A randomized phase II study of docetaxel or pemetrexed with or without the continuation of gefitinib after disease progression in elderly patients with non-small cell lung cancer harboring EGFR mutations (JMTO LC12-01).

BACKGROUND: Gefitinib (G) is a recommended molecular-targeted agent for elderly patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR-mutant NSCLC. METHODS: Elderly patients with EGFR-mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. RESULTS: This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression-free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16-0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). CONCLUSIONS: Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single-agent chemotherapy; however, it was associated with increased toxicity.

Complete and durable response of pulmonary large-cell neuroendocrine carcinoma to pembrolizumab.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive tumor with a poor prognosis and standard therapy has not yet been established. CASE: A 65-year-old male with a cough for 2 months presented to our hospital. He was clinically diagnosed with non small cell lung cancer cT3N1M0 stage IIIA and underwent right pneumonectomy. The final diagnosis was pulmonary LCNEC pT3N1M0 stage IIIA. Multiple subcutaneous masses were detected 4 months after surgery, and biopsy revealed postoperative recurrence and metastasis. Chemotherapy with carboplatin plus etoposide was initiated. Subcutaneous masses increased and multiple new brain metastases developed after two cycles. Additional tests revealed that epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 (PD-L1) expression rate in tumor cells was 40% (22C3 clones). The primary cells infiltrating the tumor were CD3-positive T cells and CD138-positive plasma cells. Second-line treatment with pembrolizumab was started. The shrinkage of subcutaneous masses was observed after one cycle, and the tumor had completely disappeared after six cycles. Treatment was continued for approximately 2 years. This response has been maintained for 4 years and is still ongoing. CONCLUSION: Pembrolizumab may be used as a treatment option for pulmonary LCNEC.

Implementation of Non-Linear Non-Parametric Persistent Scatterer Interferometry and Its Robustness for Displacement Monitoring.

To derive surface displacement, interferometric stacking with synthetic aperture radar (SAR) data is commonly used, and this technique is now in the implementation phase in the real world. Persistent scatterer interferometry (PSI) is one of the most universal approaches among in- terferometric stacking techniques, and non-linear non-parametric PSI (NN-PSI) was proposed to overcome the drawbacks of PSI approaches. The estimation of the non-linear displacements was successfully conducted using NN-PSI. However, the estimation of NN-PSI is not always stable with certain displacements because wider range of the velocity spectrum is used in NN-PSI than the conventional approaches; therefore, a calculation procedure and parameter optimization are needed to consider. In this paper, optimized parameters and procedures of NN-PSI are proposed, and real data processing with Sentinel-1 in the Kanto region in Japan was conducted. We confirmed that the displacement estimation was comparable to the measurement of the permanent global positioning system (GPS) stations, and the root mean square error between the GPS measurement and NN-PSI estimation was less than 3 mm in two years. The displacement over 2π ambiguity, which the conventional PSI approach wrongly reconstructed, was also quantitatively validated and successfully estimated by NN-PSI. As a result of the real data processing, periodical displacements were also reconstructed through NN-PSI. We concluded that the NN-PSI approach with the proposed parameters and method enabled the estimation of several types of surface displacements that conventional PSI approaches could not reconstruct.

Mycobacterium Shinjukuense Pulmonary Disease Progressed to Pleuritis after Iatrogenic Pneumothorax: A Case Report.

Mycobacterium shinjukuense is a newly identified nontuberculous mycobacteria (NTM) and its gene sequence of 16S rRNA shows high homology to that of Mycobacterium tuberculosis. We present a case of M. shinjukuense pulmonary disease progressed to pleuritis after iatrogenic pneumothorax. The patient was initially diagnosed as tuberculosis based on a positive result for the 16S rRNA of an M. tuberculosis identification kit using scrapings from the cavitary nodule. We need to bear in mind that pneumothorax following bronchoscopy may induce NTM pleuritis and M. shinjukuense infection should be considered in the differential diagnosis of mycobacterial pulmonary disease with effusion.

