and Methods: We retrospectively reviewed 50 patients with advanced NSCLC harboring EGFR mutations who underwent rebiopsy to evaluate their T790M mutation status after development of resistance to first-line EGFR-TKIs (gefitinib, erlotinib, or afatinib) and were subsequently treated with second-line platinum-based chemotherapy., Results: The median age of patients was 63 years (range, 35-77 years), and 15 (30%) patients were male. Histological examination revealed that all patients had adenocarcinoma, 39 (78%) had stage IV disease, and 11 (22%) patients had postoperative recurrence. Of all, 17 patients (34%) had the T790M mutation by rebiopsy after initial EGFR-TKI failure. The overall response rate (ORR) of platinum-doublet chemotherapy was 24% for both T790M-positive and T790M-negative patients. There was no significant difference in the progression-free survival (PFS) in T790M-positive and T790M-negative patients (median PFS, 6.0 months vs. 5.1 months; 95% confidence interval [CI], 0.1-11.9 vs. 4.4-5.8; hazard ratio [HR], 0.90 [95%CI, 0.49-1.66]; P=0.7210). None of the factors were predictive of platinum-doublet chemotherapy efficacy by the multivariate analysis., Conclusion: There were no differences in clinical outcomes of platinum-based chemotherapy according to the T790M status of NSCLC patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood. Conversely, it has been demonstrated that young age at diagnosis defines unique biology in other cancers. For this report, the effects of young age on lung adenocarcinoma are reported., Methods: The authors retrospectively screened 1746 consecutive patients who were diagnosed with stage I through IV adenocarcinoma between 2009 and 2015 and identified 81 who were aged 40 years or younger at diagnosis. The clinical and genetic characteristics of this younger population were analyzed., Results: Of the 81 younger patients identified, 36 (44%) were men, 36 (44%) were never smokers, and the median age was 36 years (range, 26-40 years). Thirty-three patients (41%) harbored anaplastic lymphoma kinase (ALK) translocations, 24 (30%) had epidermal growth factor receptor (EGFR) mutations, and 2 (2%) had v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Rare oncogenic GAs also were studied in patients who had wild-type ALK/EGFR/KRAS adenocarcinoma, including 4 patients with HER2 mutations, 2 with Ret proto-oncogene (RET) translocations, and 2 with ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) translocations. Notably, oncogenic GAs (P < .001), ALK (P < .001) and ROS1 (P = .033) translocations, and HER2 mutations (P < .001) were associated with young age, and a similar trend was observed for RET translocations (P = .108). Younger patients who had adenocarcinoma without GAs had a significantly worse prognosis compared with older patients without GAs (overall survival, 8.9 vs 16.4 months; P < .001) and patients with GAs (24.9 months; P < .001)., Conclusions: Younger patients with adenocarcinoma have a distinctly unique prevalence of oncogenic GAs. Comprehensive oncogenic GA screening is especially recommended for personalized medicine strategies in this population. Cancer 2017;123:1731-1740. © 2017 American Cancer Society., (© 2016 American Cancer Society.)

