ACTN4 is associated with the malignant potential of thymic epithelial tumors through the ß-catenin/Slug pathway.

Thymic epithelial tumors (TETs) are rare tumors arising from the mediastinum. Among TETs, thymoma type B2, B3 and thymic carcinoma are highly malignant and often present invasion and dissemination. However, the biological characteristics of TETs have not been thoroughly studied, and their mechanisms of invasion and dissemination are largely unknown. α-Actinin 4 (ACTN4) is a member of actin-binding proteins and reportedly plays important roles in the progression of several cancers. In this study, we investigated the relationship between ACTN4 and characteristics of the malignant potential of TETs, such as invasion and dissemination. In vitro experiments using Ty-82 thymic carcinoma cells revealed that overexpression of ACTN4 enhanced the proliferative and invasive ability of Ty-82 cells; conversely, knockdown of ACTN4 attenuated the proliferative and invasive potential of Ty-82 cells. In western blotting (WB) experiments, ACTN4 induced the phosphorylation of extracellular signal-regulated kinase and glycogen synthase kinase 3ß to regulate the ß-catenin/Slug pathway. Furthermore, WB analysis of cancer tissue-origin spheroids from patients with TETs showed results similar to those for Ty-82 cells. In vivo experiments showed that the knockdown of ACTN4 significantly suppressed the dissemination of Ty-82 cells. A WB and immunohistochemistry staining comparison of primary and disseminated lesions of TETs using surgical specimens showed upregulated expression of ACTN4, ß-catenin, and Slug proteins in disseminated lesions. In summary, our study suggests ACTN4 is associated with malignant potential characteristics such as invasion and dissemination in TETs via the ß-catenin/Slug pathway.

Effect of mTOR inhibitors on the mortality and safety of patients with lymphangioleiomyomatosis on the lung transplantation waitlist: A retrospective cohort study.

BACKGROUND: Although lung transplantation (LTx) is the last resort for patients with end-stage lymphangioleiomyomatosis (LAM), the high waitlist mortality is a source of concern in Japan. Discontinuation of mechanistic target of rapamycin (mTOR) inhibitors prior to LTx is recommended due to the incidence of severe adverse events. Therefore, we hypothesized that mTOR inhibitors may affect the mortality of patients with LAM on the LTx waitlist. METHODS: We retrospectively compared the characteristics of consecutive patients with LAM on the LTx waitlist who were and were not receiving mTOR inhibitors. RESULTS: Twenty-nine consecutive patients with LAM who listed our center between January 2004 and December 2021 were selected from the database and enrolled in the present study. Seventeen patients (58.6%) were receiving a mTOR inhibitor, sirolimus (treatment group). During a median listing period of 1277 days, 12 patients (41.4%) were hospitalized, six patients (20.7%) died from disease before LTx, and 15 patients underwent LTx. Among the deceased patients, four patients (66.6%) had pneumothoraces. The waitlist mortality in the treatment group was significantly lower than that in the non-treatment group (p = 0.03). Among the six patients who discontinued sirolimus in the treatment group, four patients (66.6%) were hospitalized with respiratory complications after the discontinuation of sirolimus. No mTOR inhibitor-related complications arose in the treatment group undergoing LTx (n = 7), including those on a reduced sirolimus dose. CONCLUSIONS: Administration of an mTOR inhibitor until LTx may decrease waitlist mortality. Due to life-threatening events after discontinuing sirolimus pre-LTx, a reduced dose until LTx is permissible.

Surgical resection of advanced intrathoracic tumors through a combination of the hemiclamshell and transmanubrial approaches.

