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Objective: Inflammatory pseudotumor (IPT) is a rare, locally aggressive, benign neoplasm of unknown etiology. Because of its aggressive clinical behavior and locally destructive or infiltrative features, it may be mistaken for a malignant tumor. Approximately 5%-44% of extrapulmonary IPT occur in the head and neck, primarily affecting the orbit., Study Design: Between 2008 and 2021, our hospital received referrals for seven patients (three men and four women, aged 42-73 years) with pain, swelling, mass, and trismus. Computed tomography, magnetic resonance imaging, and biopsy were performed on all patients to diagnose IPT., Results: Of the seven patients, four received low-dose prednisolone (PSL), one underwent surgery, and two were left untreated. The IPT disappeared in one of the two untreated cases, whereas it improved and later deteriorated in the other. The surgical patient had no recurrence. Low-dose PSL was effective in two patients; however, high-dose PSL and immunosuppressants were required in the remaining two cases owing to infiltration into each orbit or brain region., Conclusions: Low-dose PSL treatment was applicable in IPT cases affecting the maxillary to temporal fossa region, wherein symptoms did not improve without treatment. However, when low-dose PSL was ineffective, high-dose PSL and immunosuppressants were required., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.

In ruminants, RNA-sequence analyses have revealed many characteristics of transcripts expressed in conceptuses (embryo and extraembryonic membrane) during peri-implantation periods; however, lncRNA profiles are yet characterized. In this study, we aimed to characterize the lncRNA expression profile in conceptuses during peri-implantation periods in sheep. We analyzed the RNA-sequence data of ovine conceptuses and endometria obtained from pregnant animals on days 15, 17, 19 and 21 (day 0 = day of estrus, n = 3 or 4/day). We predicted the protein coding ability of the assembled transcripts to identify the lncRNA candidates. This analysis identified 8808 lncRNAs, 3423 of which were novel lncRNAs. Gene ontology analysis revealed that lncRNA target genes were enriched for biological processes involved in the respiratory electron transport chain (RETC). qPCR analysis demonstrated that the expression levels on transcripts encoding RETC such as mitochondrially encoded cytochrome c oxidase II (MTCO2) and mitochondria DNA copy number in conceptuses were not increased on P21, although western blotting analysis and immunohistochemistry demonstrated that MTCO2 protein in conceptuses was increased on P21. NAD/NADH assay revealed that NADH level in conceptuses was increased on P21. These results indicate that lncRNAs could regulate the RETC through post-transcriptional levels in the conceptuses. Therefore, lncRNA is a potential new regulator in ovine conceptus development during peri-implantation periods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Because a number of years may be required for normal cells to develop into carcinoma, genes involved in tumorigenesis and progression might differ among breast cancers in young women and those in older women. The present study sought to analyze subclonality during breast cancer evolution as well as diversity within each individual in our young patients' cohort., Methods: A total of 13 women aged <35 years at diagnosis with early breast cancer were recruited. Serial sections of breast samples consisting of synchronous invasive carcinoma, adjacent ductal carcinoma in situ (DCIS), normal breast tissue, and metastatic lymph nodes were collected and prepared for immunohistochemical analysis of estrogen receptor, progesterone receptor, HER2, and Ki67, and for extraction of genomic DNA. Germline and somatic gene alterations of genomic DNA were examined by targeted sequencing., Results: Genomic DNA from 13 blood samples and 36 breast tissues consisting of 14 invasive carcinomas, nine adjacent DCIS, 11 normal breast tissues, and two metastatic lymph nodes were successfully sequenced. Germline gene alterations including pathogenic variants and gene alterations that were not yet evaluated for their clinical significance were detected in all patients but one. Somatic gene alterations were identified in eight invasive carcinomas, five DCIS, and one metastatic lymph node. Different somatic gene alterations between invasive carcinoma and DCIS were detected in two patients. Somatic gene mutations were present in non-neoplastic tissues in three patients. No two patients had the same gene alterations., Conclusion: Our results reveal diversity within each individual during breast cancer progression., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-β1-induced EMT through direct transcriptional activation of Snai1. The molecular mechanism how TGF-β1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-β1-induced Notch signaling activation and EMT development. TGF-β1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-β1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-β1-induced EMT through the activation of Notch signaling., (Copyright © 2021. Published by Elsevier GmbH.)

