Characteristics of and reasons for patients with chronic obstructive pulmonary disease to continue smoking, quit smoking, and switch to heated tobacco products.

INTRODUCTION: Smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and smoking cessation is the most effective treatment for patients with COPD. However, few studies have investigated the continuation/cessation of smoking and heated tobacco products (HTP) in patients with COPD. The objective of this study was to examine the characteristics of patients with COPD, those who are current smokers and those who switched from cigarettes to HTP, and to examine the reason for the continuation or cessation of smoking. METHODS: This multicenter, cross-sectional study included 411 outpatients with COPD. Data for this study were part of a study conducted for a comprehensive evaluation of the smoking status and clinical factors in patients with COPD and their families. RESULTS: Logistic regression analysis revealed that a younger age, longer duration of smoking, fewer daily cigarettes, and lower modified Medical Research Council (mMRC) dyspnea score, and a lower Simplified Nutritional Appetite Questionnaire (SNAQ) score for appetite, were characteristics of current smokers (age OR=0.94; duration of smoking OR=1.07; number of cigarettes per day OR=0.94; mMRC OR=0.68; SNAQ OR=0.83; p<0.05). The logistic regression analysis model showed that a younger age and higher education level were associated with the use of HTP (age OR=0.83; higher education level OR=4.63; p<0.05). Many of the current smokers displayed smoking behaviors that are not guaranteed to be safe, such as reducing smoking or switching to lighter cigarettes or HTP. CONCLUSIONS: Patients with COPD who continue smoking tended to have low appetite as well as smoking behaviors that are not guaranteed to be safe. Physicians should provide appropriate guidance to these patients on smoking cessation.

Comparative Efficacy and Safety of Immunotherapeutic Regimens with PD-1/PD-L1 Inhibitors for Previously Untreated Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

Improving therapeutic strategies for extensive-stage small cell lung cancer (ES-SCLC) remains a challenge. To date, no reports have directly compared the efficacy and safety of immune checkpoint inhibitors plus platinum-etoposide (ICIs+EP) with platinum-irinotecan (IP) or directly compared different ICIs+EP for previously untreated ES-SCLC. This study used a Bayesian approach for network meta-analysis to compare efficacy and safety between ICIs+EP and IP and between each pair of three ICIs+EP. The six treatment arms were: pembrolizumab plus platinum-etoposide (Pem+EP), durvalumab plus platinum-etoposide (Dur+EP), atezolizumab plus platinum-etoposide (Atz+EP), platinum-amrubicin (AP), IP, and platinum-etoposide (EP). No significant differences in overall survival were observed between ICIs+EP and IP and between each pair of three ICIs+EP. The incidence of ≥grade 3 adverse events (G3-AEs) was significantly higher in ICIs+EP than IP, whereas no significant difference was found in G3-AEs between each pair of three ICIs+EP. The incidence of ≥grade 3 neutropenia and thrombocytopenia was significantly higher in ICIs+EP than IP, whereas the incidence of ≥grade 3 diarrhea was significantly lower in ICIs+EP than IP. These findings will help clinicians better select treatment strategies for ES-SCLC.

Nivolumab plus Ipilimumab versus Existing Immunotherapies in Patients with PD-L1-Positive Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