Background: The incidence, risk factors, and consequences of pneumonia after flexible bronchoscopy in patients with lung cancer have not been studied in detail., Methods: We retrospectively analyzed the data from 237 patients with lung cancer who underwent diagnostic bronchoscopy between April 2012 and July 2013 (derivation sample) and 241 patients diagnosed between August 2013 and July 2014 (validation sample) in a tertiary referral hospital in Japan. A score predictive of post-bronchoscopy pneumonia was developed in the derivation sample and tested in the validation sample., Results: Pneumonia developed after bronchoscopy in 6.3% and 4.1% of patients in the derivation and validation samples, respectively. Patients who developed post-bronchoscopy pneumonia needed to change or cancel their planned cancer therapy more frequently than those without pneumonia (56% vs. 6%, p<0.001). Age ≥70 years, current smoking, and central location of the tumor were independent predictors of pneumonia, which we added to develop our predictive score. The incidence of pneumonia associated with scores=0, 1, and ≥2 was 0, 3.7, and 13.4% respectively in the derivation sample (p=0.003), and 0, 2.9, and 9.7% respectively in the validation sample (p=0.016)., Conclusions: The incidence of post-bronchoscopy pneumonia in patients with lung cancer was not rare and associated with adverse effects on the clinical course. A simple 3-point predictive score identified patients with lung cancer at high risk of post-bronchoscopy pneumonia prior to the procedure., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation. Importantly, we discovered that YAP/TEAD activated CD44 transcription by binding to the CD44 promoter at TEAD-binding sites. On the other hand, CD44 regulated Merlin phosphorylation according to cell density and sequentially promoted YAP transcriptional co-activator, suggesting that CD44 plays two pivotal functional roles as an upstream suppressor of the Hippo pathway and one of downstream targets regulated by YAP/TEAD. Moreover, the YAP/CD44 axis conferred cancer stem cell (CSC)-like properties in MM cells leading to chemoresistance, which was blocked by statin. Together, our findings suggest that YAP mediates CD44 up-regulation at the transcriptional level, conferring CSC-like properties in MM cells, and statin represents a potential therapeutic option against MM by inactivating YAP., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancers can be effectively treated with an ALK tyrosine kinase inhibitor (TKI) such as crizotinib, but the response magnitude and duration are heterogeneous. Several ALK variants have been identified, but few studies have focused on the effects of different ALK variants on the efficacy of crizotinib., Patients and Methods: Among 55 patients treated with crizotinib as the initial ALK-TKI between January 2007 and December 2014, we identified 35 patients with tumor specimens that could be evaluated for ALK variants by reverse transcription polymerase chain reaction. We retrospectively evaluated the efficacy of crizotinib on the basis of the objective response rate and progression-free survival (PFS) according to the ALK variants., Results: The most frequent ALK variant was variant 1 in 19 patients (54%), followed by variant 2 in five patients (14%), variant 3a/3b in four patients (12%), and other variants in seven patients (20%). Objective response rate was 69% in all patients, whereas it was 74% and 63% in the variant 1 and non-variant 1 groups, respectively. The median PFS time was significantly longer in patients with variant 1 than in those with non-variant 1 (median PFS, 11.0 months [95% CI, 6.5 to 43.0 months] v 4.2 months [95% CI, 1.6 to 10.2 months], respectively; P < .05). Multivariable analysis identified two significant factors associated with PFS duration, ALK variant 1 (hazard ratio, 0.350; 95% CI, 0.128 to 0.929; P < .05) and advanced stage (hazard ratio, 4.646; 95% CI, 1.381 to 21.750; P < .05)., Conclusion: Our results indicate the better efficacy of crizotinib in patients with ALK variant 1 versus non-variant 1. The ALK variant status might affect the efficacy of ALK-TKIs., (© 2016 by American Society of Clinical Oncology.)

Background: Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor (EGFR) mutation on CRT efficacy., Methods: From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status., Results: Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR-mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6-19.0] versus 16.5 [95% CI: 11.8-19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR-mutant and wild-type patients, respectively (p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR-mutant patients (35%). However, locoregional recurrence was less common in EGFR-mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR-mutant and wild-type patients (51.1 [95% CI: 28.2-70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras-mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024)., Conclusion: Concurrent CRT resulted in shorter progression-free survival in EGFR-mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR-mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

A 64-year-old man presented with diplopia, muscle weakness, a pulmonary nodule and mediastinal widening on a chest radiograph. He was diagnosed with clinical stage IIIA (T2aN2M0) lung cancer. His neurological symptoms worsened following the initiation of thoracic radiation therapy (60 Gy) and chemotherapy. A diagnosis of myasthenia gravis (MG) was confirmed with a repetitive nerve stimulation test that showed a waning pattern, and a positive edrophonium test, although neither anti-acetylcholine receptor antibodies nor anti-muscle-specific tyrosine kinase antibodies were detected. The ptosis and limb muscle weakness improved with prednisolone and acetylcholinesterase inhibitor treatment, and a partial response of the lung cancer to chemoradiotherapy was obtained. However, the ptosis and limb muscle weakness worsened again following a recurrence of the lung cancer. The herein described case, in which lung cancer and MG occurred and recurred simultaneously, suggests that MG can develop as a paraneoplastic syndrome of lung cancer.