Case Presentation: A 57-year-old woman was admitted to our hospital for an abnormal chest shadow found during routine chest radiography. She had no respiratory symptoms. Her medical history included dyslipidemia, and her surgical history included conization for cervical cancer at age 38 years. She was a social drinker and ex-smoker of approximately 10 cigarettes per day (from ages 20 to 30 years); she denied recreational drug use., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Uterine infection with bacteria and the release of peptidoglycan (PGN), antigenic cell wall components of both Gram-negative and Gram-positive bacteria, can cause early pregnancy losses in ruminants, but the associated mechanisms remain unsolved. Day 7 blastocyst starts to secrete a minute amount of interferon-tau (IFNT) in the uterine horn which is required for early stage of maternal recognition of pregnancy (MRP) in ruminants, and it induces interferon stimulated genes (ISGs) for driving uterine receptivity in cows. This study investigated if PGN disrupts IFNT response through modulation of endometrial ISGs expressions. Cultured bovine endometrial epithelial cells (BEECs) were treated with embryo culture medium (ECM) or IFNT (1 ng/ml) in the presence or absence of a low level of PGN (10 pg/ml) for 24 h. A real-time PCR analyses revealed that the presence of PGN suppressed IFNT-induced ISGs (OAS1 and ISG15) and STAT1 expressions in BEECs. To visualize the impact of PGN in an ex-vivo model that resembles the in vivo status, endometrial explants were treated by IFNT (1 ng/ml) with or without PGN (10 pg/ml) for 12 h. PGN suppressed IFNT-induced gene expressions of the above factors, but not for IFNA receptor type1 (IFNAR1) or type2 (IFNAR2) in explants. Immunofluorescence analysis illustrated that PGN completely suppressed the IFNT-triggered OAS1 protein expression in the luminal epithelium of explants. Of note, PGN did not stimulate pro-inflammatory cytokines (TNFA and IL1B) or TLR2 mRNA expression in both models. These findings indicate that the presence of low levels of PGN suppresses ISGs expression induced by IFNT secreted from early embryo, at the luminal epithelium of the bovine endometrium. This could severely interfere with early stage of MRP processes in cows, leading to pregnancy failure., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudging the impartiality of the research reported., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Apoptosis is a physiological process that plays a critical maintenance role in cellular homeostasis. Previous reports have demonstrated that cells undergo apoptosis in a cell density-dependent manner, which is regulated, in part, by signal transducers and activators of transcription (STAT) 3. The molecular mechanisms regulating cell density-dependent apoptosis, however, has not been thoroughly investigated to date. Since Notch signaling is activated via direct cell-to-cell contact and plays a pivotal role in cell fate decisions, we examined the role of Notch signaling in cell density-dependent apoptosis of mouse embryonic fibroblasts NIH 3T3 cells. With the increase in cell density, IL-6 expression was induced, which was necessary for STAT3 activation as well as apoptosis regulation. Notch signaling was also activated in a cell-density dependent manner. Blocking Notch signaling either through siRNA-mediated targeting of Jagged1 expression or γ-secretase inhibitor treatment demonstrated that Notch signaling activation was necessary for IL-6 induction. Constitutive activation of Notch signaling via the overexpression of Notch1 intracellular domain was sufficient for the induction of IL-6, which was mediated via direct transcriptional activation. Taken together, our study indicates that Notch signaling regulates cell density-dependent apoptosis through IL-6/STAT3-dependent mechanism. Consequently, Notch signaling might represent a novel therapeutic target in diseases characterized by dysregulated apoptosis., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background: Although iodinated contrast (IC) agents are commonly used in endovascular aneurysm repair (EVAR), perioperative use in patients with renal dysfunction or IC allergies is avoided. Carbon dioxide (CO 2 )-guided angiography is a promising alternative. We aimed to evaluate short-term and midterm outcomes of EVAR using CO 2 -guided angiography., Methods: Three hundred eighty-one patients who underwent EVAR from January 2012 to September 2016 were retrospectively reviewed and divided into an IC-EVAR group (n = 351) and CO 2 -EVAR group (n = 30). Subjects in the CO 2 -EVAR group had severe renal dysfunction (n = 27) and IC allergy (n = 4). Intraoperative, postoperative, and follow-up variables were compared., Results: Compared with the IC-EVAR group, preoperative serum creatinine level was significantly higher (2.0 vs. 0.92 mg/dL, P < 0.0001) and mean IC dose was significantly lower (18 vs. 55 mL, P < 0.0001) in the CO 2 -EVAR group. The fluoroscopy time, operative time, number of stent grafts placed, and technical success rates of the groups were similar; no type I and/or type III endoleaks were detected on completion angiography. There was no acute kidney injury and one case of intestinal necrosis in the CO 2 -EVAR group, potentially due to cholesterol embolism. Postoperative endoleak, enlargement of aneurysms, survival, freedom from secondary intervention, and renal function change up to 3 months, postoperatively, were similar between the groups., Conclusions: CO 2 -EVAR is technically feasible and exhibits prominent renal protection. However, consideration of the aortic lumen status remains an important challenge., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 20% to 30% of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKIs., Materials and Methods: The characteristics of 124 NSCLC patients with EGFR mutations who had received EGFR-TKIs were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8 and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically., Results: Primary resistance was observed in 13.7% of the patients (17 of 124). A significant difference in smoking history was observed between patients with primary resistance and those with non-primary resistance. A lower density of total TILs and negative PD-L1 expression on immunohistochemical analysis correlated significantly with primary resistance, in contrast to that with non-primary resistance. Moreover, the negative PD-L1 expression with low TIL density, indicating immune ignorant phenotype of tumor microenvironment, was observed in those with primary resistance with a significant difference., Conclusion: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise κ scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC., Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3)., Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, κ scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64., Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided., (Copyright © 2017 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Recent studies have shown differential response to chemotherapy among the subtypes of non-small cell lung carcinoma (NSCLC). Therefore, to accurately differentiate between the types of lung cancer is of paramount importance. Transbronchial biopsy using endobronchial ultrasonography with a guide sheath (EBUS-GS) is a promising method for the diagnosis of NSCLC. The purpose of this study was to evaluate the consistency between the types of lung cancer histologically diagnosed by bronchial biopsy or cytologically by EBUS-GS, and the final diagnosis of the resected specimen., Methods: A retrospective analysis was performed on 203 patients having primary lung cancers diagnosed by EBUS-GS, who subsequently underwent curative pulmonary resection at the Hokkaido University Hospital between July 2003 and December 2011. In the present study, non-small cell carcinoma was defined as non-squamous cell carcinoma, and squamous cell carcinoma (Sq) was excluded., Results: Of the 40 cases diagnosed as Sq by EBUS-GS, 37 cases were diagnosed as Sq, and 3 cases were diagnosed as non-Sq after surgical resection. Of the 159 cases diagnosed as non-Sq by EBUS-GS, 151 cases were diagnosed as non-Sq, 6 as Sq, and 2 as small cell carcinoma after surgical resection. These results showed that the positive predictive value of EBUS-GS in the diagnosis of Sq was 93%, and its positive predictive value in diagnosing non-Sq was 95%., Conclusions: The pathological subtyping of NSCLC using small tissue and cytology samples obtained by EBUS-GS appears to effectively distinguish between Sq and non-Sq and is therefore considered useful in making a treatment decision., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs)., Materials and Methods: Eight facilities participated in this study. A total of 795 patients with 1229 SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules., Results: The mean prospective follow-up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas [MIAs], 21 adenocarcinomas in situ [AIS], and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years (p = 0.0004)., Conclusion: This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The 2004 World Health Organization classification of lung cancer contained three major forms of non-small-cell lung cancer: squamous cell carcinoma (SqCC), adenocarcinoma (AdC), and large cell carcinoma. The goal of this study was first, to assess the reproducibility of a set of histopathological features for SqCC in relation to other poorly differentiated non-small-cell lung cancers and second, to assess the value of immunohistochemistry in improving the diagnosis., Methods: Resection specimens (n = 37) with SqCC, large cell carcinoma, basaloid carcinoma, sarcomatoid carcinoma, lymphoepithelial-like carcinoma, and solid AdC, were contributed by the participating pathologists. Hematoxylin and eosin (H&E) stained slides were digitized. The diagnoses were evaluated in two ways. First, the histological criteria were evaluated and the (differential) diagnosis on H&E alone was scored. Second, the added value of additional stains to make an integrated diagnosis was examined., Results: The histologic criteria defining SqCC were consistently used, but in poorly differentiated cases they were infrequently present, rendering the diagnosis more difficult. Kappa scores on H&E alone were for SqCC 0.46, large cell carcinoma 0.25, basaloid carcinoma 0.27, sarcomatoid carcinoma 0.52, lymphoepithelial-like carcinoma 0.56, and solid AdC 0.21. The κ score improved with the use of additional stains for SqCC (combined with basaloid carcinoma) to 0.57, for solid AdC to 0.63., Conclusion: The histologic criteria that may be used in the differential diagnosis of poorly differentiated lung cancer were more precisely refined. Furthermore, additional stains improved the reproducibility of histological diagnosis of SqCC and AdC, uncovering information that was not present in routine H&E stained slides.

