[Outcomes of the Critical Pathway for Cooperative Follow-up on Patients with Postoperative Lung Cancer].

OBJECTIVES: We introduced the critical pathway (CP) for follow-up on patients with postoperative lung cancer to the staff of the Hyogo Prefectural Awaji Medical Center and regional medical institutions in Japan, in 2010. METHODS AND RESULTS: We raised awareness within our hospital and collaborating medical institutes and trained our staff on the CP before introducing it. From May 2013 through October 2023, lung cancer surgery was performed on 460 patients. Our CP was applied to 71.7% of these patients. Reasons for non-application included the high risk of recurrence due to advanced cancer stages( 39.2%) and the treatment for other types of cancer was needed in our hospital (26.2%). We reviewed the outcome of our CP. CONCLUSION: The high application rate was facilitated by preparatory actions, including training our hospital staff and collaborating medical institutions. An even higher application rate can be achieved by continuing to raise awareness and strengthening cooperation between concerned medical institutions that treat advanced lung cancer.

A case of eosinophilic pneumonia induced by lettuce.

A 56-year-old female lettuce farmer was admitted to the hospital with a low-grade fever, worsening cough, and dyspnoea. A blood test revealed eosinophilia and a high serum IgE concentration. The 3-year follow-up showed that her total IgE level increased in December, peaked in May, and suddenly decreased in August. This result was consistent with the lettuce harvest season. A chest x-ray taken on admission showed an infiltrative shadow in the upper lung field. Chest CT revealed patchy ground glass opacity on the upper lung field and thickening of the bronchial wall. The bronchoalveolar lavage fluid contained 8% eosinophils. She was treated with prednisolone, and her symptoms and radiological findings improved. The 37 kDa protein that reacted with the patient's sera was identified by immunoblot analysis.

Occupational respiratory allergy to lettuce in lettuce farmers.

BACKGROUND: Lettuce-associated respiratory allergy has never been reported before. The aim of this study was to clarify the clinical condition of lettuce-associated respiratory allergy and to identify the lettuce antigen which induces allergic symptoms. METHODS: We distributed questionnaires to 1168 lettuce farmers and performed medical examinations in those who exhibited respiratory symptoms related to occupational exposure to lettuce. We analysed specific IgE-binding proteins in the sera of patients through immunoblotting analysis and determined molecular characterization of the IgE-binding bands using liquid chromatography-mass spectrometry. RESULTS: A total of 932 farmers (80%) responded to the questionnaire. Of those, 7% exhibited lettuce-associated respiratory symptoms, during harvesting and packaging. Thirteen patients were diagnosed with allergy to lettuce and agreed to undergo further examinations. The percentage of activated basophils in these patients was significantly higher compared with that reported in negative controls (P < .05). Lettuce-specific IgE (ImmunoCAP® ) and skin prick testing was positive in 46% and 62% of patients, respectively. Notably, occupational lettuce-allergic asthma was detected in one patient through specific bronchial provocation testing. The IgE-binding bands recognized in the sera of >50% of patients were identified as epidermis-specific secreted glycoprotein EP1-like (51 kDa). CONCLUSION: The present analysis identified a novel lettuce allergen. This allergen may have clinically useful applications, such as specific IgE testing and allergen-specific immunotherapy.

An Open-Label, Multi-Institutional, Randomized Study to Evaluate the Additive Effect of a Leukotriene Receptor Antagonist on Cough Score in Patients with Cough-Variant Asthma Being Treated with Inhaled Corticosteroids.

Cough-variant asthma is one of the most common reasons for chronic cough. It is important to treat appropriately cough-variant asthma because 30% to 40% of cough-variant asthma becomes a typical asthma. However, little is known about the treatment of cough-variant asthma except for inhaled corticosteroid (ICS). The aim of this study was to validate the additive efficacy of a leukotriene receptor antagonist (LTRA) on cough score and respiratory function in patients with cough-variant asthma being treated with ICS. A total 28 patients were randomly assigned to either an ICS + LTRA group or an ICS group. There were statistically significant improvements in cough scores in the ICS + LTRA group from 0 weeks (6.7 ± 4.4) to 2 weeks (2.9 ± 3.2) (P < 0.05), 4 weeks (0.7 ± 1.1) (P < 0.001), and 8 weeks (0.8 ± 1.2) (P < 0.001). However similar improvements were not evident in the ICS group from 0 weeks (6.7 ± 4.4) to 2 weeks (5.6 ± 10.0) (P = 0.59), 4 weeks (4.6 ± 7.6) (P = 0.32), and 8 weeks (2.9 ± 5.2) (P = 0.08). On the other hand, no significant changes were evident in the forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC). In conclusion, the LTRA was useful in improving cough in patients with cough-variant asthma, even though it appeared to be ineffective in improving respiratory function.

