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Background: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood.Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients' backgrounds.Results: The Kaplan-Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome.Conclusions: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes. [ABSTRACT FROM AUTHOR]

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF‐associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF‐associated non‐small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next‐generation sequencing with a panel that targets 161 cancer‐related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS‐RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF‐associated lung cancer, and the RAS‐RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF‐associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF. [ABSTRACT FROM AUTHOR]

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Aim Hypoxia-inducible factor (HIF) contributes to the adaptation of tumor cells to hypoxic conditions, so genetic polymorphisms involved in this pathway may affect cellular response to hypoxia and be associated with cancer risk. Thus, we examined the association between the lung cancer risk and genetic polymorphisms involved in the HIF pathway. Methods This case-control study consists of 462 lung cancer cases and 379 controls from Japan. We examined the effect of HIF1A rs11549467, HIF1A rs11549465, HIF1A rs2057482, HIF2A rs13419896 and vascular endothelial growth factor A ( VEGFA) rs833061 on the risk of lung cancer using TaqMan real-time PCR assay. Logistic regression was used to estimate the odds ratio (OR) and its 95% confidence interval (CI) of lung cancer risk. The multiplicative and additive interactions with cigarette smoking were also examined. Results The AA genotype of HIF2A rs13419896 (OR = 0.54, 95% CI = 0.30-0.99) and the CC genotype of VEGFA rs833061 (OR = 0.42, 95% CI = 0.24-0.75) were significantly associated with a decreased risk of lung cancer after adjustment of potential covariates. Additive interactions between these two polymorphisms and cigarette smoking were also significant. Conclusion HIF2A rs13419896 and VEGFA rs833061 were significantly related to lung cancer risk, with possible interaction between polymorphisms and cigarette smoking. Further studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background Various polymorphisms have been detected in the UDP-glucuronosyltransferase 1 A ( UGT1A) gene, and UGT1A1 *28 and UGT1A1 *6 have important effects on the pharmacokinetics of irinotecan and the risk of severe toxicities during irinotecan therapy. This study was conducted to determine the maximum tolerated dose ( MTD) of irinotecan chemotherapy according to the UGT1A1 genotype in previously treated lung cancer patients with the UGT1A1 *28 or UGT1A1 *6 polymorphism. Methods The eligibility criteria were as follows: lung cancer patients that had previously been treated with anticancer agents other than irinotecan, possessed the UGT1A1 *28 or UGT1A1 *6 polymorphism (group A included *28/*28, *6/*6, and *28/*6, and group B included *28 /− and *6 /−), were aged ≤75 years old, had a performance score of 0-1, and exhibited adequate bone marrow function. The patients were scheduled to receive irinotecan on days 1, 8, 15, 22, 29, and 36. Results Four patients were enrolled in this trial. Two patients were determined to be ineligible. The remaining two patients, who belonged to group B, received an initial irinotecan dose of 60 mg/m2, but did not complete the planned treatment because of diarrhea and leukopenia. Thus, in group B patients, 60 mg/m2 was considered to be the MTD of irinotecan. The study was terminated in group A because of poor case recruitment. Conclusions The MTD of irinotecan for previously treated lung cancer patients that are heterozygous for the UGT1A1 * 28 or UGT1A1 * 6 gene polymorphism is 60 mg/m2. [ABSTRACT FROM AUTHOR]

Background: Uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study. Methods: Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ≥ 80, combination ≥ 50, radiation with single ≥ 50, or radiation with combination ≥ 40 mg/m²; age ≥ 20; and Eastern Cooperative Oncology Group performance score (PS) 0-2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible. Results: UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/-, *6/-, -/- observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively). Conclusion: Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed. [ABSTRACT FROM AUTHOR]

Background: Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients.Methods: West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS).Results: One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded.Conclusions: Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. [ABSTRACT FROM AUTHOR]