Introduction: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies., Methods: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group., Results: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed., Conclusion: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

We describe a case of a 64-year-old man with constrictive pericarditis of unusual anatomy. Preoperative investigations revealed the thickened and calcified pericardial ring encircling the right and left ventricular cavity at the level of the atrioventricular (AV) groove and crossing the left anterior descending coronary artery, leading to strangulation of the heart. Off-pump complete pericardiectomy was performed successfully. The patient's postoperative course was uneventful., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

This case report describes a right subclavian artery aneurysm secondary to long-term repetitive blunt trauma. A 62-year-old man with a right subclavian artery aneurysm had had a history of bird hunting using a shotgun that impacted substantially against his right clavicula and shoulder weekly for >20 years. The patient underwent open repair with partial sternotomy and distal balloon control. The aneurysmal sac was resected, and the right subclavian artery was reconstructed with a primary end-to-end anastomosis. Histopathologic examination of the resected aneurysmal wall revealed that all three layers of the arterial wall were comparatively intact, with fibrosis and lipid deposition in the intima and in various degrees of degeneration in the media, suggesting a true aneurysm., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells undergo phenotypic transition to mesenchymal cells and thus is involved in the pathogenesis of tumor metastasis and organ fibrosis. Notch signaling is a highly conserved pathway that regulates intercellular communication and directs cell fate decisions. Here, we show the critical role of Notch signaling in TGF-β1-induced EMT. Inhibition of Notch signaling either by γ-secretase inhibitor or by knocking down of Notch signaling molecules by small interfering RNA abrogated EMT in association with decreased expression of Snai1. Constitutive activation of Notch signaling was sufficient for the induction of Snai1 as well as Notch ligand Jagged1. Notch signaling induced Snai1 expression via direct transcriptional activation. Collectively, these data show that Notch signaling activation promote TGF-β1-induced EMT through the induction of Snai1. Further studies on Notch signaling may provide diagnostic and therapeutic targets for cancer and fibrotic disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: For appropriate treatment, such as the selection of antibiotics or initiation of steroid therapy, correctly diagnosing benign pulmonary diseases located at the periphery is vital. This study assessed the usefulness of bronchoscopy using endobronchial ultrasonography with a guide sheath (EBUS-GS) in the diagnosis of benign pulmonary diseases, especially those presenting peripheral nodular lesions., Methods: We retrospectively reviewed 159 patients with 171 peripheral pulmonary lesions (PPLs) that were subsequently diagnosed as benign diseases. To examine the role of bronchoscopy with EBUS-GS, the contribution of bronchoscopy was classified into 4 categories. We also retrospectively reviewed 24 patients with 25 PPLs that were subsequently diagnosed as benign diseases by bronchoscopy without EBUS-GS (historical control)., Results: The ultimate diagnosis of 171 PPLs included 45 cases of mycobacteriosis, 45 cases of bronchiolitis obliterans organizing pneumonia/chronic organized pneumonia (BOOP), 23 cases of bacterial pneumonia, 13 abscesses, 11 cases of sarcoidosis, and 34 other benign diseases. Among them, a definitive diagnosis was obtained by bronchoscopy with EBUS-GS in 99 lesions (58%). Lesions in which the probe was positioned within the lesion had a higher