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Nintedanib has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In addition, in EU countries, nintedanib plus docetaxel is used for patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. Here, we report a case of advanced NSCLC in a patient with IPF successfully treated with nintedanib monotherapy. A 69-year-old man was diagnosed with NSCLC complicated by IPF. After three lines of chemotherapy, he still had progressive disease. Because his IPF had also progressed, requiring supplemental oxygen, we decided to start best supportive care and introduced nintedanib to treat his IPF. One month later, we observed a partial remission of the primary tumor and pleural disseminations without severe adverse events. Nintedanib monotherapy might therefore be an effective therapeutic choice for NSCLC in patients with IPF who are unable to tolerate cytotoxic chemotherapy. KEY POINTS: Efficacy of nintedanib administered in a NSCLC patient with IPF. Nintedanib monotherapy might be a therapeutic option for NSCLC patients with IPF who are unable to tolerate chemotherapy.

Background We examined cross-sectional associations between depression and both inflammatory markers and fractional exhaled nitric oxide (FeNO). Methods This cross-sectional study is a secondary analysis of the data of the Iwaki Health Promotion Project 2016 (1,148 subjects). We analyzed the subjects' characteristics and laboratory data including plasma interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), and FeNO. The subjects with Center for Epidemiologic Studies Depression Scale scores ≥16 were assigned to the depression group. We performed a multivariate logistic regression analysis to determine whether inflammatory markers and FeNO were associated with depression. Results We assessed 1,099 subjects (430 males, 669 females). The depression group was 237 subjects (21.5%) [84 males (19.5%), 153 females (22.9%)]. The non-depression group was 862 subjects (346 males and 516 females). There were no significant differences in IL-6, hs-CRP, or FeNO between both groups. However, the multivariate logistic regression analysis indicated that lower FeNO was significantly associated with depression in males after adjusting for possible confounding factors (age, BMI, comorbidities, high-sensitivity troponin T, FEV1%, asthma, antidepressant use, smoker and alcohol drinker) (per 1 bpm increase, OR: 0.982; 95%CI: 0.967–0.998; p = 0.032). Conclusion Our findings indicate that lower FeNO may be associated with depression in males.

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), was approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real-world practice. Medical records of patients who received afatinib for advanced EGFR-mutant NSCLC were retrospectively reviewed. In total, 128 patients were analyzed. Seventy-six patients received afatinib as the first-line setting and 52 as the re-challenge setting (i.e., after failure of prior first-generation TKI). There was no difference in patient characteristics, such as age, sex, and PS, between the first-line and the re-challenge settings. In the first-line setting, the median progression-free survival (PFS) was 17.8 months (95% confidence interval [CI] 13.7-21.5 months). The overall survival (OS) was 39.5 months (95% CI 34.4- not reached). The response rate (RR) was 64.4%. Subset analysis indicated that patients with dose reduction showed longer PFS than those without dose reduction (18.5 months versus 7.9 months) (P = 0.016). In the re-challenge setting, the median PFS was 8.0 months (95% CI 4.9-9.5 months). The RR was 25%. Most common adverse events leading to dose modification or treatment discontinuation included diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). In the real-world practice in Japan, afatinib showed comparable or better efficacy compared with that shown in previous clinical trials in both the first-line and the re-challenge settings.

Crizotinib, which is effective in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, is sometimes associated with the generation of complex renal cysts. A 56-year-old man with ALK positive adenocarcinoma received crizotinib. Ten months after the introduction of crizotinib, a cystic lesion developed from his right kidney to the iliopsoas muscle, accompanied by fever, anemia, and hypoproteinemia. After 17 months of treatment, crizotinib was switched to alectinib, followed by the recovery of hypoproteinemia and systemic inflammation. Switching to alectinib may be beneficial in patients demonstrating crizotinib-associated complex renal cysts with systemic inflammation and exhaustion.

