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A 77-year-old man presented with a 1-month history of cough, pharyngeal discomfort, and weight loss. Chest radiography revealed a mass shadow in the right upper lung field. Bronchoscopy showed multiple white nodules along the tracheal cartilage ring. Although adenocarcinoma cells were detected in the mass, several biopsy specimens of the tracheal lesions exhibited no malignancy.

S-1, an oral fluoropyrimidine derivative, is widely used for the treatment of several solid tumors. However, there are no predictive markers for its effectiveness.We retrospectively screened 108 patients with advanced non-small cell lung cancer (NSCLC) treated via S-1 monotherapy and investigated its relationship with cytokeratin 19 fragment (CYFRA 21-1) and CEA pretreatment levels.Sixty-one patients with high CYFRA 21-1 levels had a statistically significant shorter progression-free survival (PFS) and overall survival (OS) than 46 patients with normal levels (median PFS = 42 days vs. 70 days, respectively; p = 0.0014; median OS = 197 days vs. 316 days, respectively, p = 0.0239).Serum CYFRA 21-1 levels have predictive and prognostic roles in the management of patients with advanced NSCLC on S-1 monotherapy.

The optimal chemotherapy for concurrent chemoradiotherapy (cCRT) of lung cancer is still unclear.We investigated the therapeutic effect of different chemotherapy regimens for cCRT of lung cancer in 65 patients at our hospital.Of the 65 patients, 53 were male and 12 female. The median age was 64 years and 58 participants had a smoking history. The histological type was adenocarcinoma in 34 cases, squamous cell carcinoma in 22 cases, and others in 9 cases. Induction therapy consisted of cisplatin plus vinorelbine (CDDP+VNR) in 50 cases, and weekly carboplatin plus paclitaxel (CBDCA+PTX) in 15 cases. In all patients, the overall response rate, disease control rate, median progression survival, and median overall survival were 78.5%, 95.4%, 337 days, and 1,037 days, respectively. The median progression-free survival was 337 days in total; it was significantly longer for CDDP+VNR than CBDCA+PTX. The median overall survival was 1,037 days in total; it tended to be slightly longer for CDDP+VNR than CBDCA+PTX.Different chemotherapy regimens for cCRT possibly have different therapeutic effects.

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC

The collective migration of vascular endothelial cells plays important roles in homeostasis and angiogenesis. Oxygen concentration in vivo, which is lower than in the atmosphere and changes due to diseases, is a key factor affecting the cellular dynamics of vascular endothelial cells. We previously reported that hypoxic conditions promote the internalization of vascular endothelial (VE)-cadherin, a specific cell-cell adhesion molecule, and increase the velocity of the collective migration of vascular endothelial cells. However, the mechanism through which cells regulate collective migration as affected by oxygen tension is not fully understood. Here, we investigated oxygen-dependent collective migration, focusing on intracellular protein p21-activated kinase (PAK) and hypoxia-inducing factor (HIF)-1α. A monolayer of human umbilical vein vascular endothelial cells (HUVECs) was formed in a microfluidic device with controllability of oxygen tension. The HUVECs were then exposed to various oxygen conditions in a range from 0.8% to 21% O2, with or without PAK inhibition or chemical stabilization of HIF-1α. Collective cell migration was measured by particle image velocimetry with time-lapse phase-contrast microscopic images. Localizations of VE-cadherin and HIF-1α were quantified by immunofluorescent staining. The collective migration of HUVECs varied in an oxygen-dependent fashion; the migration speed was increased by hypoxic exposure down to 1% O2, while it decreased under an extremely low oxygen tension of less than 1% O2. PAK inhibition suppressed the hypoxia-induced increase of the migration speed by preventing VE-cadherin internalization into HUVECs. A decrease in the migration speed was also obtained by chemical stabilization of HIF-1α, suggesting that excessive accumulation of HIF-1α diminishes collective cell migration. These results indicate that the oxygen-dependent variation of the migration speed of vascular endothelial cells is mediated by the regulation of VE-cadherin through the PAK pathway, as well as other mechanisms via HIF-1α, especially under extreme hypoxic conditions.

