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Aminoacyl-tRNA synthetases are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal, revealing its systemic impact on metabolism. Nuclear TyrRS deficiency (Yars ΔNLS ) led to reduced lean mass, reflecting a mild developmental defect, and reduced fat mass, possibly due to increased energy expenditure. Consistently, Yars ΔNLS mice exhibit improved insulin sensitivity and reduced insulin levels, yet maintain normoglycemia, indicative of enhanced insulin action. Notably, Yars ΔNLS mice also develop progressive hearing loss. These findings underscore the crucial function of nuclear TyrRS in the maintenance of fat storage and hearing and suggest that aminoacyl-tRNA synthetases' regulatory roles can affect metabolic pathways and tissue-specific health. This work broadens our understanding of how protein synthesis interconnects metabolic regulation to ensure energy efficiency., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by circulating autoantibodies against one of eight aminoacyl-tRNA synthetases (aaRSs). Although these autoantibodies are believed to play critical roles in ASSD pathogenesis, the nature of their roles remains unclear. Here we describe ASSD pathogenesis and discuss ASSD-linked aaRSs - from the WHEP domain that may impart immunogenicity to the role of tRNA in eliciting the innate immune response and the secretion of aaRSs from cells. Through these explorations, we propose that ASSD pathogenesis involves the tissue-specific secretion of aaRSs and that extracellular tRNAs or tRNA fragments and their ability to engage Toll-like receptor signaling may be important disease factors., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA synthetase (YRS ACT ) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRS ACT mimics inflammatory stress inducing a unique megakaryocyte (MK) population with stem cell (Sca1) and myeloid (F4/80) markers through a mechanism dependent on Toll-like receptor (TLR) activation and type I interferon (IFN-I) signaling. This mimicry of inflammatory stress by YRS ACT was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRS ACT or LCMV infection suppressed normal hematopoiesis while activating an alternative pathway of thrombopoiesis. Platelets of inflammatory origin (Sca1/EGFP + ) were a relevant proportion of those circulating during recovery from thrombocytopenia. Analysis of these "inflammatory" MKs and platelets suggested their origin in myeloid/MK-biased hematopoietic stem cells (HSCs) that bypassed the classical MK-erythroid progenitor (MEP) pathway to replenish platelets and promote recovery from thrombocytopenia. Notably, inflammatory platelets displayed enhanced agonist-induced activation and procoagulant activities. Moreover, myeloid/MK-biased progenitors and MKs were mobilized from the bone marrow, as evidenced by their presence in the lung microvasculature within fibrin-containing microthrombi. Our results define the function of YRS ACT in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.

Type 2B von Willebrand disease (VWD) is caused by gain-of-function mutations in von Willebrand factor (VWF). Increased VWF affinity for GPIba results in loss of high molecular weight multimers and enhanced platelet clearance, both contributing to the bleeding phenotype. Severity of the symptoms vary among type 2B VWD patients, with some developing thrombocytopenia only under stress conditions. Efforts have been made to study underlying pathophysiology for platelet abnormalities, but animal studies have been limited because of species specificity in the VWF-GPIba interaction. Here, we generated a severe form of type 2B VWD (p.V1316M) knockin mice in the context of human VWF exon 28 (encoding A1 and A2 domains) and crossed them with human GPIba transgenic strain. Heterozygous mutant mice recapitulated the phenotype of type 2B VWD in autosomal dominant manner and presented severe macrothrombocytopenia. Of note, platelets remaining in the circulation had extracytoplasmic GPIba shed-off from the cell surface. Reciprocal bone marrow transplantation determined mutant VWF produced from endothelial cells as the major cause of the platelet phenotype in type 2B VWD mice. Moreover, altered megakaryocyte maturation in the bone marrow and enhanced extramedullary megakaryopoiesis in the spleen were observed. Interestingly, injection of anti-VWF A1 blocking antibody (NMC-4) not only ameliorated platelet count and GPIba expression, but also reversed MK ploidy shift. In conclusion, we present a type 2B VWD mouse model with humanized VWF-GPIba interaction which demonstrated direct influence of aberrant VWF-GPIba binding on megakaryocytes.

Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a "toxin-platelet-AMR" regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background/aim: Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer., Materials and Methods: LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated., Results: LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors., Conclusion: LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Tyrosyl-tRNA synthetase (YRS) belongs to the family of enzymes that catalyzes the tRNA aminoacylation reaction for protein synthesis, and it has been recently shown to exert noncanonical functions. Although database results indicate extremely low levels of YRS mRNA in platelets, YRS protein is abundantly present. The source of YRS in platelets, as well as the physiological role of platelet-stored YRS, remains largely unknown., Objectives: To clarify how YRS accumulates in platelets and determine the potential role of platelet-stored YRS., Methods: Recombinant YRS proteins with epitope tags were prepared and tested in vitro for proteolytic cleavage in human plasma. Fluorescent-labeled YRS was examined for uptake by platelets, as demonstrated by western blotting and confocal microscopy analysis. Using RAW-Dual reporter cells, Toll-like receptor and type I interferon activation pathways were analyzed after treatment with YRS., Results: Full-length YRS was cleaved by both elastase and matrix metalloproteinases in the plasma. The cleaved, N-terminal YRS fragment corresponds to the endogenous YRS detected in platelet lysate by western blotting. Both full-length and cleaved forms of YRS were taken up by platelets in vitro and stored in the α-granules. The N-terminal YRS fragment generated by proteolytic cleavage had monocyte activation comparable to that of the constitutive-active mutant YRS (YRS Y341A ) previously reported., Conclusion: Platelets take up both full-length YRS and the active form of cleaved YRS fragment from the plasma. The cleaved, N-terminal YRS fragment stored in α-granules may have potential to activate monocytes., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by antibody-mediated platelet destruction. Different mechanisms have been suggested to explain accelerated platelet clearance and impaired thrombopoiesis, but the pathophysiology of ITP has yet to be fully delineated. In this study, we tested 2 mouse models of immune-mediated thrombocytopenia using the rat anti-mouse GPIbα monoclonal antibody 5A7, generated in our laboratory. After a single IV administration of high-dose (2 mg/kg) 5A7, opsonized platelets were rapidly cleared from the circulation into the spleen and liver; this was associated with rapid upregulation of thrombopoietin (TPO) messenger RNA. In contrast, subcutaneous administration of low-dose 5A7 (0.08-0.16 mg/kg) every 3 days gradually lowered the platelet count; in this case, opsonized platelets were observed only in the spleen, and TPO levels remained unaltered. Interestingly, in both models, the 5A7 antibody was found on the surface of, as well as internalized to, bone marrow megakaryocytes. Consequently, platelets generated in the chronic phase of repeated subcutaneous 5A7 administration model showed reduced GPIbα membrane expression on their surface. Our findings indicate that evaluation of platelet surface GPIbα relative to platelet size may be a useful marker to support the diagnosis of anti-GPIbα antibody-induced ITP., (© 2020 by The American Society of Hematology.)

Background: Super-resolution microscopy has enabled high-resolution imaging of the actin cytoskeleton in megakaryocytes and platelets. These technologies have extended our knowledge of thrombopoiesis and platelet spreading using megakaryocytes and platelets cultured in vitro on matrix proteins. However, for better understanding of megakaryocytopoiesis and platelet production, high-resolution imaging of cells in an in vivo bone marrow microenvironment is required. Development of Kawamoto's film method greatly advanced the techniques of thin cryosectioning of hard tissues such as undecalcified bones. One obstacle that remains is the spherical aberration that occurs due to the difference in the refractive index for the light path, limiting the usage of Kawamoto's film method to lower magnification observation., Objectives: To overcome the weakness of the conventional Kawamoto's film method for higher magnification observation of undecalcified bone marrow., Methods: We have modified the original method with a very simple method: flipping the film at the step of mounting the sections on the glass., Results and Conclusions: This new method successfully led to the adjustment of the refractive index and enabled super-resolution imaging of megakaryocytes in undecalcified mouse femurs. Our modified method will expand the application of Kawamoto's film method and enable precise analysis of megakaryocytopoiesis and platelet production in the bone marrow microenvironment under pathophysiological conditions., (© 2019 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (factor VIII-deficient; FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient mice, but not in transient hemophilia WT mice, after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI's protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These mechanistic insights allow targeted development of potentially new strategies to normalize vascularity and control rebleeding in HA.

The interaction of platelet glycoprotein Ibα (GPIbα) with von Willebrand factor (VWF) initiates hemostasis after vascular injury and also contributes to pathological thrombosis. GPIbα binding to the VWF A1 domain (VWFA1) is a target for antithrombotic intervention, but attempts to develop pharmacologic inhibitors have been hindered by the lack of animal models because of the species specificity of the interaction. To address this problem, we generated a knockin mouse with Vwf exon 28-encoding domains A1 and A2 replaced by the human homolog (VWF h28 ). VWF h28 mice (M1HA) were crossbred with a transgenic mouse strain expressing human GPIbα on platelets (mGPIbα null ;hGPIbα Tg ; H1MA) to generate a new strain (H1HA) with humanized GPIbα-VWFA1 binding. Plasma VWF levels in the latter 3 strains were similar to those of wild-type mice (M1MA). Compared with the strains that had homospecific GPIbα-VWF pairing (M1MA and H1HA), M1HA mice of those with heterospecific pairing had a markedly greater prolongation of tail bleeding time and attenuation of thrombogenesis after injury to the carotid artery than H1MA mice. Measurements of GPIbα-VWFA1 binding affinity by surface plasmon resonance agreed with the extent of observed functional defects. Ristocetin-induced platelet aggregation was similar in H1HA mouse and human platelet-rich plasma, and it was comparably inhibited by monoclonal antibody NMC-4, which is known to block human GPIbα-VWFA1 binding, which also inhibited FeCl 3 -induced mouse carotid artery thrombosis. Thus, the H1HA mouse strain is a fully humanized model of platelet GPIbα-VWFA1 binding that provides mechanistic and pharmacologic information relevant to human hemostatic and thrombotic disorders., (© 2018 by The American Society of Hematology.)

