Phase II trial of S-1 as third-line or further chemotherapy in patients with advanced non-small-cell lung cancer.

OBJECTIVES: This study was conducted to evaluate the efficacy and safety of S-1 in patients with advanced non-small-cell lung cancer (NSCLC), receiving two or more prior chemotherapy regimens. METHODS: S-1 was administered orally for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity occurred. RESULTS: From 2010 to 2012, 45 patients were enrolled in this study. Of the 45 patients, 4 patients [8.9 %, 95 % confidence interval (CI) 0.6-17.2 %] exhibited a partial response and 24 patients (53.3 %) exhibited stable disease. The disease control rate was 62.2 % (95 % CI 48.1-76.4 %). Median progression-free survival was 71 days, and median survival time was 205 days. Four patients had grade 3 hematological toxicities, but toxicities of grade 4 were not observed in this study. CONCLUSION: Although S-1 monotherapy as third-line treatment or beyond was well tolerated, the response rate for this regimen did not demonstrate sufficient activity for patients with advanced NSCLC.

Prediction of Spirometric Indices Using Forced Oscillometric Indices in Patients with Asthma, COPD, and Interstitial Lung Disease.

Background and Objective: Spirometry is sometimes difficult to perform in elderly patients and patients with cognitive impairment. Forced oscillometry (FOT) is a simple, noninvasive technique used for measuring respiratory impedance. The aim of this study was to develop regression equations to estimate vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1.0) on the basis of FOT indices and to evaluate the accuracy of these equations in patients with asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Materials and Methods: We retrospectively included data on 683 consecutive patients with asthma (388), COPD (128), or ILD (167) in this study. We generated regression equations for VC, FVC, and FEV1.0 by multivariate linear regression analysis and used them to estimate the corresponding values. We determined whether the estimated data reflected spirometric indices. Results: Actual and estimated VC, FVC, and FEV1.0 values showed significant correlations (all r > 0.8 and P < 0.001) in all groups. Biases between the actual data and estimated data for VC, FVC, and FEV1.0 in the asthma group were -0.073 L, -0.069 L, and 0.017 L, respectively. The corresponding values were -0.064 L, 0.027 L, and 0.069 L, respectively, in the COPD group and -0.040 L, -0.071 L, and -0.002 L, respectively, in the ILD group. The estimated data in the present study did not completely correspond to the actual data. In addition, sensitivity for an FEV1.0/FVC ratio of <0.7 and the diagnostic accuracy for the classification of COPD grade using estimated data were low. Conclusion: These results suggest that our method is not highly accurate. Further studies are needed to generate more accurate regression equations for estimating spirometric indices based on FOT measurements.

[A case of sarcoidosis with multiple nodules showing cavitary formation].

A 24-year-old woman was admitted to our hospital for examinations of multiple nodules in bilateral lung fields. Mediastinal lymph node specimen by surgical resection revealed non-caseating epithelioid cell granuloma which was compatible with sarcoidosis. Some nodules showed cavitary formation without any treatment. Bacteriological and cytological studies yielded negative results. This is a rare case of sarcoidosis with multiple nodules showing cavitary formation.

Docetaxel and cisplatin as second-line chemotherapy for advanced non-small cell lung cancer.

AIMS AND BACKGROUND: Docetaxel and cisplatin are both active against non-small cell lung cancer (NSCLC). This pilot study evaluated the efficacy and toxicity of docetaxel and cisplatin as second-line chemotherapy for patients with advanced NSCLC. PATIENTS AND METHODS: Eleven patients with advanced NSCLC who had no response to platinum-based treatment or had recurrence after a partial response were enrolled (2 stage III B, 9 stage IV; 8 men, 3 women). Median age was 58 years (range, 40 to 74 years). Seven patients had an Eastern Cooperative Oncology Group performance status of 0, and four had a performance status of 1. Four weeks or more after the end of previous therapy, all 11 patients received docetaxel 60 mg/m2 and cisplatin 80 mg/m2 on day 1 every four weeks. RESULTS: Two patients (18.2%) achieved a partial response,five (45.4%) patients had stable disease, and four (36.4%) patients showed progressive disease after initiation of second-line therapy. Median survival was 277 days. Median time to disease progression was 101 days, and the one-year survival rate was 36.4%. Hematological toxicities were moderate. Grade 3 and 4 leukocytopenia and neutropenia were observed in five (45.4%) patients. Grade 3 anemia occurred in one (9 .1%) patient. No severe non-hematological toxicities were observed except grade 3 nausea in two (18.2%) patients. CONCLUSIONS: The regimen of docetaxel and cisplatin has reasonable efficacy with moderate toxicity as second-line chemotherapy for patients with previously treated, advanced NSCLC.

Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study.

PURPOSE: As the major toxicity induced by pemetrexed plus carboplatin is severe hematologic toxicities, the aim of this study was to determine the risk factors for severe hematologic toxicities in lung cancer patients. METHODS: We retrospectively investigated data from lung cancer patients who had received pemetrexed plus carboplatin, with or without bevacizumab. This observational study was carried out at Ehime University Hospital using electronic medical records dating from July 2009 to March 2015. Severe hematologic toxicities were defined as grade 3 or 4, according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Forty-two patients were included in the study. The incidence of grade 3 or 4 hematologic toxicities during the first cycle of chemotherapy and during all cycles was 19.0% and 16.1%, respectively. Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27-54.38; p = 0.03), whereas creatinine clearance of <45 mL/min was not significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted OR: 0.91, 95% CI: 0.25-3.34; p = 0.88). CONCLUSIONS: The results suggest that severe hematologic toxicities in patients receiving carboplatin-based pemetrexed may be significantly induced by the inhibition of renal tubular pemetrexed secretion through drug-drug interactions between NSAIDs and pemetrexed rather than through glomerular filtration of pemetrexed, even with moderate to sufficient renal function.

Use of the forced-oscillation technique to estimate spirometry values.

PURPOSE: Spirometry is sometimes difficult to perform in elderly patients and in those with severe respiratory distress. The forced-oscillation technique (FOT) is a simple and noninvasive method of measuring respiratory impedance. The aim of this study was to determine if FOT data reflect spirometric indices. PATIENTS AND METHODS: Patients underwent both FOT and spirometry procedures prior to inclusion in development (n=1,089) and validation (n=552) studies. Multivariate linear regression analysis was performed to identify FOT parameters predictive of vital capacity (VC), forced VC (FVC), and forced expiratory volume in 1 second (FEV1). A regression equation was used to calculate estimated VC, FVC, and FEV1. We then determined whether the estimated data reflected spirometric indices. Agreement between actual and estimated spirometry data was assessed by Bland-Altman analysis. RESULTS: Significant correlations were observed between actual and estimated VC, FVC, and FEV1 values (all r>0.8 and P<0.001). These results were deemed robust by a separate validation study (all r>0.8 and P<0.001). Bias between the actual data and estimated data for VC, FVC, and FEV1 in the development study was 0.007 L (95% limits of agreement [LOA] 0.907 and -0.893 L), -0.064 L (95% LOA 0.843 and -0.971 L), and -0.039 L (95% LOA 0.735 and -0.814 L), respectively. On the other hand, bias between the actual data and estimated data for VC, FVC, and FEV1 in the validation study was -0.201 L (95% LOA 0.62 and -1.022 L), -0.262 L (95% LOA 0.582 and -1.106 L), and -0.174 L (95% LOA 0.576 and -0.923 L), respectively, suggesting that the estimated data in the validation study did not have high accuracy. CONCLUSION: Further studies are needed to generate more accurate regression equations for spirometric indices based on FOT measurements.

Two cases of primary pulmonary osteosarcoma.

Two cases of primary pulmonary osteosarcoma are presented. In both cases, chest computed tomography revealed a calcified pulmonary mass and technetium-99m methylene diphosphonate bone scintigraphy showed intense uptake in the pulmonary mass. Primary pulmonary osteosarcoma was suspected on the basis of these radiographic findings. Microscopic examination of tumor specimens obtained by needle biopsy revealed histologic features of osteosarcoma, and this diagnosis was confirmed by postmortem examination of a second specimen in each case. Radiographic and histopathological findings enabled us to diagnose primary pulmonary osteosarcoma, which is one of the rarest types of cancer.

Hemoperitoneum secondary to spontaneous rupture of hepatic metastasis from lung cancer.

