Urinary fluorescent metabolite O-aminohippuric acid is a useful biomarker for lung cancer detection.

INTRODUCTION: Urine contains diagnostically important metabolites that can act as natural fluorophores. However, whether these fluorescent metabolites can be used in lung cancer diagnosis is unknown. OBJECTIVES: This study was conducted to determine whether fluorescent urinary metabolites could be useful biomarkers for lung cancer detection. METHODS: A total of 46 lung cancer patients and 185 volunteers without cancer were evaluated between November 2013 and November 2014. Samples of the first urine of the day were collected from lung cancer patients and diagnosed at the Hamamatsu University School of Medicine and the Hamamatsu Medical Center prior to cancer treatment, and from volunteers without cancer at the Hamamatsu Medical Imaging Center. Fluorescent urinary metabolites were screened by high-performance liquid chromatography and select effective fluorescent substances for distinguishing cancer from non-cancer status. RESULTS: The fraction of patients at each stage of cancer severity were: 41.3% stage I, 8.7% stage II, 19.6% stage III, and 30.4% stage IV. A robust predictive biomarker for lung cancer was selected by the multivariate logistic analysis of fluorescent metabolites and identified to be O-aminohippuric acid (OAH). The area under the curve (AUC) data for OAH was 0.837 (95% CI 0.769-0.898, P < 0.001). CONCLUSION: We identified a fluorescent urinary metabolite that can predict lung cancer. OAH exceeds the AUC (0.817) of lung cancer detection by AminoIndex® cancer screening, can be analyzed non-invasively without additional sample processing, and may be a valuable addition to existing lung cancer prediction models.

Effect of eicosapentaenoic acid on prevention of lean body mass depletion in patients with exacerbation of chronic obstructive pulmonary disease: A prospective randomized controlled trial.

BACKGROUND & AIMS: Systemic inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), resulting in depletion of lean body mass (LBM) and muscle mass. Both frequent exacerbation of COPD and low LBM are associated with poor prognosis. This study aimed to evaluate whether supplementation of eicosapentaenoic acid (EPA) prevents depletion of LBM and muscle mass in hospitalized patients with exacerbation of COPD. METHODS: This was a prospective randomized controlled trial, conducted between November 2014 and October 2017. Fifty patients were randomly assigned to receive 1 g/day of EPA-enriched oral nutrition supplementation (ONS) (EPA group) or EPA-free ONS of similar energy (control group) during hospitalization. The LBM index (LBMI) and the skeletal muscle mass index (SMI) were measured using a bioelectrical impedance analyzer at the time of admission and at the time of discharge. Patients underwent pulmonary rehabilitation and wore a pedometer to measure step counts and physical activity. RESULTS: Forty-five patients that completed the experiment were analyzed. Baseline characteristics were similar between the EPA (n = 24) and control groups (n = 21). There were no significant differences in energy intake, step counts, physical activity, or length of hospitalization between the two groups. Although the plasma levels of EPA significantly increased only in the EPA group, we found an insignificant increase in LBMI and SMI in the EPA group compared with the control group (LBMI: +0.35 vs. +0.19 kg/m2, P = 0.60, and SMI: +0.2 vs. -0.3 kg/m2, P = 0.17, respectively). The change in the SMI was significantly correlated with the length of hospitalization in the EPA group, but not in the control group (r = 0.53, P = 0.008, and r = -0.09, P = 0.70, respectively). CONCLUSIONS: EPA-enriched ONS in patients with exacerbation of COPD during short-time hospitalization had no significant advantage in preservation of LBM and muscle mass compared with EPA-free ONS. EPA supplementation for a longer duration might play an important role in the recovery of skeletal muscle mass after exacerbation of COPD.

Bronchodilator Effect of Tiotropium via Respimat®Administered with a Spacer in Patients with Chronic Obstructive Pulmonary Disease (COPD).

