Search

Aim: To investigate the associations between major foods and dietary fibre with subtypes of stroke in a large prospective cohort., Methods and Results: We analysed data on 418 329 men and women from nine European countries, with an average of 12.7 years of follow-up. Diet was assessed using validated country-specific questionnaires which asked about habitual intake over the past year, calibrated using 24-h recalls. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HRs) for ischaemic and haemorrhagic stroke associated with consumption of red and processed meat, poultry, fish, dairy foods, eggs, cereals, fruit and vegetables, legumes, nuts and seeds, and dietary fibre. For ischaemic stroke (4281 cases), lower risks were observed with higher consumption of fruit and vegetables combined (HR; 95% CI per 200 g/day higher intake, 0.87; 0.82-0.93, P-trend < 0.001), dietary fibre (per 10 g/day, 0.77; 0.69-0.86, P-trend < 0.001), milk (per 200 g/day, 0.95; 0.91-0.99, P-trend = 0.02), yogurt (per 100 g/day, 0.91; 0.85-0.97, P-trend = 0.004), and cheese (per 30 g/day, 0.88; 0.81-0.97, P-trend = 0.008), while higher risk was observed with higher red meat consumption which attenuated when adjusted for the other statistically significant foods (per 50 g/day, 1.07; 0.96-1.20, P-trend = 0.20). For haemorrhagic stroke (1430 cases), higher risk was associated with higher egg consumption (per 20 g/day, 1.25; 1.09-1.43, P-trend = 0.002)., Conclusion: Risk of ischaemic stroke was inversely associated with consumption of fruit and vegetables, dietary fibre, and dairy foods, while risk of haemorrhagic stroke was positively associated with egg consumption. The apparent differences in the associations highlight the importance of examining ischaemic and haemorrhagic stroke subtypes separately., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC., Methods: This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured., Results: Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, P < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients., Conclusions: Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Associations between driving and physical-activity (PA) intensities are unclear, particularly among older adults. We estimated prospective associations of travel modes with total PA, sedentary time (ST), light-intensity PA (LPA), and moderate-to-vigorous intensity PA (MVPA) among adults aged 39-70 years., Methods: We studied 90 810 UK Biobank participants (56.1 ± 7.8 years). Driving status, specific travel modes (non-work travel; commuting to/from work) and covariates were assessed by questionnaire (2006-10). PA was assessed over 7 days by wrist-worn accelerometers (2013-15). We estimated associations using overall and age-stratified multivariable linear-regression models., Results: Drivers accumulated 1.4% more total PA (95% confidence interval: 0.9, 1.9), 11.2 min/day less ST (-12.9, -9.5), 12.2 min/day more LPA (11.0, 13.3) and 0.9 min/day less MVPA (-1.6, -0.2) than non-drivers. Compared with car/motor-vehicle users, cyclists and walkers had the most optimal activity profiles followed by mixed-mode users (e.g. for non-work travel, cyclists: 10.7% more total PA, 9.0, 12.4; 20.5 min/day less ST, -26.0, -15.0; 14.5 min/day more MVPA, 12.0, 17.2; walkers: 4.2% more total PA, 3.5, 5.0; 7.5 min/day less ST -10.2, -4.9; 10.1 min/day more MVPA, 8.9, 11.3; mixed-mode users: 2.3% more total PA, 1.9, 2.7; 3.4 min/day less ST -4.8, -2.1; 4.9 min/day more MVPA, 4.3, 5.5). Some associations varied by age (p interaction < 0.05), but these differences appeared small., Conclusions: Assessing specific travel modes rather than driving status alone may better capture variations in activity. Walking, cycling and, to a lesser degree, mixed-mode use are associated with more optimal activity profiles in adults of all ages., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Diet is an important risk factor for cancer that is amenable to intervention. Estimating the cancer burden associated with diet informs evidence-based priorities for nutrition policies to reduce cancer burden in the United States., Methods: Using a comparative risk assessment model that incorporated nationally representative data on dietary intake, national cancer incidence, and estimated associations of diet with cancer risk from meta-analyses of prospective cohort studies, we estimated the annual number and proportion of new cancer cases attributable to suboptimal intakes of seven dietary factors among US adults ages 20 years or older, and by population subgroups., Results: An estimated 80 110 (95% uncertainty interval [UI] = 76 316 to 83 657) new cancer cases were attributable to suboptimal diet, accounting for 5.2% (95% UI = 5.0% to 5.5%) of all new cancer cases in 2015. Of these, 67 488 (95% UI = 63 583 to 70 978) and 4.4% (95% UI = 4.2% to 4.6%) were attributable to direct associations and 12 589 (95% UI = 12 156 to 13 038) and 0.82% (95% UI = 0.79% to 0.85%) to obesity-mediated associations. By cancer type, colorectal cancer had the highest number and proportion of diet-related cases (n = 52 225, 38.3%). By diet, low consumption of whole grains (n = 27 763, 1.8%) and dairy products (n = 17 692, 1.2%) and high intake of processed meats (n = 14 524, 1.0%) contributed to the highest burden. Men, middle-aged (45-64 years) and racial/ethnic minorities (non-Hispanic blacks, Hispanics, and others) had the highest proportion of diet-associated cancer burden than other age, sex, and race/ethnicity groups., Conclusions: More than 80 000 new cancer cases are estimated to be associated with suboptimal diet among US adults in 2015, with middle-aged men and racial/ethnic minorities experiencing the largest proportion of diet-associated cancer burden in the United States.

Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D., Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis., Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]., Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

Background: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care., Methods: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study., Results: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient)., Conclusions: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised., Clinical Trial Registration: NCT02296125 (ClinicalTrials.gov).

Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study., Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days)., Results: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient., Conclusions: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC., Clinicaltrials.gov Identifier: NCT01828112.

Background: The purpose of this study was to test the hypothesis that the genetic backgrounds of lung cancers could affect the spatial distribution of brain metastases., Methods: CT or MR images of 200 patients with a total of 1033 treatment-naive brain metastases from lung cancer were retrospectively reviewed (23 by CT and 177 by MRI). All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Locations, depths from the brain surface, and sizes of the lesions after image standardization were analyzed., Results: The posterior fossa, the anatomic "watershed areas," and the gray-white matter junction were confirmed to be more commonly affected by lung cancer brain metastases, and brain metastases with epidermal growth factor receptor (EGFR) L858R mutation occurred more often in the caudate, cerebellum, and temporal lobe than those with exon 19 deletion of EGFR. Median depths of the lesions from the brain surface were 13.7 mm (range, 8.6-21.9) for exon 19 deleted EGFR, 11.5 mm (6.6-16.8) for L858R mutated, and 15.0 mm (10.0-20.7) for wild-type EGFR. Lesions with L858R mutated EGFR were located significantly closer to the brain surface than lesions with exon 19 deleted or wild-type EGFR (P = .0032 and P < .0001, respectively). Furthermore, brain metastases of adenocarcinoma lung cancer patients with a history of chemotherapy but not molecular targeted therapy were located significantly deeper from the brain surface (P = .0002)., Conclusion: This analysis is the first to reveal the relationship between EGFR mutation status and the spatial distribution of brain metastases of lung cancer., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice., Methods: Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years × 100., Results: The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with ≥2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status., Conclusion: Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan., (© The Author 2016. Published by Oxford University Press.)

Background: Genotyping of EGFR (epidermal growth factor receptor) mutations is indispensable for making therapeutic decisions regarding whether to use EGFR tyrosine kinase inhibitors (TKIs) for lung cancer. Because some cases might pose challenges for biopsy, noninvasive genotyping of EGFR in circulating tumor DNA (ctDNA) would be beneficial for lung cancer treatment., Methods: We developed a detection system for EGFR mutations in ctDNA by use of deep sequencing of plasma DNA. Mutations were searched in >100 000 reads obtained from each exon region. Parameters corresponding to the limit of detection and limit of quantification were used as the thresholds for mutation detection. We conducted a multi-institute prospective study to evaluate the detection system, enrolling 288 non-small cell lung cancer (NSCLC) patients., Results: In evaluating the performance of the detection system, we used the genotyping results from biopsy samples as a comparator: diagnostic sensitivity for exon 19 deletions, 50.9% (95% CI 37.9%-63.9%); diagnostic specificity for exon 19 deletions, 98.0% (88.5%-100%); sensitivity for the L858R mutation, 51.9% (38.7%-64.9%); and specificity for L858R, 94.1% (83.5%-98.6%). The overall sensitivities were as follows: all cases, 54.4% (44.8%-63.7%); stages IA-IIIA, 22.2% (11.5%-38.3%); and stages IIIB-IV, 72.7% (60.9%-82.1%)., Conclusions: Deep sequencing of plasma DNA can be used for genotyping of EGFR in lung cancer patients. In particular, the high specificity of the system may enable a direct recommendation for EGFR-TKI on the basis of positive results with plasma DNA. Because sensitivity was low in early-stage NSCLC, the detection system is preferred for stage IIIB-IV NSCLC., (© 2015 American Association for Clinical Chemistry.)