Background: Although prophylactic cranial irradiation (PCI) in limited-stage (LS) small cell lung cancer (SCLC) patients who are surgically resected and treated with adjuvant chemotherapy is considered to be a reasonable treatment option, the efficacy of PCI for those patients remains unclear., Methods: The records of 28 patients with SCLC undergoing curative surgery at the Aichi Cancer Center Hospital between 1995 and March 2008 were retrospectively reviewed to assess patterns of relapse and overall survival., Results: The patients were 27 men and 1 woman. Eight patients underwent induction chemotherapy. Fourteen patients (50%) had pathologic stage (p-stage) I disease, 7 patients (25%) had p-stage II, and 7 patients (25%) had p-stage III. Nineteen patients underwent adjuvant chemotherapy and one patient received adjuvant chemoradiotherapy. There were a total of 13 deaths and 8 were disease-related. Most patients developed hematogenous distant metastases before their death. The 5-year overall probability of survival was 47%. Ten (36%) of the 28 patients had a relapse. Two had a local relapse alone, one patient had combined local and distant relapses, and seven patients had distant metastases alone as their first site of failure. Four patients with p-stage II/III disease developed brain metastases with a cumulative incidence at 1 and 2 years of 25 and 36%, respectively., Conclusions: Our retrospective study suggested that PCI might have a role in surgically resected patients with p-stage II/III SCLC because of their relatively high frequency of brain metastasis.

The purpose of this study is to investigate associations between allelic variations of ABCG2 and ABCB1 with skin toxicity, diarrhea, liver injury and interstitial lung disease (ILD) in gefitinib-treated patients. A prospective clinical study of 83 Japanese patients with non-small-cell lung cancer was performed. Polymorphic loci in ABCG2 and ABCB1 were genotyped, and their effects on gefitinib toxicities were evaluated. ABCG2 34G>A was statistically associated with occurrence of skin rash; 13 (42%) of the 32 patients with at least one variant ABCG2 34G>A allele (G/A and A/A) developed grade 2 or worse skin rash, whereas only 10 (19%) of 51 patients homozygous for the reference allele (G/G) for the wild-type sequence for both alleles did so (P=0.046). There was no significant association between severe toxicities and polymorphisms of ABCG2 421C>A nor ABCB1 3435C>T. The results suggested that ABCG2 34G>A would be useful for predicting grade 2 or worse skin rash.

ASA404 (5,6-dimethylxanthenone-4-acetic acid, vadimezan), a flavone-8-acetic acid analogue, is a novel tumor-vascular disrupting agent. In this study, the safety and tolerability, pharmacokinetics and pharmacodynamics of ASA404 in combination with standard therapy of paclitaxel and carboplatin (P/C) were assessed. A total of 15 Japanese patients with stage IV advanced non-small cell lung cancer were enrolled and P/C plus ASA404 at three dose levels (600-1800 mg/m(2)) was administered every 3 weeks. Dose limiting toxicities were observed in two patients during Cycle 1 of ASA404 treatment (Grade 3 febrile neutropenia at ASA404 1200 mg/m(2) and Grade 3 QT prolongation at ASA404 1800 mg/m(2)) and the incidence of dose limiting toxicity was ≤1/3. The most frequently reported adverse events were injection site pain, peripheral sensory neuropathy, alopecia, neutropenia, nausea, anorexia and arthralgia, which were similar to those seen in previous Phase I/II studies. Pharmacokinetic analysis revealed the plasma area under the curve (AUC) of total ASA404 increased in a mostly dose-proportional manner within the dose range investigated. Administration of ASA404 raised plasma 5-hydroxyindole-3-acetic acid level dose-dependently by 116 and 204% after 1200 and 1800 mg/m(2) doses, respectively. Partial response was observed in four patients (27%), and seven patients (47%) exhibited stable disease. Overall, the safety and preliminary efficacy profiles were comparable to those seen in non-Japanese patients in previous Phase I and Phase II studies, and support the further evaluation of ASA404 (1800 mg/m(2)) in Phase III studies in combination with P/C in Japanese patients with advanced non-small cell lung cancer., (© 2011 Japanese Cancer Association.)

Purpose: RanBP2 is a small ubiquitin-like modifier ligase for DNA topoisomerase II (TopoII) and plays a role in maintaining chromosome stability by recruiting TopoII to centromeres during mitosis. Engineered-mice with low amounts of RanBP2 have been reported to form lung adenocarcinomas. Furthermore, in the murine embryonic fibroblasts, formation of chromatin bridges in anaphase, a distinctive feature of cells with impaired DNA decatenation by chemical inhibition of TopoII, has been reported. In this study, we tested whether the association between mRNA expression of the RanBP2 gene and chemosensitivity of a TopoII inhibitor, amrubicin could be seen., Methods: Using a panel of 20 lung cancer cell lines, the mRNA expression levels of the RanBP2, TopoII-alpha and TopoII-beta genes were examined by quantitative real-time reverse transcription PCR. The in vitro cytotoxicity of amrubicin was assessed using a tetrazolium-based colorimetric assay (MTT assay)., Results: Although RanBP2 mRNA expression was infrequently downregulated in human lung cancer cell lines, significantly higher RanBP2 transcripts were observed in small cell lung cancer than non-small cell lung cancer. There were no correlations between chemosensitivity of amrubicin and mRNA expression levels of the RanBP2, TopoII-alpha and TopoII-beta genes., Conclusions: Our in vitro results suggest that mRNA expressions of RanBP2 and TopoII isoforms are unlikely to be a predictive biomarker for the sensitivity to amrubicin.