Pemetrexed monotherapy for chemo-naïve elderly (aged ≥80) patients with non-squamous non-small cell lung cancer: results from combined analysis of two single arm phase II studies (HANSHIN002 and 003).

PURPOSE: The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC). METHODS: We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group). RESULTS: We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients. CONCLUSIONS: Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.

Phase III study comparing amrubicin plus cisplatin with irinotecan plus cisplatin in the treatment of extensive-disease small-cell lung cancer: JCOG 0509.

PURPOSE: This randomized phase III trial was conducted to confirm noninferiority of amrubicin plus cisplatin (AP) compared with irinotecan plus cisplatin (IP) in terms of overall survival (OS) in chemotherapy-naive patients with extensive-disease (ED) small-cell lung cancer (SCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with ED-SCLC were randomly assigned to receive IP, composed of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 every 4 weeks, or AP, composed of amrubicin 40 mg/m(2) on days 1, 2, and 3 and cisplatin 60 mg/m(2) on day 1 every 3 weeks. RESULTS: A total of 284 patients were randomly assigned to IP (n = 142) and AP (n = 142) arms. The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. In updated analysis, median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85), median progression-free survival was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was 72.3% (IP) versus 77.9% (AP; P = .33). Adverse events observed in IP and AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). CONCLUSION: AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan.

Synergistic effects of pemetrexed and amrubicin in non-small cell lung cancer cell lines: Potential for combination therapy.

The purpose is to examine the synergistic effect of pemetrexed (PEM) and amrubicin (AMR) on the proliferation of lung cancer cell lines. In vitro, dose-dependent synergistic effects of concurrent PEM and AMRol, which is an active metabolite of AMR were observed in A549 and H460 cells. In real-time RT-qPCR analysis and western blotting, expression of the target enzymes of PEM were suppressed in cells treated with amrubicinol alone. In vivo, AMR/PEM treatment also showed synergistic antitumor activity both in A549-bearing and H520-bearing mice. PEM and AMR work synergistically to inhibit the proliferation of several different lung cancer cell lines.

Visualized changes in respiratory resistance and reactance along a time axis in smokers: a cross-sectional study.

BACKGROUND: Early detection of changes in respiratory function in smokers is important for the prevention of chronic obstructive pulmonary disease (COPD). The objective of this study was to investigate any changes in the respiratory impedance of smokers with normal FEV1/FVC. METHODS: We assessed and compared the impedance components, respiratory resistance, and reactance in both the inspiratory and expiratory phases of nonsmokers, smokers, and COPD patients. RESULTS: Approximately 60% of smokers showed elevated resistance and a negative shift in reactance, mainly in the expiratory phase, as observed in COPD patients. Smokers showed an increased gap between the maximum and minimum R5 and X5 values (R5sub, X5sub) in comparison with nonsmokers. Furthermore, R5-R20 was significantly higher in smokers than in nonsmokers. The expiratory-inspiratory gaps in resistance and reactance were also significantly higher in smokers than in nonsmokers. In smokers and COPD patients, the magnitude of expiratory X5 was more negative than that in nonsmokers. In smokers with V·50/V·25≥3, R5-R20 was significantly higher than those in smokers with V·50/V·25<3. CONCLUSIONS: Approximately 60% of smokers were shown to exhibit apparent impedance changes despite having normal FEV1/FVC values. Smoking-induced early remodeling of the small airways may be responsible for the observed changes in airway function of smokers. Further studies are necessary to determine if the change in respiratory impedance observed in smokers is an early indicator of COPD.

