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Objectives: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib., Materials and Methods: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors., Results: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively., Conclusions: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Takehiro Tozuka has received honoraria from CHUGAI PHARMACEUTICAL and AstraZeneca. Rintaro Noro has received honoraria from CHUGAI PHARMACEUTICAL, AstraZeneca, Merck Pharmaceutical, Pfizer Pharmaceutical, Meijiseika Pharmaceutical, GlaxoSmithKline Pharmaceutical, Daiichi Sankyo Pharmaceutical, and has received Fund for the Promotion of Joint International Research (Fostering Joint International Research), and Grant-in-Aid for Scientific Research (C). Taiki Hakozaki has received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, and Eisai. Tomoyuki Naito has received honoraria from AstraZeneca. Yukio Hosomi has received honoraria from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, and Pfizer. Takashi Hirose has received honoraria from AstraZeneca. Tetsuya Okano has received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K., Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd, and has received from Payment for expert testimony from Pharmaceuticals and Medical Devices Agency. Masahiro Seike has received honoraria from AstraZeneca, MSD K.K, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, Amgen inc, and has received grants or contracts from any entity from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Nippon Kayaku, and Kyowa Hakko Kirin]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Previous studies have shown the potentials of anti-angiogenesis inhibitors in extensive-stage small-cell lung cancer (SCLC). This single-institutional phase 1b study aimed to determine the recommended dose of ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) in combination with irinotecan plus cisplatin for extensive-stage SCLC., Methods: Chemo-naïve patients with extensive-stage SCLC were enrolled and received ramucirumab (day 1 and 15) with irinotecan (60 mg/m 2 , day 1, 8, and 15) plus cisplatin (60 mg/m 2 , day 1) every 4 weeks for four cycles, followed by biweekly maintenance ramucirumab. The recommended ramucirumab dose (10 or 8 mg/kg) was determined using a traditional 3 + 3 design, and the number of patients treated at the recommended dose was set at 10 to evaluate drug efficacy and tolerability (UMIN000032671)., Results: The first 3 patients that received irinotecan plus cisplatin with ramucirumab 10 mg/kg did not experience dose-limiting toxicities. Thus, the recommended dose of ramucirumab was set at 10 mg/kg, and 10 patients received this dose. The objective response rate was 100% (95% CI, 69-100%), with a median progression-free survival of 7.2 months (95% CI, 5.3-9.0) and median overall survival of 22.4 months (95% CI, 12.1-not reached). Grade 3 neutropenia and hypertension were observed in 4 and 2 patients, respectively. No ramucirumab-related deaths were noted; hypertension and bleeding events were observed in 5 and 6 patients, respectively., Conclusions: This study showed the satisfactory tolerability and efficacy of ramucirumab at 10 mg/kg in combination with irinotecan plus cisplatin in chemo-naïve patients with extensive-stage SCLC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Pembrolizumab is recommended for patients with previously untreated non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥1%. The KEYNOTE-024 study described the efficacy of pembrolizumab in patients with previously untreated NSCLC who had a PD-L1 TPS of at least 50 %. However, patients with untreated brain metastasis (BM) were excluded from many clinical trials. Therefore, we assessed the efficacy of pembrolizumab against BM of NSCLC with high tumor PD-L1 expression., Materials and Methods: We retrospectively reviewed patients who received pembrolizumab as first-line treatment against NSCLC with PD-L1 TPS ≥ 50 % between March 2017 and September 2019. Treatment efficacy was compared between patients with (BM group) and without BM (non-BM group). In addition, the BM group was divided into patients who previously received treatment for BM before pembrolizumab (BM-T group) and those with no prior treatment for BM (BM-not T group)., Results: Eighty-seven patients (23 BM group and 64 non-BM group) were assessable for efficacy. No significant differences in patient characteristics were found between the BM and non-BM groups, but proportion of