PURPOSE: The hemiclamshell (HCS) approach provides a comprehensive view of the anterior mediastinum, whereas the transmanubrial osteomuscular sparing approach (TMA) allows sufficient exposure of the cervico-thoracic transition. We assessed the effectiveness and the outcomes of the combined HCS plus TMA approach to resect thoracic malignant tumors. METHODS: We reviewed five patients with thoracic malignant tumors invading the thoracic outlet who underwent surgery using an HCS and TMA approach between 2018 and 2021. RESULTS: The preoperative diagnosis was myxofibrosarcoma, lung cancer, thymic cancer, thymoma, and neurofibromatosis type1 in one patient each, respectively. Cardiovascular reconstruction was done on the aortic arch in two patients, on the descending aorta in one, and on the superior vena cava in one, combined with resection of the vagus nerve in three patients, of the phrenic nerve in two, and of vertebra in one, with overlap in some cases. The TMA was added because all patients required dissection of the periphery of the subclavian artery, and two had tumor extension to the neck. Macroscopic complete resection was achieved in four patients. There was no postoperative mortality. CONCLUSION: The combination of the HCS and TMA approaches at the same operation provides a comprehensive view of the mediastinum, lung, and cervico-thoracic transition and allows safe access to the thoracic great vessels and subclavian vessels.

Expression of fibroblast activation protein in intrathoracic solitary fibrous tumor.

PURPOSE: Fibroblast activation protein (FAP) is a serine integral membrane protease, the expression of which has been confirmed in various cancer types. Solitary fibrous tumors of the pleura (SFTP) are rare mesenchymal fibroblastic neoplasms. We present a case of 18F-labeled FAP inhibitor ([18F]FAPI-74) PET imaging and its correlation with histological FAP expression and review an SFTP series at our institution in relation to the extent of FAP expression. METHODS: This retrospective study included 13 patients who underwent surgery between March 2011 and December 2022 at our institute. One of the patients also underwent [18F]FAPI-74 PET imaging. We semi-quantitatively evaluated FAP expression in SFTPs using immunohistochemical staining and H-scores. RESULTS: Nine of the 13 patients were male, with a median age of 64 years (range, 28-79 years). The median tumor size was 6.6 cm (1.1, 16 cm). In the pathological findings, expression levels of Ki67 were 1-5% in 12 of 13 cases. Furthermore, FAP expression was observed in all patients, and the median H-score was 160 (range, 10-280). The H-score of FAP expression in two of the 13 patients was low (10 in both), and that in two of the 13 patients was high (240 and 280). The SUVmax value of [18F]FAPI-74 PET was 3.57 in a patient in whom the H-score of FAP expression was 180. CONCLUSIONS: SFTPs expressed FAP to varying degrees in different patients and the [18F]FAPI-74 PET results in one patient reflected FAP expression in the tumor tissue.

Native lung surgery after single lung transplantation: clinical characteristics and outcomes.

PURPOSE: Single lung transplantation (SLT) is a viable option for patients with end-stage pulmonary parenchymal and vascular diseases. However, various diseases can occur in native lungs after SLT. METHODS: Between January 2000 and December 2021, 35 patients underwent cadaveric SLT and survived for more than 30 days in our hospital. Among these 35 patients, 10 required surgery for diseases that developed in their native lungs. The clinical characteristics of these 10 patients and the outcomes of native lung surgery (NLS) were investigated. RESULTS: Among these ten patients, the indications for lung transplantation were chronic obstructive pulmonary disease and idiopathic interstitial pneumonia in three patients each, and lymphangioleiomyomatosis and collagen vascular disease-related interstitial pneumoniain two patients each. The causes of NLS included pneumothorax (n = 4), primary lung cancer (n = 2), native lung hyperinflation (n = 2), and pulmonary aspergilloma (n = 2). The surgical procedures were pneumonectomy (n = 7), lobectomy (n = 2), and alveolar-pleural fistula repair (n = 1). Only one postoperative complication, empyema, was treated with antibiotics. The 5-year overall survival rates after transplantation with and without NLS were 70.0% and 80.0%, respectively, and did not differ to a statistically extent (p = 0.56). CONCLUSION: NLS is an effective treatment option for diseases that develop in the native lungs after SLT.