Background: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3-4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m2. The incidence of grade 3-4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01-134.15; p = 0.049), higher AMR doses (40 mg/m2 or more) (OR = 5.98; 95% CI 1.77-23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04-4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to identify the modern surgical results of pathologic T3 lung cancer and to examine the heterogeneity of this group from the nationwide database. Methods: The registered data of 11,663 cases from the Japanese Joint Committee of Lung Cancer Registry conducted in 2010 were analyzed, which included patients with resected lung cancer during 2004. Of these patients, 531 with invasive T3 lung cancer constituted the study population. Results: Of the 531 patients, 466 were men and 65 women, with a mean age of 65.9 years. The 3- and 5-year survival rates and median survival time was 54.0%, 44.9%, and 46 months, respectively. A multivariate analysis showed incomplete resection, N2 disease, and no adjuvant therapy were independent prognostic factors of a poor outcome. However, pneumonectomy and N1 disease were not significantly associated with the prognosis. In terms of each involved structure, we detected 407 patients with T3 tumors involving the chest wall, 56 involving the mediastinal pleura, 45 with involvement of the bronchus within 2 cm of the carina, 31 involving the diaphragm, and 20 involving the pericardium. The corresponding 5-year survival rates were 43.2%, 40.1%, 55.2%, 42.6%, and 54.2%. Conclusions: The modern 5-year survival rates of patients with T3 lung cancer involving any neighboring structures have been 40% to 55%, and the current pT3 group was proved to have a relatively uniform prognosis. [ABSTRACT FROM AUTHOR]

Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. In this study, we tried to assess reported studies of association between polymorphism of human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys and lung cancer. We conducted MEDLINE, Current Contents and Web of Science searches using "hOGG1", "lung cancer" and "polymorphism" as keywords to search for papers published (from January 1995 through August 2010). Data were combined using both a fixed effects (the inverse variance-weighted method) and a random effects (DerSimonian and Laird method) models. The Cochran Q test was used for the assessment of heterogeneity. Publication bias was assessed by both Begg's and Egger's tests. We identified 20 case-control studies in 21 different ethnic populations. As two studies were not in the Hardy-Weinberg equilibrium, 18 case-control studies in 19 different ethnic populations (7,792 cases and 9,358 controls) were included in our meta-analysis. Summary frequencies of the Cys allele among Caucasians and Asians based on the random effects model were 20.9% (95% confidence interval (CI) = 18.9-22.9) and 46.1% (95% CI = 40.2-52.0), respectively. The distribution of the Cys allele was significantly different between Asians and Caucasians (P < 0.001). The Cys/Cys genotype was significantly associated with lung cancer risk in Asian populations (odds ratio = 1.27, 95% CI = 1.09-1.48) but not in Caucasian populations. This ethnic difference in lung cancer risk may be due to environmental factors such as cigarette smoking and dietary factors. Although the summary risk for developing lung cancer may not be large, lung cancer is such a common malignancy that even a small increase in risk can translate to a large number of excess lung cancer cases. As lung cancer is a multifactorial disease, further investigations of the gene-gene and gene-environment interactions on the hOGG1 polymorphism-associated lung cancer risk may help to better understand of the molecular pathogenesis of human lung cancer. [ABSTRACT FROM AUTHOR]

Background and objective: Although the association of hypertrophic pulmonary osteoarthropathy (HPO) with lung cancer was investigated in the 1960s, the recent incidence of clinically apparent HPO is not known. Data from a large series of patients with lung cancer were analysed, in order to assess the incidence of possible HPO, based on bone scintigraphy, as well as the incidence of clinically confirmed HPO. The clinical features of confirmed HPO were also evaluated. Methods: The medical records of patients admitted with lung cancer between January 1986 and August 2004 were reviewed. Bone scintigraphy showing symmetrical, abnormally high uptake in joints and/or long bones was considered to be suggestive of HPO. Patients who also had finger clubbing and joint pain were considered to have a confirmed diagnosis of HPO. Clinical histories and hormone levels were then investigated in these patients, to identify possible causal factors. Results: Among the 1226 lung cancer patients, 55 (4.5%) demonstrated abnormally high uptake on bone scintigraphy, suggesting possible HPO. Ten (0.8%) patients had clubbed fingers and joint pain and were eventually confirmed as having HPO. Serum hormone concentrations were abnormally high in the patients with confirmed HPO. Conclusions: This retrospective study indicated that 4.5% of lung cancer patients showed findings suggestive of HPO, a frequency similar to that reported previously. However, patients with HPO rarely showed the complete triad of signs. Although increased hormone concentrations may have caused the HPO, further investigation is required to confirm this. [ABSTRACT FROM AUTHOR]

