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The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in in vitro and xenograft studies using lung cancer cell lines. However, FOXA2 expression in primary lung tumors does not correlate with an improved patient survival rate, and the functional role of FOXA2 in primary lung tumors remains elusive. To understand the role of FOXA2 in primary lung tumors in vivo, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFRL858R or KRASG12D, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFRL858R, whereas FOXA2 promoted tumor growth driven by KRASG12D. Importantly, FOXA2 expression along with KRASG12D produced invasive mucinous adenocarcinoma (IMA) of the lung, a fatal mucus-producing lung cancer comprising approximately 5% of human lung cancer cases. In the mouse model in vivo and human lung cancer cells in vitro, FOXA2 activated a gene regulatory network involved in the key mucous transcription factor SPDEF and upregulated MUC5AC, whose expression is critical for inducing IMA. Coexpression of FOXA2 with mutant KRAS synergistically induced MUC5AC expression compared with that induced by FOXA2 alone. ChIP-seq combined with CRISPR interference indicated that FOXA2 bound directly to the enhancer region of MUC5AC and induced the H3K27ac enhancer mark. Furthermore, FOXA2 was found to be highly expressed in primary tumors of human IMA. Collectively, this study reveals that FOXA2 is not only a biomarker but also a driver for IMA in the presence of a KRAS mutation., Significance: FOXA2 expression combined with mutant KRAS drives invasive mucinous adenocarcinoma of the lung by synergistically promoting a mucous transcriptional program, suggesting strategies for targeting this lung cancer type that lacks effective therapies., (©2023 American Association for Cancer Research.)

Background: Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs., Methods: Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation., Results: Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I ( GTF2I ) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene ( RAS ) mutations were detected in three cases [ Harvey RAS ( HRAS ) in two cases of type AB thymoma and neuroblastoma RAS ( NRAS )] in one case of type B1 thymoma), and additional sex combs like 1 ( ASXL1 ) mutation was present in one case of TC. All RAS mutations were observed in GTF2I- mutated cases., Conclusions: The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the GTF2I mutation. These findings suggest that the existence of the GTF2I mutation might be related to indolent types of TETs, and RAS mutations could be candidates as therapeutic targets in TETs., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-794/coif). The authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

It is well known that oxidative stress causes certain diseases and organ damage. However, roles of oxidative stress in the acute phase of critical patients remain to be elucidated. This study aimed to investigate the balance of oxidative and antioxidative system and to clarify the association between oxidative stress and mortality in critically ill patients. This cohort study enrolled 247 patients transported to our emergency department by ambulance. Blood was drawn on hospital arrival, and serum derivatives of reactive oxidant metabolites (dROMs, oxidative index) and biological antioxidant potential (BAP, antioxidative index) were measured. Modified ratio (MR) is also calculated as BAP/dROMs/7.51. There were 197 survivors and 50 non-survivors. In the non-survivors, dROMs were significantly lower (274 vs 311, p <0.01), BAP was significantly higher (2,853 vs 2,138, p <0.01), and MR was significantly higher (1.51 vs 0.92, p <0.01) compared to those in the survivors. The AUC of MR was similar to that for the APACHE II score. Contrary to our expectations, higher BAP and lower dROMs were observed on admission in non-survivors. This may suggest that the antioxidative system is more dominant in the acute phase of severe insults and that the balance toward a higher antioxidative system is associated with mortality., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2023 JCBN.)

Background: Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model., Methods: Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses., Results: Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model., Conclusions: Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The patient was a 53-year-old man. His chief complaint was a cough and dyspnea on exertion. Computed tomography (CT) showed a 3-cm-diameter tumor in the right upper lobe with invasion from hilar lymph nodes to the superior vena cava, right main bronchus, and pulmonary artery. After being diagnosed with non-small cell lung cancer, the patient underwent preoperative induction radiochemotherapy. At surgery, right upper double sleeve lobe lobectomy was performed. The right main pulmonary artery was reconstructed using a pericardial conduit. CT 1 week after surgery showed impaired blood flow in the right pulmonary artery. A metal vascular stent was inserted into the narrow part of the constructed pulmonary artery in the hybrid operating room because thrombectomy was unsuccessful. After surgery, contrast CT showed that blood flow was maintained. The patient is currently well without any recurrence 3 years after surgery., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Lung transplantation is the only option for patients with end-stage pulmonary diseases. During recent years, satisfactory results in terms of long-term survival and quality of life have been achieved with improvements in perioperative management, surgical technique, and immunosuppression. Airway complications after lung transplantation are associated with significant morbidity and mortality. Common airway complications after lung transplantation include anastomotic granulation, airway stenosis, bronchomalacia, fistulas, and anastomotic infection. These airway complications often result in repeated hospitalisations and interventions. If bronchoscopic interventions are not effective, other alternatives like surgical intervention or re-transplantation become necessary. While numerous strategies for airway complications have been proven effective, there are still some issues that to be solved. Further research is necessary to reduce mortality and improve quality of life of these patients.