patients with stage IV at diagnosis was significantly higher in the BM group. Median progression-free survival (PFS) (6.5 months vs. 7.0 months) and overall survival (OS) (21.6 months vs. 24.6 months) did not significantly differ between the two groups. The response rate of BM was 70 %. The BM group was subdivided into 13 patients in the BM-T group and 10 patients in the BM-not T group. No significant differences in patient characteristics were found between the two groups, but maximum diameter of BM and proportion of patients with symptomatic BM were significantly greater in the BM-T group. PFS and OS did not significantly differ between the two groups. The median PFS of BM was 13.6 months in the BM-T group and 18.6 months in the BM-not T group., Conclusion: Pembrolizumab may be effective for BM caused by previously untreated NSCLC with high PD-L1 tumor expression., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Mutational signatures associated with tobacco smoking (mutational smoking signatures: SS) are characterized mainly by C > A mutations. The aim of this study was to characterize the association between the tumor immune microenvironment and the SS in lung adenocarcinoma., Methods: Lung adenocarcinomas surgically resected from 96 patients, for which whole exome sequencing data was available, were included in the study. We extracted the SS from whole exome sequencing data, calculated the weights of SS using deconstructSigs, and compared the clinicopathological features of SS positive (SS+) and negative (SS-) adenocarcinomas. We selected 18 tumor pairs from SS + and SS- adenocarcinomas (sex, EGFR mutation, and tumor size-matched) and examined the expression of five immune markers (CD20, CD8, FOXP3, CD204, and PD-L1) by immunohistochemistry., Results: Of 96 specimens, there were 33 (34 %) SS + adenocarcinoma tumors. The smoking index significantly correlated with the weight of the SS (R = 0.43). Between SS + and SS- tumors, there was no significant difference in clinicopathological factors excluding smoking history. Immunohistochemistry revealed that the number of FOXP3 + T cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 58 vs. 36, p < 0.01). Also, the number of CD20 + B cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 77 vs. 29, p < 0.01); however; these phenomena could not be confirmed when stratified by smoking history., Conclusion: In lung adenocarcinoma, SS is associated with an immunosuppressive tumor microenvironment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Loss of the chromatin remodeling SWItch/Sucrose Non-fermentable (SWI/SNF) complex is implicated in the pathogenesis of several types of neoplasms. The aim of this study was to examine the clinicopathological features of non-small cell lung cancer (NSCLC) with loss of expression of the SWI/SNF complex., Materials and Methods: Specimens from a total 1013 NSCLC cases used for tissue microarrays (TMAs) were immunohistochemically examined for expression of SWI/SNF complex (BAF) subunits, namely SMARCA4, SMARCA2, ARID1A, and ARID1B. We examined the clinicopathological features and PD-L1 expression status in NSCLC cases with loss of expression of one or more subunits of the SWI/SNF complex (BAF-Loss). Moreover, we compared the tumor mutation burden (TMB) between NSCLC cases with BAF-Loss and those with intact expression of the four subunits (BAF-Intact)., Results: Using TMA, BAF-Loss was observed in 5.4% of cases (SMARCA4: 2.4%, SMARCA2: 2.4%, ARID1A: 1.3%, and ARID1B: 0.3%). Concurrent loss of expression of two or more subunits of the SWI/SNF complex was detected in 0.7% of cases. BAF-Loss was significantly associated with smoking history, young age, male sex, pulmonary emphysema/bullae, large invasive tumor size, pleural invasion, vascular invasion, solid-predominant morphology, and absence of a lepidic growth component. A higher proportion of PD-L1-positive cases was observed among NSCLC patients with BAF-Loss than BAF-Intact (42% vs 26%, P < 0.01). In stage I NSCLC, SWI/SNF-Loss (n = 23) was associated with shorter overall survival (HR: 2.43; 95% CI: 1.18-5.01; P = 0.01) and recurrence-free survival (HR: 2.22; 95% CI: 1.17-4.24; P < 0.01) compared to BAF-Intact (n = 563). The degree of TMB was significantly higher among NSCLC patients with BAF-Loss (n = 3) than BAF-Intact (n = 7) (median 437 vs 113 mutations/whole-exome, P = 0.02)., Conclusion: The current results suggest that loss of SWI/SNF expression in NSCLC is associated with aggressive clinicopathological features, PD-L1-positive status and