Surgery for pulmonary lesions in patients with a history of urinary tract transitional cell carcinoma.

BACKGROUND: There has been little information on the actual diagnosis of pulmonary lesions in patients with a history of urinary tract transitional cell carcinoma (TCC) and short- and long- outcomes of pulmonary resection for these patients. METHODS: In the present study, the data of 37 consecutive patients with a history of TCC who underwent pulmonary resection for solitary pulmonary lesions were reviewed, and the clinical factors and short- and long-term outcomes were analyzed. RESULTS: The study population included 35 male patients, and 2 female patients. The mean age was 72.5 years. Twenty patients (80%) were smokers and showed a high incidence of chronic obstructive pulmonary disease. Pulmonary lesions and primary TCC were detected simultaneously in 5 patients and metachronously in 32 patients. The median interval between treatment for primary TCC and the detection of pulmonary lesion was 43 months. The mean tumor diameter was 23 mm. The types of resection included lobectomy (n = 19), segmentectomy (n = 8), and partial resection (n = 10). Twelve of 37 patients (32%) developed postoperative complications. The pathological diagnoses included primary lung cancer (n = 28), pulmonary metastasis from TCC (n = 7), and others (n = 2). The 5-year overall survival rate for all patients was 72%. The 5-year overall survival rate of patients with primary lung cancer was 74%, while that of patients with pulmonary metastasis from TCC was 57%. CONCLUSIONS: Surgery can be proactively considered for treating pulmonary lesions in patients with a previous history of TCC, as it provides favorable long-term outcomes.

A Novel Peroxisome Proliferator-Activated Receptor Gamma/Nuclear Factor-Kappa B Activation Pathway is Involved in the Protective Effect of Adipose-Derived Mesenchymal Stem Cells Against Ischemia-Reperfusion Lung Injury.

BACKGROUND: Adipose-derived stem cells (ADSCs) are well-recognized for their remarkable ability to suppress ischemia-reperfusion lung injury (IRLI). The primary objective of this investigation was to elucidate the underlying mechanism through which ADSCs exert protective effects against IRLI. METHODS: A warm hilar occlusion model in C57BL6J mice was used. Hilar occlusion was achieved for 1 hour (ischemic), and after 1 hour the occlusion was released (reperfusion) to recover for 3 hours. RNA sequencing, the physiological function, pathway activation, and expression of inflammatory cytokines were evaluated. RESULTS: Lung gas exchange and pulmonary edema were significantly improved in the IRLI/ADSCs group compared with the IRLI group. RNA sequencing results suggested that the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-kappa B (NF-κB) pathway was involved in the effect of the ADSCs. Administration of a PPARγ antagonist in the IRLI/ADSC group resulted in the deterioration of the physiological function. Furthermore, the PPARγ protein expression level decreased, the NF-κB protein expression level increased, and inflammatory cytokine parameters from lung tissue and blood sample worsened in the PPARγ antagonist-administered group. CONCLUSION: Administration of ADSCs exerted a significant protective effect against IRLI in mice, and the effect is attributed to the activation of the PPARγ/NF-κB pathway.

Association of the psoas muscle index with the survival of patients on a waiting list for lung transplantation: a Japanese single-institution study.

PURPOSES: Some predictive markers of death have been reported for patients on the waiting list for lung transplantation (LTx). We assessed whether or not the preoperative psoas muscle index (PMI) correlates with waitlist mortality. METHODS: In 81 patients with end-stage lung disease on the waiting list for LTx between 2011 and 2020 at Osaka University Hospital, we examined the association between baseline characteristics, including the diagnosis, respiratory function test results, blood collection items, steroid use, and psoas muscle mass on computed tomography, and survival during the waiting period using Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS: Thirty-three patients (41%) died during follow-up. Univariate and multivariate analyses showed that patients with a low PMI had a higher rate of death during follow-up than those with a high PMI (p < 0.0001 and 0.0002, respectively). In addition, a diagnosis of interstitial pneumonia (hazard ratio 3.30, 95% confidence interval 1.52-7.17, p = 0.0025) and low albumin level (hazard ratio 2.21, 95% confidence interval 1.02-4.80, p = 0.0449) were also significant predictors of survival. CONCLUSION: A low PMI at registration is associated with a decreased survival time among LTx candidates and it may be a predictive factor of mortality in patients waiting for LTx.