Objectives: Cell therapies, such as stem cell suspension injection, are used to treat bronchopleural fistula. Although it is safe and effective, injected cells cannot remain within the bronchioles of the fistula due to cell leakage into the thoracic cavity. Here, we inserted a 'bio plug' into the fistula, produced using cells and a bio-3D printer, to examine the effectiveness of bio plugs for the closure of bronchopleural fistulas, the optimal cell source and the closure mechanism., Methods: Bio plugs were made with mesenchymal stem (stromal) cells derived from bone marrow (MSCBM), fibroblasts and rat lung micro-vessel endothelial cells using a bio-3D printer with different cell mixing ratios. Six groups, according to the presence or absence and the type of bio plugs, were compared. The plugs were inserted into the bronchi of F344 rats. The obstruction ratio and histological and immunohistochemical findings were evaluated., Results: MSCBM+ rat lung micro-vessel endothelial cell group exhibited a higher obstruction ratio among all groups excluding the MSCBM group (P = 0.039). This group had fibrosis and CD31-positive cells and fewer CD68-positive cells than MSCBM and MSCBM+ fibroblast groups., Conclusions: Bio plugs with mixed cells, including stem cells, contribute to bronchial closure in the current experimental setting. Endothelial cells effectively maintain the structure in this model. Although bronchial closure for bronchopleural fistula could not be described as clinical conditions were not reproduced, we collected essential data on bronchial closure; however, further experiments are warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Malignant pleural mesothelioma (MPM) is a highly malignant disease that develops after asbestos exposure. Although the number of MPM cases is predicted to increase, no effective standard therapies have been established. The novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) enhances the effects of γ-radiation in human lung and prostate cancer cell lines and in animal models. In this study, we explored the radiosensitizing effect of SQAP and its mechanisms in MPM. The human MPM cell lines MSTO-211H and MESO-4 were implanted subcutaneously into the backs and thoracic cavities of immunodeficient KSN/Slc mice, then 2 mg/kg SQAP was intravenously administered with or without irradiation with a total body dose of 8 Gy. In both the orthotopic and ectopic xenograft murine models, the combination of irradiation plus SQAP delayed the implanted human MSTO-211H tumor growth. The analysis of the changes in the relative tumor volume of the MSTO-211H indicated a statistically significant difference after 8 Gy total body combined with 2 mg/kg SQAP, compared to both the untreated control (P = 0.0127) and the radiation treatment alone (P = 0.0171). After the treatment in each case, immunostaining of the harvested tumors revealed decreased cell proliferation, increased apoptosis and normalization of tumor blood vessels in the SQAP- and irradiation-treated group. Furthermore, hypoxia-inducible factor (HIF) 1 mRNA and protein expression were decreased, indicating reoxygenation in this group. In conclusion, SQAP improved hypoxic conditions in tumor tissue and may elicit a radiosensitizing effect in malignant mesothelioma models., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objectives: Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation., Methods: Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan., Results: During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20 ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4 days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18 years., Conclusions: Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended., (© 2021. The Japanese Association for Thoracic Surgery.)

Background: Intercostal nerve damage due to thoracotomy or thoracoscopic manipulation is a major contributor to chronic postsurgical pain after pulmonary resection. Chronic postsurgical pain may last for months or years and can negatively impair physical functioning and daily activities. Global consensus on severe postoperative pain management is lacking, and chronic pain incidence after thoracic surgery remains high. Many patients report neuropathic pain, which can be difficult to treat with currently available therapies. The efficacy and safety of mirogabalin have been demonstrated for other types of neuropathic pain; thus, this study was planned to investigate the efficacy and safety of mirogabalin to treat neuropathic pain after thoracic surgery., Methods: In this multicenter, randomized, open-label, parallel-group, interventional study, patients who are diagnosed with neuropathic pain following removal of a chest drain after lung resection will receive conventional therapy (non-steroidal anti-inflammatory drugs and/or acetaminophen) with or without the addition of a clinical dose of mirogabalin for 8 weeks. For patient stratification, a visual analog scale pain intensity score at baseline of <60 vs. ≥60 mm will be used. Treatment efficacy and safety with and without the addition of mirogabalin will be assessed using a questionnaire evaluating postoperative changes in pain severity and activity. The primary study endpoint is the change in pain intensity from baseline to Week 8, measured by the visual analog scale. Additionally, the presence of chronic pain at 12 weeks after enrollment in each treatment group will be recorded., Discussion: This protocol has been reviewed and approved by the Clinical Research Review Board of Nagasaki University. Study data will be published in the Japan Registry of Clinical Trials database and peer-reviewed journals. Mirogabalin is already approved for the treatment of other types of neuropathic pain. It is anticipated that this study will provide data to elucidate the impact of mirogabalin treatment, in combination with conventional therapy, to benefit patients with neuropathic pain following thoracic surgery., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCTs071200053., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jtd-21-741). T Miyazaki serves as an unpaid editorial board member of Journal of Thoracic Disease from Sep 2020 to Aug 2022. T Miyazaki and TN have received honoraria for lectures from Daiichi Sankyo Co., Ltd. KY, HT and KS are current employees of Daiichi Sankyo Co., Ltd. Daiichi Sankyo Co., Ltd. funded the research reflected in this manuscript, the medical writing support and the article processing charges., (2021 Journal of Thoracic Disease. All rights reserved.)

Background: The current use of prophylactic antibiotics for lung cancer surgery requires modification in aging individuals with impaired lung function. A sustained-release formulation of azithromycin (AZM-SR) could help resolve some of these challenges with its sustained antibacterial and anti-inflammatory effects. The aim of this study was to examine the safety and efficacy of AZM-SR in lung cancer surgery as well as its anti-inflammatory effect., Methods: Fifty patients were included in the study, and AZM-SR was administered 1 day prior to the surgery. The clinical course, including postoperative complications, was monitored, and the concentration of AZM, bacterial culture, and inflammatory cytokine levels of resected lung specimens were evaluated., Results: No side effects related to AZM-SR were observed. Five cases of postoperative pneumonia (10%) were observed; technical issues were involved in 3 cases. All patients recovered well. Four cases showed positive bacterial culture upon lung tissue examination; however, this was not significantly correlated with postoperative complications. A negative correlation was observed between AZM concentration in lung tissue and interleukin-6 (IL-6) expression., Conclusions: Prophylactic utilization of AZM-SR in lung cancer surgery seems feasible. The anti-inflammatory effect of AZM might contribute additional beneficial effects in the perioperative management of lung cancer surgery.