No head-to-head trials have compared the efficacy and safety of nivolumab (Niv) plus ipilimumab (Ipi) combination therapy (Niv+Ipi) and existing regimens with immunotherapies approved as first-line treatment in patients with programmed cell death ligand 1 (PD-L1)-positive previously untreated advanced non-small cell lung cancer (NSCLC). We conducted a network meta-analysis of four relevant Phase Ⅲ trials to compare the efficacy and safety of Niv+Ipi, pembrolizumab (Pem) plus platinum-based chemotherapy (PBC) (Pem+PBC), Pem, Niv, or PBC using Bayesian analysis. The primary efficacy endpoint was progression-free survival (PFS) in patients with advanced NSCLC with PD-L1 expression ≥1%. The primary safety endpoint was the incidence of Grade 3-5 drug-related adverse events (G3-5AEs). Efficacy and safety were ranked using surface under the cumulative ranking curve (SUCRA). With regard to PFS, Niv+Ipi was inferior to Pem+PBC, and superior to Pem, Niv, or PBC alone. SUCRA ranking showed Pem+PBC had the highest efficacy for PFS, followed by Niv+Ipi, Niv, PBC, and Pem. The safety outcome analysis revealed Niv+Ipi was generally well tolerated compared to existing immunotherapy regimens. These results provide clinical information regarding the efficacy and safety of Niv+Ipi and indicate the possibility of the Niv+Ipi combination as a new therapeutic option in PD-L1-positive advanced NSCLC.

Comparative Efficacy and Safety of Anti-PD-1/PD-L1 Immune Checkpoint Inhibitors for Refractory or Relapsed Advanced Non-Small-Cell Lung Cancer-A Systematic Review and Network Meta-Analysis.

The efficacy and safety of immune checkpoint inhibitors (ICIs) in refractory or relapsed advanced non-small-cell lung cancer (NSCLC) have not yet been compared with those of ramucirumab (Ram) plus docetaxel (Doc). Furthermore, comprehensive comparisons between ICIs have not been conducted to date. In the current study, a Bayesian network meta-analysis of related phase III clinical trials was performed to compare the efficacy and safety of Ram+Doc, Niv, Atz, and Doc treatments in patient groups lacking the PD-L1 constraint. Surface under the cumulative ranking area (SUCRA) revealed that the overall survival (OS) of patients treated with Niv was the highest, followed by Atz, Ram+Doc, and Doc. Regarding grades 3-5 treatment-related adverse events (G3-5AEs), the use of Niv was ranked the safest, followed by Atz, Doc, and Ram+Doc. Significant differences in OS were observed between Niv and Ram+Doc, while significant differences in G3-5AEs were observed between Ram+Doc and Niv or Atz. In the PD-L1 positive (≥1%) patient subgroup, Pem (10 mg/kg) ranked the highest in efficacy for OS, followed by Niv, Pem (2 mg/kg), Atz, and Doc. These findings may expectedly provide oncologists with useful insights into therapeutic selection for refractory or relapsed advanced NSCLC.

Acute exacerbation of idiopathic pulmonary fibrosis induced by pertussis: the first case report.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe condition with limited treatment strategies. Although respiratory infection is a major cause of AE-IPF, no reports have indicated pertussis infection as a cause. Here we report two cases of pertussis infection-induced AE-IPF. CASE PRESENTATION: Both patients presented with a chief complaint of acute respiratory distress and were previously diagnosed with idiopathic pulmonary fibrosis (IPF). Neither patient had received any pertussis vaccination since adolescence. Both patients were diagnosed with AE-IPF accompanying acute pertussis infection based on chest computed tomography and serum pertussis toxin antibody > 100 EU/mL. Both patients were treated with macrolide antibiotics and systemic corticosteroids. Both patients were able to be discharged and return home. CONCLUSIONS: The presence of pertussis infection in AE-IPF can present a diagnostic challenge, as coughing accompanying pertussis may be difficult to distinguish from IPF-associated coughing. Pertussis infection should be assayed in AE-IPF patients. Since pertussis can be prevented with vaccination and is expected to be affected by antibiotics, consideration of pertussis infection as a causative virulent factor of AE-IPF may be important for management of subjects with IPF.

Distinct Afatinib Resistance Mechanisms Identified in Lung Adenocarcinoma Harboring an EGFR Mutation.