Background/aim: Alterations of microRNA expression in three-dimensional spheroids were examined to identify novel microRNAs that might be associated with tumorigenesis., Materials and Methods: Using microRNA microarray analysis, we screened for microRNAs that were dramatically up-regulated inside three-dimensional spheroids in genetically-modified HCT116 human colon cancer cells expressing Copepoda Green Fluorescent Protein under hypoxia., Results: miR-3148 was identified as a possible candidate onco-microRNA. A growth advantage of HCT116 cells stably expressing miR-3148 (HCT116-miR3148) was observed compared to parental cells in vivo, but not in vitro. Additionally, no change in growth under hypoxic or starvation conditions was seen in these cells cultured two-dimensionally; however, HCT116-miR3148 cells maintained as three-dimensional spheroids were highly resistant to hypoxic conditions. HCT116-miR3148 cells were more sensitive to mitogen-activated protein kinase (MAPK) kinase inhibitors and extracellular signal-regulated kinase (ERK) inhibitors., Conclusion: MiR-3148 may be a novel onco-microRNA that protects cancer cells from serious stress conditions through the MAPK/ERK pathway, especially in vivo., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

New mechanisms behind blood cell formation continue to be uncovered, with therapeutic approaches for hematological diseases being of great interest. Here we report an enzyme in protein synthesis, known for cell-based activities beyond translation, is a factor inducing megakaryocyte-biased hematopoiesis, most likely under stress conditions. We show an activated form of tyrosyl-tRNA synthetase (YRS ACT ), prepared either by rationally designed mutagenesis or alternative splicing, induces expansion of a previously unrecognized high-ploidy Sca-1 + megakaryocyte population capable of accelerating platelet replenishment after depletion. Moreover, YRS ACT targets monocytic cells to induce secretion of transacting cytokines that enhance megakaryocyte expansion stimulating the Toll-like receptor/MyD88 pathway. Platelet replenishment by YRS ACT is independent of thrombopoietin (TPO), as evidenced by expansion of the megakaryocytes from induced pluripotent stem cell-derived hematopoietic stem cells from a patient deficient in TPO signaling. We suggest megakaryocyte-biased hematopoiesis induced by YRS ACT offers new approaches for treating thrombocytopenia, boosting yields from cell-culture production of platelet concentrates for transfusion, and bridging therapy for hematopoietic stem cell transplantation., Competing Interests: Conflict of interest statement: R.B., M.-H.D., X.-L.Y., and P.S. have a financial interest in aTyr Pharma, although none specifically for this work., (Copyright © 2018 the Author(s). Published by PNAS.)

The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site-specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph-node-positive non-small-cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1-2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1-2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (P = .025 and .033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (P = .040). There was significant difference in OS between 2 groups according to expressions of CXCR4 in PS and CXCL12 in MLN (P = .0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95% CI 1.08-3.04, P = .023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56% vs 25%, respectively, P < .0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph-node-positive NSCLC patients., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Trifluridine/tipiracil (TFTD, TAS-102) is an orally administrated anti-cancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC). Trifluridine (FTD) is an active cytotoxic component of TFTD and mediates the anticancer effect via its incorporation into DNA. However, it has not been examined whether FTD is incorporated into the tissues of patients who received TFTD medication. By detecting FTD incorporation into DNA by a specific antibody, we successfully detected FTD in the bone marrow and spleen cells isolated from FTD-challenged mice as well as human peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin-P and exposed to FTD in vitro. FTD was also detected in PBMCs isolated from mCRC patients who had administrated TFTD medication. Intriguingly, weekly evaluation of PBMCs from mCRC patients revealed the percentage of FTD-positive PBMCs increased and decreased in parallel with the administration and cessation of TFTD medication, respectively. To our knowledge, this is the first report to detect an active cytotoxic component of a chemotherapeutic drug in clinical specimens using a specific antibody. This technique may enable us to predict the clinical benefits or the adverse effects of TFTD in mCRC patients.