Pulmonary tuberculosis misdiagnosed as extensively drug-resistant tuberculosis due to selection of a nontuberculous mycobacterial colony from a preculture dish used for a drug-susceptibility test.

Drug-susceptibility test (DST) is important for tuberculosis care; however, there are several pitfalls with the procedure. A 70-year-old woman was diagnosed with extensively drug-resistant tuberculosis based on the result of a DST using microdilution method. Because she had no history of medication for tuberculosis and the sputum acid-fast bacillus smear test turned negative during standard treatment, identification of the strain used for DST was performed. Consequently, the strain was found to be M. intracellulare. It was assumed that a colony of M. intracellulare that had existed in the preculture solid medium was selected and used for the DST.

Evaluation of the Trend of Deformation around the Kanto Region Estimated Using the Time Series of PALSAR-2 Data.

In the Kanto region of Japan, a large quantity of natural gas is dissolved in brine. The large-scale production of gas and iodine in the region has caused large-scale land subsidence in the past. Therefore, continuous and accurate monitoring for subsidence using satellite remote sensing is essential to prevent extreme subsidence and ensure the safety of residences. This study focused on the small baseline subset (SBAS) method to assess ground deformation trends around the Kanto region. Data for the SBAS method was acquired by the Advanced Land Observing Satellite (ALOS)-2 Phased Array type L-band Synthetic Aperture Radar (PALSAR)-2 from 2015 to 2019. A comparison of our results with reference levelling data shows that the SBAS method underestimates displacement. We corrected our results using linear regression and determined the maximum displacement around the Kujyukuri area to be approximately 20 mm/year; the mean displacement rate for 2015-2019 was -7.9 ± 2.9 mm/year. These values exceed those obtained using past PALSAR observations owing to the horizontal displacement after the Great East Japan Earthquake of 2011. Moreover, fewer points were acquired, and the root mean-squared error of each time-series displacement value was larger in our results. Further analysis is needed to address these bias errors.

Mycobacterium abscessus ssp. abscessus infection progressing to empyema from vertebral osteomyelitis in an immunocompetent patient without pulmonary disease: a case report.

BACKGROUND: Pleural involvement by non-tuberculous mycobacteria (NTM) in patients without distinct pulmonary disease is extremely rare. Vertebral osteomyelitis (VO) with or without pulmonary disease is also a rare clinical presentation of NTM infection, and pleural spread of NTM from VO has not been reported. CASE PRESENTATION: A 63-year-old woman was admitted to our hospital with back pain persisting for 4 months and a 2-day history of fever and right chest pain. The patient was initially treated as right-sided empyema due to general bacteria. However, after removal of the chest tube, a previously overlooked paravertebral lesion was observed on CT. MRI confirmed VO at T7/8. Mycobacterium abscessus ssp. abscessus was detected in both the thoracic cavity and the paravertebral lesion. Both VO and the paravertebral abscess were improved by antimycobacterial treatment. CONCLUSION: VO of the thoracic spine due to non-tuberculous mycobacterial infection should be considered as a cause of pleuritis or empyema without pulmonary disease, especially in patients with back pain.

A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non-small cell lung cancer patients with interstitial lung disease.

OBJECTIVES: The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD. MATERIALS AND METHODS: A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%). CONCLUSION: This is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046).

Elevated Levels of Intelectin-1, a Pathogen-binding Lectin, in the BAL Fluid of Patients with Chronic Eosinophilic Pneumonia and Hypersensitivity Pneumonitis.