Background and objective: A multi-institutional phase II trial combining uracil-tegafur (UFT) and cisplatin (CDDP) was conducted in patients with previously untreated advanced non-small cell lung cancer (NSCLC) to evaluate the safety and efficacy of this combined treatment regimen. Methods: The entry criteria for this study were previously untreated NSCLC, measurable disease, age <80 years, performance status <2, and adequate haematological, hepatic and renal function. Patients were treated with 400 mg/m2 oral UFT from day 1 to day 14 and 80 mg/m2 cisplatin on day 15. The treatment course was repeated every 3 weeks. Results: Of the 68 patients enrolled, 64 (27 with stage IIIB and 37 with stage IV disease) were eligible for treatment. Twenty of the 64 patients responded to the chemotherapy (response rate 31.3%; 95% CI 21.2–43.4%). The median survival time was 8.6 months, and the 1-year survival was 41.5%. Haematological toxicity ≥WHO grade 3 was seen in 3 (4.7%) patients. For non-haematological toxicities, anorexia with WHO grade 3 was seen in 8 (12.5%) patients, nausea and vomiting with WHO grade 3 in 4 (6.3%), diarrhoea with WHO grade 4 in 1 (1.6%), and liver dysfunction with WHO grade 4 in 1 (1.6%) patient. Conclusions: The combination of oral UFT plus cisplatin was found to be a safe and active treatment against advanced NSCLC. The observed low toxicity of this combined regimen may warrant its application to the treatment of elderly patients. [ABSTRACT FROM AUTHOR]

Many studies have investigated lung cancer susceptibility based on the presence of low-penetrance, high-frequency single nucleotide polymorphisms. Identifying such susceptibility polymorphisms may lead to the development of tests that allow a more focused follow-up of a high-risk group. Genetic polymorphisms of xenobiotic metabolism, DNA repair, cell-cycle control, immunity, addiction and nutritional status have been described as promising candidates. Genetic polymorphisms in both metabolic activation (Phase I) and detoxification (Phase II) enzymes influence DNA damage. The DNA repair system is a critical cellular response that counteracts the carcinogenic effects of DNA. Thus, genetically determined susceptibility to carcinogens depends on the balance between metabolic and DNA repair enzymes. This review evaluates whether or not a specific polymorphism or a combination of such polymorphisms can effectively predict high-risk groups. [ABSTRACT FROM AUTHOR]

Purpose: This multicenter phase II study was conducted to investigate the efficacy and safety of carboplatin in combination with paclitaxel administered according to a biweekly schedule as a first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). Patients and methods: Eligibility criteria included histologically or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable or evaluable disease. Paclitaxel (140 mg/m2) was administered intravenously on day 1, in combination with carboplatin at an area under the concentration time curve (AUC) of 3, every 2 weeks. Results: Seventy-four patients (45 men) with a median age of 62 years (range 40–74) and a median ECOG performance status of 1 (range 0–2) were enrolled. The response rate was 35.1% [95% confidence interval (CI): 24.4–47.1%], with 26 partial responses. The median survival was 357 days, and the median time to progression was 218 days. Toxicity was generally mild; National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grades 3 and 4 neutropenia was observeded in 50.0% of the patients, and grades 3 and 4 nausea/vomiting in 4.1%. Conclusions: Biweekly carboplatin combined with paclitaxel demonstrated anti-tumor activity in advanced NSCLC, with response and survival rates similar to those of carboplatin combined with paclitaxel administered every 3 weeks but with a more favorable toxicity profile, and the present data indicate that the regimen is suitable for use on an outpatient basis. [ABSTRACT FROM AUTHOR]