Aim: The purpose of this study was to investigate the biological role of DNA damage-response genes and chromosomal instability in primary lung adenocarcinoma., Materials and Methods: We investigated 60 surgically-resected lung adenocarcinomas. Levels of checkpoint kinase 2 gene (CHEK2) and breast cancer type 1 susceptibility protein gene (BRCA1) mRNA expression were evaluated by polymerase chain reaction (PCR). Epidermal growth factor receptor (EGFR) mutations (exon 19 deletion and exon 21 mutation) were detected by the PCR clamp method. Mutations in Kirsten rat sarcoma viral oncogene homolog gene (KRAS) and TP53 were examined by direct sequencing. Expression levels of p27 and p16 proteins were assessed by immunohistochemistry. Chromosomal aberrations (CA) were examined in 20 samples with single-nucleotide polymorphism-comparative genomic hybridization., Results: CHEK2 mRNA levels were significantly increased in tumor tissues compared to normal tissues (p=0.0123, paired t-test), whereas BRCA mRNA levels were not increased. TP53 mutation positivity and BRCA1 mRNA expression were positively associated with CHEK2 mRNA expression status (p=0.022 and p=0.0008). High CHEK2 mRNA expression was associated with poor recurrence-free survival (p=0.028). CHEK2 mRNA levels were higher in samples with a high CA frequency than in those with a low CA frequency (averages: 0.326 vs. 0.185; p=0.0129)., Conclusion: The CHEK2 mRNA expression level was found elevated in lung adenocarcinoma and was related to a poor prognostic outcome. The CHEK2 pathway may be important for the proliferation of lung adenocarcinoma, especially in tumors with chromosomal instability., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background  Obtaining an accurate preoperative diagnosis of N1 in non-small cell lung cancer (NSCLC) is a major difficulty. The aim of this retrospective study was to evaluate the pathological and long-term outcomes of NSCLC patients clinically staged with N1 disease, to aid in the search for better treatment strategies. Materials and Methods  We retrospectively reviewed the clinical records of 1,180 consecutive patients with NSCLC who underwent surgery for curative intent from 1991 to 2011 in our department. Data on 96 (8.1%) patients who had cT1-2N1 disease and underwent lobectomy or more extensive surgery were available. Results  Only 32% of patients ( n  = 31) were confirmed to have pathological N1 disease, and 34 and 33% of patients were proven to have pN0 and pN2 disease, respectively. Female gender, ≤ 30 pack-year tobacco smoking history, adenocarcinoma, and left-sided disease were significantly associated with pathological upstaging ( χ 2 test). Multivariate analysis using logistic regression revealed left-sided disease to be independently associated with upstaging (relative risk 4.00, p  = 0.015). Left-sided disease was more likely to be underestimated by clinical N staging than right-sided disease ( χ 2 test, p  = 0.0001). Univariate and multivariate survival analyses demonstrated that left-sided disease was an independent prognostic factor associated with poor outcomes (Cox proportional hazards regression: hazard ratio 2.27, p  = 0.037). Conclusion  The diagnostic accuracy of clinical N1 status was poor. Left-sided disease appeared to be understaged by the preoperative assessment of N status, and therefore, patients who might benefit from preoperative induction treatment would not receive it., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Analog chest drainage systems (ACS) are generally used to monitor postoperative alveolar air leakage (PAL) after lung resection. An electronic digital chest drainage system (DCS) has recently been developed that reportedly has several advantages over the traditional ACS. Here, we report a single institution's experience of PAL management with the DCS. We also sought to establish whether DCS had superior clinical benefits and outcomes compared with ACS., Methods: We enrolled 112 consecutive patients who underwent lung resection and were subsequently managed with DCS. We compared PAL rate, duration of chest drainage, and the incidence of complications with a group of 121 consecutive patients previously managed with ACS after lung resection, using propensity score matching., Results: Mean maximum and minimum PAL rates during DCS chest drainage were 48.9 ml/min (range: 2.0-868.6 ml/min) and 0.1 ml/min (0.0-1.2 ml/min), respectively. Mean PAL rate at DCS removal was 1.3 ml/min (0.0-10.0 ml/min). After propensity score matching, mean duration of chest drainage was significantly shorter with DCS than ACS (2.7 days, range: 1-9 days, compared with 3.7 days, range: 1-21 days, respectively; P = 0.031)., Conclusions: Managing PAL with DCS after pulmonary resection appears to reduce the duration of chest drainage.

Background: Brachyury is a transcriptional regulator that plays important roles in epithelial mesenchymal transition (EMT) during development and has been reported to be essential for mesoderm formation in the early human embryo. We investigated Brachyury protein expression in hilar and mediastinal metastatic lymph nodes of non-small cell lung cancer patients and the prognostic significance of Brachyury expression at metastatic sites., Methods: Expression of Brachyury in 115 surgically resected primary lung cancer and corresponding metastatic lymph node samples was evaluated by immunohistochemical staining. The relationships between Brachyury protein expression and the patient's clinicopathological factors and prognosis were analyzed., Results: Brachyury expression in metastatic lymph nodes was significantly higher than that in the primary tumor (p = 0.012). Patients with high Brachyury expression in the metastatic lymph nodes had significantly poor prognoses (p = 0.0236) compared with patients with low expression. In addition, patients with larger differences in Brachyury expression between metastatic lymph nodes and the primary tumor had significantly poorer prognoses compared with patients with smaller differences (p = 0.0146). The Brachyury protein expression level in metastatic lymph nodes was significantly associated with the protein expression levels of other EMT-related factors (E-cadherin [inverse association], p = 0.0265; Slug, p = 0.029; and interleukin-8, p = 0.0135)., Conclusions: High expression of Brachyury protein in metastatic carcinoma cells in the intrathoracic lymph nodes was associated with poor prognosis of lung cancer patients. Increased Brachyury expression during the metastatic process may confer further potential for invasion and metastasis of cancer cells.