Large-cell neuroendocrine carcinoma of lung with epidermal growth factor receptor (EGFR) gene mutation and co-expression of adenocarcinoma markers: a case report and review of the literature.

PURPOSE: A high rate of response to treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been observed in certain patients (women, of East Asian ethnicity, with non-smoking history and adenocarcinoma histology) with mutations in exons 18 to 21 of the tyrosine kinase domain of EGFR. Some cases of high-grade neuroendocrine carcinoma of the lung harboring mutations have been sporadically reported. METHODS: We describe the case of a 78-year-old woman with large-cell neuroendocrine carcinoma of the lung, with mutation in exon 21 L858R and co-expression of adenocarcinoma markers. RESULTS: A mass (3.0 cm in diameter) was identified in the inferior lobe of the left lung, accompanied by metastases into ipsilateral mediastinal lymph nodes and elevations of serum pro-gastrin-releasing peptide and carcinoembryonic antigen. Initial transbronchial brushing cytology suggested high-grade neuroendocrine carcinoma favoring small-cell carcinoma in poorly smeared and degenerated preparations, and revealed exon 21 L858R mutation. Re-enlargement of the cancer and bone metastases was observed after chemotherapy, and further testing suggested large-cell neuroendocrine carcinoma with immunoreactivity to markers of primary lung adenocarcinoma and L858R mutation. High-grade neuroendocrine carcinoma with mutations in the tyrosine kinase domain of EGFR may be associated with adenocarcinoma, as reviewed from the literature and may also apply to our case. CONCLUSIONS: EGFR-TKI could provide better quality of life and survival in patients with advanced or relapsed high-grade neuroendocrine carcinoma with EGFR gene mutations. Further studies in this respect are warranted.

Slug increases sensitivity to tubulin-binding agents via the downregulation of ßIII and ßIVa-tubulin in lung cancer cells.

Transcription factor Slug/SNAI2 (snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage-independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin-binding agents including vinorelbine, vincristine, and paclitaxel (5.8- to 8.9-fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin-binding agents. Real-time RT-PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of ßIII and ßIVa-tubulin, which is considered to be a major factor determining sensitivity to tubulin-binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of ßIVa-tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of ßIII and ßIV-tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin-binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin-binding agents via the downregulation of ßIII and ßIVa-tubulin in lung cancer cells.

A case of acute exacerbation of idiopathic pulmonary fibrosis after proton beam therapy for non-small cell lung cancer.

There have been no reports describing acute exacerbations of idiopathic pulmonary fibrosis after particle radiotherapy for non-small cell lung cancer. The present study describes the case of a 76-year-old Japanese man with squamous cell carcinoma of the lung that relapsed in the left upper lobe 1 year after right upper lobectomy. He had been treated with oral prednisolone 20 mg/day every 2 days for idiopathic pulmonary fibrosis, and the relapsed lung cancer was treated by proton beam therapy, which was expected to cause the least adverse effects on the idiopathic pulmonary fibrosis. Fifteen days after the initiation of proton beam therapy, the idiopathic pulmonary fibrosis exacerbated, centered on the left upper lobe, for which intensive steroid therapy was given. About 3 months later, the acute exacerbation of idiopathic pulmonary fibrosis had improved, and the relapsed lung cancer became undetectable. Clinicians should be aware that an acute exacerbation of idiopathic pulmonary fibrosis may occur even in proton beam therapy, although proton beam therapy appears to be an effective treatment option for patients with idiopathic pulmonary fibrosis.

A phase I/II study of carboplatin plus gemcitabine for elderly patients with advanced non-small cell lung cancer: West Japan Thoracic Oncology Group Trial (WJTOG) 2905.