Objective: The utility of topotecan monotherapy for relapsed small-cell lung cancer (SCLC) after failure of amrubicin monotherapy has not been evaluated. We aimed to investigate the efficacy and safety of topotecan monotherapy in patients with relapsed SCLC after amrubicin monotherapy. Patients and Methods: We retrospectively analyzed data from 16 patients with relapsed SCLC who were treated with topotecan monotherapy after amrubicin monotherapy at our hospital. Results: The response rate, progression-free survival, and overall survival were 0%, 32.5 days (95% confidence interval [CI] = 18–51), and 112 days (95% CI = 55–267), respectively. The most common adverse events (grade ≥3) were leukopenia (31.3%) and thrombocytopenia (31.3%), followed by anemia, anorexia, edema, and lung infections. Conclusion: The efficacy of topotecan monotherapy for relapsed SCLC after amrubicin monotherapy is inconclusive. Therefore, further studies are warranted.

Room-temperature operations of rechargeable Mg coin-cell batteries have been achieved using a Mg alloy negative electrode and a spinel MgMn2O4 (MMO)-positive electrode. The present work focuses on clarifying the effects of the physiochemical properties of the MMO powder including the specific surface area (SBET) and porosity of the positive electrode on Mg battery performances in practical applications. Finally, optimal specific surface area and porosity parameters were obtained that ensured excellent battery performances as a standard coin-cell at room temperature. A typical MMO powder synthesized using a modified sol–gel method with propylene oxide-driven complex polymerization had a large SBET > 200 m2 g−1, and more than 90% porosity with a triple-tiered 3D open-channel network. Here we evaluated the discharge capacity and the cyclability for room-temperature operation as a function of SBET in a full cell with a Mg negative electrode as well as half cells with a carbon graphite electrode. Irrespective of whether half cells or a full cell was used, the initial discharge capacity was found to depend linearly on the SBET of the porous MMO powder in a Mg tetrakis(hexafluoroisopropyl)borate/triglyme electrolyte with a wide potential window, ΔE > 3.6 V. Eventually, the maximum discharge capacity of 220 mA h g−1 was realized at 25 °C in the full cell using the 3D open-channel nanostructure with SBET = 236 m2 g−1. The cyclability in the full cell with the Mg alloy negative electrode, however, degraded with the increasing SBET, while no cyclability degradation was observed in the half cell with the carbon electrode. A possible mechanism is discussed regarding passivation of the Mg alloy electrode in discharge/charge cycles.

Background Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored. Patients and methods This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes. Results Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model. Conclusion A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.

Purpose ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC). Methods Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected. Results There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group. Conclusions These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.

Background Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel. Methods Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups. Results In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia. Conclusions Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.

Band topology has been studied as a design principle of realizing robust boundary modes. Here, by exploring non-Hermitian topology, we propose a three-dimensional topological laser that amplifies surface modes. The topological surface laser is protected by nontrivial topology around branchpoint singularities known as exceptional points. In contrast to two-dimensional topological lasers, the proposed three-dimensional setup can realize topological boundary modes without judicious gain at the edge or symmetry protection, which are thus robust against a broad range of disorders. We also propose a possible optical setup to experimentally realize the topological surface laser. Our results provide a general guiding principle to construct non-Hermitian topological devices in three-dimensional systems., Comment: 12 pages, 12 figures