Introduction: The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD-L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD-L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD-L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes., Methods: The expression of PD-L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD-L1 positivity was determined according to the histogram of proportions of PD-L1-positive cancer cells., Results: Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD-L1 protein expression according to 5% and 1% PD-L1 cutoff values, respectively. Fisher's exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild-type EGFR. Univariate and multivariate survival analyses revealed that patients with PD-L1 positivity had poorer prognoses than those without PD-L1 protein expression at the 1% cutoff value (disease-free survival p < 0.0001, overall survival p < 0.0001)., Conclusions: PD-L1 protein expression was significantly higher in smoking-associated adenocarcinoma and in EGFR mutation-negative adenocarcinoma. PD-L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD-L1/programmed cell death 1 pathway may contribute to the progression of smoking-associated tumors in lung adenocarcinoma., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength. We aimed to investigate sarcopenia in patients with stage I non-small cell lung cancer (NSCLC) who underwent complete resection, and the relationship of sarcopenia with clinicopathological factors., Methods: All consecutive patients who underwent lung resection between January 2005 and December 2008 were enrolled in this retrospective study. Eligible patients were assigned to one of 2 groups according to the presence or absence of sarcopenia, as assessed by the sum of cross-sectional areas of skeletal muscles in the region of the third lumbar vertebra (L3) on preoperative computed tomography (CT)., Results: Sixteen of 52 male (30.8%) and 22 of 38 female (57.9%) patients were identified with sarcopenia (p=0.01). Patients with sarcopenia were more likely to have a low body mass index (BMI) (p<0.0001). Kaplan-Meier analysis showed that patients with sarcopenia had a significantly worse outcome than patients without sarcopenia (5-year-survival: 72.8% vs 85.8%, respectively, p=0.028). Multivariate analysis found that sarcopenia was a significant independent prognostic factor (hazard ratio: 7.09, p=0.0008)., Conclusions: Sarcopenia identified on a cross-sectional CT image of the L3 level was associated with poor outcome with completely resected early-stage NSCLC., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The most effective treatment for early-stage non-small cell lung cancer (NSCLC) is surgical resection. Nevertheless, up to 20% of patients, even those with stage I NSCLC, relapse after surgery and die. The prognostic nutritional index (PNI) is used to assess immunonutritional conditions or is a predictor of postoperative recurrence in patients with digestive malignancies. However, the usefulness of the PNI for lung cancer is still unknown. We retrospectively analyzed clinicopathological features of stage I NSCLC patients to identify predictors of recurrence and to investigate effects of preoperative PNI levels., Methods: We selected 141 consecutive stage I NSCLC patients who were treated from August 2005 to August 2010. We measured their preoperative PNI levels in uni- and multivariate Cox regression analyses of recurrence-free survival., Results: A low PNI was significantly associated with sex (P=0.0117), preoperative serum carcino embryonic antigen levels (P=0.0228), and postoperative recurrence (P<0.0001). In multivariate analysis, PNI (RR: 9.243; 95% CI: 3.662-25.823; P<0.0001), pleural invasion (RR: 8.664; 95% CI: 2.510-38.056; P=0.0005), and intratumoral blood vessel invasion (RR: 3.151; 95% CI: 1.259-7.681; P=0.0152) were independent prognostic factors. The low-PNI group had a significantly shorter recurrence-free survival than the high-PNI group, regardless of pathological T factors (T1a, P=0.0422; T1b, P<0.0001; T2a, P=0.0098)., Conclusions: The preoperative PNI level is a simple and novel predictor of recurrence in stage I NSCLC patients, and might help identify patients who will need multimodality therapy such as induction or adjuvant therapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

We experienced a case of the cardiopulmonary arrest due to subglottic stenosis developed on the second day after lung cancer surgery. Case : A 73-year-old female who was diagnosed with primary lung cancer was referred to our department for surgery. The second day after left lung segmentectomy, she showed respiratory discomfort symptoms and exhibited hoarseness and stridor, which were revealed as the subglottic stenosis by bronchoscopy. During the emergency airway management, she went into cardiopulmonary arrest. We performed cardiopulmonary resuscitation and simultaneous urgent tracheotomy.

Nanomedicines capable of control over drug functions have potential for developing resilient therapies, even against tumors harboring recalcitrant cancer stem cells (CSCs). By coordinating drug interactions within the confined inner compartment of core-shell nanomedicines, we conceived multicomponent nanomedicines directed to achieve synchronized and synergistic drug cooperation within tumor cells as a strategy for enhancing efficacy, overcoming drug resistance, and eradicating CSCs. The approach was validated by using polymeric micellar nanomedicines co-incorporating the pan-kinase inhibitor staurosporine (STS), which was identified as the most potent CSC inhibitor from a panel of signaling-pathway inhibitors, and the cytotoxic agent epirubicin (Epi), through rationally contriving the affinity between the drugs. The micelles released both drugs simultaneously, triggered by acidic endosomal pH, attaining concurrent intracellular delivery, with STS working as a companion for Epi, down-regulating efflux transporters and resistance mechanisms induced by Epi. These features prompted the nanomedicines to eradicate orthotopic xenografts of Epi-resistant mesothelioma bearing a CSC subpopulation.