e21078 Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced non-small cell lung cell cancer (LA-NSCLC). We previously reported the phase I study of biweekly carboplatin and nab-paclitaxel (nab-PTX) with RT. Recommended dose for phase II study was carboplatin (AUC 4) and nab-PTX (100 mg/m2) (J Clin Oncol 2015 suppl; abstr 7529). Here we report the phase II part designed to assess the efficacy of biweekly carboplatin and nab-PTX with concurrent RT (UMIN000023802). Methods: Patients with inoperable stage Ⅲ NSCLC were treated with carboplatin (AUC 4) and nab-PTX 100 mg/m2 on days 1, 15, and 29. Thoracic radiotherapy was administered from day 1 to a total dose of 60 Gy in 30 fractions. Consolidation chemotherapy after CCRT was 2 cycles of carboplatin (AUC 6) on day 1 and nab-PTX 100 mg/m2 on days 1, 8, and 15. The primary endpoint for the phase II part is 2-year overall survival (OS) rate. Assuming an expected survival rate was 60% and a lower limit was 35% (alfa 0.05, beta 0.2). Secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), OS, and safety profile. Results: A total of 28 patients (median age 66 years, male 94%) were enrolled. Of the evaluable patients (n = 28), the rate of 2-year OS was 67.8% (95% CI: 49.3–82.1). The ORR was 96%, a median follow-up time was 33.2 months. Median PFS was 18.2 months (95% CI 13.1–not reached), and median OS was not reached (95% CI, 25.6–not reached). The most common toxicities of grade 3 or higher were neutropenia (60.5%), anemia (14.2%), thrombocytopenia (7.6%) and pneumonitis (3.6%). Conclusions: This study achieved the primary endpoint. Biweekly carboplatin and nab-PTX with concurrent RT therapy was well tolerated and promising systemic antitumor activity for patients with LA-NSCLC. Clinical trial information: 000023802 .

This phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose of afatinib for phase II trial in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or older with advanced NSCLC harboring EGFR mutations were enrolled. The doses of afatinib, which were given once daily, were planned as follows: level 1, 20 mg/day; level 2, 30 mg/day; level 3, 40 mg/day. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic, persistent grade > 2 diarrhea for > 2 days despite concomitant medications or grade 3 non-hematologic toxicity. DLT was evaluated during day 1-28. Fifteen patients were enrolled. Patient characteristics were: male/female 3/12; median age 79 (range 75-87); PS 0/1, 2/13. Six patients have been treated at levels 1 and 3, and three patients at level 2. At level 1, one of six patients experienced grade 3 rush, grade 3 anorexia, and grade 3 infection as DLTs. At level 2, none of three patients experienced a DLT. At level 3, two patients developed grade 3 diarrhea, one of whom also experienced grade 3 anorexia. Most frequent adverse events of any grade were diarrhea, paronychia, rush, and nausea. Most patients at level 2 and 3 required dose reduction in 3 months. MTD was defined as 40 mg/day, and recommended dose for phase II study in elderly patients was 30 mg/day.

Sarcoidosis is an inflammatory granulomatous disease that is systemic, but bone involvement is uncommon. A 68-year-old man was referred to our hospital complaining of right shoulder pain with numbness. Computed tomography revealed systemic lymphadenopathy and multiple bone lesions. Because malignant lymphoma with a mass lesion protruding into the vertebral canal was considered, he underwent urgent radiotherapy. Thereafter, a needle biopsy of the left parasternal node was performed and showed epithelioid granulomas, confirming a diagnosis of sarcoidosis. Since his neurologic symptoms improved, the patient was not given systemic corticosteroids. Radiotherapy may be useful for local control of bone sarcoidosis.