Objectives: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cells. Aberrant expression of nestin is linked to poor prognosis in different cancers, including non-small cell lung cancer. However, the association between nestin expression and clinicopathological feature or prognosis has remained unclear for SCLC. This study examined whether nestin expression was associated with malignant features and clinical outcomes in SCLC. Materials and Methods: Using previously established Nestin knock-down cells and a newly established Nestin-overexpressing cell line, we examined the relationship between nestin expression and cell proliferation in vitro and in vivo and chemosensitivity. We also analyzed nestin expression in three drug-resistant lung cancer cell lines. Furthermore, we examined samples from 84 SCLC patients (16 patients with surgical resection, and 68 patients with biopsy), and immunohistochemically analyzed nestin expression. Results: Nestin expression correlated positively with cell proliferation, but negatively with chemosensitivity. Nestin expression in drug-resistant cell lines was upregulated compared to their parental cells. Among the 84 SCLC patients, 24 patients (28.6%) showed nestin-positive tumor. Nestin-positive ratio tended to be higher in operated patients than in biopsied patients. Nestin-positive and -negative patients showed no significant differences in response rate (RR) or progression-free survival (PFS) following first-line chemotherapy. However, positive expression of nestin was associated with shorter PFS following second-line chemotherapy (median PFS: nestin-positive, 81 days vs. nestin-negative, 117 days; P = 0.029). Conclusions: Nestin expression may be associated with malignant phenotype and worse outcome in SCLC patients.

Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored.This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes.Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model.A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.

Synchronization of coupled oscillators is a ubiquitous phenomenon found throughout nature. Its robust realization is crucial to our understanding of various nonlinear systems, ranging from biological functions to electrical engineering. On another front, in condensed matter physics, topology is utilized to realize robust properties like topological edge modes, as demonstrated by celebrated topological insulators. Here, we integrate these two research avenues and propose a nonlinear topological phenomenon, namely topological synchronization, where only the edge oscillators synchronize while the bulk ones exhibit chaotic dynamics. We analyze concrete prototypical models to demonstrate the presence of positive Lyapunov exponents and Lyapunov vectors localized along the edge. As a unique characteristic of topology in nonlinear systems, we find that unconventional extra topological boundary modes appear at emerging effective boundaries. Furthermore, our proposal shows promise for spatially controlling synchronization, such as on-demand pattern designing and defect detection. The topological synchronization can ubiquitously appear in topological nonlinear oscillators and thus can provide a guiding principle to realize synchronization in a robust, geometrical, and flexible way., Comment: 24 pages, 26 figures

Docetaxel is one of the standard second/third-line treatments for non-small-cell lung cancer (NSCLC) following a failed response to prior cytotoxic chemotherapy. The predictive biomarker for the effectiveness of docetaxel therapy remains undetermined. However, thyroid transcription factor-1 (TTF-1) is known to be a good prognostic factor for a variety of chemotherapies. To investigate the association between TTF-1 expression and docetaxel monotherapy outcome, 82 patients with non-squamous NSCLC who received second/third-line docetaxel monotherapy were retrospectively screened. All backgrounds were well-balanced whether or not tumor TTF-1 was expressed, and the present clinical outcomes were similar to those reported by previous clinical studies. A better clinical outcome was indicated in TTF-1 positive compared with TTF-1 negative patients, with disease control rates of 69% vs. 42%, respectively (P=0.03) and median overall survival of 393 days vs. 221.5 days, respectively (P

A 67-year-old man was admitted to our hospital complaining of dry cough. Chest computed tomography showed diffuse infiltrates and ground-glass opacities in the bilateral lung fields. Transbronchial lung biopsy specimens showed alveoli filled with yeast-like fungi. With a diagnosis of pneumocystis pneumonia (PCP), he was given oral sulfamethoxazole/trimethoprim, to which he responded well. However, seven months later, PCP relapsed. Analyses revealed a low bronchoalveolar lavage fluid CD4/CD8 ratio of 0.04 and CD4+ lymphocytopenia (250/μL). Despite intensive work-up, we were unable to detect the underlying cause of CD4+ lymphocytopenia; therefore, a final diagnosis of idiopathic CD4+ T-lymphocytopenia was made.