Aim: The purpose of this study was to investigate the prognostic significance of epidermal growth factor receptor (EGFR) sensitizing mutations in patients with lung adenocarcinoma who underwent complete surgical resection., Patients and Methods: We retrospectively reviewed the clinical records of 164 patients with lung adenocarcinoma who underwent surgery from 2003 to 2010. Seventy-four patients harbored EGFR mutations; two with exon 18 mutations, 27 with exon 19 mutations, and 45 with exon 21 mutations., Results: There were more female patients and more never-/light smokers among patients with EGFR mutations than among patients without EGFR mutations. Patients with EGFR mutations had a trend for better disease-free survival and overall survival compared to patients without EGFR mutations (p=0.068 and p=0.049, respectively). Patients with exon 21 mutations had significantly better disease-free survival than patients with exon 19 mutations (p=0.027)., Conclusion: Adenocarcinomas harboring EGFR exon 21 mutation were less malignant than adenocarcinomas harboring exon 19 mutation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102 (also named TFTD), which consists of FTD and a thymidine phosphorylase inhibitor. FTD is supposed to exert its cytotoxicity via massive misincorporation into DNA, but the underlying mechanism of FTD incorporation into DNA and its correlation with cytotoxicity are not fully understood. The present study shows that several antibodies against 5-bromo-2'-deoxyuridine (BrdU) specifically cross-react with FTD, either anchored to bovine serum albumin or incorporated into DNA. These antibodies are useful for several biological applications, such as fluorescence-activated cell sorting, fluorescent immunostaining and immunogold detection for electron microscopy. These techniques confirmed that FTD is mainly incorporated in the nucleus during S phase in a concentration-dependent manner. In addition, FTD was also detected by immunohistochemical staining in paraffin-embedded HCT-116 xenograft tumors after intraperitoneal administration of FTD. Intriguingly, FTD was hardly detected in surrounding matrices, which consisted of fibroblasts with marginal expression of the nucleoside transporter genes SLC29A1 and SLC29A2. Thus, applications using anti-BrdU antibodies will provide powerful tools to unveil the underlying mechanism of FTD action and to predict or evaluate the efficacy and adverse effects of TAS-102 clinically.

Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy., (©2016 American Association for Cancer Research.)

Objectives: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumor-induced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PD-L1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified., Methods: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed., Results: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine., Conclusions: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: To investigate the prognostic value of platelet-to-lymphocyte ratio (PLR) and create a new prognostic score in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP)., Methods: Of 85 patients who underwent EPP for MPM over 10 years at Toronto General Hospital, 65 patients whose blood test results before initial therapy were available were retrospectively analyzed as a training cohort to identify and develop a prognostic score. Receiver operating characteristic (ROC) analysis was performed to examine cutoff values of hematologic parameters for survival. The prognostic score was externally validated in a cohort of 32 patients who underwent EPP for MPM over 13 years at two institutes in Japan., Results: In the training cohort, multivariate analysis confirmed sex (P=0.0053) and PLR (P=0.049) as independent predictors of overall survival. The prognostic score was established using sex and PLR. The score was defined as follows: female:male =0:1 point; PLR <215:>215=0:1 point. The patients were classified into three risk groups according to the sum of the points: risk 0 (0 point), 1 (1 point), and 2 (2 points). Median survival time of the patients in the training cohort according to the risk groups were not reached, 32.0 and 19.4 months for risk 0 (n=6), 1 (n=36) and 2 (n=23), respectively (P=0.0006). In the validation cohort, median survival time was not reached, 45.9 and 14.5 months for risk 0 (n=4), 1 (n=18) and 2 (n=10), respectively (P=0.0002)., Conclusions: The new prognostic score using PLR is simple and useful for predicting the prognosis of patients with MPM undergoing EPP. Further study should be done to examine the role of this scoring system to optimize treatment strategy.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) inhibitors are effective and useful agents for treating patients who harbor EGFR-TKI-sensitive mutations or EML4-ALK rearrangement. Therefore, the importance of determining the presence of these somatic mutations when treating lung adenocarcinomas is widely accepted. However, genetic mutations are rarely evaluated in patients with adenosquamous cell carcinoma of the lung, a relatively infrequent histologic type of lung cancer, because of limited knowledge and the unclear value of assessing these oncogenic mutations in these patients. Therefore, we investigated the clinical implications of somatic mutations in surgically resected adenosquamous cell carcinoma of the lung in Japanese patients., Methods: We retrospectively analyzed 32 patients with adenosquamous cell carcinoma of the lung who underwent surgical resection at two institutes in Japan. EGFR mutations and EML4-ALK rearrangement were assessed in all of the patients., Results: Overall, 7 (21.9 %) of 32 patients had EGFR mutations: three patients had an exon 19 deletion and 4 had an exon 21, L858R mutation. There were no T790 M mutations. The median relapse-free survival was 766 days and the median overall survival was 1,152 days in the total cohort. Relapse-free survival and overall survival were not significantly different between patients with or without EGFR mutations., Conclusions: Detecting EGFR mutations in patients with adenosquamous cell carcinoma is clinically important, especially in patients with disease recurrence because EGFR-TKIs may be effective in this histologic type of lung cancer.