Immunohistochemical screening of Anaplastic lymphoma kinase (ALK) rearrangement has been regarded essential and routinely carried out to select treatment for lung adenocarcinoma. However, difficulty to approach a tumor by transbronchial lung biopsy (TBLB), it often fails to obtain tumor tissues whereas tumor cells are contained in cytology specimens simultaneously obtained when the bronchoscopy is done. Therefore we evaluated the expression of ALK protein by using immunohistochemistry (IHC) on TBLB specimens and immunocytochemistry (ICC) on brushing smear cytology slides in the same cases, and compared the concordance rate of IHC and ICC results. ICC was carried out on routine Papanicolau-stained slides after cytology diagnosis and decolorization. Results Eighteen patients with adenocarcinoma were extracted in the Hirosaki University Hospital and the Hirosaki National Hospital. IHC and ICC results showed a very high concordance rate: sensitivity of ICC in comparison with IHC was 85.7% (6/7), specificity was 100% (11/11), positive predictive value was 100% (6/6), and negative predictive value was 91.6% (11/12). Detection of ALK rearrangement using ICC on routine Papanicolau cytology slides is considered to be advantageous for lung cancer treatments.

Background We have developed a new bronchoscopy system with two independent lenses at the tip of the device. This enables measurement of object size using the principle of triangulation. This study was performed to assess the accuracy of this system. Methods The accuracy of the bronchoscopy system was confirmed by measuring the diameters of four plastic tubes and 36 airway calibres in 12 surgical patients under general anaesthesia. The measured diameters of the tubes and airway tracts were compared with the manufactured diameters of tubes and those measured by high-resolution computed tomography (HRCT)-based virtual bronchoscopy, respectively. Results Using the new bronchoscope system, tube diameters, 9, 12, 15, and 19 mm, were measured as 9.9 (0.7), 12.8 (1.4), 16.3 (1.6), and 20.1 (2.0) mm, respectively. Airway calibres obtained by a stereovision bronchoscopy and HRCT-based virtual bronchoscopy were 8.66 (4.31) and 9.38 (5.09) mm, respectively. There is a significant correlation between airway calibres with the two measurement methods ( r =0.975, P Conclusions We have confirmed that this new bronchoscopy system could provide relatively accurate quantitative data. This new system may be useful in the clinic to measure airway dimension and lesion sizes such as tumours.

Background: It is important for medical staffs to understand the state of stress of patients with cancer. The authors investigated stress assessment in patients with lung cancer undergoing chemotherapy. Materials and Method: Salivary cortisol and α-amylase were measured as stress markers before and after chemotherapy in 10 patients. Emotional status was assessed using the Profile of Mood States (POMS) questionnaire, and Quality of Life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire. Results: No significant differences were found between the before and after chemotherapy in salivary levels of cortisol or α-amylase, the POMS and QOL scores. The salivary cortisol levels correlated with the POMS subscales of anger-hostility, and confusion. A negative correlation was observed between the salivary cortisol level and the QOL full score. The FACT-L full score correlated with the POMS subscales of depression-dejection, fatigue, and confusion. Conclusions: Measurements of salivary stress markers are noninvasive and may be useful for assessing the stress state of the patients

Objective: As it is important for medical staff to understand the stress state of patients with cancer, this study investigated the stress state in patients with lung cancer undergoing chemotherapy using salivary biomarkers and questionnaires. Materials and Methods: The subjects included 19 men and 9 women, with a mean age of 66.1 ± 7.1 years who received chemotherapy for lung cancer. Salivary samples of the participants were collected before and the 7 day after chemotherapy. Simultaneously, they completed the POMS (profile of mood states) and QOL (quality of life) questionnaires. The salivary cortisol and secretory IgA as stress markers were measured by enzyme immunoassay. Results: The salivary secretory IgA level was significantly higher at the 7th day after chemotherapy than before chemotherapy (p < 0.05), although the salivary cortisol level did not change. The tension-anxiety score, which is one of POMS subclasses, and total mood disturbance score were lower at day 7 of chemotherapy than before chemotherapy (p < 0.05), although no correlations were observed between POMS scores and salivary markers. However, a negative correlation was observed between the salivary cortisol level and the QOL full score (r= -0.411, p < 0.05). Conclusion: Measurement of salivary stress markers is noninvasive and may be useful for assessing the stress state of the patients.

e21173Background: Afatinib is the second generation epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), and approved in Japan in...

