Search

Background Non–small-cell lung cancer (NSCLC) has been reported to develop in patients with interstitial pneumonia (IP); however, clinical, radiological, and pathological features remain to be elucidated. Methods We retrieved the records of 120 consecutive NSCLC patients associated with IP who underwent surgery at Toranomon Hospital between June 2011 and May 2017. We classified the patients into three groups according to NSCLC location using high-resolution computed tomography: group A, within a fibrotic shadow and/or at the interface of a fibrotic shadow and normal lung; group B, within emphysematous tissue and/or at the interface of emphysematous tissue and normal lung; and group C, within normal lung. In 64 patients, programmed death ligand-1 (PD-L1) status was assessed with immunohistostaining. Results Most of the patients (89; 70%) were classified as group A. This group tended to have squamous cell carcinoma with the usual interstitial pneumonia (UIP). These cancers were located mainly in the lower lobes and seven of the eight postoperative acute exacerbations (pAE) of IP developed in this group. NSCLC in the group B were mainly squamous cell carcinomas located in the upper lobes. No patient with PD-L1 negative was classified into group B. None of the patients in group C showed UIP. and most of the cancers were adenocarcinoma. The frequency of epidermal growth factor receptor mutation-positive NSCLC was the highest in this group. Conclusions The three groups each showed characteristic features in terms of tumor location, histopathology, PD-L1 expression, and frequency of pAEof IP.

Objective Although rare, pulmonary tuberculosis occasionally develops in patients with interstitial pneumonia (IP). In this study, we aimed to evaluate the clinicoradiological features of pulmonary tuberculosis associated with IP. Methods In this retrospective, observational, single-center study, the medical charts, high-resolution computed tomography (HRCT) findings, and bacteriological test results of patients with IP who also tested positive for Mycobacterium tuberculosis were reviewed. Patients The study included 20 patients with IP out of 329 who tested positive for M. tuberculosis in sputum or bronchoalveolar lavage fluid cultures at Toranomon Hospital between January 2006 and December 2017. Results The HRCT patterns were usual interstitial pneumonia (UIP) in 11 patients and non-UIP in 9 patients. Consolidations (80%) were the most frequent HRCT findings, followed by cavities (60%) and nodules (45%), which are generally characteristic of pulmonary tuberculosis. Consolidations often developed in relation to fibrotic or emphysematous lesions. Tuberculosis lesions could not be identified in one patient. All patients were treated with anti-tuberculosis drugs according to WHO guidelines, and 13 patients achieved a WHO category of “Treatment success.” No patient died of tuberculosis, and the median survival time for the 20 patients was 1,196 days. Conclusion Although the HRCT findings for pulmonary tuberculosis associated with IP are atypical, appropriate tuberculosis treatments can lead to favorable outcomes.

Background Factors affecting the safety of bronchoscopy in patients with malignant hematologic disorders have not been well described. We evaluated the safety of bronchoscopy and describe factors affecting its complication rate in such patients. Methods Between January 2009 and December 2018, 316 bronchoscopies in 282 patients with malignant hematologic disorders and pulmonary infiltrates were performed at our institution. The bronchoscopic procedure used and its complications were evaluated. Results The most common underlying disease was acute myeloid leukemia (134/282 patients, 47.5%). Platelet transfusion was performed the day before or the day of bronchoscopy in 42.4%, supplemental oxygen was administered before the procedure in 23.1%, and midazolam was used in 74.4%. Thirty-five bronchoscopies (11.1%) were complicated by hemoptysis and 7 patients developed pneumothorax, 4 of whom required thoracic drainage. Two patients (0.6%) were intubated within 48 h of the procedure and prolonged oxygen desaturation (> 48 h) occurred in 3.8%. Multivariate analysis showed that only use of midazolam significantly reduced the risk of prolonged oxygen desaturation (hazard ratio 0.28, 95% confidence interval 0.09–0.85, p = 0.03). Transbronchial lung biopsy significantly increased the risk of hemoptysis (hazard ratio 10.40, 95% confidence interval 4.18–25.90, p = 0.00), while use of midazolam significantly reduced the risk (hazard ratio 0.31, 95% confidence interval 0.14–0.73, p = 0.01). Conclusions Bronchoscopy is relatively safe in patients with malignant hematologic disorders. Caution and judicious use of sedatives may improve the patient’s procedural tolerance and lower complications.

Background: To evaluate the safety of bronchoscopy and describe factors affecting its complication rate in patients with hematologic disorders. Methods: Between January 2009 and December 2018, 316 bronchoscopies in 282 patients with hematologic disorders and pulmonary lesions were performed at our institution. The bronchoscopic procedure used and its complications were evaluated. Results: The most common underlying disease was acute myeloid leukemia (134/282 patients, 47.5%). Platelet transfusion was performed the day before or the day of bronchoscopy in 42.4%, supplemental oxygen was administered before the procedure in 23.1%, and midazolam was used in 74.4%. Two patients (0.6%) were intubated within 48 hour of the procedure and prolonged oxygen desaturation (>48 hour) occurred in 3.8%. Multivariate analysis showed that only use of midazolam significantly reduced the risk of prolonged oxygen desaturation ( p = 0.01, hazard ratio 0.23, 95% confidence interval 0.07–0.75). Conclusions: Bronchoscopy is relatively safe in patients with hematologic disorders. Sedation with midazolam may reduce the risk of prolonged oxygen desaturation.