Background: With the recent popularization of living-donor liver transplantation (LDLT), it has become important to provide treatment for comorbidities in recipients. We report the case of a patient who was successfully treated with LDLT, followed by left upper lobectomy for lung cancer concomitant with decompensated liver cirrhosis., Case Report: A 67-year-old female was admitted for treatment for severe liver cirrhosis. The lung cancer was identified preoperatively using computed tomography. We initially performed LDLT to improve liver function and coagulopathy; the patient was discharged postoperatively on day 39 without complication. Three months after LDLT, we performed a left upper lobectomy., Results: The patient's postoperative course was uneventful and she was discharged after 11 days., Conclusion: We conclude that an aggressive and appropriate surgical strategy, including LDLT, is an effective curative treatment in patients with controllable malignancy, concomitant with severe liver dysfunction., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objectives: The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy., Methods: From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival., Results: The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8%, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months)., Conclusions: It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background/aim: Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement often have a better prognosis when they are treated with specific inhibitors than when treated with cytotoxic agents. However, the associations between gene mutations and cytotoxic chemosensitivity are still unclear. The objective of the present study was to identify which clinicopathological factors, including genetic mutations, influence chemosensitivity, determined using the succinate dehydrogenase inhibition (SDI) test in patients with NSCLC., Materials and Methods: The chemosensitivity of tumor tissues from 96 patients with NSCLC who underwent surgical resection was evaluated using the SDI test., Results: In patients with adenocarcinoma, tumors with EGFR gene mutations were significantly more sensitive to 5-fluorouracil (5-FU) than tumors without EGFR gene mutations (p<0.0149)., Conclusion: Our data suggest that patients with adenocarcinoma harboring EGFR gene mutations may be susceptible to 5-FU., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Although metastases to the lung from other organs are usually removed with limited lung resections (e.g., wedge resections or segmentectomies), pulmonary lobectomies are often required to remove whole pulmonary tumors. This study investigated the clinical applicability of pulmonary lobectomies to treat metastatic lung tumors., Methods: We retrospectively reviewed clinical records of 143 consecutive patients with metastatic tumors in the lung who underwent surgery in our department, including data sets for 100 patients treated for their first metastatic lung tumors., Results: Of the 100 patients, 23 received pulmonary lobectomies, 69 received wedge resections and eight received segmentectomies. Patients in the lobectomy group were more likely to be younger, have larger and/or multiple tumors, and to have tumors of musculoskeletal origin (sarcomas) than those who underwent segmentectomies or wedge resections (the limited resection group). The two groups did not significantly differ in survival (3-year survival rate; lobectomy vs limited resection: 75.2% vs 80.4%, P = 0.15), or post-operative morbidity, although the only post-operative morbidity was associated with post-operative prognosis in the lobectomy group., Conclusions: Pulmonary lobectomy is a safe and applicable surgical procedure for metastatic lung tumors when long survival is expected after the tumor resection.

Backgrounds: The purpose of this study was to investigate the relationship between the level of tobacco smoking and the clinicopathological features of non-small cell lung cancer (NSCLC) patients, individually for adenocarcinoma (Ad) and squamous cell carcinoma (Sq)., Patients and Methods: We retrospectively reviewed the clinical records of 1825 consecutive lung cancer patients who underwent surgery in our department. Among these, the data sets of 750 Ad patients and 364 Sq patients who received lobectomy or more extensive resection were available., Results: In Ad patients, those who had never smoked (never-smokers) (n=309) were more likely to be female, to have less advanced stage tumors, and to have a significantly better prognosis than those who had ever smoked (ever-smokers) (n=441) (5-year OS: never-smokers, 67.9%; ever-smokers, 53.7%, p<0.0001). In Sq patients, the never-smokers (n=15) were more likely to be female than the ever-smokers (n=349). Among ever-smokers, the light-smokers (PY≤30; n=56) were associated with more female patients, more advanced stage tumors, and significantly worse prognoses than were the heavy smokers (PY>30; n=292) (p=0.0003). The multivariate survival analysis showed that light smoking was related to a worse prognosis compared with heavy smoking (HR=2.06, 95% CI 1.43-2.98, p=0.0001)., Conclusions: The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients. There may be factors other than tobacco carcinogens that influence the development of Sq in never and/or light smokers., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined., Methods: Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated., Results: Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %)., Conclusion: Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.

Background: Although patients with the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene (EML4-ALK) re-arrangement and epidermal growth factor gene EGFR mutations have proven sensitive to specific inhibitors, there is currently no consensus regarding the sensitivity of non-small cell lung cancer (NSCLC) patients with such mutations to cytotoxic chemotherapy., Patients and Methods: The responses to first-line cytotoxic chemotherapy were retrospectively compared between advanced or postoperative recurrent patients with non-squamous NSCLC who harbor the EML4-ALK fusion gene (ALK+), EGFR mutation (EGFR+), or neither abnormality (wild-type)., Results: Data for 22 ALK+, 30 EGFR+, and 60 wild-type patients were analyzed. The ALK+ group had a significantly lower response rate than the other two groups. Progression-free survival was significantly shorter in the ALK+ cohort compared to the EGFR+ (p<0.001) and wild-type cohorts (p=0.0121)., Conclusion: NSCLC patients with the EML4-ALK fusion gene might be relatively insensitivite to cytotoxic chemotherapy., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