We describe a rare case of hemoperitoneum secondary to spontaneous rupture of hepatic metastasis from lung cancer. A 72-year-old man with non-small cell lung cancer was admitted to our hospital with sudden onset of right upper abdominal pain and hypovolemic shock. Laboratory tests showed severe anemia. Abdominal contrast-enhanced computed tomography revealed massive ascites and multiple liver metastases. Rupture of a metastatic liver tumor was suspected. Only palliative therapy was performed. The patient's general condition gradually worsened, and he died 2 months after admission. Autopsy examination revealed hemoperitoneum due to a ruptured metastatic liver tumor originating from pulmonary squamous cell carcinoma.

Histopathologic changes in serum bile acid fractions in pressure ulcer patients.

BACKGROUND/AIMS: Bile acids are synthesized in the liver and released into the intestinal tract to aid in digestion and absorption by increasing permeability via alteration of the cell membrane. Bedridden elderly patients typically have pressure ulcers that may be due to both physical local pressure as well as skin cell changes induced by the physiologic effects of bile acids. METHODOLOGY: This study investigated 31 elderly bedridden patients with pressure ulcers (mean age, 81.7 years) and 19 healthy elderly (mean age, 79.7 years). Five serum bile acid fractions were summed to determine total bile acid, and transaminase and cholesterol levels were also measured. RESULTS: Total cholesterol levels were significantly lower (p<0.05) in pressure ulcer patients and transaminase levels were not significantly different between the two groups. The primary bile acids were generally higher and the secondary and tertiary bile acids lower in pressure ulcer patients. In particular, the secondary bile acid deoxycholic acid was significantly higher in all pressure ulcer patients. When analyzed by grade of pressure ulcer, the primary bile acids were significantly lower in pressure ulcer patients. CONCLUSIONS: Secondary bile acid fraction deoxycholic acid measurements may indicate bedridden patients at higher risk for pressure ulcers.

[A case of small cell lung cancer with intramedullary spinal cord metastasis].

An 83-year-old man was admitted with paraplegia and loss of all sensation below the level of umbilicus, with bowel and bladder dysfunction. Stage IV small cell lung cancer had been diagnosed two years ago and had received several courses of chemotherapies. A magnetic resonance imaging revealed an enhanced mass in the intramedullary spinal cord at the level of Th10-L1. Metastatic spinal tumor was diagnosed by clinical and radiological examinations. This is a rare case of small cell lung cancer with intramedullary spinal cord metastasis which caused various neurological symptoms.

A case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-tyrosine kinase inhibitors with MET amplification and epithelial-to-mesenchymal transition.

EGFR mutant lung cancer responds to EGFR tyrosine kinase inhibitors (TKIs), but all patients eventually develop resistance to EGFR-TKIs. Herein we report a case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-TKI with MET amplification and epithelial-to-mesenchymal transition (EMT). A 73-year-old woman was diagnosed with adenocarcinoma harboring an EGFR exon 19 deletion. She received gefitinib as second-line therapy. Tumors were reduced 1 month after gefitinib therapy. However, only a few months later, chest computed tomography results indicated cancer progression. Gefitinib therapy was stopped and docetaxel therapy started. However, she died 13 days after admission. Microscopic examination of postmortem specimens revealed a diffuse proliferation of atypical giant cells in primary and metastatic lesions, but no adenocarcinomatous components as in the antemortem specimens. Immunohistochemical analyses showed that antemortem tumor specimens were positive for CDH1 but negative for VIM. In contrast, postmortem tumor specimens were positive for VIM but negative for CDH1. Genetic analyses revealed MET amplification. We concluded that resistance to EGFR-TKI might be caused by MET amplification and EMT. To our knowledge, no clinical studies have reported that MET amplification and EMT together may be associated with acquired resistance to EGFR-TKI. Second biopsy after the development of EGFR-TKI resistance may be recommended to determine the best therapeutic strategy.

Combined atypical carcinoid tumour and squamous cell carcinoma of the lung.

A 71-year-old man diagnosed with lung cancer in the right lower lobe with invasion to the middle lobe underwent right lower and middle lobectomy with mediastinal lymph node dissection. The cancer was pathologically diagnosed as stage IIB (pT3N0M0) with combined squamous cell carcinoma and an atypical carcinoid tumour. To the best of our knowledge, this is the first report of a combined atypical carcinoid tumour and non-small cell lung cancer. This case further expands the histological spectrum of combined neuroendocrine tumours.