Objective Human intelectin-1 (hITLN-1) binds to galactofuranosyl residues, which are present in the microbial cell wall, but which are absent in mammalian tissues, and has been suggested to play an immunological role against microorganisms. However, the involvement of hITLN-1 in the pathogenesis of diffuse pulmonary diseases remains unknown. The aim of this study was to compare the hITLN-1 concentrations in the bronchoalveolar lavage (BAL) fluid of patients with diffuse pulmonary diseases. Methods The cell components and concentrations of hITLN-1 were analyzed in the BAL fluid of 8 patients with idiopathic chronic eosinophilic pneumonia (ICEP), 3 patients with drug-induced eosinophilic pneumonia, 4 patients with hypersensitivity pneumonitis (HP), 11 patients with sarcoidosis, 9 patients with cryptogenic organizing pneumonia, and 5 patients with idiopathic fibrosing interstitial pneumonia (fibrosing nonspecific interstitial pneumonia or usual interstitial pneumonia). Results The hITLN-1 concentrations in the BAL fluid of patients with ICEP and HP were higher than in those with other diseases. In the ICEP group, no significant difference was observed in the hITLN-1 concentrations of patients with or without a history of bronchial asthma. Conclusion The results of the present study suggest that hITLN-1 may be involved in the pathogenesis of ICEP and HP, and that an increase in the hITLN-1 concentration in the BAL fluid may represent a new biomarker for these diseases.

Notch3-dependent ß-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC.

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of ß-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which ß-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of ß-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call "adaptive persisters". We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with ß-catenin, leading to increased stability and activation of ß-catenin. We demonstrate that the combination of EGFR-TKI and a ß-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and ß-catenin inhibition in patients with EGFR mutant lung cancer.

Spatiotemporal deformation patterns of the Lake Urmia Causeway as characterized by multisensor InSAR analysis.

We present deformation patterns in the Lake Urmia Causeway (LUC) in NW Iran based on data collected from four SAR sensors in the form of interferometric synthetic aperture radar (InSAR) time series. Sixty-eight images from Envisat (2004-2008), ALOS-1 (2006-2010), TerraSAR-X (2012-2013) and Sentinel-1 (2015-2017) were acquired, and 227 filtered interferograms were generated using the small baseline subset (SBAS) technique. The rate of line-of-sight (LOS) subsidence of the LUC peaked at 90 mm/year between 2012 and 2013, mainly due to the loss of most of the water in Lake Urmia. Principal component analysis (PCA) was conducted on 200 randomly selected time series of the LUC, and the results are presented in the form of the three major components. The InSAR scores obtained from the PCA were used in a hydro-thermal model to investigate the dynamics of consolidation settlement along the LUC based on detrended water level and temperature data. The results can be used to establish a geodetic network around the LUC to identify more detailed deformation patterns and to help plan future efforts to reduce the possible costs of damage.

Fan-shaped ground-glass opacity (GGO) as a premonitory sign of pulmonary infarction: a case report.

Radiological findings of pulmonary infarction have been well characterized mainly in established infarction. However, the early course CT appearance of patients who develop pulmonary infarction has not yet been fully elucidated. A 50-year-old female with a history of postmenopausal hormone replacement therapy (HRT) presented with dry cough and high-resolution computed tomography (HRCT) findings of fan-shaped segmental ground-glass opacity (GGO) in the right lower lobe. As the parenchymal density in the GGO gradually enlarged over a period of 4 weeks in spite of antibiotic treatment, the patient was referred to our hospital on clinical suspicion of bronchioloalveolar cell carcinoma. However, the pathological findings of a transbronchial biopsy of the lesion were compatible with pulmonary infarction. After an endoscopic examination, the typical CT appearance of established pulmonary infarction was observed. Moreover, enhanced CT detected an intraluminal filling defect in the right lower lobe artery suggesting peripheral pulmonary emboli. Our case was a peripheral pulmonary infarction probably induced by HRT, and suggested that fan-shaped GGO may be a premonitory sign of pulmonary infarction.

Phase II study of tailored S-1 monotherapy with a 1-week interval after a 2-week dosing period in elderly patients with advanced non-small cell lung cancer.