Purpose Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation. Patients and Methods Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m2 on days 1 through 3) or topotecan (1.0 mg/m2 on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. Results From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival. Conclusion Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

The aim of this study was to investigate the clinical outcome of stereotactic body radiotherapy (SBRT) of 54 Gy in nine fractions for patients with localized lung tumor using a custom-made immobilization system. The subjects were 19 patients who had localized lung tumor (11 primaries, 8 metastases) between May 2003 and October 2005. Treatment was conducted on 19 lung tumors by fixed multiple noncoplanar conformal beams with a standard linear accelerator. The isocentric dose was 54 Gy in nine fractions. The median overall treatment time was 15 days (range 11–22 days). All patients were immobilized by a thermo-shell and a custom-made headrest during the treatment. The crude local tumor control rate was 95% during the follow-up of 9.4–39.5 (median 17.7) months. In-field recurrence was noted in only one patient at the last follow-up. The Kaplan-Meier overall survival rate at 2 years was 89.5%. Grade 1 radiation pneumonia and grade 1 radiation fibrosis were observed in 12 of the 19 patients. Treatment-related severe early and late complications were not observed in this series. The stereotactic body radiotherapy of 54 Gy in nine fractions achieved acceptable tumor control without any severe complications. The results suggest that SBRT can be one of the alternatives for patients with localized lung tumors.

Background Lung cancers with anaplastic lymphoma kinase rearrangements are highly sensitive to anaplastic lymphoma kinase tyrosine kinase inhibition, underscoring the notion that such cancers are addicted to anaplastic lymphoma kinase activity. Several anaplastic lymphoma kinase inhibitors have been identified and are being evaluated in clinical trials. However patients with poor performance status (3 or 4) were not involved in these clinical trials, it has been unclear to use anaplastic lymphoma kinase–tyrosine kinase inhibitors for these patients. Here, we report an anaplastic lymphoma kinase-positive non small cell lung cancer patient with performance status 4, who was successfully treated with alectinib. Case presentation We report on a 52-year-old patient diagnosed as non small cell lung cancer harboring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. His performance status was 4 because of severe respiratory failure. We treated this patient with alectinib as the first line therapy. Dramatic response was obtained and his performance status improved from 4 to 1 without severe adverse events. Conclusion Alectinib is a therapeutic option for the anaplastic lymphoma kinase positive patients with poor performance status.

Background Listeria monocytogenes is a facultative intracellular parasitic bacterium that is Gram positive, catalase positive, oxidase negative, and a facultative anaerobe. It is known to infect humans through food. It is a bacillus with low virulence, but can cause meningitis and sepsis in infants and immunocompromised patients. Case presentation A case of 75-year-old Japanese female with small cell carcinoma of the thymus and pleural dissemination is described. She was treated with carboplatin and etoposide and showed a partial response. However, the tumor recurred 6 months later. Therefore, we again administered carboplatin and etoposide. Though peritoneal dissemination was suspected based on abdominal computed tomography findings after two courses, the assessment was stable disease. She was occasionally treated for constipation. She developed chills, rigor, and diarrhea, necessitating admission on the 7th day of the third course of chemotherapy. We suspected intestinal infection, and cefepime was thus administered. However, her blood pressure dropped and neutropenia manifested on the 4th day of admission. We therefore switched the antibiotic from cefepime to meropenem and also administered granulocyte-colony stimulating factor. Listeria monocytogenes was detected by two blood cultures, and the antimicrobial medication was thus switched to ampicillin, in consideration of sensitivity. Her general condition improved and she was able to leave the hospital on the 19th day after admission. Conclusions During chemotherapy, factors such as impaired bowel movements, malnutrition, and myeloablation can contribute to the development of severe infections. It is necessary to comprehensively assess a patient’s state and treat all aspects of illness.