Active systems exhibit spontaneous flows induced by self-propulsion of microscopic constituents and can reach a nonequilibrium steady state without an external drive. Constructing the analogy between the quantum anomalous Hall insulators and active matter with spontaneous flows, we show that topologically protected sound modes can arise in a steady-state active system in continuum space. We point out that the net vorticity of the steady-state flow, which acts as a counterpart of the gauge field in condensed-matter settings, must vanish under realistic conditions for active systems. The quantum anomalous Hall effect thus provides design principles for realizing topological metamaterials. We propose and analyze the concrete minimal model and numerically calculate its band structure and eigenvectors, demonstrating the emergence of nonzero bulk topological invariants with the corresponding edge sound modes. This new type of topological active systems can potentially expand possibilities for their experimental realizations and may have broad applications to practical active metamaterials. Possible realization of non-Hermitian topological phenomena in active systems is also discussed., Comment: 6+5 pages, 4+4 figures, to appear in PRL, see also supplementary movie published with the manuscript

令和1年度

Topological materials exhibit edge-localized scattering-free modes protected by their nontrivial bulk topology through the bulk-edge correspondence in Hermitian systems. While topological phenomena have recently been much investigated in non-Hermitian systems with dissipations and injections, the fundamental principle of their edge modes has not fully been established. Here, we reveal that, in non-Hermitian systems, robust gapless edge modes can ubiquitously appear owing to a mechanism that is distinct from bulk topology, thus indicating the breakdown of the bulk-edge correspondence. The robustness of these edge modes originates from yet another topological structure accompanying the branchpoint singularity around an exceptional point, at which eigenvectors coalesce and the Hamiltonian becomes nondiagonalizable. Their characteristic complex eigenenergy spectra are applicable to realize lasing wave packets that propagate along the edge of the sample. We numerically confirm the emergence and the robustness of the proposed edge modes in the prototypical lattice models. Furthermore, we show that these edge modes appear in a model of chiral active matter based on the hydrodynamic description, demonstrating that active matter can exhibit an inherently non-Hermitian topological feature. The proposed general mechanism would serve as an alternative designing principle to realize scattering-free edge current in non-Hermitian devices, going beyond the existing frameworks of non-Hermitian topological phases., Topological phenomena appear in non-Hermitian systems but the fundamental principles of the edge modes remain less understood. Here, Sone et al. report robust gapless edge modes due to topological structure around an exceptional point rather than bulk-edge correspondence.

A 39-year-old man presented to our hospital with a four-week history of headache and a two-week history of low-grade fever. Chest X-rays showed a tumor of approximately 50 mm in size in the right lower field. A histopathological examination of a transbronchial lung biopsy specimen from the right S9/10 revealed numerous fungal elements that appeared as encapsulated yeast with clear halos. Gadolinium-enhanced brain magnetic resonance images showed multiple cerebral nodules. Cryptococcus gattii (Genotype VGIIa) was isolated from the bronchial lavage and cerebrospinal fluid specimens. The patient was an immunocompetent Japanese man who had not recently traveled to a C. gattii-endemic area.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene. Following nivolumab as a sixth-line treatment, an EGFR-T790M-encoding mutation in EGFR exon 20 was identified by re-biopsy. Osimertinib was therefore initiated as a seventh-line treatment. A partial response was subsequently noted; however, 63 days after initiation of the treatment the patient presented with dyspnea with decreased oxygenation in the absence of fever and sputum. A computed tomography scan revealed the emergence of ground-glass opacities with bronchiectasis in both lungs, and a diagnosis of ILD due to osimertinib was made. Following steroid pulse therapy with discontinuation of osimertinib, the patient's chest findings and respiratory condition improved. Therefore, it is considered that anti-PD-1 therapies may be associated with a risk of ILD during subsequent osimertinib treatment.