Purpose: To evaluate the relationship between the epidermal growth factor receptor (EGFR) mutation status and the effectiveness of gefitinib monotherapy or chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)., Methods: We retrospectively analyzed a cohort of 100 patients with stage IIIB/IV NSCLC screened for two major EGFR mutations (exon 19 deletions and L858R mutation)., Results: Forty-six out of 48 EGFR mutation-positive patients (96%) received gefitinib, whereas only 3 out of 52 EGFR mutation-negative patients (6%) received gefitinib. Favorable objective response rates to gefitinib as first- and second-line treatment (87 and 80%, respectively) were observed in EGFR mutation-positive patients. Overall response rate to chemotherapy as first-line treatment did not differ significantly between patients with EGFR mutations and those without mutation (32 vs. 28%, respectively; P = 0.7198). As to first-line treatment, EGFR mutation-positive patients treated with gefitinib experienced significantly longer progression-free survival (PFS) than did patients who received chemotherapy (median survival, 7.8 months vs. 5.1 months, respectively; P = 0.0323). Similarly, as to second-line treatment, EGFR mutation-positive patients treated with gefitinib had significantly longer PFS than did patients who received chemotherapy (median survival, 6.5 months vs. 4.0 months, respectively; P = 0.0048). Patients with EGFR mutations survived longer than those without EGFR mutations after first-line treatment (median, 24.3 vs. 12.6 months, respectively; P = 0.0029)., Conclusion: EGFR mutation-positive patients benefit from either first- or second-line gefitinib monotherapy. Further large-scale prospective studies to confirm this finding are needed.

Gefitinib is an orally bioavailable, EGF receptor tyrosine kinase inhibitor and was the first targeted drug to be approved for non-small-cell lung cancer (NSCLC). Identification of objective tumor regressions with gefitinib in NSCLC patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of gefitinib in NSCLC. A recent large international Phase III study (IRESSA NSCLC Trial Evaluating Response and Survival Against Taxotere [INTEREST]) comparing gefitinib and docetaxel in unselected pretreated patients showed equivalent survival with better tolerability and quality of life. In addition, a Phase III study (WJTOG0203) evaluating gefitinib as sequential therapy after platinum-doublet chemotherapy showed the improved progression-free survival time. Furthermore, a large-scale randomized study (IRESSA Pan-Asia study [IPASS]) comparing gefitinib monotherapy with carboplatin/paclitaxel for previously untreated patients with adenocarcinoma who were never- or light-smokers showed an improved progression-free survival time in the gefitinib arm. A smaller Phase III study of pretreated Japanese patients (V-15-32) also demonstrated no difference in overall survival compared with docetaxel, with a statistically greater overall response rate. Somatic mutations in the EGFR gene, the target of gefitinib, were associated with dramatic and durable regressions in patients with NSCLC. Currently, investigators are trying to determine the optimal approach to select patients for treatment with gefitinib. This article aims to briefly summarize the profile of gefitinib, EGFR mutations, landmark trials with gefitinib and, also, ongoing trials that may herald an era of individualized therapy in at least some NSCLC patients.

Purpose: The vast majority of epidermal growth factor receptor (EGFR) mutations occur in lung adenocarcinoma, and even rare cases of other subtypes with this mutation, such as adenosquamous cell carcinoma, are associated with adenocarcinoma histology. According to this adenocarcinoma-specific nature of EGFR mutation, analysis of EGFR mutations with small cell lung cancers (SCLC) may provide a clue to its histogenesis., Experimental Design: The mutational status of the EGFR gene was accessed in a cohort of 122 patients with SCLC; all patients were from a single institute. When the EGFR mutated, its gene copy number was also examined., Results: EGFR mutations were detected in five SCLCs (4%). The patients were mainly in the light smoker and histologic combined subtype. All but one of the tumors harbored gene amplifications. Notably, in three tumors of the combined SCLC subtype, both components of adenocarcinoma and SCLC harbored an EGFR mutation, whereas gene amplification was detected only in the adenocarcinoma component. A partial response was achieved in a patient (with an EGFR mutation) who was treated with gefitinib., Conclusions: Although EGFR mutations are rare in SCLC, a combined subtype of SCLC with adenocarcinoma in light smokers may have a chance of harboring EGFR mutations. For patients with an EGFR mutation, EGFR tyrosine kinase inhibitor can be a treatment option. In terms of molecular pathogenesis, it is suggested that some SCLCs may have developed from pre-existing adenocarcinomas with EGFR mutations, but the development may not be simply linear, taking into consideration the discordant distribution of EGFR amplification.