high TMB., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: This study assessed the associations between the molecular signatures and clinical information in non-small cell lung cancer (NSCLC) patients with postoperative disease-free survival (p-dfs) to identify novel prognostic factors, focusing on associations with driver gene alterations., Materials and Methods: Between February 2014 and September 2015, 242 patients with NSCLC, including 192 patients with adenocarcinoma (Ad) and 50 patients with squamous cell carcinoma (Sq), underwent surgery and were enrolled in this study. Surgically resected tissues were subjected to whole exome sequencing. Mt detected in 138 cancer-related genes were evaluated as driver mutations. A multivariate analysis using the multi-state model was used to establish the associations between co-variables and p-dfs., Results: Postoperative recurrence (p-rec) was observed in 49 (20.2%) and 19 (7.9%) patients with Ad and Sq, respectively. The median (range) follow-up period for all the censored cases was 2.5 (2.0-3.5) years. The characteristics of the patients with postoperative recurrence were as follows: median age (range), 71 (50-87) years; male, 38 (56%); smoker, 51 (75%); p-stage (I/II/III), 30 (44%)/19 (28%)/19 (28%); histological type (Ad/Sq), 49 (72%)/19 (28%); adjuvant chemotherapy (yes/no), 30 (44%)/38 (56%); and driver gene alteration (presence/absence), 65 (96%)/3 (4%). In univariate analyses, age (<70/≧70 years), smoking history (yes/no), p-stage (I, II/III), histological type (Ad/Sq), and driver mutation (presence/absence) were favorable prognostic factors (P = .017, P = .048, P = .0002, P = .006, P = .029, respectively). A multivariate analysis also revealed a significant association between the driver mutation status and p-dfs (P = .046; odds ratio [OR], 2.86; 95% confidence interval [CI], 1.02-8.08), when adjusted according to histological type (P = .10), smoking status (P = .09), gender (P = .51), age (P = .008) and p-stage (P = .00003)., Conclusion: The driver mutation status may be an independent prognostic factor of p-dfs in NSCLC., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are commonly excluded from most clinical trials because of acute exacerbation (AE) of ILD triggered by chemotherapy. Data on the efficacy and feasibility of chemotherapy are limited in this patient population. Recently, the ILD-GAP index and staging system was reported as a clinical prognostic factor associated with mortality in patients with ILD. Therefore, we evaluated the incidence of ILD-AE during the surveillance term in this study and the prognosis in patients with NSCLC and ILD using a modified ILD-GAP (ILD-NSCLC-GAP) index scoring system., Materials and Methods: The medical records of patients with NSCLC and ILD who underwent a pulmonary function test before initiation of platinum-based chemotherapy as first-line treatment at the Shizuoka Cancer Center between September 2002 and December 2014 were reviewed retrospectively. Among these patients, we compared the incidence of ILD-AE, one-year survival rate, and overall survival (OS) between the ILD-NSCLC-GAP index scores and stages., Results: Of the 78 patients included, 21 (27%; 95% confidence interval [CI], 18%-38%) had ILD-AE during the surveillance term in this study. The one-year survival and median OS rates were 49% and 11.3 months, respectively. The incidence of ILD-AE increased gradually and the one-year survival and median OS rates decreased gradually with increasing ILD-NSCLC-GAP index scores and stages., Conclusion: The ILD-NSCLC-GAP index scoring and staging system may be a useful tool to calculate a prediction of the incidence of ILD-AE and its prognosis for patients with NSCLC and ILD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Epidermal growth factor receptor (EGFR) mutation testing is a companion diagnostic to determine eligibility for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Recently, plasma-based EGFR testing by digital polymerase chain reaction (dPCR), which enables accurate quantification of target DNA, has shown promise as a minimally invasive diagnostic. Here, we aimed to evaluate the accuracy of a plasma-based EGFR mutation test developed using chip-based dPCR-based detection of 3 EGFR mutations (exon 19 deletions, L858R in exon 21, and T790M in exon 20)., Materials and Methods: Forty-nine patients with NSCLC harboring EGFR-activating mutations were enrolled, and circulating free DNAs (cfDNAs) were extracted from the plasma of 21 and 28 patients before treatment