Circulating tumour DNA (ctDNA) is an emerging field of cancer research. However, current ctDNA analysis is usually restricted to one or a few mutation sites due to technical limitations. In the case of massively parallel DNA sequencers, the number of false positives caused by a high read error rate is a major problem. In addition, the final sequence reads do not represent the original DNA population due to the global amplification step during the template preparation. We established a high-fidelity target sequencing system of individual molecules identified in plasma cell-free DNA using barcode sequences; this system consists of the following two steps. (i) A novel target sequencing method that adds barcode sequences by adaptor ligation. This method uses linear amplification to eliminate the errors introduced during the early cycles of polymerase chain reaction. (ii) The monitoring and removal of erroneous barcode tags. This process involves the identification of individual molecules that have been sequenced and for which the number of mutations have been absolute quantitated. Using plasma cell-free DNA from patients with gastric or lung cancer, we demonstrated that the system achieved near complete elimination of false positives and enabled de novo detection and absolute quantitation of mutations in plasma cell-free DNA., (© The Author 2015. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Insulin resistance (IR) and pancreatic β-cell dysfunction lead to type 2 diabetes mellitus (DM). We tested whether risk factors would differ for DM that was preceded predominantly by IR, β-cell dysfunction, or both among 4,384 older adults (mean age, 72.7 (standard deviation, 5.6) years) in the Cardiovascular Health Study, which was conducted in North Carolina, California, Maryland, and Pennsylvania (1989-2007). When evaluating established risk factors, we found older age, greater adiposity, higher systolic blood pressure, a lower high-density lipoprotein cholesterol level, a higher triglyceride level, and a lower alcohol intake to be independently associated with greater IR but, conversely, with better β-cell function (P < 0.001). The prospective associations between some risk factors and incident DM varied significantly depending on whether DM was preceded predominantly by IR, β-cell dysfunction, or both. For example, obesity and lower high-density lipoprotein cholesterol levels were positively associated with DM preceded predominantly by IR (hazard ratio (HR) = 5.02, 95% confidence interval (CI): 2.81, 9.00; and HR = 1.97, 95% CI: 1.32, 2.93, respectively), with a significant association with and an insignificant trend toward a lower risk of DM preceded predominantly by β-cell dysfunction (HR = 0.33, 95% CI: 0.14, 0.80; and HR = 0.78, 95% CI: 0.43, 1.39, respectively). In conclusion, among older adults, DM risk factors were differentially associated with DM preceded predominantly by IR or β-cell dysfunction. Biologic and clinical implications of putative subtypes of DM require further investigation.

The analytic approaches used in nutritional epidemiology for dietary pattern analyses share common characteristics with those of genetic epidemiology. In this issue of the Journal, Gorst-Rasmussen et al. (Am J Epidemiol. 2011;173(10):1097-1104) discuss one such approach. Application of methods used in genetic pattern analyses to nutritional epidemiology could prove valuable but raises important issues that need to be considered because dietary and genetic studies often address different types of questions in analyzing interrelated variables. These different aims require statistical methods that assume different characteristics of the underlying patterns. The authors briefly describe such differences to facilitate interpretation and applications of previous and future pattern studies.

The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991-2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of > or =9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk.

Infliximab, an anti-tumor necrosis factor alpha antibody, is among the most effective therapies for rheumatoid arthritis (RA). In this study, we report a patient with early RA of 6 months who has Sjögren's syndrome and pulmonary nodular lesions concomitantly. The patient did not respond to methotrexate (MTX, 6;Smg per week) for 3 months. When introduction of infliximab therapy is considered, we need to exclude the possibility of pulmonary granulomatous infection and malignancy. With the use of computed tomography-guided percutaneous needle biopsy and subsequent histological examinations, this case was rapidly and confidently diagnosed as localized pulmonary nodular amyloidosis. Immunochemical staining showed light chain type nodular amyloidosis by a deposition of immunoglobulin kappa light chains, which is a rare condition in a patient with Sjögren's syndrome. We started combination therapy of infliximab (200;Smg per infusion) and MTX (6;Smg per week). Because of severe systemic eruption, this therapy was stopped halfway through the third infusion of infliximab, and MTX monotherapy was continued. Despite the withdrawal of infliximab therapy, the C-reactive protein values were decreased to an undetectable level at week 14, and the disease activity score for 28 joints was 3.1 at week 22. Clinical remission has been maintained more than 14 months with MTX alone. Infliximab has been used only for patients with recalcitrant RA, because the cost of its lifelong use would be an economic burden in most cases. An optimal and affordable strategy for the treatment of early RA should be developed. Our findings may support the idea that the combination therapy of infliximab and MTX for early RA alters the course of the disease.