Lung specimens were collected from 161 non-smoking male patients with carcinoma to determine the deposition of carbon particles and oxidative damage in lung tissues. Morphologically, carbon particles deposited in human lungs with carcinoma were similar to those of diesel exhaust like particles, and mass of particles showed a significant increase with the increasing age of the patients. An increasing age of patient with carcinomas was also associated with 8-oxodeoxy-guanosine (8-oxo-dG) formation, which was analyzed using the HPLC-electrochemical detector method. In addition, it was found that 8-oxo-dG increased in cancerous tissues rather than in non-cancerous ones. To determine whether particles in lung tissues were associated with 8-oxo-dG formation, carbon particles deposited in lung tissues were partially purified by cycling of alkali fusion with 1M KOH; mutagenic chemicals in particles were extracted and excluded by removal with an equal volume of benzene/methanol and dichloromethane. It was also found that 8-oxo-dG was formed by non-mutagenic particles, and enhanced in the in vivo test using mouse rather than in the in vitro using RAW 254.7 tissue cultured cells. The 8-oxo-dG formation in vivo was due to the fact that hydroxyl radicals might be involved with phagocytosis of non-mutagenic particles in inflammatory cells, and the mutation was induced by hydroxylation of guanine residue on DNA. These results were also demonstrated by the occurrence of alveolar macrophages and neutrophils after intratracheal instillation of particles. These observations suggest that small particles from lung cancer patients further promote oxidative damage when used to treat the mouse lung. Especially, particles from which organic chemicals were removed were highly reactive to oxidative damage and formed 8-oxo-dG. [ABSTRACT FROM AUTHOR]

Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.Cancer Gene Therapy (2005) 12, 737–748. doi:10.1038/sj.cgt.7700838; published online 29 April 2005 [ABSTRACT FROM AUTHOR]

The aim of the present study is to identify the optimal anticancer agents for use in combination with gene therapy using wild-type (wt) p53 gene transfer. We used adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects of wt p53 gene transfer in combination with 12 anticancer agents on a human pulmonary squamous cell carcinoma cell line, NCI-H157, and a human pulmonary large cell carcinoma cell line, NCI-H1299. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions; after a 5-day incubation period, the anticancer activity was then evaluated by a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Each 50% inhibitory concentration was calculated based on the dose-response curves. The agents showing a high degree of effectiveness on NCI-H157 cells were cisplatin (CDDP), 5-fluorouracil (5-FU), bleomycin, and 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan (CPT-11); conversely, cyclophosphamide and paclitaxel showed a low degree of effectiveness. Based on these data, an isobologram was performed to investigate the interaction between AdCAp53 and some anticancer agents. A supra-additive effect was thus observed for 5-FU and SN-38 on NCI-H157 cells. An additive effect was also observed for CDDP, paclitaxel, bleomycin, and cyclophosphamide on NCI-H157 cells. CDDP, paclitaxel, 5-FU, and SN-38 had an additive effect on NCI-H1299 cells. No drug showed any subadditive or protective effects. These findings suggest that CPT-11 and 5-FU may thus be useful as possible anticancer agents for use in a combination therapy regimen using wt p53 gene transfer. CDDP and CPT-11 had a significant antitumoral effect on H157 cell xenografts of nude mice in vivo. These results indicate that CPT-11 as well as CDDP would be a candidate for the combination of chemotherapy and gene therapy for non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug. [ABSTRACT FROM AUTHOR]

Crizotinib is the first clinically available tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and is associated with the development of complex renal cysts. We now describe a 39-year-old woman who developed infected complex renal cysts during crizotinib treatment. After 10 months of such treatment, she presented with a high fever and low back pain. Computed tomography findings were consistent with complex renal cysts and perilesional inflammation. Interventions including cyst drainage and antibiotic administration contributed to diagnosis and management of the infected cysts. [ABSTRACT FROM AUTHOR]