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

Background Pneumatosis intestinalis (PI) is a rare complication of chemotherapy, characterized by multiple gas accumulations within the bowel wall. Case presentation A 71-year-old woman with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma was admitted to our hospital because of reduced consciousness. She was diagnosed as having leptomeningeal carcinomatosis (LM) using lumbar puncture. Because she could not swallow a tablet, erlotinib was administered via a feeding tube. Her state of consciousness gradually improved, but she experienced diarrhea several times a day. After 3 weeks of erlotinib therapy, PI occurred. Erlotinib was discontinued and PI was resolved after treatment with conservative therapies. Erlotinib was re-administrated and PI occurred again. After improvement of erlotinib-induced PI, gefitinib was administered by a feeding tube and the patient did not experience PI or diarrhea. The patient survived 8 months from the diagnosis of LM. Conclusion PI is one of the side effects of erlotinib, and consecutive therapies are useful for the treatment of PI. In this patient, gefitinib was successfully administered after erlotinib-induced PI.

Background Pneumatosis intestinalis is a rare adverse event that occurs in patients with lung cancer, especially those undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Osimertinib is the most recently approved EGFR-TKI, and its usage is increasing in clinical practice for lung cancer patients who have mutations in the EGFR gene. Case presentation A 74-year-old woman with clinical stage IV (T2aN2M1b) lung adenocarcinoma was determined to have EGFR gene mutations, namely a deletion in exon 19 and a point mutation (T790 M) in exon 20. Osimertinib was started as seventh-line therapy. Follow-up computed tomography on the 97th day after osimertinib administration incidentally demonstrated intra-mural air in the transverse colon, as well as intrahepatic portal vein gas. Pneumatosis intestinalis and portal vein gas improved by fasting and temporary interruption of osimertinib. Osimertinib was then restarted and continued without recurrence of pneumatosis intestinalis. Overall, following progression-free survival of 12.2 months, with an overall duration of administration of 19.4 months (581 days), osimertinib was continued during beyond-progressive disease status, until a few days before the patient died of lung cancer. Conclusions Pneumatosis intestinalis should be noted as an important adverse event that can occur with administration of osimertinib; thus far, such an event has never been reported. This was a valuable case in which osimertinib was successfully restarted after complete recovery from pneumatosis intestinalis, such that further extended administration of osimertinib was achieved.

A man in his mid-60's 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.

Background Patients with sensitive gene mutations could achieve better overall survival by taking targeted drugs. Many trials have shown that non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EFGR) mutation responded to PD-1/PD-L1 inhibitors worse than EGFR wild-type. And subgroups of trials have also reported the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with other sensitive gene mutations. So, we conducted a complementary systematic review and meta-analysis to compare efficacy of PD-1/PD-L1 inhibitors for NSCLC patients with sensitive gene mutations. Methods PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials (Central) databases were searched for all clinical trials in NSCLC until 5th of January 2019. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients with sensitive gene mutations. The hazard ratio (HR) and 95% confidence intervals (CIs) of overall survival (OS) or progression-free survival (PFS) were used. Results We analyzed 193 patients in this study. Among cumulative total of 210 patients, 197 were treated with PD-1 or PD-L1 inhibitors. Another 8 and 5 patients were treated with CTLA-4 inhibitor alone and combination with PD-1 inhibitor, respectively. This study included non-small cell lung cancer (n = 106; 50.5%), kidney (n = 23; 10.9%), melanoma (n = 30; 14.3%), gastric (n = 19; 9.0%), Hodgkin lymphoma (n = 11; 5.2%), urothelial carcinoma (n = 10; 4.8%) and others (n = 10; 4.8%). Any grade of irAEs occurred in 73 (34.8%) cumulative patients, and among them, 28 (13.3%) were classified as grade 3-5. The most common irAEs in any grade were skin disorders (n = 29) and endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 28). Eosinophilia occurred in 57 cumulative patients (27.1%), and 21 patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.010) and multivariate (p = 0.0463) analyses. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure Y. Miura: Honoraria (self): Ono; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Chugai. T. Takano: Honoraria (self): Daiichi Sankyo; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Eisai; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Taiho; Research grant / Funding (self): Novartis; Research grant / Funding (self): Chugai. All other authors have declared no conflicts of interest.