EGFR tyrosine kinase inhibitors (TKI) are associated with significant responses in non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations. However, acquired resistance to reversible EGFR-TKIs remains a major obstacle. In particular, although the second-generation irreversible EGFR-TKI afatinib is currently used for treating NSCLC patients, the mechanisms underlying acquired afatinib resistance remain poorly understood. Here, heterogeneous mechanisms of acquired resistance were identified following long-term exposure to increasing doses of afatinib in EGFR-mutant lung adenocarcinoma PC-9 cells. Notably, three resistant cell lines, PC-9AFR1, PC-9AFR2, and PC-9AFR3 (AFR1, AFR2, and AFR3, respectively) employed distinct mechanisms for avoiding EGFR inhibition, with increased EGFR expression being detected in all resistant cell lines. Moreover, an activating EGFR mutation was partially lost in AFR1 and AFR2 cells. AFR1 cells exhibited afatinib resistance as a result of wild-type KRAS amplification and overexpression; however, these cells showed a progressive decrease and eventual loss of the acquired KRAS dependence, as well as resensitization to afatinib, following a drug holiday. Meanwhile, AFR2 cells exhibited increased expression of insulin-like growth factor-binding protein 3 (IGFBP3), which promoted insulin-like growth factor 1 receptor (IGF1R) activity and subsequent AKT phosphorylation, thereby indicating a potential bypass signaling pathway associated with IGFR1. Finally, AFR3 cells harbored the secondary EGFR mutation T790M. Our findings constitute the first report showing acquired wild-type KRAS overexpression and attenuation of afatinib resistance following a drug holiday.Implications: The heterogeneous mechanisms of afatinib resistance should facilitate the development of more effective therapeutic strategies for NSCLC patients. Mol Cancer Res; 15(7); 915-28. ©2017 AACR.

Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI-Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation.

Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 µmol/L gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, PC-9DR4, and PC-9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with HSP90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment. Mol Cancer Ther; 15(12); 3040-54. ©2016 AACR.

[Successful Treatment of Seasonal Influenza A (H3N2) infection-related Hemophagocytic Lymphocytosis in an Elderly Man].

A 79-year-old man experienced severe chronic obstructive pulmonary disease (COPD) and was receiving treatment for ischemic heart disease. Starting from dizziness and chilliness, he lost consciousness after few days. He was taken to our emergency department. On initial evaluation, he complained of dyspnea and was afebrile with a pulse rate, blood pressure, and respiratory rate of 105 beats/min, 112/98mmHg, and 28 breath/min, respectively. His respiratory sounds were clear and chest radiography did not show any abnormal shadows, but his arterial blood gas examination showed type II respiratory failure. Because the nasopharyngeal seasonal influenza A virus (IAV) test was positive, the patient was admitted with the diagnosis of acute exacerbation of COPD due to IAV. We administered peramivir, a specific anti-influenza drug, and started mechanical ventilation. Over time, he started to show signs of disseminated intravascular coagulation, such as multiple organ failure and thrombocytopenia. Subsequently, blood tests showed elevation of ferritin and soluble interleukin 2 receptor (sIL2R); microscopic examination of the peripheral blood revealed hemophagocytosis. Secondary hemophagocytic lymphohistiocytosis (HLH) due to IAV was diagnosed and together with corticosteroid therapy, intravenous gamma globulin was administered from the 3rd clinical day. The patint was saved with our early diagnosis and treatment of HLH and was discharged on the 92nd clinical day. Viral-induced HLH, formerly known as virus-associated hemophagocytic syndrome (VAHS), leads to multiple organ failure due to a cytokine storm scattered by viral-infected pathogenic inflammatory cells. It is well known that pandemic swine flu causes secondary HLH leading to poor outcomes. Currently, not much is known about HLH due to seasonal flu; particularly, IAV (H3N2)-related HLH cases are rare and reported cases showed poor outcomes as well. With an early diagnosis and minimum immunotherapy, we report herein on a case of IAV (H3N2)-related HLH which was treated successfully.