Objective Among elderly patients with chronic obstructive pulmonary disease (COPD), there are some patients who cannot inhale tiotropium via Respimat® due to poor hand-lung coordination. This study aimed to examine whether or not tiotropium inhalation therapy using Respimat® with a spacer increased the forced expiratory volume in 1 s (FEV1) in patients with COPD. Methods A randomized, crossover, single-center study was conducted in 18 patients with stable COPD. Tiotropium (5 µg) via Respimat® with or without a spacer (AeroChamber®) was administered for 2 weeks. Following a 2-week washout period using a transdermal tulobuterol patch (2 mg per day), participants were then crossed over to the other inhalation therapy with respect to spacer use. The trough FEV1 was measured at every visit using a spirometer. A questionnaire regarding inhalation therapy was administered to patients at the final visit. Results The administration of tiotropium via Respimat® both with and without a spacer significantly increased the trough FEV1 from baseline during each treatment period, with mean differences of 115.0±169.6 mL and 92.8±128.1 mL, respectively. There was no significant difference in the change in the trough FEV1 between the 2 procedures (p=0.66). A total of 86% of patients reported that inhalation using a spacer was not difficult, and more than half also rated both the usage and maintenance of the AeroChamber® as easy. Conclusion Tiotropium inhalation therapy administered via Respimat® using a spacer exerted a bronchodilatory effect similar to that observed with tiotropium Respimat® alone.

Prospective open-label randomized comparative, non-inferiority study of two initial antibiotic strategies for patients with nursing- and healthcare-associated pneumonia: Guideline-concordant therapy versus empiric therapy.

BACKGROUND AND OBJECTIVE: The nursing- and healthcare-associated pneumonia guideline, proposed by the Japan Respiratory Society, recommends that patients at risk of exposure to drug-resistant pathogens, classified as treatment category C, be treated with antipseudomonal antibiotics. This study aimed to prove the non-inferiority of empirical therapy in our hospital compared with guideline-concordant therapy. METHODS: This was a randomized controlled trial conducted from December 2011 to December 2012. Patients were randomized to the Guideline group receiving guideline-concordant therapy, and the Empiric group treated with sulbactam/ampicillin or ceftriaxone. The primary endpoint was in-hospital relapse of pneumonia and mortality within 30 days, with a predefined non-inferiority margin of 10%. The secondary endpoints included duration, adverse effects, and cost of antibiotic therapy. RESULTS: One hundred and eleven patients were assigned to the Guideline group (n = 55) and the Empiric group (n = 56; 3 of which were excluded). The incidence of relapse and death within 30 days was similar in the Guideline and the Empiric groups (31% vs. 26%, risk difference -4.5%, 95% CI -21.5% to 12.5%). While the duration of antibiotic therapy was slightly shorter in the Guideline group than in the Empiric group (7 vs. 8 days), there were no significant differences in adverse effects or cost. CONCLUSIONS: The efficacy of empiric therapy was comparable to guideline-concordant therapy, although non-inferiority was not proven. The administration of broad-spectrum antibiotics to patients at risk of exposure to drug-resistant pathogens may not necessarily improve the prognosis. TRIAL REGISTRATION: UMIN000006792.

Phase II study of erlotinib in elderly patients with non-small cell lung cancer harboring epidermal growth factor receptor mutations.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are key drugs in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. We assessed the efficacy and safety of one EGFR tyrosine kinase inhibitor, erlotinib, in elderly Japanese patients with EGFR-mutated NSCLC. METHODS: Elderly patients aged 75 or older with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) were enrolled in this prospective phase II trial. Patients received 150 mg erlotinib per day orally. The primary end point was the overall response rate. RESULTS: Between March 2013 and November 2014, 32 patients were enrolled with median age 80 years. All tumors had adenocarcinoma histology, and 20 patients (62.5 %) had an L858R mutation. The response rate was 56.3 % [95 % confidence interval (CI) 39.4-72.0 %], and the disease control rate was 90.6 % (95 % CI 75.2-97.6 %). Median progression-free survival was 15.5 months (95 % CI 11.2-not reached). Skin disorder was the most common adverse event, and grade 4 drug-related interstitial lung disease occurred in one patient. CONCLUSIONS: Erlotinib is effective and tolerated in elderly patients with EGFR mutation-positive NSCLC.

Idiopathic bronchocentric granulomatosis in an asthmatic adolescent.