diagnostic yield (64%) than did lesions in which the probe was positioned adjacent to the lesion (52%) or outside the lesion (20%; P=0.01). The diagnostic yield of bronchoscopy with EBUS-GS was higher compared with that of the historical control (58% versus 28%; P=0.04)., Conclusions: Bronchoscopy using EBUS-GS is a reasonable option as a diagnostic procedure for PPLs, even if they are suspected to be benign in nature., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Environmental exposure to formaldehyde is commonly associated with clinical symptoms such as mucosal irritation and olfactory disorders. However, the impact of such exposure on the development of mucosal inflammation and its outcome has not been carefully evaluated., Methods: The observational non-comparative study was planned. The study population consisted of group of 41 medical students who had signed up for a cadaver dissection course as part of their gross anatomy teaching at the school of medicine Chiba University in Japan. During such dissection course, the students are exposed to variable levels of environmental formaldehyde routinely employed for the preservation the cadavers. The subjects were evaluated by a detailed medical examination. We measured their serum IgE levels. In addition, an olfaction test and nasal mucosal sensitivity to histamine was serially determined, immediately before and after the course and 6 months after the completion of the course., Results: Olfactory abnormalities were observed in 13/41 (32%) subjects and increased nasal mucosal hypersensitivity to histamine was observed in 17/41 (41%) during and immediately after completion of the course. These subjects had evidence of preexisting allergic rhinitis. 6/41 (15%) other students with no prior evidence of allergic rhinitis also exhibited formaldehyde associated clinical symptoms during the dissecting course. However, the symptoms disappeared upon completion of the course in all subjects studied., Conclusions: Temporary abnormalities in the olfaction test and increased nasal mucosal hypersensitivity to histamine were observed in a few students with preexisting allergic rhinitis after environmental exposure of high concentrations of formaldehyde. These effects appeared to be transient.

Aim: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT)., Patients and Methods: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re-evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory., Results: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up., Conclusions: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Information on the clinical behavior of the recently proposed primary duodenal follicular lymphoma (DFL) is limited., Patients and Methods: Demographic data, signs, symptoms, disease stage, and treatment of the patients diagnosed in National Cancer Center Hospital from 1999 to 2007 were collected and analyzed., Results: Twenty-seven patients were studied. Nineteen patients were asymptomatic at the time of diagnosis. Twenty patients had stage I disease. The histological grade was 1 or 2 in 26 patients. IgH/BCL2 fusion was shown in 20 of the examined 24 cases (83%). Fourteen patients received therapy upon diagnosis (local radiotherapy in 2 patients and chemotherapy in 12 including rituximab therapy), their response rate was 85%, and the estimated progression-free survival (PFS) rate at 3 years was 70%. One patient developed histological transformation. The other 13 patients were followed up; their estimated PFS rate at 3 years was 74%. Five among six cases responded to treatment even after progressive disease. All 27 patients have survived with a median follow-up time of 47.9 months., Conclusions: The majority of primary DFL patients have a localized tumor of low-grade histology and are positive for t(14;18). Watchful waiting might be an alternative approach for its indolent course; however, further studies are warranted.