Phase II study of concurrent chemoradiotherapy with carboplatin and vinorelbine for locally advanced non-small-cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) have locally advanced disease with poor prognosis. Although concurrent chemoradiotherapy is the standard treatment, more effective regimens are required. The aim of this study was to assess the safety and efficacy of concurrent chemoradiotherapy with a divided schedule of carboplatin and vinorelbine in patients with locally advanced NSCLC. Patients with unresectable, stage IIIA or IIIB NSCLC were eligible for enrollment if they exhibited a performance status of 0-2 and were ≤75 years of age. Patients were treated with carboplatin at an area under the plasma concentration vs. time curve of 2.5 mg/ml/min and vinorelbine at 20 mg/m2 on days 1 and 8 every 3 weeks. Thoracic radiotherapy at a total dose of 60 Gy was concurrently administered (2 Gy per fraction). Twenty-eight patients (23 men and 5 women; median age, 67 years; range 47-75 years) were enrolled in the present study. The overall response rate was 85.7% [95% confidence interval (CI), 67.3-96.0%] and the disease control rate was 96.4% (95% CI, 81.7-99.9%). The median survival time (MST) was 23 months and the median progression-free survival (PFS) time was 8 months. Grade 3-4 toxicities included neutropenia, thrombocytopenia, anemia and infection in 100, 14, 46 and 36% of patients, respectively. One patient (4%) developed grade 3 radiation esophagitis that resolved completely without residual dilation. Grade 3 radiation pneumonitis occurred in 2 patients (7%); however, the symptoms and radiographic abnormalities subsided with corticosteroid therapy. In conclusion, concurrent chemoradiotherapy with a divided schedule of carboplatin and vinorelbine is well-tolerated and effective in patients with locally advanced NSCLC.

Evaluation of the safety and efficacy of combination chemotherapy with vinorelbine and platinum agents for patients with non-small cell lung cancer with interstitial lung disease.

BACKGROUND: Acute chemotherapy-associated exacerbation of interstitial lung disease (ILD) can occur in patients with non-small cell lung cancer (NSCLC). The safety and efficacy of cytotoxic chemotherapy has not yet been established for NSCLC with ILD. Thus, patients with advanced NSCLC with ILD usually receive only best supportive care. The aim of this study was to assess the safety and efficacy profiles of the combination chemotherapy of vinorelbine and a platinum agent in patients with advanced NSCLC with ILD. PATIENTS AND METHODS: Nineteen patients with advanced NSCLC with ILD treated with vinorelbine and a platinum agent, either cisplatin or carboplatin, were retrospectively reviewed to examine acute exacerbation of ILD, toxicity, response rate, and survival time. Additionally, possible predictive factors for acute chemotherapy-associated exacerbation of ILD were analyzed. RESULTS: The response rate was 42.1%, the progression-free survival time was 4.4 months, the median survival time was 7.4 months, and the one-year survival rate was 36.8%. Neutropenia was the most frequent grade 3 to 4 toxicity and it occurred in 63.2% of patients. Acute chemotherapy-associated exacerbation of ILD occurred in three patients (15.8%) and caused the death of one of these patients (5.3%). No variables were identified as being predictive factors for acute chemotherapy-associated exacerbation of ILD. CONCLUSION: The combination chemotherapy with vinorelbine and a platinum agent can be considered as a treatment option for patients with advanced NSCLC with ILD, with careful management after sufficient evaluation of the risks and the benefits.

Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer.