Background: Interferon (IFN)-γ-inducible protein of 10 kDa (IP-10/CXCL10) is a potent chemoattractant for activated T and NK cells, and elevated levels of IP-10 are identified in bronchoalveolar lavage fluids from patients with pulmonary disorders related to Th-1-type immunity, which is a prerequisite for elimination of viral pathogens. Bronchial epithelial cells play an important role in respiratory infections as the initiator of airway inflammation by releasing chemokines and expressing cell surface membrane molecules involved in leukocyte adhesion. Polyinosinic-polycytidylic acid (poly IC) is a synthetic double-stranded RNA (dsRNA) and induces antiviral reactions in cells. Objectives: We investigated the regulation of IP-10 in BEAS-2B bronchial epithelial cells in response to poly IC, and also addressed the possible role of retinoic-acid-inducible gene-I (RIG-I) and IFN-regulatory factor 3 (IRF-3), two genes involved in the signaling induced by viral infection. Methods: The expressions of IP-10 mRNA and protein were analyzed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. The overexpression of RIG-I or IRF-3 was performed by transfection of BEAS-2B cells with each cDNA. Results: Poly IC enhanced the expression of IP-10 mRNA and protein in concentration- and time-dependent manners. Overexpression of RIG-I or IRF-3 potentiated the poly-IC-induced upregulation of IP-10. Conclusions: IP-10 may contribute to antiviral activity through the activation of Th-1-type immunity, and RIG-I and IRF-3 may be involved in this reaction.

Objective To clarify the clinical significance of vascular endothelial growth factor (VEGF) in Japanese patients with small cell lung cancer (SCLC).Materials and Methods We measured serum VEGF levels using an enzyme-linked immunosorbent assay in 45 patients with SCLC before treatment and in 38 patients with benign pulmonary disease and in 32 healthy subjects (71 non-malignant subjects). VEGF immunostaining was performed in tissue biopsies obtained from 23 SCLC patients during bronchoscopic examination.Results Median serum VEGF level was 332 pg/ml in patients with SCLC and 160 pg/ml in non-malignant subjects, respectively. The 95% cut-off level to exclude non-malignant subjects was 500 pg/ml. An elevated VEGF level (>500 pg/ml) was found more frequently in patients with extensive disease of SCLC than in those with the limited disease (p

The purpose of this study was to determine the safety and efficacy of nedaplatin and paclitaxel when given concurrently with radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC).Nedaplatin was administered at a fixed dose of 20 mg/m(2), and paclitaxel was administered at a starting dose of 30 mg/m(2) with an incremental increase of 5 mg/m(2) until dose-limiting toxicity (DLT) occurred in more than one-third of the patients. The chemotherapy was administered once a week for 6 weeks. The RT was given at a single daily dose of 2 Gy for 5 days per week. The pharmacokinetics of nedaplatin and paclitaxel were investigated.Overall, 20 patients were recruited and assigned to three different treatment groups: group 1 (paclitaxel 30 mg/m(2)), group 2 (paclitaxel 35 mg/m(2)) and group 3 (paclitaxel 40 mg/m(2)). Pulmonary toxicity was the main toxicity which occurred in 16 of 20 patients. In group 3, grades 3 and 4 pulmonary toxicity occurred in two of six patients and grade 3 esophagitis in one patient. The maximum tolerated dose of paclitaxel in this study was 40 mg/m(2) and the recommended dose of paclitaxel was therefore 35 mg/m(2). Four complete and 11 partial responses were observed, resulting in a 75% overall response rate. The area under the concentration-time curve of paclitaxel in group 3 was significantly higher than that in group 1.Nedaplatin 20 mg/m(2) and paclitaxel 35 mg/m(2) could be safely administered for NSCLC with concurrent thoracic RT, and this regimen was effective. The most important DLT was pulmonary toxicity.