Disrupted hematopoiesis and delayed immune reconstitution are life-threatening complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although graft-versus-host disease (GVHD) is a major risk factor for the bone marrow (BM) insufficiency, how GVHD impairs BM hematopoiesis has been largely unknown. We hypothesized that BM stromal niche could be a target of GVHD. In major histocompatibility complex (MHC)-mismatched murine models of GVHD, we have demonstrated the early destruction of osteoblasts that especially affected B-cell lineages. The defective B lymphopoiesis was due to the impaired ability of BM stroma and osteoblasts to support the hematopoiesis, as evidenced by the failure of GVHD-affected BM to reconstitute the hematopoietic cells. The administration of anti-CD4 monoclonal antibody (mAb) ameliorated these effects and improved B lymphopoiesis while preserving graft-versus-tumor effects. Genetic ablation of Fas-Fas ligand signaling also partially restored B lymphopoiesis. Our present study provided evidence of BM GVHD, with the identification of osteoblasts as the main target for GVHD in BM. Moreover, our data showed the potential for mAb therapies to enhance immune reconstitution in vivo for patients undergoing allo-HSCT.

Aortic dissection commonly affects the thoracic aorta and is associated with high morbidity and mortality rates. Localized dissections originating from the infrarenal abdominal aorta are extremely rare. We report a rare case of localized dissecting aneurysm originating from the infrarenal abdominal aorta in a 62-year-old man. Open surgical repair was successfully performed without any complications.

Introduction: As there is little information on the histologic characteristics of adenocarcinoma in smokers, we histologically examined the effect of smoking on the carcinogenesis and progression of peripheral small lung adenocarcinomas., Methods: Two hundred thirty-six consecutive patients with peripheral adenocarcinoma of the lung 30 mm or less in diameter were studied. Prognosis, histology, and location of the adenocarcinoma were compared among patients with a Brinkman index (B.I.) of 0, 1 to 500, and more than 500., Results: The ratio of smokers to nonsmokers was 1.4:1. The rate of carcinogenesis in the upper region of the lung (S1-3) was 1.4 times as high that in the lower region (S4-10) in smokers, but almost equal in the two regions in nonsmokers. Outcome tended to be worse in patients with a B.I. of more than 500 than in those with a B.I. of less than or equal to 500 for adenocarcinomas 30 mm or less in diameter (p = 0.0855), and was significantly worse for adenocarcinomas 20 mm or less in diameter (p = 0.0359). Patients with a high B.I. tended to have invasive adenocarcinoma (IAC) without a bronchioloalveolar carcinoma (BAC) component (IAC - BAC) or IAC with a BAC component (IAC + BAC) rather than noninvasive adenocarcinoma. For adenocarcinomas as a whole, B.I. was correlated with several pathologic prognostic factors, including pathologic stage, lymphatic permeation, vascular invasion, presence of a solid component, necrosis, and modified scar grade, particularly in the upper region. Specifically, in IAC + BAC, B.I. was correlated with modified scar grade and the presence of a solid component. In IAC - BAC, B.I. was correlated with the presence of a solid component and necrosis., Conclusions: Small adenocarcinoma in smokers seems to occur frequently in the upper region of the lung, shows invasive features more frequently, and shows greater progression and dedifferentiation than that in nonsmokers. Tobacco-smoking may have an effect on the carcinogenesis and multistep progression of peripheral lung adenocarcinoma 30 mm or less in diameter.

Background: Cigarette smoke induces bronchial mucus secretion. However, the mechanism of this induction is still unidentified. In this study, we investigated the role of the putative calcium-activated chloride channel 1 (CLCA1) and its blocker, niflumic acid, in cigarette smoke-induced mucin synthesis both in vivo and in vitro., Methods and Results: Sprague-Dawley rats were exposed to cigarette smoke for 4 weeks. The CLCA1, epidermal growth factor receptor (EGFR), and MUC5AC expressions were increased in the trachea and lung tissues. Goblet-cell hyperplasia with marked mucin staining was detected in the tracheal and bronchial epithelium. In the human bronchial epithelial cell line NCI-H292, cigarette smoke solution also induced mucin production as well as the RNA and protein expressions of CLCA1, EGFR, and MUC5AC. Both in vivo and in vitro, the induction of MUC5AC and mucin synthesis were inhibited by niflumic acid, and/or a selective EGFR tyrosine kinase inhibitor, AG-1478. Niflumic acid also blocked the epidermal growth factor-induced MUC5AC and mucin staining in the NCI-H292 cell line., Conclusion: Both EGFR and niflumic acid-sensitive chloride channels (probably CLCA1) are dependently affecting the mucin production as a part of a single complex signaling pathway. CLCA1 may be a key signaling member that can be targeted with pharmacologic interventions to treat mucus hypersecretion.