INTRODUCTION: Monotherapy with a third generation anticancer agent has been regarded as the standard therapy for elderly patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether elderly patients with a good performance status can tolerate platinum-doublet chemotherapy like younger patients. METHODS: A combination phase I/II study was conducted in chemo-naive elderly patients with NSCLC to establish the toxicity and maximum tolerated dose (MTD) and to investigate the antitumor activity of carboplatin (CBDCA) plus gemcitabine (GEM). GEM was infused on days 1 and 8, and CBDCA on day 1 every 3 weeks. RESULTS: Seventy-five patients were enrolled. The most frequent toxicities were hematological, especially thrombocytopenia. Three of three patients experienced a dose-limiting toxicity at dose level 3: 1000 mg/m(2) GEM with AUC 5 CBDCA (MTD), and one of seven patients at level 2a: 1000 mg/m(2) GEM with AUC 4 CBDCA (recommended dose). In the phase II study, the overall response rate was 22.2% and the median overall survival time was 14.2 months. CONCLUSIONS: Although the recommended dosage is restricted to a lower level compared to younger patients, combination therapy using CBDCA with GEM is tolerable and promising for elderly patients with advanced NSCLC.

Ewing's sarcoma family of tumors originating in the main bronchus.

Ewing's sarcoma family tumors (ESFT), which include Ewing's sarcoma and primitive neuroectodermal tumors (PNET), have been reported to originate in a variety of sites, mostly in the extremities. Previous reports have shown ESFT originating in the thoracic region, such as chest wall and peripheral lung. We herein report the first case of the ESFT that originated in the main bronchus. Endobronchial snare resection was followed by five courses of chemotherapy (VDC-IE; including vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide) and sequential radiation. After the treatment, the patient's condition has improved, and he has remained disease-free for the past year.

An open-label, prospective clinical study to evaluate the efficacy of prophylactic antibiotics after diagnostic bronchoscopy.

The aim of this study was to prospectively examine the effect of prophylactic antibiotic use on the development of respiratory infections and on the worsening of symptoms after diagnostic fiberoptic bronchoscopy procedures. This study was an open-label, multicenter, controlled, clinical trial. Patients were alternately assigned to a group given prophylactic antibiotics after bronchoscopy (prophylaxis(+) group) and a group not given antibiotic prophylaxis after bronchoscopy (prophylaxis(-) group), and they were followed-up for 1 week. 158 patients were assigned to the prophylaxis(-) group and 153 to the prophylaxis(+) group. Therapeutic antibiotic administration was needed in 3 patients (1.90%) in the prophylaxis(-) group and 5 patients (3.27%) in the prophylaxis(+) group (risk ratio 1.014, 95% confidence interval 0.978-1.052; p=0.446). Worsening of symptoms after bronchoscopy occurred in 57.6% of all patients by day 7, but no significant differences were observed between the 2 study groups. Prophylactic antibiotic use after bronchoscopy did not prevent the development of infectious events and worsening of symptoms, suggesting that prophylactic antibiotics might not be necessary for routine diagnostic bronchoscopic procedures.

Long-term outcome after multidisciplinary approach for leptomeningeal carcinomatosis in a non-small cell lung cancer patient with poor performance status.

The present study describes a case of a 60-year-old Japanese man who was histologically diagnosed with lung adenocarcinoma harboring L858R mutation of epidermal growth factor receptor. He was successfully treated with gefitinib, but eventually developed leptomeningeal carcinomatosis. He underwent ventriculoperitoneal shunting for hydrocephalus and received erlotinib in place of gefitinib with concurrent whole brain radiotherapy; this resulted in dramatic improvement in his symptoms and performance status from four to one and he survived for as long as 13.6 months after the initiation of erlotinib therapy. This multidisciplinary approach may be particularly useful in terms of increasing survival and improving quality of life.

Antigen-Specific IgG ameliorates allergic airway inflammation via Fcγ receptor IIB on dendritic cells.