Background: Airway eosinophilia is one of the hallmarks of asthma. Eotaxin may play an important role in eosinophil recruitment. Objectives: To examine the relationship between eotaxin levels in the sputum and eosinophilic inflammation. Methods: The sputum was obtained from 11 non-smokers, 14 smokers and 13 asthmatic patients using a sputum induction method. Eotaxin and interleukin (IL)-5 levels in the sputum were determined by ELISA and immunocytochemical analysis. Results: Asthmatic patients had eosinophilia and smokers showed neutrophilia in their sputum. The eotaxin level in the sputum was significantly higher in smokers (median 412.5, range 91.1–872.2 pg/ml) and asthmatic patients (351.0, 185.0–928.0 pg/ml) compared with non-smokers (123.2, 0–369.0 pg/ml; both p < 0.05). IL-5 was detected in the sputum of 1 non-smoker, none of the smokers and 4 asthmatic patients. The percentage of eotaxin-positive cells was higher in smokers and asthmatic patients than in non-smokers, but the percentage of IL-5-positive cells was significantly higher only in asthmatic patients (p < 0.05). Conclusions: These findings suggest that the elevated eotaxin level in the sputum does not always accompany the increase in eosinophils, and cooperation with another cytokine such as IL-5 may be required for the recruitment of eosinophils.

Galectin-9 is a member of the galectin family and has been identified as an eosinophil chemoattractant produced by activated T lymphocytes. Vascular endothelial cells play an important role in the initial step of eosinophil recruitment and activation in immune and inflammatory responses. We have addressed the stimulation of galectin-9 expression in endothelial cells. Galectin-9 was detected in membrane and cytosolic fractions of human umbilical vein endothelial cells stimulated with interferon-γ (IFN-γ). IFN-γ also enhanced the adhesion of human eosinophilic leukemia-1 cells to endothelial monolayers, and it was inhibited by the presence of lactose. Interleukin-4, which induces eotaxin expression, did not affect the expression of galectin-9. The in situ endothelium from patients with inflammatory diseases was found to express galectin-9. IFN-γ-induced production of galectin-9 by endothelial cells may play an important role in immune responses by regulating interactions between the vascular wall and eosinophils.

Background and Objectives Ignition accidents during bronchoscopic laser irradiation have occasionally been reported, but the mechanisms responsible for the ignition accidents are not fully understood. We examined causative factors including ignition site, oxygen concentration, and role of airflow through the laser fiber. Study Design/Materials and Methods Porcine muscle tissue was placed in a bottle and irradiated by laser under various conditions. Also, a piece of porcine muscle was wedged in a main bronchus of the isolated porcine lungs and irradiated by laser in the same way. Results Flashing occurred on the tissue exposed to the laser, and this flashing reached the ignition when the oxygen concentration was above 30%. Increasing airflow through the laser fiber prevented the ignition even at an oxygen concentration at 100%. Conclusions In laser irradiation, the tissue exposed to the laser can be the ignition site of fire. Increasing airflow through the laser fiber was an effective technique to prevent airway fire. Lasers Surg. Med. 31:211–215, 2002. © 2002 Wiley-Liss, Inc.

BACKGROUND Transforming growth factor-β1 (TGF- β1) is a multifunctional factor and is known to affect tumor growth in malignant tumors. The effects of TGF-β1 on angiogenesis, stromal formation, and immune function suggest its possible involvement in tumor progression. The authors examined whether TGF-β1 levels may be correlated with angiogenesis, clinicopathologic factors, and survival in patients with surgically resected lung carcinoma. METHODS TGF-β1 protein was extracted from 53 nonsmall cell lung carcinoma tissue samples (19 squamous cell carcinomas, 33 adenocarcinomas, and 1 adenosquamous cell carcinoma), and its level was measured by enzyme-linked immunosorbent assay. To assess tumor angiogenesis, microvessel density (MVD) was determined by CD31 immunostaining. RESULTS The protein level of TGF-β1 was 289 picograms per milligram of protein (pg/mg protein), ranging from 94 pg/mg protein to 584 pg/mg protein. The TGF-β1 protein level was significantly higher in patients with lymph node metastasis compared with patients who were without lymph node metastasis (P = 0.02), and the TGF-β1 protein level was significantly higher in patients with Stage III disease (TNM classification) compared with patients who had Stage I and II disease (P = 0.03). There was no significant correlation between the TGF-β1 protein level and any of the other clinicopathologic factors that were considered. A significant positive correlation between TGF-β1 protein level and MVD was noted (P < 0.01). Furthermore, in patients with adenocarcinoma, a significant correlation between TGF-β1 protein level and prognosis was detected by multivariate analysis (P = 0.028). CONCLUSIONS TGF-β1 seems to affect tumor angiogenesis and to play an important role in tumor progression in patients with nonsmall cell lung carcinoma. Furthermore, the TGF-β1 protein level may be an independent predictor of survival in patients with adenocarcinoma of the lung. Cancer 2001;91:964–71. © 2001 American Cancer Society.