Objective The aims of this study were to evaluate the efficacy and safety of continuous morphine infusion for dyspnea in patients with acute exacerbation (AE) of end-stage interstitial pneumonia (IP). Methods We conducted a retrospective study. Based on the subjective clinical effectiveness ratings of "good," "moderate," "poor," or "unknown," the efficacy of continuous morphine infusion treatment was evaluated as defined as symptom relief that was "good" or "moderate." Patients This study included 22 consecutive opioid-naive patients who received continuous morphine infusion in the palliative treatment of dyspnea resulting from AE-IP. Results Of 22 patients, nine achieved good dyspnea relief, eight had moderate relief, four had a poor response and one response was "unknown" within 24 hours of starting morphine infusion. Using an operational definition of dyspnea relief that was rated "good" or "moderate," the efficacy rate of morphine was 77% (n=17). There was a significant change in the respiratory rate (25 respirations per minute at baseline vs. 17 respirations per minute after 12 hours, p=0.02), however, none of the patients studied had fewer than eight respirations per minute. Conclusion We conclude that continuous morphine infusion is an effective and safe therapy for severe dyspnea in terminal AE-IP patients without any serious adverse events.

The dissociation rates of unlabeled drugs have been well studied by kinetic binding analyses. Since kinetic assays are laborious, we developed a simple method to determine the kinetic binding parameters of unlabeled competitors by a preincubation endpoint assay. The probe binding after preincubation of a competitor can be described by a single equation as a function of time. Simulations using the equation revealed the degree of IC50 change induced by preincubation of a competitor depended on the dissociation rate koff of the competitor but not on the association rate kon To validate the model, an in vitro binding assay was performed using a smoothened receptor (SMO) and [(3)H]TAK-441, a SMO antagonist. The equilibrium dissociation constants (KI) and koff of SMO antagonists determined by globally fitting the model to the concentration-response curves obtained with and without 24 h preincubation correlated well with those determined by other methods. This approach could be useful for early-stage optimization of drug candidates by enabling determination of binding kinetics in a high-throughput manner because it does not require kinetic measurements, an intermediate washout step during the reaction, or prior determination of competitors' KI values.

DNA sensing at a single nucleotide resolution is achieved using a hairpin-shaped, unmodified (unlabeled) RNA probe or the precursor double-stranded DNA (dsDNA) in a prokaryotic cell-free translation medium. The molecular-beacon-like probe consists of a loop region that is complementary to the target sequence and a stem composed of a ribosome-binding site (RBS) and its docking domain; the RBS is followed by the gene for a reporter protein such as luciferase or beta-galactosidase. Target binding at the loop opens the hairpin to make RBS accessible by the ribosome to start translation of the reporter protein. This sensing system is signal amplifying by virtue of catalytic DNA-to-RNA transcription when using a dsDNA probe, catalytic RNA-to-protein translation, catalytic signal transduction by the enzymatic reaction of the translated reporter protein and, in the presence of RNase H, catalytic or even irreversible translation-activation of the target-probe heteroduplex. Preparation of a probe takes 1-3 d and gene sensing using the probe takes 1-3 h.

We previously reported a molecular beacon-mRNA (MB-mRNA) strategy for nucleic acid detection/sensing in a cell-free translation system using unmodified RNA as a probe. Here in this presentation, we report that a combination with RNase H activity, which induces an additional process of irreversible cleavage of MB-domain, achieves an improved sequence selectivity (one nucleotide selectivity) and an enhanced sensitivity. This improved system finally enabled visible sensing of target nucleic acid sequence at a single nucleotide resolution under isothermal conditions.

Background Recent phase 3 trials have demonstrated that first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improved the progression-free survival (PFS) in good performance status (PS) patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. We aimed to study the safety and efficacy of EGFR TKIs in patients with activating EGFR mutation-positive NSCLC in a normal clinical setting. Materials and methods Between August 2006 and October 2011, 487 patients with NSCLC were examined for EGFR mutations by the peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp method at Toranomon Hospital. One hundred and forty-two patients were tested positive for EGFR mutations: 82 patients had exon 19 deletions and 60 patients had L858R mutations in exon 21. Of these 142 patients, EGFR TKIs were administered in 97 patients (51 men and 46 women, with a median age of 68 years). We retrospectively studied the clinical data to determine the efficacy and toxicity of EGFR TKIs that were administered to these patients. The overall survival and PFS from the start date of EGFR TKI therapy were calculated using the Kaplan–Meier method. Results Thirty-one patients were aged 75 or more. Fourteen patients had a poor PS of 3 or 4 and 57 patients had previously undergone chemotherapy. Gefitinib was administered to 76 patients, erlotinib to 56 patients, and both drugs to 35 patients. The response rate was 49%. The median PFS was 10.6 months and the median survival time was 26.4 months. The following grade 3 or 4 toxicities were observed: skin rash (n = 6), increased aminotransferase levels (n = 4), and interstitial lung disease (n = 6). Conclusion Although patients who are elderly, those with poor PS, and those who had previously undergone chemotherapy were included in this study, EGFR TKIs for 97 patients with EGFR mutation-positive NSCLC in clinical practice showed a median PFS of 10.6 months and a median survival time of 26.4 months without treatment-related death. The results of this study were consistent with those of the recent phase 3 trials. Disclosure All authors have declared no conflicts of interest.