Background/aim To investigate whether TTF-1 expression predicts a beneficial response of non-squamous non-small-cell lung cancer (NS-NSCLC) patients to bevacizumab. Patients and methods We retrospectively screened 118 advanced NS-NSCLC patients who were treated with pemetrexed plus platinum derivatives alone (Bev(-)) or with bevacizumab (Bev(+)), and investigated the relationship between expression of TTF-1 and treatment outcomes. Results Among the 92 TTF-1-positive patients, clinical outcomes in the Bev(+) group were significantly better than those in the Bev(-) group (response rate, 51.4% vs. 27.3%, p=0.027; median progression-free survival, 216 days vs. 137 days, p=0.012). Overall survival in the Bev(+) group tended to be longer than that in the Bev(-) group. However, the addition of bevacizumab to the standard treatment of 26 TTF-1-negative patients offered no clinical benefit. Conclusion TTF-1 expression may serve as a predictive marker to identify patients who may benefit from the addition of bevacizumab to platinum doublet therapy.

Background Tyrosine kinase inhibitors (TKIs) directed against epidermal growth factor receptor (EGFR) are important in the treatment of non-small cell lung cancer (NSCLC), especially those harboring EGFR mutations. But little is known regarding the clinical value of serum tumor marker levels measured prior to treatment. Patients and methods We retrospectively reviewed 95 patients with advanced NSCLC treated with EGFR-TKIs, and inspected the relationship between serum tumor marker levels and clinical outcome. Results Forty-three patients with an elevated serum level of cytokeratin 19 fragment (CYFRA 21-1) had shorter progression-free (PFS) and overall (OS) survival than 52 patients with normal serum CYFRA 21-1 levels (99 vs. 123.5 days p=0.011; and 385 vs. 607 days, respectively, p=0.001). Regardless of EGFR mutation status, patients had shorter progression-free survival when serum CYFRA 21-1 was elevated. Conclusion Serum CYFRA 21-1 level may be a predictive factor for patients with NSCLC treated with EGFR-TKIs, regardless of EGFR mutation status.

BACKGROUND/AIM The aim of the present study was to determine the clinical value of tumor marker levels for previously treated NSCLC patients. PATIENTS AND METHODS We retrospectively screened 113 previously treated patients with advanced NSCLC who were treated with docetaxel monotherapy regarding the pretreatment serum level of cytokeratin 19 fragment (CYFRA21-1) and carcinoembryonic antigen (CEA). RESULTS The thirty-two patients with normal CYFRA21-1 levels and high CEA levels had a significantly higher response rate than the other 81 patients (25% vs. 8.6%, p=0.031). The former group showed statistically longer progression-free survival (PFS) and overall survival (OS) than the latter group (median PFS, 180 vs. 59 days, p

With the recent decrease in the number of tuberculosis wards and increase in elderly tuber- culosis patients with comorbidities, the role of regional refer- ral hospitals has become more important in tuberculosis management. [Objective]. This study aimed to assess the current state of tuberculosis management and related issues in a general hospital lacking a tuberculosis ward. [Methods] We retrospectively evaluated the clinical char- acteristics and course of patients diagnosed with tuberculosis by culture testing from April 2008 to March 2015 at Kainan Hospital. [Results] A total of 146 patients (83 males and 63 females; mean age 76, range 18-94 years) were diagnosed with active tuberculosis. Of these, 129 were diagnosed with pulmonary tuberculosis (23 had pulmonary tuberculosis with pleurisy), and 17 patients were diagnosed with extrapulmonary tuber- culosis. The chief complains were cough/sputum in 40 cases, fever in 24, and no symptoms in 36. Associated major comorbidities included diabetes mellitus, chronic kidney disease, and malignancy. In 33 patients, over 30 days were required to diagnose tuberculosis after initial evaluation. Drug-resistant strains were detected in 14 patients. 57 were diagnosed with smear-positive pulmonary tuberculosis, and 66 were transferred to a tuberculosis hospital. Modify in anti- tuberculosis therapy due to adverse reactions were reported in 27 patients. [Conclusion] This study evaluated the current state of tuberculosis management in our hospital. Further educational guidance regarding tuberculosis is needed for the hospital staff, and is important for improvement of tuberculosis management in our hospital.