The aim of this study was to investigate the relationship of the number of circulating tumor cells (CTCs) with the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We prospectively evaluated CTCs in the peripheral blood of patients with previously untreated metastatic NSCLC. From May 2008 through August 2010, 33 patients (23 men and 10 women; median age, 64 years; range, 46-74 years) were enrolled. All patients received combination chemotherapy with gemcitabine and carboplatin. The CTCs were captured from samples of peripheral blood with a semiautomated system using an antibody against epithelial cell adhesion molecule. Blood samples with one or more CTC per 7.5 ml were defined as positive. Of total 33 patients, 12 (36.4%) had positive CTCs and 5 (15.2%) had five or more CTCs before chemotherapy. There were no differences in response rates to cytotoxic chemotherapy between CTC-positive patients and CTC-negative patients. On the other hand, the rate of progressive disease in cytotoxic chemotherapy was significantly higher in CTC-positive patients (66.7%) than in CTC-negative patients (23.8%, p = 0.02). In conclusion, the number of CTCs could be a useful predictive factor for the effectiveness of cytotoxic chemotherapy in patients with metastatic NSCLC.

Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer.

Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55-73 years). Patients received the combination of amrubicin (30 mg/m(2) on days 1-3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0-57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7-84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9-15.4%; p=0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1-42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p=0.004). The median progression-free survival (PFS) time was 3 months (range: 1-14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p=0.01). The most frequent grade 3-4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3-4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC.

Cooperative activation of CCL5 expression by TLR3 and tumor necrosis factor-alpha or interferon-gamma through nuclear factor-kappaB or STAT-1 in airway epithelial cells.

BACKGROUND: CCL5/RANTES contributes to prolonged eosinophilic inflammation and asthma exacerbation after a viral infection. We studied the mechanism of CCL5 expression using viral product double-stranded RNA (dsRNA), a ligand of Toll-like receptor 3 (TLR3), and inflammatory cytokines in airway epithelial cells. METHODS: The airway epithelial cell line BEAS-2B was used in our in vitro study, and the levels of CCL5 mRNA and CCL5 protein expression were determined using real-time PCR and ELISA. The activity of the CCL5 promoter region and nuclear factor (NF)-kappaB was assessed by dual luciferase assay using specific luciferase reporter plasmids. We used actinomycin D to assess the stability of mRNA. Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was analyzed by Western blot. RESULTS: Synthetic dsRNA up-regulated the expression of CCL5 mRNA and CCL5 protein. Adding TNF-alpha or IFN-gamma to dsRNA further increased the expression of CCL5. The combination of TNF-alpha and dsRNA cooperatively activated the CCL5 promoter region and the NF-kappaB-specific reporter. IFN-gamma did not activate these reporters. However, it increased the stability of CCL5 mRNA induced by dsRNA. IFN-gamma phosphorylated STAT-1, but dsRNA did not. The effects of IFN-gamma were not evident in the cells transfected with short interfering RNA for STAT-1. CONCLUSIONS: Cross-talk between TLR3 signaling and inflammatory cytokines regulates the expression of CCL5 in airway epithelial cells. In this mechanism, TNF-alpha may activate NF-kappaB, in cooperation with TLR3 signaling. IFN-gamma may stabilize CCL5 mRNA up-regulated by TLR3. This mechanism may depend on STAT-1.

The UGT1A1*28 genotype and the toxicity of low-dose irinotecan in patients with advanced lung cancer.

The association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan has been controversial, and few studies have examined this association in patients with lung cancer. The aim of this study was to assess the association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan in Japanese patients with lung cancer. From December 2005 through July 2008, 53 Japanese patients with advanced lung cancer who underwent chemotherapy that included low-dose irinotecan (50 or 60 mg/m2) as a single agent or in combination chemotherapy were retrospectively analyzed. Genomic DNA was extracted from peripheral blood. Genotypes for the UGT1A1*28 were denoted as wild-type for 6/6, heterozygous for 6/7, or homozygous for 7/7 depending on the number of TA repeats found in each allele. Of the 53 patients, 42 (79.2%) were wild-type, 9 (17.0%) were heterozygous, and 2 (3.7%) were homozygous for the UGT1A1*28 genotype. The UGT1A1*28 genotype was not associated with grade 3 or 4 neutropenia, thrombocytopia, diarrhea, or febrile neutropenia. The frequency of dose reduction of irinotecan did not differ between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In addition, there were no significant differences in response rates and survival between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In conclusion, the UGT1A1*28 genotype did not predict the severe toxicity of low-dose irinotecan in patients with lung cancer. Therefore, low-dose irinotecan could be administered without reducing starting dose in patients with UGT1A1*28 genotype.