Integrated cardiothoracic team approach for complex lung transplantation procedures in Japan-current status and future direction.

The first lung transplant procedure in the world was performed in 1983, while in Japan that was first accomplished in 1998. Over the following 25 years, lung transplantation has become a viable treatment option for Japanese patients with a variety of end-stage lung diseases. Seventy cadaveric-donor lung (41 single, 29 bilateral), 11 bilateral living-donor lobar lung, and three heart-lung transplants have been performed with use of an integrated cardiothoracic team approach at medical facilities associated with Osaka University. Extremely advanced clinical and surgical skill sets are required to complete a lung transplant procedure, including surgical knowledge and techniques, as well as management of cardiovascular surgery, especially in regard to mechanical circulatory support (MCS), vascular anastomosis in difficult cases, and concomitant cardiac surgery. We have found that a collaborative effort by general thoracic and cardiac surgeons is an important key for success with lung transplantation. Complex lung transplant surgery and management in Japan are performed by use of an integrated cardiothoracic team approach, which has led to a synergistic impact on successful lung transplantation cases by capitalizing greatly on the experiences, techniques, and expertise of cardiac and thoracic experts. The present review is focused on the role of cardiac surgeons from the viewpoint of our experience with these cases.

Evaluation of LAT1 Expression in Patients With Lung Cancer and Mediastinal Tumors: 18F-FBPA PET Study With Immunohistological Comparison.

PURPOSE OF THE REPORT: L-type amino acid transporter-1 (LAT1) is a tumor-specific transporter expressed in various tumor types, with minimal expression in normal organs. We previously demonstrated 18F-fluoro-borono-phenylalanine (18F-FBPA) as a selective PET probe for LAT1 in a preclinical study. Herein, we evaluated LAT1 expression in preoperative patients with lung or mediastinal tumors using 18F-FBPA PET and immunofluorescence staining. PATIENTS AND METHODS: The study population included patients with histopathological diagnosis (n = 55): primary lung cancers (n = 21), lung metastases (n = 6), mediastinal tumors (n = 15), and benign lesion (n = 13). PET scanning was performed 1 hour after the injection of 18F-FBPA (232 ± 32 MBq). Immunofluorescence staining was performed on the resected tumor sections using LAT1 antibody. LAT1 staining was graded on a 4-grade scale and compared with the SUVmax on 18F-FBPA PET. RESULTS: A positive correlation was observed between the SUVmax of 18F-FBPA PET and LAT1 expression by immunofluorescence staining (r = 0.611, P < 0.001). The SUVmax of 18F-FBPA was 3.92 ± 1.46 in grade 3, 3.21 ± 1.82 in grade 2, 2.33 ± 0.93 in grade 1, and 1.50 ± 0.39 in grade 0 of LAT1 expression. Although 18F-FBPA PET showed variable uptake in lung cancers and mediastinal tumors, benign lesions showed significantly lower SUVmax than those in malignant lesions (P < 0.01). CONCLUSIONS: Uptake on 18F-FBPA PET reflected the expression level of LAT1 in lung and mediastinal tumors. It was suggested that 18F-FBPA PET can be used for the precise characterization of the tumor in pretreatment evaluation.

Outcomes of surgical resection for pulmonary metastasis from pancreatic cancer.

PURPOSE: As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer. METHOD: We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed. RESULTS: The observation period was 20 (range, 1-101) months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15 months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival. CONCLUSION: A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15 months. Our findings suggest that the disease-free interval may influence the prognosis.