Background: The current standard postoperative treatment for stage II-IIIA non-small cell lung cancer (NSCLC) is a regimen of platinum doublet adjuvant chemotherapy. These regimens, which are the same as for solid NSCLC tumors, often cause severe adverse reactions in the treated patients. Therefore, an effective treatment regimen with fewer side effects is needed., Methods/design: The purpose of this study is to evaluate the effectiveness and safety of S-1 monotherapy (80 mg/m 2 orally administrated twice daily, at day 1-14, 16 cycles) and cisplatin with vinorelbine combination therapy (cisplatin 80 mg/m 2 at day 1,vinorelbine 25 mg/m 2 at day 1, 8, 4 cycles) in patients with II/IIIA stage non-small-cell lung cancer who underwent a total resection. In addition, we will also evaluate the level of treatment side effects by assessing quality of life (QOL), work productivity and activity performance. The primary endpoint is a 2-year relapse free survival (RFS) and the second primary endpoints are 2-year overall survival (OS), rate of treatment completion, safety, work productivity and activity, and quality of adjusted life years (QALY). At the same time, we aim to obtain precise information required to perform future phase 3 randomized controlled trials. The study is designed to estimate the primary endpoint with accuracy determined as the width of its 95% confidence interval to be less than 20%. Recruitment started in May 2017 and is ongoing., Discussion: This study has been conceived to establish a superior regimen for completely resected NSCLC based on efficacy, safety and QOL., Trial Registration: Registry number: UMIN000027435 . Registered May 22, 2017.

Three-dimensional (3D) printers are increasingly being used for a variety of applications. In the surgical field, patient-specific organ models are increasingly being used as preoperative simulators for complicated surgeries. In this study, we describe the use of patient-specific 3D models for tracheal resection. We performed preoperative simulations for two patients diagnosed with tracheal ganglioneuroma and adenoid cystic carcinoma; the mimic operations suggested the necessity of a short cuff intubation tube across the surgical field, indicating the recommended amount of dissection around the trachea and bilateral hilum prior to tracheal reconstruction. The postoperative courses were free from any anastomotic or pulmonary complications. We described the availability of preoperative simulations for complicated tracheal resection and reconstruction using patient-specific 3D printed models. Mimic operations using the 3D printed models allowed accurate preparation and confidence in selection of the optimal surgical strategy.

Background/aim: To compare operative results between venous puncture (P) with real-time ultrasonography vs. cut-down (CD) with preoperative ultrasonography for totally implantable central vein access device (TICVAD) implantation performed by residents (R) vs. senior surgeons (S)., Patients and Methods: Adult oncologic patients (n=268) undergoing TICVAD implantations were retrospectively compared between 172 Ps and 96 CDs. Then, we compared Ps performed by R (P-R, n=131) and S (P-S, n=41) and CDs performed by R (CD-R, n=59) and S (CD-S, n=37)., Results: Median operation times were 40 min in the P group and 53.5 min in the CD group, and times were significantly shorter for P-S and CD-S. Completion rates were comparable for each method and each surgeon. Intraoperative complication rates were 3.8% (P-R), 2.4% (P-S), and 0% (CD-R and CD-S)., Conclusion: P with real-time ultrasonography did not avoid complications compared to CD with preoperative ultrasonography. The latter performed safely even by residents., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC., Methods: Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m 2 /day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012., Results: Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered., Conclusion: A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC., Trial Registration: UMIN identifier: UMIN000005921 ; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).

Three-dimensionally printed organ models that facilitate preoperative simulations have the potential to improve outcomes of surgical procedures. Here, we report a case involving a 54-year-old man diagnosed with lung cancer of the right upper bronchus that was invading the right main bronchus. A right upper lobectomy with carinoplasty was performed. Although complete excision of the tumor was achieved, exertional dyspnea redeveloped 4 months post-surgery. Chest computed tomography revealed that airway stenosis caused by granulation had deformed the airway. Ablation of the granulation and airway stenting was required to improve the patient's symptoms. Prior to performing airway stenting, a three-dimensionally printed airway model was constructed, and the Y-shaped silicone stent used was modified in accordance with the model. After stenting, both the right and left bronchi were preserved, and the patient's symptoms improved. The three-dimensional printed airway model enhanced the accuracy and safety of the airway stenting procedure performed.

Objective: We compared outcomes after surgery or stereotactic body radiotherapy (SBRT) among patients with metachronous primary lung cancer (MPLC)., Methods: Patients with MPLC were treated with either surgery (2008-2018) or SBRT (2010-2018). We used propensity score matching (PSM) to reduce bias from various clinicopathological factors. MPLC was defined by the Martini and Melamed criteria., Results: Of 77 patients, 51 underwent surgery and 26 received SBRT. Most median clinicopathological characteristics did not significantly differ between the surgery and SBRT groups (male sex: 67% vs 65%; age: 73 vs 77 years; time after first surgery: 6.2 vs 4.7 years; lobectomy as first procedure: 82% vs 85%; second tumor size: 11 vs 12 mm; clinical stage I: 96% vs 100%; CEA: 2.9 vs 3.0 ng/ml). However, the surgery group had significantly more ipsilateral second tumors (n = 71, 58%, P = 0.003), better performance status (P = 0.03), and preserved lung function (P = 0.02). Surgery, thus, tended to be selected for patients with good physical function and for the MPLC in the contralateral side. Five-year overall survival did not significantly differ between the surgery and SBRT groups, either before PSM (86.5% vs 65.8%, P = 0.24, log-rank) or after PSM (100% vs 84.4%, P = 0.73)., Conclusions: Surgery and SBRT for MPLC patients are safe and feasible treatments with similar outcomes. However, this finding should be verified by a random controlled trial with a larger study cohort.