Objectives: We conducted a systematic review to determine the incidence of postoperative incision hernia in patients with abdominal aortic aneurysm compared to those with aortoiliac occlusive disease., Methods: Studies which compared the incidence of postoperative incision hernia in patients with abdominal aortic aneurysm and aortoiliac occlusive disease undergoing midline incision for arterial reconstruction were identified. MEDLINE was searched for articles published between January 1966 and September 2005., Results: Our search identified seven studies including data on 1132 patients, 719 with abdominal aortic aneurysm and 413 with aortoiliac occlusive disease. Pooled analysis demonstrated that patients with abdominal aortic aneurysm had a 2.9-fold increased risk of inguinal hernia (odds ratio 2.85, 95% confidence interval 1.71-4.77, p<0.0001), and a 2.8-fold risk of incisional hernia (2.79, 1.88-4.13, p<0.0001). Adjusting for other known risk factors patients with aortic aneurysm had a 5-fold increased risk of incisional hernia (5.45, 2.48-11.94, p<0.0001)., Conclusions: Patients with abdominal aortic aneurysm appear to have an approximately 3-fold increased risk for both inguinal and postoperative incision hernia compared to patients with aortoiliac occlusive disease. A large multi-centre prospective study is needed to confirm the results of this review.

It is difficult to distinguish multiple primary lung cancers from pulmonary metastasis. We experienced a case of surgically resected lung tumors that showed multiple ground-glass opacities on thoracic computed tomographic scan. There were eight nonsolid and two part-solid ground-glass opacities in the bilateral lungs. Surgical resection was performed because all tumors had a ground-glass opacity appearance on computed tomographic scan, which is compatible with a finding of primary lung adenocarcinoma. The postoperative pathologic diagnoses were two cases of invasive adenocarcinoma, six cases of bronchioloalveolar carcinoma, and eight cases of atypical adenomatous hyperplasia. The patient remains alive without any evidence of recurrence 40 months after surgery. A ground-glass opacity appearance on computed tomographic scan could be interpreted as supportive evidence for multiple primary lung adenocarcinoma rather than pulmonary metastases.

Study Objectives: We performed ultrathin bronchoscopy for pulmonary peripheral lesions using a system that displays virtual bronchoscopy (VB) images to the lesion simultaneously with actual images and navigates the bronchoscope to the target bronchus. We then evaluated the system with regard to its usefulness and problems., Design: A pilot study., Setting: A tertiary teaching hospital., Patients: The subjects were consecutive patients with small pulmonary peripheral lesions (< or = 30 mm)., Interventions: Using this system, the rotation, advancement, and retreat of VB images were possible, and the bronchus into which the bronchoscope was to be advanced was displayed. VB images were displayed along with actual images, and the ultrathin bronchoscope was advanced to the target bronchus under direct vision. Under CT and radiographic fluoroscopy, a pair of forceps was inserted into the lesion via the bronchoscope. Thin-section CT images were obtained; after confirming the advancement of the bronchoscope into the target bronchus and the arrival of the forceps at the lesion, a biopsy was performed., Results: Study subjects included 37 patients with 38 lesions. VB images to a median of the sixth- (third- to ninth-) order bronchi could be produced. Using this system, the ultrathin bronchoscope could be advanced into the planned route for 36 of the 38 lesions (94.7%). The system was used for a median of 2.6 min, and the median examination time was 24.9 min. The biopsy forceps could be advanced to the lesion in 33 of the 38 lesions (86.8%), and diagnosis was possible for 31 lesions (81.6%)., Conclusions: This navigation system is useful for ultrathin bronchoscopy for pulmonary peripheral lesions.