To determine the predictive value of the expression of p53 and glutathione S-transferase-π (GST-π) with respect to chemotherapy response, immunostaining was performed on transbronchial biopsy specimens from previously untreated patients with non-small cell lung cancer. Of the 54 patients, 34 patients (63%) and 37 patients (69%) were positive for p53 and GST-π, respectively. The response rates in the p53-positive and p53-negative group were 15 and 45%, and those in GST-π-positive and GST-π-negative groups were 16 and 47%, respectively. A multiple logistic regression analysis revealed that positive immunostaining for GST-π was a significant risk factor for clinical chemotherapy resistance. The combination of these two markers was the most important independent factor in predicting a response to chemotherapy in multiple logistic regression analysis. Immunohistochemical expression of p53 and GST-π was independently related to clinical chemoresistance in patients with non-small cell lung cancer. Combined use of these two biomarkers may be a useful predictor of clinical chemoresistance.Copyright © 1999 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Lessons Learned: Updated survival data for a phase I/II study of carboplatin plus nab‐paclitaxel and concurrent radiotherapy were collected.In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2‐year overall survival rate was 66.1% (95% confidence interval, 52.1%–76.8%).Results reveal encouraging feasibility and activity for this regimen. Background: We report the updated survival data for a phase I/II study of carboplatin plus nab‐paclitaxel (nab‐P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non‐small cell lung cancer (NSCLC). Methods: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab‐paclitaxel at 50 mg/m2 for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3‐week cycles of nab‐paclitaxel (100 mg/m2 on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression‐free survival (PFS). Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow‐up time of 26.0 months (range, 4.0–49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2‐year OS rate was 66.1% (95% CI, 52.1%–76.8%). The median PFS was 11.8 months (95% CI, 8.2–21.0 months), and the 2‐year PFS rate was 35.9% (95% CI, 23.1%–48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long‐term follow‐up of toxicities did not identify new safety signals, and no treatment‐related deaths occurred during the study period. Conclusion: Concurrent chemoradiation with nab‐P/C was safe and provided a long‐term survival benefit for patients with locally advanced NSCLC. [ABSTRACT FROM AUTHOR]

Lessons Learned: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement‐positive non‐small cell lung cancer and a poor performance status.Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. Background: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement‐positive non‐small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long‐term survival benefit in such patients. Methods: Eighteen patients with ALK rearrangement‐positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. Results: The median follow‐up time for all patients was 27.3 months. The median progression‐free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1–30.8 months), and the median survival time (MST) and the 3‐year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8–64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p =.886). Conclusion: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement‐positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated. [ABSTRACT FROM AUTHOR]

Lessons Learned: The biweekly GEM plus CBDCA dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.The biweekly GEM plus CBDCA regimen could be considered an alternative to the 3‐week regimen in NSCLC. Background: The gemcitabine (GEM)‐carboplatin (CBDCA) combination is widely used for non‐small cell lung cancer (NSCLC) and has some efficacy in elderly patients; however, a high incidence of thrombocytopenia is observed, and the optimal dosage and administration schedules are unknown. This multicenter phase II trial evaluated the efficacy and tolerability of GEM‐CBDCA for elderly patients with chemotherapy‐naive NSCLC. Methods: Patients with chemotherapy‐naive performance status 0–1 and with stage IIIB/IV NSCLC were administered chemotherapy biweekly (GEM 1,000 mg/m2 with CBDCA area under the blood concentration‐time curve (AUC) 3 on days 1 and 15 every 4 weeks). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety. Results: Forty‐eight patients were enrolled. Median age was 76 years (range, 70–83); 35 patients were men (73%), and 27 patients had adenocarcinoma (56%). The ORR was 29.2% (95% confidence interval [CI], 17.0–44.1). The median PFS, median OS, and 1‐year survival was 5.9 months (95% CI, 4.1–6.6), 13.3 months (95% CI, 8.3–23.5), and 58%, respectively. Grade ≥3 hematological toxicities included neutropenia (29.2%), thrombocytopenia (4.2%), and anemia (20.8%). The incidence of grade ≥3 nonhematological toxicities was <5%. Conclusion: This GEM‐CBDCA combination administered biweekly showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