BACKGROUND Pretreatment serum tumor marker levels predict outcome in non-small cell lung cancer (NSCLC). However, little is known about the clinical value of such measurements for patients treated with pemetrexed plus a platinum-derivative. PATIENTS AND METHODS We retrospectively screened 100 chemotherapy-naive patients with advanced non-squamous NSCLC treated with pemetrexed plus a platinum-derivative in relation to the pretreatment level of cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA). RESULTS Sixty one patients with a high CYFRA 21-1 level had statistically shorter progression-free and overall survival than 39 patients with a normal CYFRA 21-1 level (median progression-free survival=127 days vs. 191 days, respectively; p=0.046; median overall survival=360 days vs. 781 days, respectively, p

A 39-year-old man presented to our hospital with a four-week history of headache and a two-week history of low-grade fever. Chest X-rays showed a tumor of approximately 50 mm in size in the right lower field. A histopathological examination of a transbronchial lung biopsy specimen from the right S9/10 revealed numerous fungal elements that appeared as encapsulated yeast with clear halos. Gadolinium-enhanced brain magnetic resonance images showed multiple cerebral nodules. Cryptococcus gattii (Genotype VGIIa) was isolated from the bronchial lavage and cerebrospinal fluid specimens. The patient was an immunocompetent Japanese man who had not recently traveled to a C. gattii-endemic area.

Objectives In this study, we investigated whether single nucleotide polymorphisms (SNPs) in folylpoly-γ-glutamate synthase (FPGS), which catalyzes the polyglutamation of pemetrexed (PEM), is related to FPGS expression and the response to PEM in non-small cell lung cancer (NSCLC). Materials and methods We first examined FPGS protein expressions according to FPGS SNPs genotype groups in 15 lung adenocarcinoma cell lines. Next, 101 non-squamous NSCLC patients treated with PEM and platinum drugs were classified into FPGS SNP genotype groups to investigate the relation between FPGS SNP genotypes and treatment outcome. Results When the 15 adenocarcinoma cell lines were classified into FPGS SNP 2572C > T genotype groups, we found that the FPGS protein expression was significantly higher in the CC genotype group than in the TT + CT genotype group (p = 0.0022). In contrast, there was no significant difference in FPGS expression when another FPGS SNP was analyzed. We also examined the FPGS SNP 2572C > T genotype in 101 non-squamous NSCLC patients treated with PEM and platinum drugs. Among these 101 patients, response rate was significantly higher in the CC genotype group than in the TT + CT genotype group (p = 0.0034). When we examined the patients treated with PEM, platinum drugs and Bev, almost all (29/33) were classified into the TT + CT genotype group. The response rate, progression-free survival, and over-all survival were all significantly better in the patients of the TT + CT genotype group who also received Bev than in those who did not receive Bev (p = 0.034, 0.021, 0.018, respectively). Conclusion FPGS SNP 2572C > T is a predictive marker of the efficacy of PEM and platinum drugs for NSCLC.

The problem of an emergency large-scale illumination with the high-intensity discharge (HID) lamp is the lack of radiation intensity because of inappropriate energy balance. Some researchers have researched that the radiation power depended on the arc temperature increases with increasing the current. However, the heat loss as well as the radiation power increases with increasing the current excessively. Moreover, the lamp efficiency decreases with increasing the current excessively because of ultra violet rays increment. It is necessary that the arc volume increases while the arc temperature maintains a high temperature with the low current. Therefore, the arc temperature is controlled by changing the wall radius in order to increase the radiation power. However, the wall is melted by a high temperature when the wall radius is narrowed. In this paper, the wall-stabilized arc of water-cooled vortex type with small caliber for high intense radiation is developed. As a result, the arc temperature at small caliber is higher than that at large caliber. However, the radiation power decreases because the arc volume decreases with small caliber. Therefore, the appropriate caliber plays an important role for the wall-stabilized arc.