T cell immunity in interstitial lung disease with non-small cell lung cancer patients.

OBJECTIVES: Limited treatment options are available for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD). The rationale for immunotherapy and its adverse events for NSCLC with ILD remains unclear. In this study, we examined T cell profiles and functions in the lung tissues of NSCLC patients with or without ILD to provide evidence for the potential mechanism of immune checkpoint inhibitor (ICI)-related pneumonitis in NSCLC patients with ILD. MATERIAL AND METHODS: We investigated T cell immunity in the lung tissues of NSCLC patients with ILD to support the application of immunotherapy for these patients. We analyzed T cell profiles and functions in surgically resected lung tissues from NSCLC patients with and without ILD. The T cell profiles of infiltrating cells in lung tissues were analyzed by flow cytometry. T cell functions were measured based on cytokine production by T cells stimulated with phorbol 12-myristate 13-acetate and ionomycin. RESULTS: The percentages of CD4+ T cells expressing immune checkpoint molecules (Tim-3, ICOS, and 4-1BB), CD103+CD8+ T cells, and regulatory T (Treg) cells were higher in NSCLC patients with than in those without ILD. A functional analysis of T cells in lung tissues indicated that CD103+CD8+ T cells positively correlated with IFNγ production, whereas Treg cells negatively correlated with IFNγ and TNFα production. Cytokine production by CD4+ and CD8+ T cells did not significantly differ between NSCLC patients with and without ILD, except for TNFα production by CD4+ T cells being lower in the former than in the latter. CONCLUSION: In NSCLC patients with ILD stable for surgery, T cells were active participants and balanced in part by Treg cells in lung tissues, suggesting the potential development of ICI-related pneumonitis in NSCLC patients with ILD.

Significance of the Surgical Treatment with Lymph Node Dissection for Neuroendocrine Tumors of Thymus.

BACKGROUND: Neuroendocrine tumors of a thymus (NETTs) are rare, accounting for approximately 2-5% of all thymic epithelial tumors, and have a poor prognosis due to frequent lymph nodes or distant metastasis. METHODS: We retrospectively reviewed the clinicopathological background and outcomes of 40 patients who underwent resection or surgical biopsy with histologically diagnosed NETTs from 1986 to 2022. RESULTS: The most common pathological type was atypical carcinoid. Surgical resection was performed in 35 patients, with lymph node dissection in 33 and surgical biopsy in five. The overall survival (OS) rate for all patients was 81.4% and 52.3% at 5 and 10 years, respectively. The 2-year survival rate was 20% for the biopsy group, which was significantly worse than that of the resected group (p < 0.001). The relapse-free survival rates were 61.7% and 37.6% at 5 and 10 years, respectively, in 34 patients with complete resection. The univariate analysis revealed better the OS rate in the resected cases but with no significant differences between histological grade, lymph node metastasis, tumor size, or Ki67 index. CONCLUSIONS: Surgical complete resection is considered to improve prognosis regardless of histologic type. NETTs frequently develop lymph node metastasis, thus, lymph node dissection seems necessary for complete resection.

Stereotactic ablative body radiotherapy with a central high dose using CyberKnife for metastatic lung tumors.