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We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted. • Concomitant medications affect clinical outcomes from immune checkpoint inhibitors. • We previously validated a prognostic drug score in European patients with NSCLC. • We explored the prognostic ability of the drug score in Japanese patients with NSCLC. • The use of probiotics might mitigate the deleterious effect of antibiotics. • Racial differences should be considered when investigating this topic. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) mutations are present in ∼3% of patients with non–small cell lung cancer (NSCLC), with exon-20 insertions accounting for ∼90% of such HER2 mutations and having been identified as driver oncogenic alterations. Antibody–cytotoxic drug conjugates including trastuzumab deruxtecan have shown an excellent efficacy for NSCLC with HER2 mutations. We have now performed a phase II study to evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) for NSCLC positive for HER2 exon-20 insertion mutations. Eligible patients with HER2 exon-20 insertion mutations confirmed by next-generation sequencing or multiplex polymerase chain reaction platforms and a history of one or two lines of chemotherapy received T-DM1 (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study was the objective response rate (ORR). Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0–55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations. JapicCTI-194620 • Ado-trastuzumab emtansine was tested for patients with non-small cell lung cancer. • The objective response rate for T-DM1 in these patients was 38.1%. • Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. [ABSTRACT FROM AUTHOR]

Summary: Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Although cigarette smoking is the main cause of lung cancer, not all smokers develop lung cancer, and a fraction of lifelong non-smokers will die from lung cancer. Genetic host factors have recently been implicated to account for some of the observed differences in lung cancer susceptibility. Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, may result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent genetic association studies on lung cancer risk have focused on identifying effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide base repair (BER) pathway, focusing on 8-oxoguanine DNA glycosylase 1, X-ray cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1. The 399Gln/Gln genotype of the XRCC1 Arg399Gln polymorphism was associated with an increased risk of lung cancer among Asians (OR=1.34, 95% CI=1.16–1.54) but not among Caucasians. Little evidence of associations has been found between other BER genes and lung cancer risk. Considering the data available, it can be conjectured that if there is any risk association between single SNP and lung cancer, this risk increase/decrease will probably be minimal. Advances in identification of new polymorphisms and in high-throughput genotyping techniques will facilitate analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples of cases and controls. [Copyright &y& Elsevier]

• Cytotoxic chemotherapy and EGFR-TKI osimertinib induced prominent cell surface expression of CRT (ecto-CRT) in six NSCLC cell lines. • Systemic anticancer therapies-triggered ecto-CRT expression in NSCLC cells was positively correlated with extent of apoptosis. • Increased plasma levels of soluble CRT in advanced NSCLC patients treated with systemic anticancer therapies may serve as an indicator of ICD. Synergistic anticancer efficacy of combination treatment with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) may be attributable in part to the phenomenon of immunogenic cell death (ICD), which is characterized by the release of damage-associated molecular patterns (DAMPs) from dying tumor cells. The ability of cytotoxic chemotherapeutic agents and molecularly targeted drugs such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to induce DAMPs during the treatment of NSCLC has remained unclear, however. We investigated the ability of seven cytotoxic chemotherapeutic agents and the third-generation EGFR-TKI osimertinib to induce translocation of the DAMP calreticulin to the cell surface in multiple NSCLC cell lines. The plasma concentration of soluble CRT in advanced NSCLC patients treated with cytotoxic chemotherapy or osimertinib was measured. Antimetabolites and microtubule inhibitors induced expression of CRT at the cell surface (ecto-CRT) to a greater extent than did platinum agents in six NSCLC cell lines, exhibiting higher up-regulation of phosphorylation of eukaryotic initiation factor-2α (eIF2α). Ecto-CRT expression was positively correlated with apoptosis induction in NSCLC cells treated with these various chemotherapeutic agents. The drug-induced up-regulation of ecto-CRT in NSCLC cells was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Osimertinib similarly increased ecto-CRT expression in association with apoptosis induction in five EGFR -mutated NSCLC cell lines. Furthermore, the plasma concentration of soluble CRT in 16 NSCLC patients treated with single-agent pemetrexed or docetaxel and in nine EGFR -mutated NSCLC patients treated with osimertinib was increased after treatment onset. Our findings indicate that antimetabolites, microtubule inhibitors, and osimertinib are effective inducers both of CRT exposure in NSCLC cell lines and of soluble CRT release in patients with advanced NSCLC, suggesting that these agents might prove effective for promotion of antitumor immunity in combination immunotherapy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. We enrolled and studied 11 patients with advanced cancer (aged 39–70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non–small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis. • Specific human leucocyte antigen types were correlated with pituitary immune-related adverse events (irAEs). • This was seen especially in patients with secondary adrenal insufficiency. • This information may enable effective prediction of irAEs. • These data could enable safer treatment with immune checkpoint inhibitors. • This study provides clues regarding the aetiology of these adverse events. [ABSTRACT FROM AUTHOR]