Diagnosing active tuberculosis in elderly patients presents problems due to nonspecific symptoms and complications such as aspiration pneumonia. The current study presents two cases of pulmonary tuberculosis with bilateral pulmonary infiltrates associated with aspiration pneumonia. The two elderly patients developed acute respiratory distress syndrome as a result of aspiration pneumonia. The diagnoses of pulmonary tuberculosis were delayed in both cases, as the patients were diagnosed with active tuberculosis following discharge from hospital. The sputum test for acid-fast bacillus at the time of administration was smear-negative/culture-positive in these patients. They were treated with isoniazid, rifampicin and ethambutol, and nosocomial transmission of tuberculosis from these patients was not reported. The number of elderly patients with aspiration pneumonia is predicted to increase rapidly, and aspiration pneumonia combined with pulmonary tuberculosis is a major medical and healthcare concern in Japan. The present study concludes that physicians should always consider the complication of pulmonary tuberculosis when treating pneumonia patients, in particular in treating elderly patients with pulmonary infiltrates.

Liquid metal coolants have a significant role in the design of advanced fusion reactors. There is a need for an investigation of the thermal behavior of the liquid metal in working reactor environment, such as when fluid flow at low Prandtl number ( Pr ) with a buoyancy effect, is subjected to a magnetic field. In the present study, a direct numerical simulation (DNS) for a low Pr number fluid flow resulting in turbulent heat transfer with buoyancy effect under a magnetic field has been carried out between two vertical plates kept at different temperatures. In this simulation, the values of the Hartmann number ( Ha ) were 0 and 6, Pr number was 0.06 and Grashof numbers were 6.4 × 10 5 , 9.6 × 10 5 , and 1.6 × 10 6 . The turbulent quantities of the parameters such as the mean temperature, turbulent heat flux, and temperature variance were obtained by direct numerical simulation (DNS). The Reynolds number ( Re ) for channel flow based on friction velocity averaged by both walls, viscosity, and channel half-width was set to be constant as Re τ * = 150. A uniform magnetic field was applied in a direction perpendicular to the walls of the channel. The profiles of mean velocity and velocity fluctuations became asymmetric, and the tendency was enhanced with the increasing buoyancy effect. However, by the application of a magnetic field the tendency decreased. In other words, thermal transport between the walls became weak due to the magnetic effect.

Introduction: ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs including antifolates 5-fluorouracil (5-FU), pemetrexed and methotrexate. ABCC11 has functional genetic variant which regulate the protein expression of ABCC11. However, the relationship between the genetic variant of ABCC11 and the efficacy of anticancer drugs remains to be elucidated. An oral 5-FU derivative S-1 composed of tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP; a potent inhibitor of dehydropyrimidine dehydrogenase), and potassium oxonate, is used against non-small cell lung cancer (NSCLC) treatment; however the biomarker for S-1 is not fully examined. In this study, we examined whether ABCC11 single nucleotide polymorphism (SNP) which regulate the expression of ABCC11 is related with the efficacy of S-1. Method and results: We introduced ABCC11 showing 538G or 538A expression vector and parental plasmid into HeLa cells and established HeLa/ABCC-538G, HeLa/ABCC-538A and HeLa/mock cells, respectively. The protein expression of ABCC11 was higher in the HeLa/ABCC-538-G cell than in the other cells. Futhermore, the IC50 for 5-FU with CDHP was 0.94, 9.75 and 0.64 times higher in the HeLa, HeLa/ABCC-538G and HeLa/ABCC-538A cells than in the HeLa/mock cells, respectively. This result indicates that this ABCC11 SNP is related with 5-FU cytotxocity. Then we analyzed 21 human NSCLC cell lines, classifing NSCLC cell lines into two groups based on the genotype of the SNP 538G>A in ABCC11: a combined G/G and G/A genotype group, and an A/A genotype group. The distribution of the cytotoxicity for 5-FU in combination with CDHP was significantly lower in the A/A genotype group than in the combined G/G and G/A genotype group. Next, we examined the clinical usefulness of the ABCC11 SNP in S-1 treatment of 68 NSCLC patients. In these 68 patients, the median progression-free survival (PFS) was 73days, and the disease control rate was 50%. These data was similar to previous reports. Classified these 68 patients into each ABCC11 538G>A genotype group, we found that the disease control rate was significantly better in the A/A genotype group than in the combined G/G and G/A genotype group (A/A:59.2%, G/G and G/A:35.7%, respectively), but the PFS had no significant difference between these two genotype groups. Conclusion: SNP 538G>A in the ABCC11 gene is a potential determinant for S-1 treatment in NSCLC. Citation Format: Satoshi Fukuda, Takehiro Uemura, Tetsuya Oguri, Akira Takeuchi, Kazuki Sone, Takamitsu Asano, Yoshihiro Kanemitsu, Masaya Takemura, Hirotsugu Ohkubo, Ken Maeno, Yutaka Ito, Akio Niimi. ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3895.