A 32-year-old man presented with a mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose (FDG) accumulation (maximum standardized uptake value = 22.21) and extremely elevated blood alpha-fetoprotein (AFP) level (9203.0 ng/ml). The patient underwent 4 cycles of neoadjuvant chemotherapy (cisplatin, bleomycin, and etoposide), which normalized the AFP level and reduced the tumor size, allowing complete resection without a support of extracorporeal circulation. Despite preoperative positron emission tomography revealing increased FDG uptake in the residual tumor (maximum standardized uptake value = 3.59), the pathologic evaluation revealed that no viable germ cell tumor cells remained. We believe FDG uptake should not be used as a criterion for surgical resection after neoadjuvant chemotherapy. It is appropriate to resect the residual tumor regardless of FDG uptake after induction chemotherapy if a tumor is resectable and the AFP level normalizes.

A 77-year-old male was referred to our department due to lung cancer (cT3N0M0) of the right lower lobe. During right lower lobectomy, a thin duct structure was recognized in the hilar region between the middle and lower lobes that was identified to be a supernumerary bronchus upon a review of the preoperative chest CT images. Although bronchial anomalies are rare, it is important to carefully view preoperative images for any such anomalies in order to more safely perform surgery.

We herein report a case involving a 58-year-old female patient with multiple cystic lesions in the right lobe of the lung. The lesions were revealed on chest computed tomography in 2002 and followed up. Transbronchial lung biopsy showed no malignancy in June 2013. The lesions gradually increased in size and thickness and were associated with fluid-filled cysts. We performed a right lower lobectomy in November 2013. Pathological examination revealed inflammatory pseudotumor. Such a case of inflammatory pseudotumor presenting as a pulmonary cyst has not been previously described. Intractable infection and inflammation are regarded as common causes of inflammatory pseudotumor. This condition should be considered in patients with a medical history consistent with infectious disease and a pulmonary cyst found on chest computed tomography.

A 65-year-old male underwent a chest CT scan, which revealed an 8 mm nodule on the wall of a bulla in the left lower lobe of the lung, and was thus suspected to be lung cancer. Pulmonary wedge resection of the left lower lobe by means of video-assisted thoracoscopic surgery was thus performed. A specimen of the lung revealed the presence of intrapulmonary lymph node on the wall of a bulla. The histopathological findings of the resected lung specimen showed non-caseating granulomas in the lymph node, and adenocarcinoma in situ. We concluded that the sarcoid-like reaction observed in the intrapulmonary lymph node was therefore related to the adenocarcinoma in situ.

Objective: Thymic carcinoma is a rare mediastinal neoplasm, and the prognosis of patients with advanced thymic carcinoma is poor. No standard chemotherapeutic regimen has yet been established for the disease. This is the first report to evaluate the role of amrubicin, a novel anthracycline anticancer drug, in second-line and beyond treatment for patients with platinum-refractory advanced thymic carcinoma., Methods: This study was a review of thymic carcinoma patients who had received amrubicin monotherapy between June 2003 and December 2011 for the progression of disease previously treated with platinum-based chemotherapy. Amrubicin was administered at 35 or 40 mg/m(2) for three consecutive days every 3 weeks, until progression., Results: Nine patients with recurrent thymic carcinoma were registered. Their median age was 61 years (range 45-72), and the patients included five males and four females. All nine patients had Masaoka's Stage IVb disease. There were three squamous cell carcinomas, one adenocarcinoma, one small-cell carcinoma and two other histological types. The mean number of chemotherapy cycles was five (range 2-13). Grade 3 or higher toxicities included mainly neutropenia (55.5%), anemia (25.0%) and febrile neutropenia (11.1%). No treatment-related deaths were observed. The response rate was 44.4% (95% confidence interval: 19-73). The median progression-free survival after the amrubicin monotherapy was 4.9 months, while the median overall survival was 6.4 months., Conclusions: Single-agent amrubicin was found to be potentially useful as second-line and beyond chemotherapy for patients with advanced thymic carcinoma. Further multi-institutional prospective studies are warranted.

Anaplastic lymphoma kinase (ALK) fuses echinoderm microtubule-associated protein-like 4 (EML4) to acquire a transforming activity in lung adenocarcinomas. However, the presence of an EML4-ALK fusion gene in other lung cancer histologies is an extremely rare phenomenon. A 43-year-old female was referred to our department due to dyspnea on effort and left back pain. Computed tomography (CT) showed a large mass in the upper lobe of the left lung and a massive left pleural effusion, while a CT-guided needle biopsy confirmed a diagnosis of small-cell lung cancer (SCLC). Surprisingly, the tumor was genetically considered to harbor the EML4-ALK fusion gene (variant 2). Although the patient underwent two regimens of cytotoxic chemotherapy for SCLC, she died approximately seven months after the administration of first-line chemotherapy. Our analysis of 30 consecutive patients with SCLC for EML4-ALK revealed that two patients, including the current patient and a patient we previously reported, harbored the EML4-ALK fusion gene., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)