Objectives Expression of programmed cell death–ligand 1 (PD-L1) has been associated with clinical outcome of programmed cell death–1 (PD-1) pathway blockade in non–small cell lung cancer (NSCLC). The PD-L1 IHC 22C3 pharmDx assay, the only companion diagnostic for pembrolizumab therapy, has revealed that ∼30% of all NSCLCs express PD-L1 at a high level. The frequency of high PD-L1 expression in NSCLCs with known driver oncogenes has remained unclear, however. Materials and methods We retrospectively evaluated PD-L1 expression with the 22C3 assay in tumor tissue of 80 lung adenocarcinoma patients including 71 with EGFR mutations and 9 with ALK rearrangements, all of whom were treated with corresponding tyrosine kinase inhibitors (TKIs). Results Of the 80 tumors analyzed, 26 (32.5%) had a PD-L1 tumor proportion score (TPS) of 1%–49% and 9 (11.3%) had a PD-L1 TPS of ≥50%; 35 (43.8%) thus had a PD-L1 TPS of ≥1%. Of the 71 tumors with EGFR mutations, 23 (32.4%) had a PD-L1 TPS of 1%–49% and 7 (9.9%) had a PD-L1 TPS of ≥50%. A PD-L1 TPS of ≥1% was not associated with any clinical characteristic examined. Progression-free survival on initial TKI treatment was significantly poorer for patients with a PD-L1 TPS of ≥1% than for those with a PD-L1 TPS of <1% ( p  = .016). Conclusions A subset of patients with EGFR mutations or ALK rearrangements had a PD-L1 TPS of ≥50%. Prospective studies are thus warranted to examine the efficacy of PD-1/PD-L1 inhibitors in such patients. [ABSTRACT FROM AUTHOR]

Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene ( EGFR ) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR . C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment. [ABSTRACT FROM AUTHOR]

Background: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival.Methods: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants.Findings: Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6-15·6) than in the cisplatin group (11·4 months,10·2-12·2; hazard ratio 0·81, 95% CI 0·65-1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively.Interpretation: Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.Funding: West Japan Oncology Group and Sanofi. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The clinicopathological characteristics and surgical results of young lung cancer patients were investigated. Materials and methods: Seven hundred and four (6.0%) patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10,959 patients older than 50 years. This epidemiological study is based on the single year registration of surgically treated patients in the major institutes in Japan. Results: The 5-year overall survival rate (5Y-OS) and the 5-year lung cancer-related survival rate was 79.2%/69.0% (p <0.001) and 81.3%/76.6% (p =0.005) in the young/old groups, respectively. In the young/old groups, lobectomy and pneumonectomy was performed in 76.9%/78.0% and 5.7%/3.2%, respectively; adjuvant therapies were given preoperatively in 10.4%/4.7% (p <0.001) and postoperatively in 31.4%/24.5% (p <0.001). The proportions of patients with p-stage IIIA (18.2%) and adenocarcinoma histology (78.7%) were higher in the young group. The 5Y-OS was 94.8%/86.2% for p-stage IA (p <0.001), 87.0%/73.2% for p-stage IB (p =0.001), 61.0%/61.6% for p-stage IIA (p =0.595), 71.0%/48.4% for p-stage IIB (p =0.003), 49.6%/39.4% for p-stage IIIA (p =0.020), and 80.0%/24.8% for p-stage IIIB (p =0.012); it was 83.5%/80.7% for females (p =0.106) and 75.1%/62.3% for males (p <0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was 17.9%/13.4% in the young/old groups (p =0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p =0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p =0.013). Age up to 50 years was identified as an independent better prognostic factor on multivariate analysis. Conclusions: The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years. [Copyright &y& Elsevier]