Background: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cell. Aberrant expression of nestin is linked to malignant characteristics and poor prognosis in different cancers, including non-small cell lung cancer. However, in SCLC, the association between nestin expression and clinicopathological feature or prognosis has remained unclear. In this study, we examined whether the expression of nestin affect malignant feature and clinical outcome in SCLC. Material and methods: To assess the function of nestin, a short hairpin RNA (shRNA) targeting nestin and a forced expression vector of the nestin gene were transfected into SCLC cell lines (DMS53 and SKLC17). And three lung cancer cell lines (PC6, PC9 and PC14) and their cisplatin-resistant sub-lines were also analyzed. Nestin expression levels were assayed using Western blotting. Cell proliferation assay was performed using both nestin knock-down and overexpressed cell lines. Growth in vivo was assessed in SCID mice using a nestin knock-down cell line. Chemosensitivity was expressed as the drug concentration for IC50 in MTS cell proliferation assay. Then we retrospectively examined 84 SCLC patients. Correlations between immunohistochemical expression of nestin and various clinicopathological features were evaluated. Result: In nestin knock-down and overexpression cell lines, nesin expression was related to cell proliferation in vitro and vivo and resistance to anticancer drugs (cisplatin, etoposide and SN-38). Nestin expression levels of three cisplatin-resistant cells were increased than their parent cell lines. In 84 SCLC patients (16 patients were surgically resected, and 68 patietns were biopsied), 24 patients had nestin positive tumor. Nestin positive ratio tended to be higher in operated patients than biopsied patients. Nestin expression was not associated with age, sex, smoking status, disease stage and serum pro-gastrin releasing peptide (ProGRP) levels. There were no significant differences between nestin positive and negative patients for response rate (RR), progression free survival (PFS) and overall survival (OS) in 1st line chemotherapy. However, positive expression of nestin was associated with shorter PFS in 2nd line chemotherapy (median PFS; nestin positive 81 days vs negative 117 days, P=0.03). Conclusion: Nestin expression lead to resistance to chemotherapy and worse outcome in SCLC patients. Citation Format: Kazuki Sone, Ken Maeno, Eiji Kunii, Osamu Takakuwa, Akira Takeuchi, Satoshi Fukuda, Takamitsu Asano, Yoshihiro Kanemitsu, Hirotsugu Ohkubo, Masaya Takemura, Yutaka Ito, Tetsuya Oguri, Akio Niimi. Expression of nestin affect resistance to chemotherapy and clinical outcome in small cell lung caner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4620.

A 71-year-old man with myelodysplastic syndrome (MDS) was admitted to our hospital because of recurrent high-grade fever. He was examined for bacterial and fungal infections and treated with antibiotics and antifungal agents. However, he did not achieve a definitive diagnosis and had no apparent improvement for more than a month. Bone marrow aspiration revealed transformation of MDS to acute myeloid leukemia and hemophagocytosis. In addition, Mycobacterium intracellulare was isolated from both a bone marrow specimen and a blood sample. Therefore, he was diagnosed with disseminated Mycobacterium avium complex (MAC) infection with hemophagocytosis. An antibody test was negative for human immunodeficiency virus (HIV). His general condition improved with anti-mycobacterial drug and steroid treatments. Clinicians should suspect disseminated nontuberculous mycobacterial infections in unexplained febrile patients with hematological disorders.