Humidifier lung: possible contribution of endotoxin-induced lung injury.

A 56-year-old man was admitted with cough, fever, myalgia, and arthralgia. Chest computed tomography demonstrated bilateral diffuse ground-glass opacities predominantly in the upper lungs. Subpleural non-segmental consolidation was observed in the late phase. Hypersensitivity pneumonitis was suspected, and an environmental provocation test with the incidental use of a home ultrasonic humidifier was positive. Unlike typical hypersensitivity pneumonitis, serum KL-6 levels were normal. Although several microorganisms were isolated from the humidifier water, there was no evidence for immune sensitization. We detected high amounts of endotoxin in the humidifier water, which may have contributed to the lung injury of this patient.

[Successful treatment of bronchiolitis obliterans organizing pneumonia with cyclosporin and steroids].

A 71-year-old woman with fever and dry cough was admitted to our hospital. Chest computed tomography, bronchoalveolar lavage and transbronchial lung biopsy were performed, and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed. The patient was treated with corticosteroid, and marked improvement was noted. However, when the dosage was tapered, the BOOP recurred. We increased the dosage of corticosteroid and also put the patient on a daily regimen of cyclosporin. The cyclosporin was administered orally, and was effective, so that we could gradually decrease the dosage of corticosteroid. We concluded that cyclosporin may be useful in the treatment of refractory BOOP.

[A case of primary adenocarcinoma of the trachea].

Primary adenocarcinoma of the trachea is rare. We present a case that was successfully treated with radiotherapy followed by surgical resection. A 66-year-old man was admitted to our hospital because of cough, sputum and dyspnea. A chest CT film showed a tracheal tumor, and transtracheal biopsy specimen showed well-differentiated papillary adenocarcinoma. Other examinations excluded the diagnosis of metastatic adenocarcinoma from other organs. Since stenosis of the trachea was rapidly progressive, a tracheal stent was inserted to alleviate the obstruction. After radiotherapy, the tumor size decreased, after which surgical resection was performed. No recurrence had been observed 26 months after the operation.

[Cardiac tamponade with paroxysmal atrial flutter controlled by antituberculous therapy].

We report a rare and unique case of possible extrapulmonary tuberculosis in an 83-year-old man who had cardiac tamponade and paroxysmal atrial flutter. The patient was admitted to our hospital because of syncope. The cardiac tamponade and paroxysmal atrial flutter were treated by pericardiocentesis and drainage of bloody pericardial fluid. Mycobacterium tuberculosis was not detected in diagnostic specimens, nor was any evidence of malignancy found. The remarkable elevation of adenosine deaminase and the predominance of lymphocytes in the pericardial fluid, considering the past history of tuberculosis, led to a diagnosis of extrapulmonary tuberculosis. After receiving standard antituberculous therapy by ethambutol, isoniazid, and rifampicin, the patient recovered and has remained well up to the present day. Thirty-six months have passed since his recovery without the recurrence of cardiac tamponade or any other cardiac events.

[A case of interstitial pneumonia caused by gosha-jinki-gan].

A 74-year-old woman was admitted to the hospital of Ehime University School of Medicine because of slight fever, dry cough and dyspnea on exertion. Chest X-ray films on admission showed diffuse infiltrations in both lungs. Drug-induced pneumonia due to the herbal medicine Gosha-jinki-gan was suspected, as Gosha-jinki-gan had been administered for 5 months for the treatment of a right knee pain. Her symptoms and the X-ray abnormality improved after cessation of administration. The lymphocyte stimulation test against Gosha-jinki-gan was positive. To the best of our knowledge, this is the first case of interstitial pneumonia caused by Gosha-jinki-gan.

[A case of pregnant woman with severe obsessive-compulsive disorder successfully treated by modified-electroconvulsive therapy].