Biomaterials have been used for a long time in the field of medicine. Since the success of "tissue engineering" pioneered by Langer and Vacanti in 1993, tissue engineering studies have advanced from simple tissue generation to whole organ generation with three-dimensional reconstruction. Decellularized scaffolds have been widely used in the field of reconstructive surgery because the tissues used to generate decellularized scaffolds can be easily harvested from animals or humans. When a patient's own cells can be seeded onto decellularized biomaterials, theoretically this will create immunocompatible organs generated from allo- or xeno-organs. The most important aspect of lung tissue engineering is that the delicate three-dimensional structure of the organ is maintained during the tissue engineering process. Therefore, organ decellularization has special advantages for lung tissue engineering where it is essential to maintain the extremely thin basement membrane in the alveoli. Since 2010, there have been many methodological developments in the decellularization and recellularization of lung scaffolds, which includes improvements in the decellularization protocols and the selection and preparation of seeding cells. However, early transplanted engineered lungs terminated in organ failure in a short period. Immature vasculature reconstruction is considered to be the main cause of engineered organ failure. Immature vasculature causes thrombus formation in the engineered lung. Successful reconstruction of a mature vasculature network would be a major breakthrough in achieving success in lung engineering. In order to regenerate the mature vasculature network, we need to remodel the vascular niche, especially the microvasculature, in the organ scaffold. This review highlights the reconstruction of the vascular niche in a decellularized lung scaffold. Because the vascular niche consists of endothelial cells (ECs), pericytes, extracellular matrix (ECM), and the epithelial-endothelial interface, all of which might affect the vascular tight junction (TJ), we discuss ECM composition and reconstruction, the contribution of ECs and perivascular cells, the air-blood barrier (ABB) function, and the effects of physiological factors during the lung microvasculature repair and engineering process. The goal of the present review is to confirm the possibility of success in lung microvascular engineering in whole organ engineering and explore the future direction of the current methodology., (Copyright © 2020 Tsuchiya, Doi, Obata, Hatachi and Nagayasu.)

Purpose: We investigated, in patients who underwent lung resection for non-small cell lung cancer (NSCLC), the magnitude of early limitation in functional exercise capacity and the associations with pre- and postoperative factors. Methods: Consecutive patients with preoperative clinical stage I to IIIA NSCLC who underwent lung resection were prospectively enrolled. We measured functional exercise capacity (6-minute walk distance [6MWD]) and skeletal muscle strength (handgrip [HF] and quadriceps force [QF]) within 2 days prior to surgery and on day 7 postoperatively. Results: Two hundred eighteen participants were recruited (median age 69 years) of whom 49 developed postoperative complications (POCs). 6MWD was markedly decreased (514 m vs 469 m, P < .001); HF and QF were slightly decreased following surgery. Multiple linear regression showed that preoperative vital capacity ( P < .01), QF ( P < .05), the duration of chest tube drainage ( P < .001), and presence of POCs ( P < .05) were significant predictors. However, intraoperative factors were not significantly associated with the decline in 6MWD. Conclusions: These results suggest that patients with preoperative impairments in pulmonary function and muscle strength, and those who require prolonged chest tube drainage or develop POCs are likely to have impaired exercise capacity. Therefore, individual assessment and follow-up of patients with such factors is indicated.

Regenerated organs are expected to solve the problem of donor organ shortage in transplantation medicine. One approach to lung regeneration is to decellularize the organ and reseed it with selected cells. An advantage of the procedure is reduced immunogenicity, because all cells can be theoretically replaced by autologous cells. However, little is known regarding the extracellular matrix (ECM) damage during decellularization and ECM reconstruction process in the organ regeneration. We aimed to evaluate ECM damage and reconstruction of the decellularized-recellularized rat lung, including the removal of alpha-gal xenoantigens. Rat lungs were perfused with sodium dodecyl sulfate and Triton X-100 via the pulmonary artery, after which the decellularized scaffold was reseeded with rat or human endothelial cells and adipose-derived stem cell (ASCs). The ECM and alpha-gal antigen were evaluated using immunohistochemistry, western blotting, and a glycosaminoglycan assay. Alcian blue staining revealed increased production of proteoglycan following the addition of ASCs to the rat lung recellularized with rat lung microvascular endothelial cells. Glycosaminoglycan levels decreased in the decellularized lung and increased in the recellularized lung, especially in the ASC-treated group. Immunohistochemical expression of the alpha-gal protein was decreased to an undetectable level in the decellularized lung tissue and disappeared after recellularization with human cells. In western blot analysis, the bands of alpha-gal protein almost disappeared after recellularization with human cells. In conclusion, characteristics of the regenerated ECM might depend on the species and type of cells used for recellularization. Therefore, alpha-gal antigen might be eliminated after a prolonged culture, when using human cells., (© 2019 John Wiley & Sons, Ltd.)

Objectives: Because chemoradiotherapy using cisplatin and S-1, an oral fluoropyrimidine, is effective for unresectable non-small cell lung cancer (NSCLC), an induction setting was used in a multicenter phase II study (Clinical trial number: UMIN000008205). The correlations of relapse and clinicopathological factors were analyzed., Methods: We defined locally advanced NSCLC as pathologically proven chest wall invasion or hilar and/or mediastinal lymph node metastases by endobronchial ultrasound-guided transbronchial needle aspiration. The patients received two courses of S-1 administration for 14 days and intravenous cisplatin injection on day 8. A total dose of 40 Gy radiotherapy was concurrently received. Surgical resection was performed after completion of the treatment., Results: Of the 23 eligible patients, 18 had stage IIIA and 5 had stage IIB NSCLC. Twenty of the eligible patients (87.0%) completed the regimen. Six (26.1%) complete responses were identified and 12 cases (52.2%) were histopathologically downstaged by induction chemoradiotherapy (ICRT). The 3-year overall survival rate was 58.1% and relapse-free survival (RFS) rate was 52.0%, respectively. Among several clinicopathological parameters, univariate RFS analysis identified that only downstaging was significantly associated with longer RFS times (p = 0.003). The radiological response did not reflect pathological response. When the variables of preoperative pathologically proven N2 metastasis, pathological ICRT effectiveness, and downstaging were included in the Cox proportional hazard modes, only the parameter of downstaging displayed significant hazard ratio (hazard ratio 0.13, p = 0.010)., Conclusion: This protocol is considered an option among preoperative therapies and has obvious benefits for pathologically downstaged cases., Clinical Trial Number: UMIN000008205., Trial Registration Date: June 19, 2012.