and after progression following EGFR-TKI treatment, respectively., Results: Using reference genomic DNA containing each mutation, the detection limit of each assay was determined to be 0.1%. The sensitivity and specificity of detecting exon 19 deletions and L858R mutations, calculated by comparing the mutation status in the corresponding tumors, were 70.6% and 93.3%, and 66.7% and 100%, respectively, showing similar results compared with previous studies. T790M was detected in 43% of 28 cfDNAs after progression with EGFR-TKI treatment, but in no cfDNAs before the start of the treatment., Conclusion: This chip-based dPCR assay can facilitate detection of EGFR mutations in cfDNA as a minimally invasive method in clinical settings., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A 57-year-old male current smoker was diagnosed with an aggressive variant of ALK-rearranged inflammatory myofibroblastic tumor (IMT) arising in the pleural cavity. First line treatment with ASP3026 was initiated at a dose of 125mg once daily. A follow-up CT scan revealed drastic regression of the pleural lesion. After disease progression with ASP3026 treatment, LDK378 (ceritinib) was initiated at a dose of 750mg once daily. A follow-up CT scan revealed a second drastic regression of the pleural lesion. Furthermore, it is noteworthy that this case represents the use of serum hyaluronan levels to assist in monitoring of treatment efficacy in an IMT. Herein, we present the first case of a patient with a highly aggressive ALK-rearranged IMT arising in the pleural cavity, who showed both initial and subsequent drastic response to two ALK inhibitors while being monitored for serum hyaluronan., (Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC., Patients and Methods: Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40-60 mg) and leucovorin (25mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety., Results: Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths., Conclusions: S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood., Patients and Methods: Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 and amplifications in EGFR, MET, PIK3CA, FGFR1, and FGFR2. In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes., Results: Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc.) by deep sequencing., Conclusions: Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Advances in the molecular profiling of lung adenocarcinoma over the past decade have led to a paradigm shift in its diagnosis and treatment. However, there are very few reports on the molecular profiles of small cell lung cancers (SCLCs). We therefore conducted the present Shizuoka Lung Cancer Mutation Study to analyze genomic aberrations in patients with thoracic malignancies., Materials and Methods: We collected samples of SCLC from a biobank system and analyzed their molecular profiles. We assessed 23 mutations in nine genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2) using pyrosequencing plus capillary electrophoresis. We also amplified EGFR, MET, PIK3CA, FGFR1, and FGFR2 using quantitative real-time polymerase chain reaction (PCR) and the fusion genes ALK, ROS1, and RET using reverse transcription PCR., Results: Between July 2011 and January 2013, 60 SCLC patients were enrolled in the study. Samples included eight surgically resected snap-frozen samples, 50 formalin-fixed paraffin-embedded samples, and seven pleural effusion samples. We detected 13 genomic aberrations in nine cases (15%), including an EGFR mutation (n=1, G719A), a KRAS mutation (n=1, G12D), PIK3CA mutations (n=3, E542K, E545K, E545Q), an AKT1 mutation (n=1, E17K), a MET amplification (n=1), and PIK3CA amplifications (n=6). EGFR and KRAS mutations were found in patients with combined SCLC and adenocarcinoma. No significant differences were detected in the characteristics of patients with and without genomic aberrations. However, serum neuron-specific enolase and progastrin-releasing peptide levels were significantly higher in patients without genomic aberrations than in those with aberrations (p=0.01 and 0.04, respectively)., Conclusion: Genomic aberrations were found in 15% SCLC patients, with PIK3CA amplifications most frequently observed. To further our understanding of the molecular profiles of SCLC, comprehensive mutational analyses should be conducted using massive parallel sequencing., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: To investigate whether decrease in the serum levels of pro-gastrin releasing peptide (ProGRP) and