Obsessive-compulsive disorder (OCD) is rare psychiatric disorder during pregnancy, and is often therapy-resistant. We report a 36-year-old pregnant woman with severe obsessive-compulsive disorder successfully treated by modified-electroconvulsive therapy. During the pregnancy, severe mysophobia and compulsive washing appeared, so severely that she was unable to lie down, endangering the life of the fetus. Since the pharmacotherapy was ineffective, modified electroconvulsive therapy (m-ECT) was performed in cooperation with the obstetrician and the anesthesiologist, along with monitored cardiotocography throughout the procedure. During the second therapy late deceleration on the fetal cardiotocogram occurred, but rapid intravenous administration of ritodrine led to the cessation of abnormal uterine contraction. Two courses of m-ECT markedly diminished her symptoms, and she delivered a healthy infant without complications. M-ECT can be an alternative treatment for pregnant patients with OCD.

Cell stress induces upregulation of osteopontin via the ERK pathway in type II alveolar epithelial cells.

Osteopontin (OPN) is a multifunctional protein that plays important roles in cell growth, differentiation, migration and tissue fibrosis. In human idiopathic pulmonary fibrosis and murine bleomycin-induced lung fibrosis, OPN is upregulated in type II alveolar epithelial cells (AEC II). However, the mechanism of OPN induction in AEC II is not fully understood. In this study, we demonstrate the molecular mechanism of OPN induction in AEC II and elucidate the functions of OPN in AEC II and lung fibroblasts. Human lung adenocarcinoma cells (A549) and mouse alveolar epithelial cells (MLE12), used as type II alveolar epithelial cell lines for in vitro assays, and human pulmonary alveolar epithelial cells (HPAEpiC) were treated with either bleomycin, doxorubicin or tunicamycin. The mechanism of OPN induction in these cells and its function as a pro-fibrotic cytokine on A549 and lung fibroblasts were analyzed. The DNA damaging reagents bleomycin and doxorubicin were found to induce OPN expression in A549, MLE12 and HPAEpiC. OPN expression was induced via activation of the extracellular signal-regulated protein kinase (ERK)-dependent signaling pathway in A549 and MLE12. The endoplasmic reticulum (ER) stress-inducing reagent tunicamycin induced OPN mRNA expression in A549, MLE12 and HPAEpiC, and OPN mRNA expression was induced via activation of the ERK-dependent signaling pathway in A549 and MLE12. Another ER stress-inducing reagent thapsigargin induced the expression of OPN mRNA as well as the subsequent production of OPN in A549 and MLE12. Furthermore, OPN promoted the proliferation of A549 and the migration of normal human lung fibroblasts. Inhibition of OPN by small interference RNA or neutralizing antibody suppressed both of these responses. The results of this study suggest that cell stress induces the upregulation of OPN in AEC II by signaling through the ERK pathway, and that upregulated OPN may play a role in fibrogenesis of the lung.

Combination therapy with sivelestat and recombinant human soluble thrombomodulin for ARDS and DIC patients.

BACKGROUND: Neutrophil elastase, alveolar thrombin generation, and fibrin deposition play crucial roles in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). However, the usefulness of combination therapy with a selective neutrophil elastase inhibitor, sivelestat, and recombinant human soluble thrombomodulin (rhTM) for patients with ARDS and DIC remains unknown. METHODS: We conducted a retrospective data analysis of 142 ARDS patients with DIC to assess the effects of sivelestat combined with rhTM. Patients were divided into four groups: control (no sivelestat or rhTM treatment), sivelestat treatment alone, rhTM treatment alone, and combined treatment with sivelestat and rhTM. A Cox proportional hazard model was used to assess subject mortality rates. The efficacy of these drugs was evaluated based on survival rate, number of ventilator-free days, and change in PaO2/FIO2 (P/F) ratios and DIC scores before and at 7 days after a diagnosis of ARDS with DIC. RESULTS: Multivariate analysis showed that patient age, combination therapy, gas exchange, organ failure, cause, associated disease score, and serum C-reactive protein levels were predictors of mortality for patients with ARDS and DIC. As compared with untreated controls, combination therapy significantly improved the 60-day survival rate of patients with ARDS and DIC. There were significantly more ventilator-free days for those who received combination therapy than for untreated controls. P/F ratios and DIC scores were significantly improved with sivelestat alone, rhTM alone, or their combination as compared with untreated controls. CONCLUSION: Our results suggest that combined treatment with sivelestat and rhTM has beneficial effects on survival and the respiratory and DIC status of patients with ARDS and DIC.