EGFR ligands (e.g., EGF and TGFA) have been shown to be clinically associated with poor survival in lung cancer. Since TGFA itself initiates autochthonous tumors in liver, breast, and pancreas but not in the lung in transgenic mice in vivo, it would appear that an EGFR ligand may not initiate but rather promote lung cancer. However, it has not been proven in vivo whether lung cancer is promoted by an EGFR ligand. Using transgenic mouse models conditionally expressing EGFR L858R or Kras G12D with TGFA (an EGFR ligand) in lung epithelium, we determined that TGFA promoted the growth of EGFR L858R -lung tumors in airway regions but not that of Kras G12D -lung tumors. Analysis of TCGA datasets identified ΔNp63 and AGR2 as potential key tumor-promoting regulators, which were highly induced in the TGFA-induced EGFR L858R -lung tumors. The expression of AGR2 was positively correlated with the expression of TGFA in human EGFR-mutant lung adenocarcinomas. The expression of TGFA in human EGFR-mutant lung adenocarcinomas but not in the EGFR wild-type lung adenocarcinoma was associated with poor survival. These results suggest that targeting EGFR ligands may benefit patients who carry EGFR-mutant lung tumors but will not benefit patients with KRAS-mutant lung tumors.

Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung Tumor Signature of 143 genes, which was unexpectedly enriched in mucin-producing gastrointestinal, pancreatic, and breast cancers. The signature genes included transcription factors FOXA3, SPDEF, HNF4A, mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1 / B7-H4 (but not PD-L1 / B7-H1 ). Importantly, induction of FOXA3 or SPDEF along with mutant KRAS in lung epithelium was sufficient to develop benign or malignant mucinous lung tumors, respectively, in transgenic mice. FOXA3 and SPDEF induced MUC5AC and MUC5B, while HNF4A induced MUC3 in human mucinous lung cancer cells harboring a KRAS mutation. ChIP-seq combined with CRISPR/Cas9 determined that upstream enhancer regions of the mucin genes MUC5AC and MUC5B , which were bound by SPDEF, were required for the expression of the mucin genes. Here, we report the molecular signature and gene regulatory network driving mucinous lung tumors., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

A 66-year-old woman underwent right lower lobectomy and partial resection of the middle lobe for Stage I A double lung cancer. Five years after the operation, a routine computed tomography (CT) scan showed a mass on the staple line at the middle lobe. The mass was enlarged on CT scan after 6 months. A definitive diagnosis could not be made by bronchoscopic examination and fluoro-2-deoxy-glucose(FDG)/positron emission tomography( PET)-CT showed FDG uptake in the mass( early phase:SUVmax=3.24, late phase:SUVmax=4.31). Local recurrence of lung cancer was not completely denied, and right middle lobectomy was performed. Histopathologically, the resected specimen revealed granuloma with foreign body reaction. We should keep in mind the possibility of granuloma as differential diagnosis of lung cancer when using stapler.

Lung herniation is rare. We describe two cases; one cured by surgery, and the other observed without surgery. A 61-year-old man underwent minimally invasive cardiac surgery for mitral valve plasty. Four weeks postoperatively, chest computed tomography (CT) revealed exacerbating lung herniation and emergency surgery was performed. A 75-year-old man with metastatic tumor underwent partial resection of the left lower lobe through a 10-cm access window. Three months postoperatively, follow-up chest CT revealed prolapse of a small part of the upper lobe at the site of incision. However, he remained asymptomatic and was observed on an outpatient basis.

Anastomotic airway complications still remain an important issue after lung transplantation. Most of the complications are stenosis and anastomotic leakage. Stent insertion is one option for the stenosis. We review the anastomotic airway complications and report our recent experience of stent insertion using 3-dimensional printed airway model.

Purpose: Pulmonary emphysema is the pathological prototype of chronic obstructive pulmonary disease and is also associated with other lung diseases. We considered that observation with different approaches may provide new insights for the pathogenesis of emphysema., Patients and Methods: We reviewed tissue blocks of the lungs of 25 cases with/without emphysema and applied a three-dimensional observation method to the blocks. Based on the three-dimensional characteristics of the alveolar structure, we considered one face of the alveolar polyhedron as a structural unit of alveoli and called it a framework unit (FU). We categorized FUs based on their morphological characteristics and counted their number to evaluate the destructive changes in alveoli. We also evaluated the number and the area of pores of Kohn in FUs. We performed linear regression analysis to estimate the effect of these data on pulmonary function tests., Results: In multivariable regression analysis, a decrease in the number of FUs without an alveolar wall led to a significant decrease in the diffusing capacity of the lung for carbon monoxide (DLCO) and DLCO per unit alveolar volume, and an increase in the area of pores of Kohn had a significant effect on an increase in residual capacity., Conclusion: A breakdown in the lung framework and an increase in pores of Kohn are associated with a decrease in DLCO and DLCO per unit alveolar volume with/without emphysema.