neuron-specific enolase (NSE) were correlated with the radiological response in patients with small-cell lung cancer (SCLC)., Methods: Of the 196 patients, we retrospectively reviewed 118 patients elevated baseline levels of ProGRP and NSE prior to the initial therapy (IT) who survived for more than 1 month. The radiological response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)., Results: Decrease in the serum ProGRP was strongly correlated with the decrease of the sum of the tumor diameters (SOD) before the third course (ρ=0.50) and after the fourth course (ρ=0.42) of IT. Decrease in the serum NSE was weakly correlated with the decrease of the SOD after the fourth course (ρ=0.27), but not before the third courses (ρ=0.22). In the receiver operating characteristic (ROC) curves predicting 1-year survivors, the area under the curve (AUC) for percent changes in serum ProGRP before the third course were significantly larger than those for NSE (0.714 vs. 0.527, p=0.004)., Conclusions: Percent changes in serum ProGRP showed better correlation to SOD and prognostic impact than that of NSE., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: It remains unclear whether thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) expressions are associated with the pathogenesis of thymic epithelial tumors. Therefore, we investigated the expression of TS, OPRT and DPD in thymic epithelial tumors., Patients and Methods: Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for TS, OPRT, DPD, microvessel density (MVD) determined by CD34, and p53. We also conducted in vitro study of TS, OPRT and DPD expression using thymic carcinoma, thymic tumor and thymic fibroblast cell lines., Results: TS, OPRT and DPD were expressed in 61%, 48% and 41%, respectively. High grade malignancy is significantly associated with higher expression of TS, OPRT and DPD in thymic epithelial tumors. These biomarkers were closely associated with p53 and MVD, and the overexpression of TS and DPD was a prognostic marker for predicting poor outcome in univariate analysis. Our in vitro study showed that marked overexpression of TS and OPRT was observed in thymic carcinoma cells, but not in thymic tumor cells, or thymic fibroblast cells., Conclusions: The expression of TS, OPRT and DPD was closely related to the grade of malignancy in thymic epithelial tumors. A positive expression of TS, DPD and OPRT might be an important factor in predicting the effectiveness of 5-FU based chemotherapy in this disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Based on previous reports, patients who experience isolated central nervous system (CNS) failure may not have systemic acquired resistance to EGFR-TKI therapy. However, because there are few articles that have reported on the clinical efficacy of continuous EGFR-TKI administration following progressive disease (PD) in isolated CNS metastasis, we retrospectively investigated the possibility of using the treatment., Patients and Methods: From July 2002 to December 2009, 17 non-small cell lung cancer patients showed isolated CNS failure after clinical benefit (partial response or stable disease longer than 6 months) from EGFR-TKIs and continuously received EGFR-TKIs following radiotherapy (whole brain radiotherapy or stereotactic radiotherapy) to the CNS metastases., Results: The response rate and the disease control rate of CNS lesions were 41% and 76%, respectively. The median progression free survival, extracranial progression free survival and the median overall survival time were 80 days, 171 days and 403 days, respectively. The toxicities which were observed during the first EGFR-TKI treatments were sustained, but did not worsen during this study period. The acute toxicities caused by radiotherapy to the CNS were controllable. There were no remarkable late toxicities related to the treatment., Conclusions: Continuous administration of EGFR-TKI following radiotherapy after PD in isolated CNS metastasis appears to be a valid treatment option., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Because of the number of elderly patients with NSCLC is increasing, it is becoming a public health problem world wide. In elderly patients with advanced NSCLC, mono-chemotherapy is the standard treatments. But little information is available for patients aged ≥80 regarding the management of advanced NSCLC., Purpose: The purpose of the present study is to evaluate the efficacy and safety of chemotherapy for patients aged ≥80., Methods: 110 patients aged ≥75 with advanced NSCLC were retrospectively