BACKGROUND: There have been few reports on the role of Fc receptors (FcRs) and immunoglobulin G (IgG) in asthma. The purpose of this study is to clarify the role of inhibitory FcRs and antigen presenting cells (APCs) in pathogenesis of asthma and to evaluate antigen-transporting and presenting capacity by APCs in the tracheobronchial mucosa. METHODS: In FcγRIIB deficient (KO) and C57BL/6 (WT) mice, the effects of intratracheal instillation of antigen-specific IgG were analysed using the model with sensitization and airborne challenge with ovalbumin (OVA). Thoracic lymph nodes instilled with fluorescein-conjugated OVA were analysed by fluorescence microscopy. Moreover, we analysed the CD11c+ MHC class II+ cells which intaken fluorescein-conjugated OVA in thoracic lymph nodes by flow cytometry. Also, lung-derived CD11c+ APCs were analysed by flow cytometry. Effects of anti-OVA IgG1 on bone marrow dendritic cells (BMDCs) in vitro were also analysed. Moreover, in FcγRIIB KO mice intravenously transplanted dendritic cells (DCs) differentiated from BMDCs of WT mice, the effects of intratracheal instillation of anti-OVA IgG were evaluated by bronchoalveolar lavage (BAL). RESULTS: In WT mice, total cells and eosinophils in BAL fluid reduced after instillation with anti-OVA IgG1. Anti-OVA IgG1 suppressed airway inflammation in hyperresponsiveness and histology. In addition, the number of the fluorescein-conjugated OVA in CD11c+ MHC class II+ cells of thoracic lymph nodes with anti-OVA IgG1 instillation decreased compared with PBS. Also, MHC class II expression on lung-derived CD11c+ APCs with anti-OVA IgG1 instillation reduced. Moreover, in vitro, we showed that BMDCs with anti-OVA IgG1 significantly decreased the T cell proliferation. Finally, we demonstrated that the lacking effects of anti-OVA IgG1 on airway inflammation on FcγRIIB KO mice were restored with WT-derived BMDCs transplanted intravenously. CONCLUSION: Antigen-specific IgG ameliorates allergic airway inflammation via FcγRIIB on DCs.

A metabolomic approach to lung cancer.

Lung cancer is one of the most common cancers in the world, but no good clinical markers that can be used to diagnose the disease at an early stage and predict its prognosis have been found. Therefore, the discovery of novel clinical markers is required. In this study, metabolomic analysis of lung cancer patients was performed using gas chromatography mass spectrometry. Serum samples from 29 healthy volunteers and 33 lung cancer patients with adenocarcinoma (n=12), squamous cell carcinoma (n=11), or small cell carcinoma (n=10) ranging from stage I to stage IV disease and lung tissue samples from 7 lung cancer patients including the tumor tissue and its surrounding normal tissue were used. A total of 58 metabolites (57 individual metabolites) were detected in serum, and 71 metabolites were detected in the lung tissue. The levels of 23 of the 58 serum metabolites were significantly changed in all lung cancer patients compared with healthy volunteers, and the levels of 48 of the 71 metabolites were significantly changed in the tumor tissue compared with the non-tumor tissue. Partial least squares discriminant analysis, which is a form of multiple classification analysis, was performed using the serum sample data, and metabolites that had characteristic alterations in each histological subtype and disease stage were determined. Our results demonstrate that changes in metabolite pattern are useful for assessing the clinical characteristics of lung cancer. Our results will hopefully lead to the establishment of novel diagnostic tools.

Successful erlotinib treatment for a patient with gefitinib-related hepatotoxicity and lung adenocarcinoma refractory to intermittently administered gefitinib.

A 73-year-old Japanese man was histologically diagnosed with lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor. The patient was treated with gefitinib for 6 weeks until he developed substantially elevated hepatic enzyme levels that resulted in the discontinuation of gefitinib. Gefitinib was reintroduced with an intermittent treatment schedule after the transaminase levels normalized, but the patient's enzyme levels rose again, and the cancer progressed. Gefitinib was eventually replaced with erlotinib. There was stable disease for 7 weeks without any signs of liver toxicity. Thus, erlotinib may be a beneficial and well-tolerated treatment option for patients with gefitinib-related hepatotoxicity.

Chemotherapy improves thymoma-associated graft-versus-host-disease-like erythroderma.

Graft-versus-host-disease (GVHD) with erythroderma can rarely occur in the context of thymoma and is associated with a poor prognosis due to an increased risk of infection-related death. The present study describes a case of a 50-year-old man with malignant thymoma who developed sepsis in addition to skin manifestations similar to that seen in GVHD. This patient experienced marked improvement in skin lesions in response to steroids and combination chemotherapy with carboplatin and paclitaxel, with subsequent resolution of infection. The present study describes the clinical course of this patient, followed by a review of pertinent reports of thymoma associated with GVHD with particular focus on the efficacy of treatment strategies.