Hironori Uruga

Semiquantitative Assessment of Tumor Spread through Air Spaces (STAS) in Early-Stage Lung Adenocarcinomas

Introduction: Tumor spread through air spaces (STAS) has recently been reported as a form of tumor invasion having an unfavorable prognosis, but the significance of a small amount of STAS is not known. The aim of this study was to perform a semiquantitative assessment of STAS. Methods: Small (≤2 cm) stage I lung adenocarcinomas surgically resected at our institution between 2003 and 2009 were assessed semiquantitatively in the most prominent area as no STAS, low STAS (1–4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS) by using a 20× objective and a 10× ocular lens. A statistical analysis was performed to determine the impact of clinicopathologic parameters on STAS and to clarify the relationship between STAS and patient survival. Results: STAS was assessed as no STAS in 109 of 208 cases (52.4%), as low STAS in 38 cases (18.3%), and as high STAS in 61 cases (29.3%). There were statistically significant associations between higher STAS and solid predominant invasive adenocarcinoma (p < 0.001), pleural invasion (p < 0.001), lymphatic invasion (p < 0.001), vascular invasion (p < 0.001), and tumor size of 10 mm or more (p = 0.037). There was a significant association between increasing STAS and shorter recurrence‐free survival (RFS) in univariate analysis (no STAS, 154.2 months; low STAS, 147.6 months; and high STAS, 115.6 months). In a multivariate Cox proportional hazards model, only STAS (p = 0.015) remained a significant predictor of RFS. Conclusions: We found that one‐third of resected small adenocarcinomas had high STAS. Higher STAS was predictive of worse RFS.

Pathogens in COPD exacerbations identified by comprehensive real-time PCR plus older methods

Respiratory infection is a major cause of exacerbation in chronic obstructive pulmonary disease (COPD). Infectious contributions to exacerbations remain incompletely described. We therefore analyzed respiratory tract samples by comprehensive real-time polymerase chain reaction (PCR) in combination with conventional methods. We evaluated multiple risk factors for prolonged hospitalization to manage COPD exacerbations, including infectious agents. Over 19 months, we prospectively studied 46 patients with 50 COPD exacerbations, collecting nasopharyngeal swab and sputum samples from each. We carried out real-time PCR designed to detect six bacterial species and eleven viruses, together with conventional procedures, including sputum culture. Infectious etiologies of COPD exacerbations were identified in 44 of 50 exacerbations (88%). Infections were viral in 17 of 50 exacerbations (34%). COPD exacerbations caused by Gram-negative bacilli, including enteric and nonfermenting organisms, were significantly associated with prolonged hospitalization for COPD exacerbations. Our results support the use of a combination of real-time PCR and conventional methods for determining both infectious etiologies and risk of extended hospitalization.

Identification of pathogens by comprehensive real-time PCR versus conventional methods in community-acquired pneumonia in Japanese adults

Abstract Background: Community-acquired pneumonia (CAP) has high morbidity and mortality. Unfortunately, the pathogen detection rate using conventional culture methods is relatively low. We compared comprehensive real-time polymerase chain reaction (real-time PCR) analysis of nasopharyngeal swab specimens (NPS) and sputum samples against conventional methods for ability to detect causative pathogens of CAP. Methods: We prospectively enrolled adult CAP patients, including those with prior antibiotic use, from December 2012 to May 2014. For each patient, causative pathogens were investigated conventionally and by real-time PCR that can identify 6 bacterial and 11 viral pathogens. Results: Patients numbered 92 (mean age, 63 years; 59 male), including 30 (33%) with prior antibiotic use. Considering all patients, identification of causative pathogens by real-time PCR was significantly more frequent than by conventional methods in all patients (72% vs. 57%, p = 0.018). In patients with prior antibiotic use, identification rates also differed significantly (PCR, 77%; conventional, 50%; p = 0.027). Mixed infections were more frequent according to real-time PCR than conventional methods (26% vs. 4%, p < 0.001). By the real-time PCR, Streptococcus pneumoniae was most frequently identified (38%) as a causative pathogen, followed by Haemophilus influenzae (37%) and Mycoplasma pneumoniae (5%). PCR also identified viral pathogens (21%), with sensitivity enhanced by simultaneous examination of both NPS and sputum samples rather than only NPS samples. Conclusions: Real-time PCR of NPS and sputum samples could better identify bacterial and viral pathogens in CAP than conventional methods, both overall and in patients with prior antibiotic treatment.

Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes‐resistant human leukocyte antigen DRB1*15:02 treated with nivolumab

Anti‐programmed cell death‐1 (PD‐1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute‐onset insulin‐dependent diabetes after anti‐PD‐1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti‐PD‐1 therapy. We describe an atypical case of hyperglycemia after anti‐PD‐1 antibody administration. A 68‐year‐old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA‐A*24:02 and ‐DRB1*09:01) and resistant (HLA‐DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti‐PD‐1 antibody‐induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.

Marked Improvement with Pirfenidone in a Patient with Idiopathic Pulmonary Fibrosis

A man in his mid-60s with idiopathic pulmonary fibrosis and hepatitis B-related liver cirrhosis developed exertional dyspnea and a dry cough lasting for three months. High-resolution computed tomography (HRCT) showed increasing bilateral ground-glass opacity superimposed on the usual interstitial pneumonia pattern. Six months after starting pirfenidone therapy, the partial pressure of arterial oxygen at rest increased from 81 to 101 torr, the predicted forced vital capacity (FVC) value increased from 75% to 94% and the ground-glass opacity on HRCT improved. The FVC value was subsequently maintained near or above baseline for 43 months. We concluded that our patient was a super-responder to pirfenidone therapy.

The Efficacy and Safety of Long-term Pirfenidone Therapy in Patients with Idiopathic Pulmonary Fibrosis

Objective Pirfenidone (PFD) is often used for years, but the efficacy and safety of long-term PFD therapy in patients with idiopathic pulmonary fibrosis (IPF) are not fully understood. Methods and Patients We retrospectively evaluated 46 patients with IPF who received PFD between February 2009 and August 2014. The efficacy and safety of PFD therapy were compared between 2 groups: long-term therapy patients who received PFD for over 1 year (group L, n=30, 65%) and short-term therapy patients who could not receive PFD for more than 1 year due to worsening of their condition or side effects (group S, n=16, 35%). Results The median age of the 46 patients was 70.5 years, and the median baseline % predicted forced vital capacity (%FVC) was 70.0%. The changes in the FVC in group L were -120 mL and -170 mL at 12 and 24 months after receiving PFD, respectively. The respective median survival times after PFD therapy in groups L and S were 1,612 days and 285 days (p<0.001). The patients in group L experienced a longer time free of acute exacerbation of IPF than those in group S (947 days vs. 145 days, p=0.001). A multivariate analysis revealed that %FVC <60% was a predictor of the inability to receive PFD for over 1 year (odds ratio 0.240, 95% confidence interval 0.060-0.958; p=0.043). With regard to grade 3-5 adverse events, only one patient exhibited grade 3 hyponatremia. Conclusion Long-term PFD therapy is effective, with few severe adverse events.

Detection of pathogens by real-time PCR in adult patients with acute exacerbation of bronchial asthma

BackgroundRespiratory tract infection is a major cause of acute exacerbation of bronchial asthma (AEBA). Although recent findings suggest that common bacteria are causally associated with AEBA, a comprehensive epidemiologic analysis of infectious pathogens including common/atypical bacteria and viruses in AEBA has not been performed. Accordingly, we attempted to detect pathogens during AEBA by using real-time polymerase chain reaction (PCR) in comparison to conventional methods.MethodsWe prospectively enroled adult patients with AEBA from August 2012 to March 2014. Infectious pathogens collected in nasopharyngeal swab and sputum samples were examined in each patient by conventional methods and real-time PCR, which can detect 6 bacterial and 11 viral pathogens. The causal association of these pathogens with AEBA severity and their frequency of monthly distribution were also examined.ResultsAmong the 64 enroled patients, infectious pathogens were detected in 49 patients (76.6%) using real-time PCR and in 14 patients (21.9%) using conventional methods (p < 0.001). Real-time PCR detected bacteria in 29 patients (45.3%) and respiratory viruses in 28 patients (43.8%). Haemophilus influenzae was the most frequently detected microorganism (26.6%), followed by rhinovirus (15.6%). Influenza virus was the significant pathogen associated with severe AEBA. Moreover, AEBA occurred most frequently during November to January.ConclusionsReal-time PCR was more useful than conventional methods to detect infectious pathogens in patients with AEBA. Accurate detection of pathogens with real-time PCR may enable the selection of appropriate anti-bacterial/viral agents as a part of the treatment for AEBA.

