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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 This study aimed to determine the radiologic predictors and clarify the clinical features related to survival in patients with combined pulmonary fibrosis and emphysema (CPFE) and lung cancer. Methods We retrospectively reviewed the medical chart data and high-resolution computed tomography (HRCT) findings for 81 consecutive patients with CPFE and 92 primary lung cancers (70 men, 11 women; mean age, 70.9 years). We selected 8 axial HRCT images per patient, and visually determined the normal lung, modified Goddard, and fibrosis scores. Multivariate analysis was performed using the Cox proportional hazards regression model. Results The major clinical features were a high smoking index of 54.8 pack-years and idiopathic pulmonary fibrosis (n = 44). The major lung cancer profile was a peripherally located squamous cell carcinoma (n = 40) or adenocarcinoma (n = 31) adjacent to emphysema in the upper/middle lobe (n = 27) or fibrosis in the lower lobe (n = 26). The median total normal lung, modified Goddard, and fibrosis scores were 10, 8, and 8, respectively. TNM Classification of malignant tumors (TNM) stage I, II, III, and IV was noted in 37, 7, 26, and 22 patients, respectively. Acute exacerbation occurred in 20 patients. Multivariate analysis showed that a higher normal lung score and TNM stage were independent radiologic and clinical predictors of poor survival at the time of diagnosis of lung cancer. Conclusions A markedly reduced area of normal lung on HRCT was a relevant radiologic predictor of survival.

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.

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.

Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNAPro using ATP, l-proline, and tRNAPro as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported. In this study, we discovered a novel series of pyrazinamide PRS inhibitors from a compound library using pre-transfer editing activity of human PRS enzyme. Steady-state biochemical analysis on the inhibitory mode revealed its distinctive characteristics of inhibition with proline uncompetition and ATP competition. The binding activity of a representative compound was time-dependently potentiated by the presence of l-proline with Kd of 0.76 nM. Thermal shift assays demonstrated the stabilization of PRS in complex with l-proline and pyrazinamide PRS inhibitors. The binding mode of the PRS inhibitor to the ATP site of PRS enzyme was elucidated using the ternary complex crystal structure with l-proline. The results demonstrated the different inhibitory and binding mode of pyrazinamide PRS inhibitors from preceding halofuginone. Furthermore, the PRS inhibitor inhibited intracellular protein synthesis via a different mode than halofuginone. In conclusion, we have identified a novel drug-like PRS inhibitor with a distinctive binding mode. This inhibitor was effective in a cellular context. Thus, the series of PRS inhibitors are considered to be applicable to further development with differentiation from preceding halofuginone.

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.

Background To evaluate the benefits of using a CT image case database (DB) with content-based image retrieval system for the diagnosis of typical non-cancerous respiratory diseases. Methods Using this DB, which comprised data on 191 cases covering 69 diseases, 933 imaging findings that contributed to differential diagnoses were annotated. Ten test cases were selected. Image similarity between each marked test case lesion and the lesions of the top 10 retrieved cases were assessed and classified as similar, somewhat similar, or dissimilar by two physicians in consensus. Additionally, the accuracy of five internal medicine residents’ abilities to interpret CT findings and provide disease diagnoses with and without the proposed system was evaluated by image interpretation experiments involving five test cases. The rates of concordance between the subjects’ interpretations and the correct answers prepared in advance by two specialists in consensus were converted into scores. Results The mean (± SD) of image similarity among the 10 test cases was as follows: 5.1 ± 2.7 (similar), 2.9 ± 1.0 (somewhat similar), and 2.0 ± 2.4 (dissimilar). Using the proposed system, the subjects’ mean score for the correct interpretation of CT findings improved from 15.1 to 28.2 points (p = 0.131) and for the correct disease diagnoses, from 9.3 to 28.2 points (p = 0.034). Conclusions Although this was a preliminary small-scale assessment, the results suggest that this system may contribute to an improved interpretation of CT findings and differential diagnosis of non-cancerous respiratory diseases, which are difficult to diagnose for inexperienced physicians.

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 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.