BACKGROUND: The CyberKnife system features a robotically-positioned linear accelerator to deliver real-time image-guided stereotactic ablative body radiotherapy (SABR). It achieves steep dose gradients using irradiation from hundreds of different directions and increases the central dose of the gross tumor volume (GTV) without increasing the marginal dose to the planning target volume. We evaluated the effectiveness and safety of SABR with a central high dose using CyberKnife for metastatic lung tumors. METHODS: A total of 73 patients with 112 metastatic lung tumors treated with CyberKnife were retrospectively analyzed. Local control, progression-free survival, and overall survival were calculated using the Kaplan-Meier method. The median age was 69.2 years. The most common primary sites were the uterus (n = 34), colorectum (n = 24), head and neck (n = 17), and esophagus (n = 16). For peripheral lung tumors, the median radiation dose was 52 Gy in 4 fractions, whereas for centrally located lung tumors, it was 60 Gy in 8-10 fractions. The dose prescription was defined as 99% of the solid tumor components of the GTV. The median maximum dose within the GTV was 61.0 Gy. The GTV and planning target volume were enclosed conformally by the 80% and 70% isodose lines of the maximum dose, respectively. The median follow-up period was extended to 24.7 months; it was 33.0 months for survivors. RESULTS: The 2-year local control, progression-free survival, and overall survival rates were 89.1%, 37.1%, and 71.3%, respectively. Toxicities of grade ≥ 2 were noted as grade 2 and 3 radiation pneumonitis in one patient each. The two patients with grade 2 or higher radiation pneumonitis had both received simultaneous irradiation at two or three metastatic lung tumor sites. No toxicity of grade ≥ 2 was observed in patients with metastasis in one lung only. CONCLUSIONS: SABR with a central high dose using CyberKnife for metastatic lung tumors is effective with acceptable toxicity. TRIAL REGISTRATION: Number: 20557, Name: Stereotactic ablative radiotherapy using CyberKnife for metastatic lung tumor, URL: http://www.radonc.med.osaka-u.ac.jp/pdf/SBRT.pdf , Date of registration: April 1, 2021 (retrospectively registered), Date of enrollment: May 1, 2014.

[Ingenuities of Segmentectomy for Small Lung Cancer in Uniportal Video-assisted Thoracic Surgery].

Our department has been performing uniportal thoracoscopic lobectomy since April 2019 and now also performs segmentectomy for small malignant tumors. A skin incision of approximately 4 cm is created between the anterior fifth intercostal space on the left and right sides. Based on our experience, uniportal segmentectomy does not follow the learning curve unique to segmentectomy. For dissection of segmental surface, an automatic suture is used to prevent pulmonary fistulas. If the cutting line between the segments is straight, dissection can be performed easily even in uniportal surgery, in which the automatic suturing device is inserted from one direction. For inter-area identification, we use an air-containing collapsed line with normal ventilation, after which thoracoscopic indocyanine green( ICG) imaging is introduced. However, there have been cases in which a difference in inter-area identification occurred between ICG identification and the air-containing collapsed line. As such, it is better to utilize both methods in cases with masses close to the inter-areas.

Resection of a colloid adenocarcinoma of the lung: A case report.

Colloid adenocarcinoma of the lung is a rare subtype of lung adenocarcinoma, accounting for only about 0.24% of lung cancers. Because of its rarity, long-term postoperative prognostic reports are limited. In this report, we describe a case of colloid adenocarcinoma of the lung with a 5-year recurrence-free follow-up. The patient is a 66-year-old woman. During postoperative follow-up for ovarian cancer, chest CT showed a 45 × 30 mm sized mass in the left lung with mixed low-absorption areas inside that were suspicious of cystic lesion. We suspected metastatic lung tumour, and performed lower lobectomy. Pathological examination revealed pale tumour cells forming a glandular lumen with internal mucus production. Based on the results of immunostaining we diagnosed colloid adenocarcinoma of the lung. She received postoperative adjuvant chemotherapy and is alive 4 years postoperatively without recurrence. Colloid adenocarcinoma of the lung, even if large, may have a good prognosis if completely resected.

Therapeutic Targeting of Cancer-Associated Fibroblasts in the Non-Small Cell Lung Cancer Tumor Microenvironment.