Bronchocentric granulomatosis in asthmatic patients has been generally considered to be associated with allergic bronchopulmonary aspergillosis and represent a histopathologic manifestation of fungal hypersensitivity. Here we report a case of an idiopathic bronchocentric granulomatosis in a 17-year-old man with a history of asthma. He was admitted to the hospital with a fever and cough, and a chest CT scan showed peribronchial consolidation in the pulmonary parenchyma, which was unresponsive to antibiotic therapy. The pathological findings obtained by video-assisted thoracoscopic lung biopsy revealed necrotizing granulomatous inflammation centered on bronchi and bronchioles and there was no evidence of fungal colonization, resulting in a diagnosis of idiopathic bronchocentric granulomatosis. Systemic corticosteroid therapy led to clinical and radiological recovery. Physicians should take into account the possibility of the idiopathic process in bronchocentric granulomatosis of asthmatic patients.

Procalcitonin-guided antibiotic therapy in aspiration pneumonia and an assessment of the continuation of oral intake.

BACKGROUND: Procalcitonin-guided antibiotic therapy for community-acquired pneumonia is effective and safe. However, the usefulness of procalcitonin for aspiration pneumonia and its nutrition-related outcomes are unknown. METHODS: We conducted a noninferiority randomized controlled study in patients with aspiration pneumonia who were admitted to our hospital between September 2010 and January 2012. We randomly assigned 105 patients to groups with different durations of antibiotic therapy based on the procalcitonin levels upon admission (procalcitonin group) or according to the standard guidelines (control group). The primary endpoints were relapse of aspiration pneumonia and death within 30 days, with a predefined noninferiority boundary of 10%. Secondary endpoints included duration of antibiotic exposure. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined continuation of oral nutritional intake, relapse of pneumonia, and in-hospital death. RESULTS: The rate of relapse and death within 30 days were similar in the procalcitonin and control groups (25% versus 37.5%; difference, -12.5%; 95% confidence interval, -30.9% to 5.9%). Procalcitonin-guided antibiotic therapy significantly shortened the median duration of antibiotic exposure (5 versus 8 days; p<0.0001); however, the continuation of oral intake was not increased (56% versus 50%; p=0.54). A multivariable analysis showed a significant association between the continuation of oral nutritional intake and the body mass index upon admission. CONCLUSIONS: Procalcitonin-guided antibiotic therapy for aspiration pneumonia can shorten the duration of antibiotic exposure, but it does not increase the continuation of oral intake (UMIN000004800).

Intrathoracic administration of OK-432 elevates the serum procalcitonin levels.

OBJECTIVE: The intrathoracic administration of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of type 3, group A Streptococcus pyogenes, is performed in Japan for pleurodesis of malignant pleural effusion or pneumothorax. Persistent fever is often observed after pleurodesis. To elucidate whether procalcitonin (PCT) is useful for distinguishing between the side effects of OK-432 and infection, we measured the serum PCT levels before and after pleurodesis. METHODS: We performed a prospective study of 12 patients with refractory pleural effusion or pneumothorax who required pleurodesis using OK-432 between August 2011 and February 2012. The serum PCT and C-reactive protein (CRP) levels were measured on days 1 and 3. RESULTS: Of the 12 patients, five had pneumothorax and seven had uncontrolled pleural effusion with carcinomatous pleurisy. The median serum levels of PCT and CRP increased from 0.055 to 1.59 ng/mL (p=0.0022) and from 1.52 to 16.82 mg/dL (p=0.0022), respectively. The fevers subsided without antibiotic administration. CONCLUSION: The serum PCT level may not be useful for distinguishing fever caused by side effects of OK-432 from that caused by bacterial infection. The intrathoracic administration of OK-432 increased the serum levels of both PCT and CRP in the absence of any bacterial infection.

Chyloptysis after ligation of the thoracic duct.

Chyloptysis is a very rare clinical finding. We describe a 44-year-old man who presented with cough and milky-white sputum. Fiberoptic bronchoscopy revealed white sputum, which originated from the right B(6) bronchus. The finding of elevated triglyceride levels in his sputum led to the diagnosis of chyloptysis. He had a surgical history of ligation of the thoracic duct for idiopathic chylopericarditis 7 years-previously. He also suffered from postoperative bilateral empyema. Since then, his pleural cavity has been adhered bilaterally. It is thought that his abnormal postoperative lymphatic flow caused the chyloptysis.

[Retrospective analysis of pemetrexed plus cisplatin chemotherapy for elderly advanced non-small-cell lung cancer].