Human serine palmitoyltransferase (SPT) is a PLP-dependent enzyme residing in the endoplasmic reticulum. It catalyzes the synthesis of 3-ketodihydrosphingosine (3-KDS) from the substrates palmitoyl-CoA and l-serine. It is a rate-limiting enzyme for sphingolipid synthesis in cells. In the present study, we characterized and pharmacologically profiled a series of tetrahydropyrazolopyridine derivatives that potently inhibit human SPT enzymatic activity, including two cell-active derivatives and one fluorescent-labelled derivative. These SPT inhibitors exhibited dual inhibitory activities against SPT2 and SPT3. We used a fluorescent-labelled probe to molecularly assess the inhibitory mechanism and revealed its binding to the SPT2 or SPT3 subunit in the small subunit (ss) SPTa/SPT1/SPT2/or ssSPTa/SPT1/SPT3 functional complexes. One of the SPT inhibitors exhibited a significantly slow dissociation from the SPT complex. We confirmed that our SPT inhibitors suppressed ceramide content in non-small-cell lung cancer cell line, HCC4006, by performing a target engagement analysis. The potency of ceramide reduction correlated to that observed in a recombinant SPT2 enzyme assay. We thus elucidated and provided a fundamental understanding of the molecular mode of action of SPT inhibitors and developed potent, cell-active SPT inhibitors that can be used to clarify the biological function of SPT.

e14110 Background: ICIs such as anti-PD-1/-L1 Inhibitor and anti-CTLA-4 Inhibitor have been used in many types of cancer, and irAEs occur in a considerable proportion of patients. Predictive biomarkers could help us to manage irAEs promptly. Methods: We retrospectively analyzed the consecutive patients treated with nivolumab, pembrolizumab, atezolizumab or ipilimumab, not used as investigational drugs, between March 2015 and December 2018 based on the electric medical records in our institution. We evaluated the relationship between clinical and laboratory factors (gender, age, body mass index, lymphocyte-to-monocyte ratio and eosinophilia) and the occurrence of irAEs using univariate and multivariate analyses. Eosinophilia was defined as absolute eosinophil count over 500/mm3 at least once between initiation of treatment and the occurrence of irAEs. We graded irAEs according to CTCAE v. 5.0. Results: Among 139 patients analyzed in this study, 136, 13 and 6 patients were treated with PD-1, PD-L1 and CTLA-4 inhibitors, respectively (cumulative total of 155 patients). This study included non-small cell lung cancer (n = 78; 56.1%), renal cell carcinoma (n = 17; 12.2%), melanoma (n = 16; 11.5%), gastric cancer (n = 15; 10.8%), Hodgkin lymphoma (n = 7; 5.0%), urothelial carcinoma (n = 3; 2.2%), head and neck carcinoma (n = 3; 2.2%) and mesothelioma (n = 1; 0.7%). Any grade and grade 3-5 irAEs occurred in 60 (38.7%) and 23 (14.8%) cumulative patients, respectively. The most common irAEs in any grade were endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 21) and skin disorders (n = 20). Eosinophilia occurred in 43 cumulative patients (27.7%). Eighteen 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 = 0.0193) and multivariate (p = 0.0464) analysis. 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.

Monoacylglycerol acyltransferase (MGAT) 2 is an endoplasmic reticulum membrane enzyme that catalyzes the synthesis of diacylglycerol (DAG) from fatty acyl-CoA and monoacylglycerol as substrates. It is important for the resynthesis of triacylglycerol in the intestine. We have identified a series of aryl-sulfonamide MGAT2 inhibitors and demonstrated pharmacological inhibition of MGAT2 improved hyperlipidemia, obesity, and diabetes in animal models. However, its mechanism of action has not been elucidated in molecular and cellular levels. In the present study, we have characterized a series of aryl-sulfonamide derivatives that potently and selectively inhibit human MGAT2 and determined their pharmacological profiles. Analyses on the molecular mechanism of a representative aryl-sulfonamide MGAT2 inhibitor revealed a reversible inhibitory activity and a binding activity to MGAT2. The aryl-sulfonamide derivatives exhibited potent inhibitory activities against both human and mouse intestinal MGAT activities, which were correlated to those determined using recombinant human and mouse MGAT enzymes. We have developed a cellular assay using Liquid Chromatography-Mass Spectrometry and confirmed that the aryl-sulfonamide derivatives suppressed DAG synthesis in the cellular context. We have thus elucidated their pharmacological profiles and provided the fundamental clues for understanding the molecular and cellular actions of the aryl-sulfonamide MGAT2 inhibitors.

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.