[Chemotherapy-induced myelosuppression and treatment efficacy in extensive-stage small cell lung cancer].

We examined the association between chemotherapy-induced myelosuppression and prognosis in extensive-stage small cell lung cancer (ED SCLC). We retrospectively analysed 91 patients with ED SCLC who received a combination of cisplatin or carboplatin, etoposide or irinotecan between November 1995 and December 2007. Patients were categorized into two groups (grade 0 to 2 or grade 3 to 4) according to the worst neutropenia, thrombocytopenia, or anemia during first-line chemotherapy and were analysed for overall survival (OS) and time to progression (TTP). By univariate analysis, OS and TTP were significantly better in patients who developed grade 3 to 4 neutropenia than those who developed grade 0 to 2. Additionally, performance status (PS), LDH (lactate dehydrogenase), and neuron-specific enolase were prognostic factors for OS. By multivariate analysis, PS was an independent prognostic factor for OS. There were no independent prognostic factors for TTP. Myelosuppression during chemotherapy is not a prognostic factor in ED SCLC.

Induction chemoradiotherapy followed by surgery for locally advanced non-small cell lung cancer.

We examined the efficacy and toxicity of a divided schedule of cisplatin and vinorelbine with concurrent radiotherapy followed by surgery in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with clinical stage IIIA or IIIB NSCLC were eligible if they had a performance status of 0 or 1, were 75 years or younger, and had adequate organ function. Patients were treated with cisplatin (40 mg/m2) and vinorelbine (20 mg/m2) on days 1 and 8 every 3 weeks. Thoracic radiotherapy (2 Gy per fraction; total dose, 40 Gy) was given concurrently. Surgical resection was performed after induction therapy had been completed. If disease was considered clinically inoperable after induction therapy, patients received 2 additional cycles of the chemotherapy and 20 Gy of additional radiotherapy. Twenty-three patients (20 men and 3 women; median age, 63 years; age range, 45-72 years) were enrolled. The overall response rate was 78.3%. Although grade 3-4 toxicities included neutropenia in 95.7% of patients and anemia in 39.1%, no grade 3-4 radiation pneumonitis or esophagitis occurred. Thirteen patients (56.5%) underwent thoracotomy and complete resection. There were no treatment-related deaths. The median survival time was 36 months (range, 4-78 months), the 2-year survival rate was 74%, and the median time to disease progression was 15 months (range, 2-59 months). This trimodality therapy is effective and well tolerated and is an acceptable therapeutic option for patients with locally advanced NSCLC.

Combination effect between bortezomib and tumor necrosis factor alpha on gefitinib-resistant non-small cell lung cancer cell lines.

Tumor cells that have acquired resistance to gefitinib may complicate the future treatment of patients with non-small cell lung cancer (NSCLC). To investigate the mechanisms of acquired resistance, an acquired gefitinib-resistant cell line, PC-9/ZD2001, has been established using a gefitinib-sensitive NSCLC cell line, PC-9. PC-9/ZD2001 showed collateral sensitivity to tumor necrosis factor (TNF)-alpha. Bortezomib is a proteasome inhibitor and enhances TNF-alpha-induced cell death. These observations suggest that the combination of bortezomib and TNF-alpha might have effects against gefitinib-resistant cells. To verify this hypothesis, a combination effect between these drugs was examined using MTT assay and immunoblotting. This combination showed synergistic cytotoxic effect in NSCLC cell lines with either acquired or intrinsic gefitinib resistance. However, this combination effect was not observed in gefitinib-sensitive cells. On the other hand, bortezomib inhibited TNF-alpha-induced IkappaB degradation in all cell lines. From these observations, it is concluded that the combination of bortezomib and TNF-alpha could be used to overcome gefitinib-resistance.