reviewed. Data was collected from the electronic medical records of our hospital from January 2005 to August 2008. The patient population was divided into three age groups: patients aged ≥80 who received chemotherapy (group A), patients aged 75-79 who received chemotherapy (group B), and patients aged ≥75 who received only best supportive care (group C). Date cut-off of this study was on 20th June, 2009. We evaluated and compared the survival and the toxicity between three groups., Results: Among 110 patients, there were 21 patients in group A, 55 patients in group B, 34 patients in group C. Among group C, there were 8 patients aged 75-79 and the main reasons for BSC were poor PS in 7 patients, and there were 26 patients aged ≥80 and the main reason for BSC were age itself in 17 patients. Response rate and disease control rate were similar in group A and group B (16.4% vs. 23.8%, and 57.1% vs. 49.1%). MST was 237 days in group A with PS 0-2 and was 232 days in group C with PS 0-2. Median PFS and MST were 86 and 237 days in group A with PS 0-2 and was 107 and 263 days in group B. Toxicity profile of group A seems to be acceptable: over grade 3 leucopenia was observed 33%; over grade 3 neutropenia was 52%; but no febrile neutropenia; over grade 3 non-hemotological toxicity was observed 14%., Conclusion: There was no obvious difference between patients aged ≥80 and 75-79 in terms of safety and efficacy of chemotherapy. Patients aged ≥80 with advanced NSCLC who have good PS might be good candidates for the chemotherapy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary pleomorphic carcinoma is a rare epithelial tumor, and little is also known about the information on the usefulness of 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) positron emission tomography (PET). Therefore, we conducted the study including the underlying biologic analysis of ¹⁸F-FDG uptake., Methods: Fifteen patients with pulmonary pleomorphic carcinoma who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); cell proliferation (Ki-67 labeling index); vascular endothelial growth factor (VEGF); microvessels (CD34); cell cycle control marker (p53); and apoptosis marker (bcl-2). These parameters were correlated with a control group of patients with other non-small cell lung cancer (NSCLC) (n=33)., Results: The maximal standardized uptake value (SUV(max)) of the primary tumors in 15 patients ranged from 6.1 to 26.8 (median 19.3). There were positive correlation between ¹⁸F-FDG uptake and Glut1 (p=0.0016), Glut3 (p=0.0080), VEGF (p=0.0048), and microvessel density (MVD) (p=0.0005). HIF-1α, p53 and bcl-2 showed no positive correlation with ¹⁸F-FDG uptake. ¹⁸F-FDG uptake, Glut1, Glut3, HIF-1α, VEGF and Ki-67 were significantly higher in patients with pulmonary pleomorphic carcinoma than those with other NSCLC., Conclusion: ¹⁸F-FDG uptake in pulmonary pleomorphic carcinoma is closely associated with the presence of glucose metabolism (Glut1 and Glut3) and angiogenesis (VEGF and MVD). The relationship between ¹⁸F-FDG uptake and these biomarkers may lead to a more rational use of PET scan in pulmonary pleomorphic carcinoma., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) shares several features with small cell lung carcinoma (SCLC). Most histologic diagnoses of LCNEC are currently obtained by surgical specimens. While the diagnosis of LCNEC by biopsy specimens is challenging, a definitive diagnosis of this highly malignant tumor is critical in unresectable cases to determine the optimal therapeutic strategy. The objective of this study was to assess the efficacy of chemotherapy for unresectable high-grade non-small cell neuroendocrine carcinoma (HNSCNEC) called by us, which likely includes most LCNECs except for combined types, and to compare the efficacy of chemotherapy for HNSCNEC, with that for extended disease SCLC (ED-SCLC)., Methods: Between September 2002 and October 2007, we reviewed 14 patients with HNSCNEC, which was defined using biopsy specimens according to histological and immunohistological criteria proposed by us. We simultaneously evaluated the clinical response to the chemotherapy and survival time of the 14 HNSCNEC and 77 ED-SCLC patients., Results: The chemotherapy regimens in the 14 patients with unresectable HNSCNEC were platinum-based combination regimens or irinotecan or vinorelbine or docetaxel alone. The chemotherapy regimens in the 77 patients with ED-SCLC were platinum-based combination regimens. We assessed an objective response rate, a one-year survival rate, and median