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. The most common lung cancer is non-small cell lung cancer (NSCLC), with an overall 5-year survival rate of around 20% because NSCLC is a metastatic disease. A better understanding of the mechanism underlying lung cancer metastasis is therefore urgently needed. The tumor microenvironment involves different types of stromal cells and functions as key components in the progression of NSCLC. Through epithelial-mesenchymal transition (EMT), in which epithelial cells lose their polarity and acquire mesenchymal potential, cancer cells acquire metastatic abilities, as well as cancer stem-cell-like potential. We previously reported that cancer-associated fibroblasts (CAFs) interact with lung cancer cells to allow for the acquisition of malignancy and treatment resistance by paracrine loops via EMT signals in the tumor microenvironment. Furthermore, CAFs regulate the cytotoxic activity of immune cells via various cytokines and chemokines, creating a microenvironment of immune tolerance. Regulation of CAFs can therefore affect immune responses. Recent research has shown several roles of CAFs in NSCLC tumorigenesis, owing to their heterogeneity, so molecular markers of CAFs should be elucidated to better classify tumor-promoting subtypes and facilitate the establishment of CAF-specific targeted therapies. CAF-targeted cancer treatments may suppress EMT and regulate the niche of cancer stem cells and the immunosuppressive network and thus may prove useful for NSCLC treatment through multiple mechanisms.

Protective Effect of Calpain Inhibition During Cold Ischemia on Ischemia-reperfusion Injury After Lung Transplantation.

BACKGROUND: Necroptosis, one of the types of regulated necrosis, causes ischemia-reperfusion (IR) lung injury. N-acetyl-leucyl-leucyl-norleucinal (ALLN), a calpain inhibitor, is known to attenuate necroptosis and apoptosis, and the purpose of this study was to evaluate the protective effect of ALLN during cold ischemia against IR injury in a rat lung transplant model. METHODS: Male Lewis rats (250-350 g) were divided into 3 groups: sham group (n = 4), nontransplantation; control group (n = 8), transplantation with IR lung injury; and ALLN group (n = 8), transplantation with IR lung injury/ALLN. Rats in the sham group underwent a simple thoracotomy, and the remaining 2 groups of rats underwent an orthotopic left lung transplant. Cold ischemic time was 15 h. After 2 h of reperfusion, physiological function, inflammatory cytokine expression, pathway activation, and the degrees of necroptosis and apoptosis were evaluated. RESULTS: Lung gas exchange (PaO 2 /FiO 2 ) was significantly better, and pulmonary edema was significantly improved in the ALLN group compared with the control group ( P = 0.0009, P = 0.0014). Plasma expression of interleukin-1ß was significantly lower in the ALLN group than in the control group ( P = 0.0313). The proportion of necroptotic and apoptotic cells was significantly lower in the ALLN group than in the control group ( P = 0.0009), whereas the proportion of apoptotic cells remained unchanged ( P = 0.372); therefore, the calpain inhibitor was thought to suppress necroptosis. CONCLUSIONS: The administration of ALLN during cold ischemia appears to improve IR lung injury in a lung transplant animal model via the inhibition of necroptosis.

Clinicopathological analysis of a superior sulcus tumor treated by salvage surgery after concurrent definitive chemoradiotherapy followed by durvalumab: A case report.

Surgical treatment of superior sulcus tumors (SSTs) is clinically challenging. Definitive chemoradiotherapy (CRT) is a standard treatment for SST. In operable cases, multimodal therapy (CRT followed by surgery) is another option, at least for experienced institutions. Immune checkpoint inhibitors (ICIs) have recently been developed, and several clinical trials have investigated definitive CRT followed by ICIs for consolidation or maintenance therapy of unresectable local advanced non-small cell lung cancer (NSCLC), including SSTs. Clinical studies of salvage surgery after CRT followed by ICIs are also ongoing. However, the clinical outcomes of salvage surgery after multimodal therapies and histopathological analyses of surgical specimens after such treatments remain unclear. Here, we report the case of a patient with SST comprising squamous cell carcinoma with invasion of the second to third rib and vertebrae who underwent salvage surgery after concurrent definitive CRT followed by the ICI durvalumab, and show the results of clinicopathological analyses of the resected specimen.