Highlights: [•] The presumed “at-risk” allele of CRP rs174520 was associated with an increased risk of lung cancer. [•] The presumed “at-risk” allele of IL6 rs1800796 was associated with a decreased risk of lung cancer. [•] Smoking and inflammation-related polymorphism interactions were not significant. [•] A significant interaction was observed between TNFA rs1799724 and MPO rs2333227. [Copyright &y& Elsevier]

Abstract: Lung cancer is sometimes difficult to differentiate from benign lung diseases expressing nodular shadow in imaging study. We assessed the diagnostic value of two commonly used tumor markers in distinguishing primary lung cancer from benign lung disease. The serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) were retrospectively analyzed in 655 lung cancer patients and 237 patients with benign lung disease. The standard cut-off levels of 3.2ng/mL CEA and 3.5ng/mL CYFRA 21-1 and twice these respective levels (6.4ng/mL and 7.0ng/mL) were used. CEA and CYFRA 21-1 levels were elevated in 32% and 11% of benign lung disease patients, respectively. CEA sensitivity and specificity for lung cancer diagnosis was 69% and 68% respectively, while that for CYFRA 21-1 was 43% and 89%, respectively. Thus, the combined value for the specificity of the two tumor markers was greater than either alone. Patients were grouped depending on their hospital status, and prevalence rates were determined. The prevalence rate of lung cancer in admitted patients was 51%, the prevalence rate of lung cancer in outpatients was 12%, and the prevalence rate of lung cancer identified during health check-ups was 0.1%. Positive predictive values (PPVs) were calculated using Bayes’ theorem, and varied with the serum tumor marker and prevalence rate: PPVs of CEA [prevalence rate] were 69.2% [51%], 22.7% [12%], and 0.22% [0.1%], while PPVs of CYFRA 21-1 were 80.3% [51%], 34.8% [12%], and 0.39% [0.1%]. However, PPVs for lung cancer diagnosis at a prevalence rate of 51% were 87.3% or higher when the patient exhibited positive CEA and CYFRA 21-1, or CEA or CYFRA 21-1 levels twice the standard cut-off. Our results indicate that CEA and CYFRA 21-1 are reliable serum tumor markers for the diagnosis of lung cancer in addition to CT scans when combined or used individually at twice the standard cut-off level in high prevalence rate groups. The prevalence rate should therefore be taken into account when these serum tumor markers are used as diagnostic tools for lung cancer. [Copyright &y& Elsevier]

Abstract: High expression levels of TrkB and BDNF are associated with aggressive malignant behavior in tumor cells and a poor prognosis in patients with various types of cancer. In this study, we aimed to identify the relationship between TrkB and BDNF expression and clinicopathological variables and prognosis in non-small cell lung cancer (NSCLC). We evaluated TrkB and BDNF expression in the tumor cells of 102 NSCLC patients by immunohistochemistry. Out of all clinicopathological factors examined, only vascular invasion was significantly correlated with TrkB (P =0.010) and BDNF (P =0.015) expression. TrkB-positive tumors had significantly worse disease-free survival (P =0.0094) and overall survival (P =0.0019) than TrkB-negative tumors, and TrkB expression was an independent prognostic factor for disease-free survival (HR 3.735, 95%C.I. 1.560–11.068, P =0.002) and overall survival (HR 4.335, 95%C.I. 1.534–15.963, P =0.004) in multivariate analysis. Finally, our analysis revealed that co-expression of TrkB and BDNF conferred poorer prognosis compared with overexpression of either protein alone. Our results indicate that expression of TrkB and BDNF is associated with poor prognosis in NSCLC patients. [Copyright &y& Elsevier]

Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non-small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of the viral receptors, coxsackievirus and adenovirus receptor, and decayaccelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well tolerated without treatment-related deaths. In addition, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non–small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non–small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m2) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m2). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade ≥4 esophagitis and neutropenic fever and Grade ≥3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient. [Copyright &y& Elsevier]