Methotrexate (MTX) pneumonia is an unpredictable and sometimes life-threatening adverse effect occurring in the treatment of rheumatoid arthritis (RA). We present a case of MTX pneumonia lacking severe respiratory symptoms and typical radiographic findings. A 66-year-old man with early RA presented with intermittent fever and nonproductive cough during the MTX therapy, but neither hypoxemia nor dyspnea was a complaint. His chest X-ray films revealed multiple bilateral consolidations, but interstitial infiltrates were not observed. High-resolution computed tomography showed no ground-glass opacities. In contrast, the histological findings of transbronchial lung biopsy (TBLB) samples were characterized by the interstitial infiltration of mononuclear cells and hyperplasia of type II alveolar cells, which are the main features of drug-induced interstitial inflammation. Special stains for microorganisms were negative for the TBLB samples. Although cultures of bronchoalveolar lavage (BAL) fluids were slightly positive for Haemophilus influenzae, intensive antibiotic therapy was ineffective. A discontinuation of MTX followed by steroid therapy induced the patient's dramatic recovery. A new treatment with tacrolimus was started for RA. We would like to emphasize that the histological examinations and microbiological studies using BAL and TBLB are useful for the exclusion of other causes and the diagnosis of MTX pneumonia, especially in a case without typical respiratory symptoms and radiographic patterns.

Infliximab, an anti-tumor necrosis factor (TNF)-alpha antibody, was introduced to a 66-year-old woman with methotrexate (MTX)-resistant rheumatoid arthritis (RA). Although the TNF-blocking therapy was successful, she developed noninfectious interstitial pneumonia (IP) after a second infusion of infliximab. In most cases reported previously, infliximab-associated noninfectious IP occurred after a second or third infusion of infliximab, and this type of IP was more fatal in comparison with cases associated with MTX treatment alone. Keeping a sharp lookout on IP development during this period is crucial to the success of infliximab treatment. After MTX discontinuation and steroid pulse therapy, our patient made a dramatic recovery from IP.

We report that a-63-year-old woman developed Pneumocystis jiroveci pneumonia (PCP) as a complication from treatment with infliximab for rheumatoid arthritis. Although there was neither symptoms of dyspnea nor typical observations on a chest X-ray examination, low levels of oxygen saturation and findings of high-resolution chest computed tomographic scanning suggested a possibility of interstitial pneumonia. A polymerase chain reaction-based detection of Pneumocystis jiroveci in induced sputum allowed an early diagnosis of PCP and subsequent effective treatment.

Background: More than 30% of cases of non-small cell lung cancer (NSCLC) arise in patients aged > or =70 years. The efficacy and safety of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced NSCLC were evaluated in a phase II trial., Methods: Twenty-five patients aged > or =70 years (median, 76; range, 70-83) with chemotherapy-naive advanced NSCLC were enrolled between January 2001 and July 2003. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients received carboplatin at an area under the curve of 5 mg/ml/min and paclitaxel at 180 mg/m(2) on the first day of consecutive 3 week periods., Results: The patients included four with stage IIIB, 19 with stage IV and two with recurrent disease. The median number of treatment cycles was three (range, 1-4). One complete response and six partial responses, yielding an objective response rate of 28%, were obtained. The median survival time was 12.3 months and the 1-year survival rate was 52%. Hematological toxicities of grade 3 or 4 included leukopenia (40%), neutropenia (68%) and anemia (4%). Non-hematological toxicities of grade 3 included arthralgia-myalgia (16%) and neuropathy (12%). The objective response rate for patients aged > or =75 years (n = 15) was 26%, and no evidence of excessive toxicity in these patients was apparent compared with those aged <75 years., Conclusion: The combination carboplatin-paclitaxel at these doses is a feasible treatment option with a favorable toxicity profile for fit elderly patients with advanced NSCLC.

An in vitro monolayer model for cancer invasion was developed, comprising cultured layers of human pleura-derived mesothelial cells (PM cells). The cells were isolated from normal human pleura at autopsy and cultured in RPMI-1640 supplemented with 10% fetal calf serum; they were polygonal in shape, forming a pavement-like structure, and preserved the morphologic characteristics of mesothelial cells. When small cell lung cancer cells (OC-10 cells) were seeded on to the monolayer of PM cells, they attached themselves to the monolayer, invaded it and formed flattened cancer cell nests beneath it. By counting the number of cancer cells penetrated, the in vitro invasiveness (invasive capacity) of the cancer cells was assayed. The invasive capacity of poorly invasive cells (10N), which were cloned from OC-10 cells, was five times less than that of the parental OC-10 cells. These results indicate our system to provide a useful model for studying human cancer cell invasion.