Recent studies have demonstrated that Th2 cytokines, such as interleukin-4 and interleukin-13, enhance fibrotic processes by activating fibroblast proliferation and collagen production, whereas interferon-gamma, a Th1 cytokine, inhibits these processes. Th1 and Th2 cells both differentiate from common T precursor cells, with transcription factor GATA-3 a key regulator of Th2 differentiation. In the present study, therefore, we examined the effects of GATA-3 overexpression on the development of pulmonary fibrosis in a mouse model. Wild-type C57BL/6 mice and GATA-3-overexpressing (GATA-3-tg) mice of the same background were intratracheally treated with bleomycin. The survival rate after bleomycin was significantly decreased in GATA-3-tg mice compared with wild-type mice. The degree of pulmonary fibrosis was much greater in GATA-3-tg mice than in wild-type mice 28 days after bleomycin treatment. Lung interferon-gamma concentration was significantly decreased in GATA-3-tg mice compared with wild-type mice by 7 days after either saline or bleomycin treatment. The concentration of transforming growth factor-beta, a fibrogenic cytokine, was significantly higher in GATA-3-tg mice than in wild-type mice. Exogenous administration of interferon-gamma to GATA-3-tg mice improved the degree of pulmonary fibrosis and thus increased survival. These results indicate that overexpression of GATA-3 enhances the development of pulmonary fibrosis, possibly by reducing interferon-gamma levels in the lung.

Situs inversus totalis refers to a mirror-image reversal of the normal position of the internal organs. The recognition of concomitant anomalies, such as in the cardiac, venous, gastrointestinal, and urinary systems, is extremely important because these anomalies may disturb the surgical procedure for the concurrent disease in situs inversus totalis. The authors describe a case of successfully repaired abdominal aortic aneurysm with a false aneurysm of the right external iliac artery in situs inversus totalis. The coexistence of abdominal aortic aneurysm has been seldom encountered. The presence of anatomical anomalies significantly increases operative risk. The surgical management of patients with abdominal aortic aneurysm in situs inversus totalis is discussed.

Background: The majority of lymphomas in the ocular adnexa are low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma). Although radiotherapy is the most frequently applied management, cataract and dry eye are problematic complications., Patients and Methods: Between 1973 and 2003, the clinical features of 36 patients with ocular adnexal MALT lymphoma with no symptoms who were managed with no initial therapy after biopsy or surgical resection were retrospectively analyzed., Results: The median patient age was 63 years (range 22-84) and all patients had stage I disease, consisting of 31 unilateral cases and five bilateral cases. With a median follow-up of 7.1 years, 25 (69%) did not require treatment. The median time until the initiation of treatment in the remaining 11 patients (31%) was 4.8 years. Six patients (17%) died, and among them only two (6%) died due to progressive lymphoma. Seventeen patients (47%) progressed, but histologic transformation was recognized in only one (3%). The estimated overall survival rates of the 36 patients after 5, 10 and 15 years were 94%, 94% and 71%, respectively., Conclusions: In selected patients with ocular adnexal MALT lymphoma, no initial therapy might be an acceptable approach, because 70% of patients remained untreated at a median of 8.6 years, and their survival was comparable to that of reports on immediate therapy.

Proximal ulnar artery aneurysms, including pseudoaneurysms, have not been described in the English literature. We report a nontraumatic pseudoaneurysm of the proximal ulnar artery with eosinophilia in a 54-year-old man. Radial, coronary, and hepatic artery aneurysms associated with eosinophilia in idiopathic hypereosinophilic syndrome or allergic granulomatous angiitis (Churg Strauss syndrome) have been reported. Although it is unclear in the present case whether eosinophilia was associated with the pseudoaneurysm of the ulnar artery, eosinophil infiltration into the aneurysmal wall may have influenced vascular injury as the cause of the pseudoaneurysm formation.

ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.

Intercostal artery pseudoaneurysm is extremely rare, and only six cases have been reported in the English literature. We describe a case of intercostal artery pseudoaneurysm due to a stab wound, review the literature, and discuss therapeutic modalities. Intercostal artery pseudoaneurysm is at risk for early rupture, and diagnosis before rupture is mandatory. Although embolization is considered to be a feasible therapeutic method, we would emphasize the significance of the anatomic features of the intercostal arteries: multiple blood supplies into the pseudoaneurysm, such as the anterior and posterior intercostal arteries, and musculophrenic artery.