Background/aim: Oxidative stress is defined as an imbalance between the pro-oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases., Materials and Methods: Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients., Results: Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057)., Conclusion: The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objectives: The Japanese Board of General Thoracic Surgery and the annual survey by the Japanese Association for Thoracic Surgery (JATS) of certified hospitals began in 2005; since then, over 1300 specialists and 650 hospitals have been certified by this system. To evaluate how this system contributes to improving the outcomes of general thoracic surgery, the effects of the number of certified general thoracic surgeons (GTSs) and hospital volume on 30-day mortality or hospital mortality were evaluated., Methods: Using data from the annual survey of JATS from 2005 to 2012, the outcomes of 211 619 patients who underwent lung resection for lung cancer were evaluated. The patients were divided into four groups by the level of surgery: first level, partial resection; second level, segmentectomy and lobectomy; third level, sleeve segmentectomy and lobectomy; and fourth level, pneumonectomy, sleeve pneumonectomy and pleuro-pneumonectomy. Multiple logistic regression analysis was used to examine the associations between operative mortality and the number of GTSs, hospital volume and level of surgical procedure., Results: Overall 30-day and hospital mortality rates were 0.40 and 0.77%, respectively. The 30-day and hospital mortality rates for each surgical level were 0.20 and 0.35% for the first level, 0.36 and 0.73% for the second level, 1.02 and 1.81% for the third level and 2.42 and 4.26% for the fourth level, respectively. The number of GTSs was associated with lower 30-day and hospital mortality rates (P < 0.0001). On logistic analysis, number of GTSs (<3 vs ≥3), hospital volume (<50 vs ≥50) and level of procedure (1 vs 2, 3 vs 2, 4 vs 2) were significantly associated with 30-day and hospital mortality rates. For 30-day mortality, the odds ratios were 0.688 (P < 0.0001) for higher number of GTSs and 0.856 (P = 0.0510) for higher volume hospitals. In the subgroup analysis by surgical level, low 30-day and hospital mortality rates in the second and fourth surgical levels were correlated with a higher number of GTSs., Conclusions: The current decrease in overall 30-day mortality rates from the JATS data showed greater dependence on the number of GTSs than on the hospital volume. We believe that the certification system in Japan is useful for the establishment of GTS status., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Sublobar resection procedures, such as segmentectomy and wedge resection, can be used for resectable lung cancer when the cancer is small or the condition of the patient is poor. In such cases, intraoperative lymph node (LN) exploration is necessary to avoid incomplete resection of potential N1 or N2 disease. The semi-dry dot-blotting (SDB) method was developed to detect intraoperative LN metastasis as a quick, cost-effective procedure that does not require special technical expertise. This study examined whether SDB can sufficiently identify LN metastasis in lung cancer patients., Methods: This study prospectively examined 147 LNs from 50 lung cancer patients who underwent surgery at Nagasaki University Hospital between April 2011 and June 2013. The SDB method uses antigen-antibody reactions with anti-pancytokeratin as the primary antibody and detects cancer cells using chromogen. To identify LN metastases, each LN was examined by the SDB method during surgery along with intraoperative pathological diagnosis (ope-Dx) and permanent pathological diagnosis (permanent-Dx)., Results: Compared with permanent-Dx, SDB offered 94.7% sensitivity, 97.7% specificity and 97.2% accuracy, while ope-Dx exhibited 84.2% sensitivity, 100% specificity and 98.0% accuracy. For 3 cases, micrometastases were detected by the SDB method but not by ope-Dx. Three LNs from lobar stations showed pseudo-positive results by the SDB method because of the presence of alveolar epithelium., Conclusions: The SDB method offers acceptably high accuracy in detecting LN metastasis, especially for mediastinal LNs, and represents a potential alternative for the intraoperative diagnosis of LN metastasis, even in the absence of a pathologist., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The purpose of this study was to evaluate the factors contributing to the outcomes of bronchoplasty for lung cancer by analysing a single institution's data for a 30-year period., Methods: A retrospective review of 213 patients who underwent bronchoplasty for lung cancer between 1980 and 2010 was undertaken. The patients were divided into two groups by the date of surgery: the first period was 1980-95, and the second period was 1996-2010., Results: Bronchoplasty and broncho-angioplasty were performed in 100 (75.8%) and 32 (24.2%) patients, respectively, in the first period and 61 (75.3%) and 20 (24.7%) patients, respectively, in the second period. Overall 90-day operative morbidity and mortality rates were 25.8 and 9.8%, respectively, in the first period and 45.7 and 2.5%, respectively, in the second period. Thirty-day mortality rates were 6.8% in the first period and 0% in the second period. Five-year survival was 41.1% (n = 132) in the first period and 61.5% (n = 81) in the second period (P = 0.0003). Comparing bronchoplasty and broncho-angioplasty, the 5-year survival was 45.6 and 26.5%, respectively, in the first period (P = 0.0048) and 60.9 and 62.1%, respectively, in the second period (P = 0. 8131). Using multivariate analysis to identify potential prognostic factors, the type of operation (broncho-angioplasty), postoperative complications and histology (non-squamous cell carcinoma) were significant factors affecting survival in the first period, but none of the factors significantly affected survival in the second period. When the rates of pN2 or N3 histological type disease were compared in each period, the rate of pN2 or N3 disease in non-squamous cell carcinoma was 51.4% in the first period and 45.5% in the second period; both were significantly higher than in squamous cell carcinoma (31.6 and 16.9%, respectively; P = 0. 0365 and 0.0073)., Conclusions: The present study suggests that progress in the preoperative staging system and perioperative medical management, as well as surgery, has contributed to current improvements in patients undergoing bronchoplasty and broncho-angioplasty. However, since nodal status in non-squamous cell carcinoma is not precisely evaluated before the operation, the indication for bronchoplasty should be considered carefully., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Reactive oxygen species function as key metabolites that can impair biological processes. In lung transplantation, severe oxidative stress is expected when ischemia/reperfusion injury, acute allograft rejection, and various infections occur., Case Report: Two clinical cases in which serial measurements of the oxidative stress response (levels of diacron-reactive oxygen metabolites) were taken during hospitalization using a Free Radical Elective Evaluator are reported. In the first case, a 30-year-old man underwent right single lung transplantation for juvenile pulmonary emphysema. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. The oxidative stress response fluctuated significantly (p<0.01) during the infections caused by bronchial stenosis compared to the stable condition. No acute rejection was seen during hospitalization. In the second case, a 44-year-old woman underwent right single lung transplantation for lymphangioleiomyomatosis. Immunosuppression was maintained by the same regimen as in case 1. The patient's postoperative course was uneventful, and there was no allograft rejection or infection. The oxidative stress response remained at the non-stress level., Conclusions: The oxidative stress response was measured by the levels of diacron-reactive oxygen metabolites in lung transplantation. High oxidative stress responses were seen during exposure to infections. This might become a non-invasive marker of complications after transplantation.