Antemortem diagnosis of pulmonary tumor thrombotic microangiopathy in a patient with recurrent breast cancer: a case report

BackgroundPulmonary tumor thrombotic microangiopathy (PTTM), a rare complication of advanced cancer, is histologically characterized by tumor embolisms and fibrocellular intimal proliferation of small pulmonary arteries and arterioles. PTTM usually has an extremely poor prognosis, and antemortem diagnosis is very difficult.Case presentationA 65-year-old woman with a 5-year history of clinical stage IIA (T2N0M0) invasive ductal carcinoma of the left breast was hospitalized for worsening shortness of breath, hemoptysis, and cough since 2 months. She had previously received neoadjuvant chemotherapy and left mastectomy. Because the cancer cells were positive for human epidermal growth factor receptor 2 (HER2), four cycles of trastuzumab had been administered as adjuvant chemotherapy. On admission, chest computed tomography (CT) showed peripheral consolidations in both the lower lobes and a mediastinal mass. Specimens obtained on video-assisted thoracoscopic surgical biopsy revealed tumor cell embolism, intimal fibrocellular proliferation of small arteries, fibrin thrombi, recanalization, and infarction in the left lower lobe, as well as metastasis to the mediastinal pleura. Immunohistochemical staining of the tumor cells revealed positivity for HER2, and a diagnosis of recurrent breast cancer with PTTM was made. Four cycles of trastuzumab resulted in rapid improvement of her symptoms and CT findings of peripheral consolidations and the mediastinal mass.ConclusionAn antemortem diagnosis of PTTM was made in a patient with HER2-positive recurrent breast cancer. Trastuzumab was effective for not only breast cancer but also PTTM.

Nebulized liposomal amphotericin B for treating Aspergillus empyema with bronchopleural fistula.

Aspergillus empyema is an uncommon condition associated with a high mortality rate (1). Treatment options for this condition include surgical drainage and antifungal therapy, but intravenous antifungal monotherapy is usually inefficient in the advanced stages of the disease, as discussed in several case reports (2–7). Treatment can fail because of insufficient drug delivery and penetration into the pleural space by intravenous administration of antifungal agents. We describe a case of Aspergillus empyema with a bronchopleural fistula and the clinical use of liposomal amphotericin B delivered directly to the infection site using a nebulizer.

OK-432 pleurodesis for the treatment of pneumothorax in patients with interstitial pneumonia

BACKGROUND Pneumothorax occasionally develops in patients with interstitial pneumonia (IP) and is often intractable. As there exists no well-established treatment for pneumothorax with IP, we evaluated the efficacy and safety of pleurodesis with OK-432, a lyophilized preparation of Streptococcus pyogenes Su strain that has been inactivated by benzylpenicillin. METHODS We retrospectively evaluated the efficacy and safety of pleurodesis using OK-432 in 39 patients treated for IP-related pneumothorax between January 2006 and May 2017. Five to 10 Klinische Einheit (KE) of OK-432 was injected through the chest tube of each patient. Pleurodesis was considered successful if 1) the chest tube was removed without air leaks and 2) there was no recurrence of pneumothorax within 4 weeks after tube removal, and no additional treatment was required. RESULTS OK-432 pleurodesis was performed 46 times in 39 patients. The median number of OK-432 intrapleural injections received was 1 (range, 1-6), and median dose was 10 KE (range, 5-55 KE). The success rate was 63% (29/46) and recurrence rate was 17.4% (8/46). Grade 5 adverse events were observed in eight patients, including two patients who developed acute exacerbation of IP. Patients in whom the first OK-432 pleurodesis was successful had a significantly longer median survival time than patients in whom it was unsuccessful (322 days vs. 70 days, p = 0.036). CONCLUSIONS Our results show that OK-432 pleurodesis is an effective treatment for pneumothorax associated with IP; however, clinicians should be aware of the possibility of adverse events, especially in patients who are critically ill.