Phase II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer.

BACKGROUND: To date, no phase II trial of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC) has been published. The safety and efficacy of the combination of nedaplatin and weekly paclitaxel in patients with NSCLC was examined. PATIENTS AND METHODS: Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a performance status of 0 to 2, were 75 years or younger and had adequate organ function. Patients were treated with nedaplatin (80 mg/m(2) on day 1) and weekly paclitaxel (90 mg/m(2) on days 1, 8 and 15). RESULTS: From March 2005 through March 2008, 47 patients (31 men and 16 women; median age, 66 years; age range, 38 to 75 years) were enrolled. The overall response rate was 53.2% (95% confidence interval, 38.1% to 67.9%). The median survival time was 13 months (range, 1 to 36 months), the 1-year survival rate was 62% and the median time to disease progression was 5 months (range, 1 to 19 months). Grade 3 to 4 hematologic toxicities included neutropenia in 38.3% of patients, thrombocytopenia in 2.1% and anemia in 23.4% . Although frequent non-hematologic toxicities were nausea, hepatic dysfunction and peripheral neuropathy, all cases were of only mild to moderate severity. Although 1 patient had grade 3 pulmonary toxicity due to drug-induced pneumonia, this patient recovered after receiving steroid therapy. CONCLUSION: This combination chemotherapy is effective and well tolerated and is an acceptable therapeutic option for patients with untreated advanced NSCLC.

A case of intimal sarcoma of the pulmonary artery treated with chemoradiotherapy.

We report on a 45-year-old woman with intimal sarcoma of the pulmonary artery. She presented with a chief complaint of shortness of breath. Computed tomography (CT) of the chest showed an intraluminal hypoattenuated area extending from the main pulmonary artery into the right main pulmonary artery and bilateral lobar pulmonary arteries. She underwent resection of the lobulated mass from the pulmonary artery. The tumor was diagnosed as an intimal sarcoma. Although she received chemotherapy with amrubicin and carboplatin when the tumor recurred, the tumor enlarged. After radiotherapy was performed, CT of the chest showed shrinkage of the tumor and the regression of consolidation and ground-glass opacity. Radiotherapy and chemotherapy are treatment option for patients with pulmonary artery sarcoma.

Patient willingness to undergo chemotherapy and thoracic radiotherapy for locally advanced non-small cell lung cancer.

OBJECTIVES: To determine how Japanese patients with lung cancer weigh the chance of cure and potential survival against the potential toxicity of different treatment strategies for locally advanced non-small cell lung cancer (NSCLC). METHODS: We used a questionnaire describing a hypothetical situation involving locally advanced NSCLC. Seventy-three patients with lung cancer who had received chemotherapy and a control group of 120 patients without cancer were asked to state the minimal benefit that would make two hypothetical treatments acceptable. RESULTS: Patients with lung cancer were significantly more likely than were patients without cancer to accept either intensive or less-intensive chemoradiotherapy for a potentially small benefit for 'chance of cure' and 'response but not cure'. The percentages of patients who would accept intensive or less-intensive chemoradiotherapy to prolong survival did not differ significantly between the two groups. When the chance of cure was 20%, 56 and 64% of patients with lung cancer were willing to receive intensive and less-intensive chemoradiotherapy, respectively. If their lives were prolonged by 6 months, 20 and 30% of patients with lung cancer would choose to receive intensive and less-intensive chemoradiotherapy, respectively. The chance of cure and the survival advantage that patients require for accepting chemoradiotherapy varied widely. No factors were associated with the choice of chemoradiotherapy in patients with lung cancer. CONCLUSIONS: Physicians must consider the substantial range of attitudes to chemoradiotherapy among patients when selecting treatment and give patients opportunities to be included in the treatment-selection process.