Background and Objective: Expression of genes involved in DNA repair and/or DNA synthesis, including ribonucleotide reductase M1 (RRM1) and excision repair cross-complementation 1 (ERCC1) has been reported to be associated with chemosensitivity to platinum agents and gemcitabine. The aim of this study was to test whether similar associations would be seen between mRNA expression for the RRM1, ERCC1 and ERCC2 genes and in vitro chemosensitivity in lung cancer., Methods: Using a panel of 20 lung cancer cell lines, including 15 NSCLC and 5 small cell lung cancers (SCLC), the mRNA expression levels for the RRM1, ERCC1 and ERCC2 genes were examined by quantitative real-time reverse transcription PCR. The in vitro cytotoxicity of cisplatin, carboplatin and gemcitabine was assessed using a tetrazolium-based colorimetric assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) assay)., Results: Significantly, higher RRM1 mRNA expression was found in SCLC compared with NSCLC. However, there were no correlations between mRNA expression of the ERCC1, ERCC2 and RRM1 genes and chemosensitivity to cisplatin, carboplatin or gemcitabine., Conclusions: These in vitro results suggest that further studies are needed to evaluate the expression of the RRM1, ERCC1 and ERCC2 genes as predictive biomarkers for sensitivity to platinum agents and gemcitabine.

In the resected lung, additional small lesions are occasionally found incidentally, and include the full spectrum of preinvasive to invasive lesions under the current putative schema of the sequential development of lung cancer. In this study, we examined EGFR and KRAS gene mutations in 119 synchronous pulmonary lesions, including 40 precursor lesions (atypical adenomatous hyperplasia, AAH), 26 carcinomas in situ (non-mucinous bronchioloalveolar carcinoma, BAC), 14 minimally invasive adenocarcinomas, 34 overt invasive adenocarcinomas, and five of other subtypes of cancer. Although the mutually exclusive nature of KRAS and EGFR gene mutations was maintained even in preinvasive lesions, the incidences of the lesions along the putative progression schema were quite different. The KRAS gene was mutated in 33% of AAH, 12% of carcinomas in situ, 8% of minimally invasive adenocarcinomas and 0% of well-differentiated adenocarcinomas, whereas the frequencies of EGFR mutation did not fluctuate greatly, at 25%, 51%, 36%, 86% and 67%, respectively. These results are consistent with the findings of a published gene-targeted mouse model; the mice expressing oncogenic KRAS developed AAH but not invasive adenocarcinoma, whereas a spectrum of preinvasive to invasive adenocarcinomas was observed in the mice expressing mutant EGFR. Taking these factors together, it is suggested that AAH could develop by either KRAS or EGFR gene mutation, but AAH harbouring a KRAS gene mutation might not progress further to an invasive cancer., (Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Introduction: We evaluated the efficacy of gefitinib monotherapy prospectively in patients with advanced or pretreated non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations., Methods: Patients with NSCLC were examined for EGFR exon 19 deletion mutations by fragment analysis and for EGFR L858R point mutations by the Cycleave polymerase chain reaction technique. EGFR mutation-positive patients with locally advanced, metastatic, or recurrent/refractory NSCLC that was not curable with surgery or thoracic radiotherapy were candidates for gefitinib treatment administered at 250 mg/day until disease progression., Results: Mutations of the EGFR gene were detected in 27 (41%) of 66 patients. Ten had exon 19 deletion, and 17 had L858R. Twenty-one patients harboring EGFR mutations were treated with gefitinib and were considered assessable for responses and adverse events. Nineteen patients with EGFR mutations achieved objective responses (three complete responses and 16 partial responses), resulting in an overall response rate of 90.5% (95% confidence interval, 69.6%-98.8%). The median progression-free survival was 7.7 months (95% confidence interval, 6.0 mo to not reached). The median overall survival has not been reached. Common adverse events were skin toxicity, diarrhea, and elevated aminotransferases, but no pulmonary toxicity was observed., Conclusions: Detection of common EGFR mutations seems to be useful for selecting patients with NSCLC who would likely benefit from gefitinib monotherapy.