BACKGROUND: The efficacy of pemetrexed(PEM)plus cisplatin(CDDP)therapy for chemotherapy-naive non-squamous cell lung cancer has been reported, but the effectiveness of such a regimen for elderly patients is unknown. PURPOSE: The aim of this study is to examine the efficacy and toxicity of CDDP plus PEM therapy for elderly patients, retrospectively. METHODS: We performed a retrospective analysis of six patients 75 years old or older with non-squamous lung cancer, who underwent CDDP plus PEM therapy from June 2009 to May 2010. RESULTS: The mean age was 79. 2 years old(range, 76-82), gender: 3 males/3 females; stage: III B/IV; 1/5, pathology: all patients had adenocarcinoma without epidermal growth factor receptor (EGFR)mutation, line: first/third; 5/1. The scheduled chemotherapy of four courses was completed in four patients. The overall response rate was 50%, and the disease control rate was 83%. Grade 3/4 neutropenia and thrombocytopenia were observed in 1/2 and 1/1 patients, respectively, but no blood transfusions were needed. Severe myelosuppression was shown in patients who were impaired in renal function. Grade 3 nausea or anorexia was also observed in 50%of patients. Therefore, two patients were terminated in one courses of therapy and long-term hospitalization for them was needed. CONCLUSION: Although CDDP plus PEM therapy for elderly patients has sufficient patients compliance because of its tolerable myelosuppression, it is necessary to pay attention to deterioration in renal function and to care for nausea during chemotherapy.

[A case of Wegener's granulomatosis with orbital inflammatory pseudotumor].

An 80-year-old woman, who had been received steroid therapy to treat diffuse alveolar hemorrhage from July, 2007, was admitted because of fever, eye pain and exophthalmos on 23 July, 2008. Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) was positive, but pulmonary involvement did not recur. 67Ga scintigraphy revealed intense uptake in bilateral orbital walls and Gd-enhanced MRI indicated orbital inflammatory pseudotumor and hypertrophic pachymeningitis. Although proteinase 3 (PR3)-ANCA was negative, we diagnosed Wegener's granulomatosis (WG) based on the following ELK criteria: upper airways (E); saddle nose, chronic otitis media and exophthalmos, lungs (L); alveolar hemorrhage, and kidneys (K); occult-blood and protein positive urine. Combination therapy with increased doses of prednisolone and cyclophosphamide improved her symptoms satisfactorily. We report a rare case of WG accompanied by orbital inflammatory pseudotumor without exacerbation of sinonasal involvement.

[A case of pulmonary alveolar proteinosis presenting with peripheral ground-glass opacitiy].

A 65-year-old asymptomatic nonsmoker woman was found to have bilateral ground glass opacities in subpleural areas. The bronchoalveolar lavage fluid had a light-milky appearance and transbronchial lung biopsy revealed alveolar filling with PAS-positive acellular material. The patient was given a diagnosis of pulmonary alveolar proteinosis (PAP). Chest CT 18 months later showed no changes in the shadows. It may be possible to follow asymptomatic PAP with patchy peripheral air-space disease without treatment.

[A case of gastric cancer with bilateral chylothorax].

The patient, a 77 year-old woman, visited our hospital with chief complaints of coughing and dyspnea. Chest radiography revealed bilateral pleural effusion especially on the right side, and she was admitted to our hospital to undergo a more thorough examination. The pleural effusion was identified as chyle. In cytodiagonosis, a number of adenocarcinoma cells in clumps were detected. After admission, her general condition worsened, and she died. Her condition was diagnosed as advanced gastric carcinoma on pathological dissection. Generally malignant lymphoma is most often reported as a cause of non-traumatic chylothorax. Because gastric carcinoma associated with bilateral chylothorax is very rare, we report the results of our study with some discussion based on a review of the literature.

[A case of multicentric Castleman's disease with metachronous pulmonary and nephric (renal) involvement].