Mutations in the parkin gene are related with early-onset Parkinson's disease. Parkin is identified as an E3-ligase that combines target proteins with ubiquitin. alpha-Synuclein and synphilin-1 are substrates for E3-ligase activity of parkin and considered to be involved in the pathogenesis of Parkinson's disease. We previously demonstrated both alpha-synuclein and synphilin-1 are expressed in vascular endothelial cells (VEC). In the present study, we addressed possible expression of parkin in VEC. Parkin immunoreactivity was detected in vascular endothelial cells in postmortem human brain. Expressions of parkin mRNA and protein in human umbilical vein endothelial cells (HUVEC) were demonstrated by reverse-transcription polymerase-chain reaction (RT-PCR) and western blotting. Expression of parkin in HUVEC was not altered with tunicamycin treatment, which exerts unfolded protein stress on cells. We conclude that parkin is expressed in VEC, and that unfolded protein stress may not regulate its expression.

気管支結石症の2症例を提示する.症例1は46歳女性.乾性咳嗽を主訴に受診し,胸部X線上右中下葉の含気の低下, CTで中間幹に石灰化腫瘤.気管支鏡下に9mmの結石を摘出し,結石下の瘢痕性狭窄部にレーザー治療を行った.症例2は48歳男性.咳嗽を主訴.胸部X線上右S3の肺炎像, CTで右B3aに石灰化結節を認めた.気管支鏡にて8mmの結石を摘出した. 2症例ともに可動性があり,気管支鏡下に治療が可能であった.

The patient was a 36-year-old male. He visited our department in February 2004 as a prior chest X-ray revealed multiple nodular shadows. After further examinations, he was diagnosed with stage IV adenocarcinoma of the lung. As treatment, 5 courses of carboplatin (CBDCA)+docetaxel (DOC), 3 courses of CBDCA+gemcitabine (GEM), 6 weeks of gefitinib, and 3 courses of GEM were administered. However, the tumor progressed, and S-1 (120 mg/day, 2 weeks on, 1 week off) was administered as the sixth regimen from May 2006. No severe side effects were observed, and an antitumor action was achieved over a relatively long period. Therefore, it was suggested that a single administration of S-1 for non-small cell lung cancer, which had been treated with other multiple regimens, is safe, and long-term control of the disease can be expected.

癌性胸膜炎に対するCisplatin (CDDP) の胸腔内投与物質としての有用性を評価するために, 1) CDDPの家兎胸膜刺激作用, 2) 癌性胸膜炎患者におけるCDDPの体内動態, 3) その臨床効果について検討した. その結果, CDDPは強い胸膜刺激作用を持ち, 比較的長時間胸腔内に維持できる薬剤であると考えられた. また臨床的にも奏効率73%, 平均生存期間220.3日と, 従来癌性胸膜炎に用いられてきた胸腔内投与物質と比較しても遜色のないものであった.

To find predicted values of respiratory function tests in young persons in Japan, we measured slow vital capacity and forced vital capacity in 1,141 subjects aged from 10 to 20 years. The values obtained from 636 persons (363 males and 273 females) who were not smokers or had no suspected rhinitis or asthma were analyzed. Although FEV1% by the Gaensler and Tiffeneau methods were almost constant regardless of age, all other values of respiratory function tests increased with age and then reached a plateau level in late teens. Excluding the Gaensler and Tiffeneau FEV1%, in a single regression analysis using gender, age, and height, both the contribution ratio and regression coefficient were the highest using height, followed by age. In addition, the result was similar with multiple regression analysis. Therefore, for a young person aged from 10 to 20 years, body height is the most important predictor variable of respiratory function tests, compared to gender and age. For each respiratory function test, we showed the prediction relation according to gender obtained from multiple linear regression analysis using 2 variables of height and age.