The number of patients with cardiovascular comorbidities is increasing due to aged society. We evaluated perioperative management of primary lung cancer patients with cardiovascular comorbidities. Between 2010 and 2013, 458 patients underwent lung cancer surgery at out hospital. 60(13%)patients had cardiovascular comorbidities (excluding hypertension and arrhythmia). Forty three(72%) patients were angina pectoris and myocardial infarction, and 7 (12%)were valve disease. In patients with cardiovascular comorbidities, high age, renal dysfunction, low % diffusing capacity for carbon monoxide and limited lymph node dissection were significantly seen. There was one patient with no symptoms of angina with the calcification of coronary artery detected by chest computed tomography(CT)before surgery. Percutaneous coronary artery intervention followed elective lung surgery was successfully performed. Short-term surgical results of patients with cardiovascular comorbidities were acceptable compared to those without.

Objectives: The number of elderly lung cancer patients requiring surgery has been increasing due to the ageing society and less invasive perioperative procedures. Elderly people usually have various comorbidities, but there are few simple and objective tools that can be used to determine prognostic factors for elderly patients with clinical stage I non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the prognostic factors of surgically treated, over 80-year old patients with clinical stage I NSCLC., Methods: The preoperative data of 97 over 80-year old patients with clinical stage I NSCLC were collected at Nagasaki University Hospital from 1990 to 2012. As prognostic factors, inflammation-based scoring systems, including the Glasgow Prognostic Score (GPS) determined by serum levels of C-reactive protein and albumin, the neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) were evaluated, as well as other clinicopathological factors, including performance status, body mass index, carcinoembryonic antigen, Charlson comorbidity index and type of surgical procedure., Results: The median age was 82 (range, 80-93) years. There were 62 (64.0%) clinical stage IA cases and 35 IB cases. Operations included 64 (66.0%) lobectomies, 15 segmentectomies and 18 wedge resections. The pathological stage was I in 76 (78.4%) patients, II in 12 (12.4%), III in 8 (8.2%) and IV in 1 (1.0%). Twelve (12.4%) patients underwent mediastinal lymph node dissection. Overall survival and disease-specific 5-year survival rates were 55.5 and 70.0%, respectively. The average GPS score was 0.4 (0-2). Disease-specific 5-year survival was significantly longer with GPS 0 than with GPS 1-2. (74.2%, 53.7%, respectively, P = 0.03). Overall 5-year survival was significantly longer with GPS 0 than with GPS 1-2. (59.7%, 43.1%, respectively, P = 0.005). Both the NLR (median value = 1.9) and the PLR (median value = 117) were not correlated with disease-specific and overall 5-year survival. On multivariate analysis, pathological stage I (P = 0.01) and GPS 0 (P = 0.04, hazard ratio: 2.13, 95% confidence interval 1.036-4.393) were significant prognostic factors., Conclusions: The preoperative GPS appears to be a useful predictor of overall survival and could be a simple prognostic tool for elderly patients with clinical stage I NSCLC., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aim: The present study was designed to define the clinicopathological characteristics of multiple cancers (MC) in 597 patients with hepatobiliary and pancreas (HBP) malignancies who underwent curative resection, in order to clarify risk factors and prognostic significance., Patients and Methods: Patients' demographics, clinicopathological parameters and survival rates were compared between solitary (SC) and MC HBP malignancies for 267 patients with hepatocellular carcinoma (HCC), 77 with intrahepatic cholangiocarcinoma (ICC), 84 with extrahepatic bile duct carcinoma (BDC), 72 with gallbladder carcinoma (GBC) and 97 with pancreatic cancer (PC)., Results: MC was observed in 66 patients (11%) and more than three cancers were observed in 13 (2.2%). The mean age of patients of the MC group was significantly higher than that of the SC group. The proportion of Nagasaki atomic bomb survivors among the MC group was significantly higher than among the SC group. These findings were significant in HCC and ICC. The histopathological aggressiveness of malignancies was lower with HCC, BDC and PC. In HCC, the disease-free survival of MC patients with more than three tumors was significantly lower than those with SC and double cancers. In GBC, the overall survival of the MC group was significantly better than the SC group. In PC, the disease-free and overall survival were significantly better in MC than SC., Conclusion: Careful follow-up for second or third occurrence of primary malignancies after primary curative treatment for HBP malignancy is necessary., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aims: To clarify improvement of hepatic resection in the recent years, we examined surgical records of 544 patients who underwent hepatectomy in 3 periods between 1994 and 2011 at a single academic institute., Methodology: Subjects were divided into 3 groups: group 1 (1994-1999, n = 156), group 2 (2000-2006, n = 228) and group 3 (2007-2011, n = 160). Clinical factors, surgical records and post-hepatectomy outcomes during hospitalization were compared between groups., Results: In group 3, patient age was significantly higher and the incidences of alcoholic or fatty liver and obstructive jaundice were significantly higher than in group 1 (p < 0.05). Preoperative liver function was not different between groups, and only prothrombin activity was significantly better in group 1 in comparison with the other groups (p < 0.05). In comparison with group 1, the incidence of resident surgeons as the main operator were significantly higher than in group 3 (p < 0.01). Incidences of laparoscopic hepatectomy and thoraco-abdominal approach were increased in group 3 (p < 0.01). Incidences of combined organ and major vessels resections were significantly higher in group 3 in comparison with group 1 (p < 0.01). Use of omental wrapping and hemostatic devices were significantly more frequent in group 3 than in group 1 (p < 0.01). Surgical records were not different between groups but the red cell transfusion rate in group 3 was significantly lower than in group 1 (p < 0.05). Hospital stay in group 3 was significantly shorter than in group 1. Incidence of hepatectomy-related complication, particularly bile leakage, was significantly lower in group 3 than in group 1 (p < 0.05)., Conclusions: According to this evaluation of different time periods, surgical outcomes have been improved with new surgical procedures and perioperative management.