A 52-year-old woman was referred to our hospital due to cough and sputum in January, 1996. Chest CT scans showed multiple hilar and mediastinal lymphadenopathy and laboratory tests revealed anemia, strong inflammatory reaction, polyclonal hyperimmunoglobulinemia, and an elevated interleukin-6 level. Video-assisted thoracoscopic lung biopsy revealed lymphocytic and plasmacytic infiltration around the bronchovascular band, suggesting a diagnosis of Castleman's disease, and so we began to administer steroids. Although her pulmonary symptoms improved, anemia and hyperimmunoglobulinemia continued. In 2001, her feeling of malaise worsened and gallium scintigraphy revealed new accumulation in her kidneys. Renal biopsy revealed lymphocytic and plasmacytic infiltration mimicking her prior pulmonary involvement. We therefore diagnosed multicentric Castleman's disease with renal involvement. Case in which lymphocytes and plasmacytes infiltrated both the lungs and kidneys metachronously are unusual. We discuss it in relation to the pertinent literature.

[A fatal case of pulmonary non-tuberculous mycobacteriosis with reactive AA amyloidosis].

We report a very rare fatal case of reactive AA amyloidosis following pulmonary non-tuberculous mycobacteriosis (PNTM). A 61-year-old woman with a history of PNTM since 1992, whose treatment was difficult because of liver dysfunction and drug eruption caused by antibiotics, had been hospitalized due to recurrent pulmonary bacterial infection. She complained of leg edema in January, 2000, and nephrotic syndrome was diagnosed in February. After diarrhea and abdominal pain appeared in March, she was admitted to our hospital with worsening edema, and dizziness on April 28. Despite treatment, she died on May 5, 2000. Autopsy revealed PNTM and diffuse systemic depositions of amyloid A protein in heart, kidney and gastrointestinal tract. PNTM, often resistance to antibacterial agents, is increasing recently. This case suggests that it is necessary to take care of amyloidosis when various systemic symptoms are observed in chronic inflammatory disease.

[A case of lymphangioleiomyomatosis found due to chylous ascites, pleural effusion and pelvic lymphadenopathy].

We report a case of lymphangioleiomyomatosis, complaining initially of abdominal distension due to massive chylous ascites. The patient was a 28-year-old woman in whom abdominal ultrasound had strongly suggested the existence of both pelvic lymphadenopathy and massive ascites, the latter subsequently turning out to be chylous. Pelvic lymph node biopsy yielded a diagnosis of lymphangioleiomyomatosis. High-resolution computed tomography (HRCT) of the chest showed no remarkable findings except for very few cystic changes in the lung parenchyma. Pulmonary function had remained normal except for a temporary constrictive pattern when chylous pleural effusion developed. No airflow obstruction was detected on pulmonary function tests. Although lymphangioleiomyomatosis is often associated with pulmonary symptoms, we should bear in mind the possibility of lymphangioleiomyomatosis even in the absence of such symptoms when facing any woman of child-bearing age with abdominal chylous ascites of unknown etiology.

Macroscopic and histological findings in the healing process of inhalation injury.

Although many investigators reported the diagnostic and therapeutic value of bronchoscopy in the early stage of inhalation injury, few findings in the late stage of inhalation injury have been reported. We investigated histopathological changes of in trachea and bronchi after inhalation injury. Five survivors with inhalation injury underwent bronchoscopic examinations combined with biopsies from the early stage to the late stage. Although the bronchotracheal membranes improved to near normal under the bronchoscopic findings in the late or recovery stage, invasion of inflammatory cells and the capillary dilatation in the subepithelial region were still remarkable histologically. Goblet cells also increased on the surface of mucous membranes. In cases of the inhalation injury with severe burn, pulmonary edema, bronchial edema and secretions tended to be prolonged. Results suggested that continuous secretions in the respiratory tracts sometimes cause airway obstruction. Bronchoscopic and histologic findings in the healing process of inhalation injury predict long-term pulmonary functional outcome. Moreover, the aggressive pulmonary toilet seemed to be effective in removing foreign particles and accumulated secretions which also cause the inflammatory response and the obstruction in inhalation injury.

[A case of Ortner syndrome caused by primary pulmonary hypertension].

Left vocal cord palsy is a rare complication of pulmonary hypertension (also known as Ortner syndrome). Here we report a case of a patient with Ortner syndrome caused by primary pulmonary hypertension (PPH). The patient was a 28-year-old woman, who complained of persistent hoarseness and dyspnea on effort. A left vocal cord palsy, as well as PPH, was diagnosed, suggesting that pulmonary artery dilatation associated with PPH led to left recurrent laryngeal nerve palsy. This case suggests that PPH should be suspected in any case with unexplained left vocal cord palsy.