BACKGROUND: S-1 is an oral fluoropyrimidine that is active in the treatment of non-small cell lung cancer (NSCLC); however, an optimal treatment schedule and appropriate dose adjustments of S-1 in elderly patients have not yet been established. METHODS: We conducted a phase II trial to evaluate the efficacy and safety of a 2-week S-1 monotherapy treatment followed by a 1-week interval as a first-line treatment of elderly NSCLC patients, by adjusting the dose based on the individual creatinine clearance (Ccr) and body surface area (BSA). The primary endpoint was the disease control rate. RESULTS: Forty patients were enrolled. The disease control and response rates were 89.5% (95% confidence interval [CI] = 79.8-99.2) and 7.9% (95% CI = 0.0-16.4), respectively. The median progression-free survival and overall survival times were 4.4 months (95% CI = 4.2-8.5) and 17.0 months (95% CI = 11.2-18.7), respectively. Neutropenia, anorexia, hyponatremia, hypokalemia, and pneumonia of grade ≥ 3 occurred in 5.0%, 7.5%, 5.0%, 2.5%, and 2.5% of patients, respectively. Among the patient-reported outcomes, most of the individual factors in the patients' quality of life, including upper intestine-related symptoms improved with the treatment, except for dyspnea, which slightly albeit continuously worsened throughout the study. CONCLUSIONS: In elderly patients with previously untreated advanced NSCLC, a 2-week S-1 monotherapy treatment, tailored to both the Ccr and BSA, with a 1-week interval was well tolerated and demonstrated promising efficacy. This study was registered at the University Hospital Medical Information Network (UMIN) Center (ID: UMIN000002035), Japan.

Analysis of acute exacerbation of interstitial lung disease associated with chemotherapy in patients with lung cancer: A feasibility of S-1.

BACKGROUND: Interstitial lung disease (ILD) is commonly concomitant with lung cancer, and its acute exacerbation (AE) is the most serious complication in patients receiving treatment for lung cancer. METHODS: To investigate the incidence and characteristic features of AE of ILD, we conducted a retrospective study of 665 consecutive patients with lung cancer who were treated at our institute between 2008 and 2014. RESULTS: Among the 665 patients, 74 (11.1%) had preexisting ILD, and 64 of them received chemotherapy. Four of the 64 patients (6.3%) had experienced AE of ILD, and two (3.1%) died of respiratory failure during first-line chemotherapy. The use of a combination of carboplatin with tegafur-gimeracil-oteracil potassium (S-1) or paclitaxel as a first-line chemotherapy for non-small cell lung cancer led to a lower frequency of AE, at 8.3% (1/12) and 9.1% (1/11), respectively. The incidence of AE rose to 12.8% (5/39) during second-line treatment, and 14 (total: 15 times) of the 64 patients (21.9%) experienced AE from the time of diagnosis to the end of treatment. The incidence of AE was 17.7% (6/34), 15.8% (3/19), 5.0% (2/40), and 4.2% (1/24) in the paclitaxel-, vinorelbine-, etoposide-, and S-1-containing regimens, respectively. No difference in clinical features and laboratory data was detected between the AE and non-AE groups. CONCLUSIONS: Although this was a small retrospective study, its findings showed that S-1 and etoposide may be relatively safe options for the treatment of patients with lung cancer and concomitant ILD.

Disseminated tuberculosis after pregnancy progressed to paradoxical response to the treatment: report of two cases.

BACKGROUND: Early postpartum women are more likely to develop tuberculosis than nonpregnant women mainly due to immune reconstitution after delivery. Paradoxical response (PR) during antituberculosis treatment also arises via recovery from immunosuppression. However, no study focused on PR during antituberculosis treatment in a postpartum patient has been reported. CASE PRESENTATION: We present two sequential cases (Patient 1: 26-year-old; Patient 2: 29-year-old) of postpartum tuberculosis with pulmonary and extrapulmonary lesions (Patient 1: peritonitis; Patient 2: psoas abscess secondary to spondylitis). Both cases progressed to PR (worsening of pre-existing lung infiltrations (Patients 1, 2) and new contralateral effusion (Patient 2)) in a relatively short time after initiation of treatment (Patient 1: 1 week; Patient 2: 3 weeks), suggesting that immune modulations during pregnancy and delivery may contribute to the pathogenesis of both disseminated tuberculosis and its PR. The pulmonary lesions and effusion of both cases gradually improved without change of chemotherapy regimen. CONCLUSION: Physicians should recognize PR in tuberculosis patients with postpartum and then evaluate treatment efficacy.