To clarify the reason why central fibrosis (CF) is an important histological prognostic factor in small adenocarcinoma (SA) of the lung, tumor tissues from 50 patients with SA < or = 2 cm in diameter were investigated using immunohistochemical and in situ hybridization analysis for factors relating to extracellular matrix and vessels. CF was observed in 33/50 cases (66%). In adenocarcinoma areas, positive activity was observed with both primary antibodies and probes for matrix metalloproteinase-2 (MMP-2) in 11/50 patients (22%), membrane-type 1 matrix metalloproteinase (MT1-MMP) in 39/50 patients (78%) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in 49/50 patients (98%). In CF areas, the positive activity of fibroblastic cells was seen for only TIMP-2 in 32/33 patients (97%). In CF areas, both CD34-positive (blood and lymphatic) vessels and D2-40-positive lymphatic vessels were semiquantitatively increased in 16/33 patients (48.5%) by immunohistochemistry. Tumors with increased vessel density were associated with statistically lower disease-free survival curves compared with tumors without increased vessels. Lymphatic vessels in some CF showed intravasation by carcinoma cells. In conclusion, CF could be an important histological prognostic factor in SA chiefly because of its association with angiogenesis and lymphangiogenesis.

Summary Background Diagnosing tuberculous pleural effusion (pTB) is often difficult because the culturing of tubercle bacilli results in a negative test in the majority of cases. Serological tests for the detection of antibodies to tuberculous glycolipid (TBGL) and lipoarabinomannan (LAM) have been introduced for the diagnosis of pulmonary tuberculosis. We examined the levels of these antibodies, adenosine deaminase (ADA) and interferon- γ (IFN- γ ) in the pleural effusion and compared their diagnostic values in pTB. Methods We studied 65 patients with pleural effusion. Of those, 19 patients were diagnosed as having pTB according to our broad case definition. The etiologies in the other 46 patients were malignant effusion, transdative effusion and miscellaneous diseases. Determiner TBGL antibody ® (D-TBGL-Ab) and MycoDot ® were used for the detection of anti-LAM and anti-TBGL antibodies, respectively, in the pleural effusion. Results The sensitivity of ADA was 78.9% (15/19) and the specificity 97.8% (45/46). The sensitivity of IFN- γ was 84.2% (16/19) and the specificity 93.5% (43/46). The sensitivities of D-TBGL-Ab and MycoDot ® were both 52.6% (10/19) and their specificities were 95.7% (44/46) and 97.8% (45/46), respectively. When DTBGL-Ab (cutoff point: 2.0U/ml) and ADA activity (cutoff point: 57IU/l) were combined, the sensitivity was 94.7% (18/19) and the specificity 93.5% (43/46). Conclusions In the diagnosis of pTB, D-TBGL-Ab and MycoDot ® each have low sensitivity but high specificity. When D-TBGL-Ab is used in combination with ADA, the sensitivity and specificity are both >90%. We conclude that D-TBGL-Ab and ADA in combination are useful in the diagnosis of pTB.

BEAS-2B bronchial epithelial cells were treated with polyinosinic-polycytidylic acid (poly IC), a synthetic double-stranded RNA (dsRNA) analog, and the expressions of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein were analyzed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Poly IC enhanced the expression of MCP-1 and release of mononuclear cell chemotactic activity, which were inhibited by dexamethasone pre-treatment. The poly IC-induced up-regulation of MCP-1 was blocked by 2-aminopurine, a specific inhibitor of dsRNA-dependent protein kinase, but not by nuclear factor (NF)-kappaB inhibitor SN50.