survival time as 50% (7/14), 34% and 10 months, respectively, in the 14 HNSCNEC patients, and as 53% (41/77), 48% and 12.3 months, respectively, in the 77 ED-SCLC patients., Conclusion: The clinical efficacy of chemotherapy for unresectable HNSCNECs, including most LCNECs, is comparable to that for ED-SCLC., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The use of erlotinib after gefitinib failure in patients with non-small cell lung cancer (NSCLC) is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of erlotinib after failure of gefitinib., Methods: We searched published reports including erlotinib and gefitinib. Eleven reports were identified (published between November 2004 and December 2008). Advanced NSCLC who documented progressive disease (PD) for gefitinib 250 mg/day, received erlotinib 150 mg once daily., Results: A total of 106 patients were pooled from these studies. Asian was observed in 70.8%, women in 72.6%, adenocarcinoma in 85.1%, never smoker in 75.3%. In erlotinib therapy, there was observed in 9.9% in partial response (PR), 18.9% in stable disease (SD) and 70.8% in PD. Disease control (DC) rate for gefitinib and erlotinib was 71.7% and 29.2%, respectively. No significant difference of disease control rate (37.5% vs 21.7%, p=0.1503) and response rate (6.3% vs 8.7%, p=1.000) was observed between patients with EGFR mutations and those with wild type EGFR. The significantly different response on erlotinib therapy was observed in patients who had shown SD for gefitinib therapy (p=0.0095) and those who had a PFS of more than 6 months during gefitinib treatment (p=0.0261). The common toxicities were skin rash and diarrhea., Conclusion: Erlotinib may produce clinical benefits in patients who had shown long SD on prior gefitinib therapy. Moreover, EGFR mutations were not positive predictors for erlotinib response after gefitinib failure., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Thymic carcinoma is a very rarely encountered neoplasm and no optimal chemotherapeutic regimen has been established yet., Methods: The records of previously untreated thymic carcinoma patients with unresectable disease who had been treated with paclitaxel and carboplatin as first-line chemotherapy between 2003 and 2008 were reviewed, retrospectively. Paclitaxel was administered at the dose of 200mg/m(2) and carboplatin at an AUC of 6 on day 1, with the treatment cycle repeated every 3 weeks., Results: Eleven patients were registered, and a total of 45 cycles of carboplatin/paclitaxel were administered (median cycles per patient, 4; range, 2-6). Although the principal toxicity of this regimen was neutropenia, with grade 3 or more severe neutropenia being observed in nine patients (82%), there were no cases of febrile neutropenia. There were also no cases of grade 3 or more severe peripheral sensory neuropathy. Thus, the toxicity profile of the treatment regimen was acceptable. The overall response rate was 36%, and the median survival time and median progression-free survival were 22.7 months and 7.9 months, respectively., Conclusion: Combined paclitaxel+carboplatin therapy exhibits activity and acceptable toxicity in the first-line setting in patients with unresectable thymic carcinoma., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of this study is to evaluate the rate of long-term survival of more than 5 years in advanced non-small cell lung cancer (NSCLC)., Methods: One-hundred and twenty-four patients with advanced NSCLC treated with chemotherapy from September 2002 to October 2003 were reviewed., Results: Ten (8%) patients survived for more than 5 years. The median survival time (MST) for the 10 patients was 61.5 months, ranging from 60.1 to 81.0 months. All of the 10 patients had performance status (PS) 0 or 1 and adenocarcinoma. As the initial treatment, 9 patients were treated with a platinum-containing chemotherapy [median progressive free survival (PFS), 10.7 months] and 8 patients received gefitinib as the second or third line chemotherapy (median PFS, 28.7 months). Nine patients received cytotoxic agents after first line chemotherapy (median duration of the chemotherapy, 22.4 months). A mean regimen of chemotherapy was three (range, 1-8). Re-challenge of gefitinib was performed in 2 patients, and surgical resection of solitary brain metastasis was performed as the initial treatment in 2 patients., Conclusion: Our results suggest that good performance status, adenocarcinoma and EGFR-TKI therapy play an important role in the long-term survivors of more than 5 years.