The present study aimed to elucidate the relationship between cancer stem cells markers (CSCs), according to cell adhesion molecule (CD44) and glioma-associated oncogene homolog-1 (GLI1) expression, and clinicopathological factors and prognosis in 38 patients with intrahepatic cholangiocarcinoma (ICC) who underwent hepatectomy. CD44 and GLI1 expression was examined by immunohistochemical staining methods. The relationship with tumor angiogenesis or proliferation activity was also analyzed. Positivity of CD44 was 18% and that of GLI1 was 39%, but there was no significant correlation between the expressions of both. On macroscopic findings, CD44 expression in the periductal infiltration-type of ICC was significantly higher than in other types (p<0.01), and this type showed significantly worse survival after hepatectomy. Positive expression of GLI1 was significantly associated with older age. Although expression of neither CD44 nor GLI1 was significantly associated with disease-free survival, positive expression of both CD44 and GLI1 led to a significantly lower 3-year disease-free survival rate (0%; p<0.05). With respect to 5-year overall survival after hepatectomy, expression of both CD44 and GLI1 was not significantly associated with survival rate. CSCs might be useful markers for tumor-free survival in patients with ICC after hepatectomy and further investigation in larger series is warranted.

The efficacy of adjuvant photodynamic therapy (PDT) using the new photosensitizer, talaporfin sodium (TPS), was assessed in 7 patients with bile duct carcinoma (BDC). The 664-nm semiconductor laser (100 J/cm(2)) was applied through endoscopy to the tumor lesion within 6 h after injection of TPS. Cases included three non-resectable and 4 resected BDC with remnant cancer cells at the bile duct stump. Radiated lesions exhibited mild inflammatory responses. Locally advanced tumor occluding bile duct was relieved by PDT and patency was maintained for 16 months. Two patients developed mild photodermatitis but no severe morbidity. One patient died of other disease, and two patients died of liver metastasis within 6 months, but local recurrence was not observed. Three patients maintained cancer-free survival for 6-13 months. One patient survived with good status for 24 months. Adjuvant TPS-PDT is a safe and useful treatment for local control of BDC. Compared to the conventional PDT, the patient's quality of life is remarkably improved.

This study describes minimally invasive surgery using video-assisted thoracic surgery (VATS) for thymic diseases. Our procedure has been changed in the last decade from sternum-lifting thoracoscopic surgery with mini-thoracotomy to complete thoracoscopic surgery. Indications for this method include benign thymic disease, non-invasive thymoma or myasthenia gravis (MG). We performed these procedures for 27 cases, including 12 cases of thymic cyst, 10 cases of thymoma without MG, 3 cases of thymoma with MG and 2 cases of MG alone. In all cases of thymoma, tumor size was less than 5 cm. Complete VATS, VATS with mini-thoracotomy and sternum-lifting VATS were performed in 20, 4 and 3 patients, respectively. Complications were phrenic nerve palsy in 2 cases and postoperative bleeding in 1 case. We always use ultrasonic devices in this procedure. No recurrences have been identified in any cases. Even though definitive evidence is lacking for use of a unilateral approach with VATS for thymoma and MG, VATS thymectomy appears acceptable as a less-invasive procedure with less pain and rapid recovery.

A 59-year-old woman was pointed out isotope uptake at the right pulmonary hilum by positron emission tomography/computed tomography (PET/CT) performed for postoperative follow up of thyroid cancer. Chest enhanced CT showed a mass in the right pulmonary artery, which was diagnosed as sarcoma of pulmonary artery origin by a transcatheter biopsy. Chemotherapy by doxorubicin with anticoagulation therapy was started 1st due to the secondary pulmonary hypertension. Pulmonary hypertension was improved, but the size of the tumor enlarged. She underwent right pneumonectomy with mediastinal dissection. The tumor was completely resected, but brain metastases developed. Postoperative pathological diagnosis was leiomyosarcoma. A rare case of preoperatively diagnosed pulmonary arterial sarcoma was reported.

Organ-specific endonuclease might play a role in the age-related increase in apoptosis in laboratory rodent tissues. In nuclear extracts from liver tissues of male F344 rats, the DNase activity gel system identified DNase gamma, Ca(2+)/Mg(2+)-dependent endonuclease. The enzyme activity, which was measured at 3, 6, 16, and 24 months (mo) of age, was significantly increased between 16 and 24mo in control rats fed ad libitum (AL). The expression level of DNase gamma-mRNA, estimated by a semi-quantitative reverse transcription-polymerase chain reaction method, was also increased at 24mo in group AL. The proportion of immunohistochemically DNase gamma-positive cells, most of which were light-microscopically confined to apoptotic cells, was also significantly increased between 16 and 24mo. Dietary restriction, a powerful anti-aging intervention, which was achieved by providing 70% of the mean food intake in group AL from 6 weeks of age, inhibited the age-related increase in the enzyme activity and the proportion of immunostained cells; for the mRNA level, statistical significance was not obtained. The present study suggests that DNase gamma is involved in an age-related increase in the apoptosis of rat liver, and that CR inhibits the increase as it minimized the age-related increase in the fraction of DNA-damaged hepatocytes susceptible to apoptosis.

A reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is associated with an extension of lifespan in laboratory rodents. Several phenotypes of such animal models resemble those induced by caloric restriction (CR). Using a transgenic male Wistar rat model whose GH-IGF-1 axis was moderately suppressed by overexpression of the antisense GH transgene (tg), we elucidated a relationship between the effects of a reduced GH-IGF-1 axis and CR for some biomarkers of aging, lifespan, and pathologies. Heterozygous (tg/-) rats fed ad libitum (AL) had a dwarf phenotype similar to that of control nontransgenic (-/-) rats subjected to 30% CR from 6 wk of age. Both the reduced GH-IGF-1 axis and CR extended lifespan to a similar extent, although the effect of CR seemed to be greater. There was an additive effect of CR to lifespan extension when tg/- rats were subjected to CR. Pathologic analyses indicated that the preventive effect of CR on selected diseases was greater than that of the reduced GH-IGF-1 axis. The present study suggests that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effects partly through the reduced GH-IGF-1 axis.