It has been demonstrated that lung cancers, specifically a subset of pulmonary adenocarcinomas, with epidermal growth factor receptor (EGFR) mutation are highly sensitive to EGFR-targeted drugs. Therefore, a rapid, sensitive assay for mutation detection using routine pathological specimens is demanded in clinical practice to predict the response. We therefore developed a new assay for detecting EGFR mutation using only a paraffin section of a small biopsy specimen. The method was very sensitive, detecting as few as 5% cancer cells in a background of normal cells, the results usually being obtained within 4 hours. Furthermore, it was accurate, as shown by the high concordance with reverse transcriptase-polymerase chain reaction-coupled direct sequencing (186 of 195, 95%). The practical application of this assay to 29 cases treated with gefitinib resulted in a high prediction rate: 10 of the 11 responders were shown to be positive for the mutation, and all patients with progressive disease were negative. In addition, a mutation at codon 790, conferring gefitinib resistance, was successfully analyzed in a similar manner. In conclusion, the assay is a rapid, sensitive method using paraffin sections of biopsy specimens without a tumor cell-enrichment procedure and is quite useful to select a treatment of choice in clinical practice.

We here describe a case of multiple pyomyositis in a 62-year-old man who had systemic chemotherapy for recurrent lung cancer. His initial symptoms consisted of fever and general fatigue, followed by progressive pain and swelling in his extremities, which mimicked deep venous thrombosis along with bacterial infection. He was admitted to the hospital for intravenous administration of antibiotics. MRI appeared very useful to find the intramuscular fluid collections with circumferential inflammatory changes, which confirmed diagnosis of the multiple pyomyositis. Surgical drainage as well as intravenous administration of antibiotics worked very well and improved clinical symptoms in a few weeks after the treatments. He could resume normal activities with minimum functional impairments in the extremities. Pyomyositis should be kept in mind as one of the adverse effects after chemotherapy for malignant tumors.

Lung cancers with neuroendocrine features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined. The basic helix-loop-helix protein, achaete-scute complex-like 1/achaete-scute homologue 1 (ASH1), is expressed in normal fetal pulmonary neuroendocrine cells and lung cancers with neuroendocrine elements and is suggested to be involved in lung carcinogenesis. In the present study, we show inhibition of ASH1 expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASH1 expression through G2-M cell cycle arrest and accumulation of sub-G1 populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASH1 expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASH1 clearly induced rescue from G2-M arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established and significantly inhibited not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASH1-RNAi adenovirus. The present study therefore suggests that ASH1 plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features.

We previously reported silencing of the TGF-beta type II receptor gene (TGFbetaRII), involving histone deacetylation, instead of DNA methylation (DNA-Me). Because different histone modifications may play crucial roles in the epigenetic alterations, we further studied links with silencing of the TGFbetaRII gene promoter in six lung cancer cell lines. ChIP assays demonstrated three chromatin patterns for this gene silencing (Pattern I: histone H3 acetylation (H3-Ac)(+/-)/histone H3 lysine 4 methylation (H3K4-Me)(+)/DNA-Me(-), Pattern II; H3-Ac(-)/H3K4-Me(+/-)/DNA-Me(-), and Pattern III; H3-Ac(-)/H3K4-Me(-)/DNA-Me(+)), indicating possible progressive alterations with H3K4-Me alteration. With exposure to a histone deacetylase inhibitor (HDAC-I), trichostatin A, cell lines with the pattern II demonstrated strong and persistent induction of TGFbetaRII expression, while those with the pattern III showed only weak or no induction. ACC-LC-91 cell line, one of the pattern II examples demonstrated strong and continuous induction of H3K4-Me similar to TGFbetaRII expression. In contrast, ACC-LC-176 with the pattern III showed only weak and transient induction of H3K4-Me, similar to TGFbetaRII expression. Treatment with 5-aza-2'-deoxycytidine (5aza-dC) in addition to HDAC-I resulted in strong and continuous induction of TGFbetaRII expression and H3K4-Me in ACC-LC-176, although 5aza-dC alone was without such effects. In ACC-LC-91, both H3-Ac and H3K4-Me were promptly and simultaneously induced by HDAC-I, and similarly inhibited by wortmannin, a PI3K family inhibitor, together with TGFbetaRII induction. These findings suggested progressive alterations of chromatin configuration including H3K4-Me alteration in TGFbetaRII gene silencing. A possible involvement of a wortmannin-sensitive kinase in histone modification was also suggested.