Living-donor Lobar Lung Transplantation - Initiation and Development - Secondary Publication.

Due to the difficulty of finding brain-dead donors, in October 1998, I performed the first living-donor lobar lung transplantation (LDLLT) for a ventilator-dependent 24-year-old female patient with bronchiectasis using lobes from her parents. The patient is still alive and in good health 25 years after the transplantation. Over time, the indications for LDLLT have expanded to include pulmonary hypertension, pulmonary fibrosis, congenital genetic diseases, pulmonary complications after stem cell transplantation, and, more recently, severe lung injury due to COVID-19 infection. In 2022, we successfully performed an ABO-incompatible LDLLT. To address size mismatches, we have developed new LDLLT techniques, such as right-to-left inverted transplantation, upper lobe-sparing transplantation, and segmental lung transplantation. Our published studies cover a range of topics, encompassing both basic and clinical research. Of particular significance is the observation that LDLLT offers immunological advantages over cadaveric lung transplantation (CLT). Having conducted 353 cases of lung transplantation, including 161 LDLLTs and 192 CLTs, our 5-year survival rates were 83% after LDLLT and 74% after CLT, surpassing the 55% 5-year survival rate reported by the International Society for Heart and Lung Transplantation. We have hosted numerous observers and research fellows from 15 countries. In addition, I have contributed to LDLLT procedures not only in Japan but also abroad. It brings me great satisfaction to think that my educational efforts may ultimately lead to saving the lives of those suffering from end-stage respiratory failure around the world.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Clinical outcomes of left upper segmentectomy vs. lobectomy for early non-small-cell lung cancer: a nationwide database study in Japan.

PURPOSE: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. METHODS: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. RESULTS: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). CONCLUSION: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe.

Effect of revised organ transplant law in Japan on lung transplantation.

PURPOSE: To investigate how revision of the organ transplant law in Japan affected lung transplantation in this country. METHODS: Lung transplant candidates registered between January, 2000 and December, 2009 were designated as the pre-revision group (n = 396) and those registered between January, 2011 and December, 2020, as the post-revision group (n = 1326). Both groups were analyzed retrospectively using data collected by the Japanese Society of Lung and Heart-Lung Transplantation. RESULTS: The number of patients who underwent brain-dead donor lung transplantation (BDLT) increased significantly after the law amendment (32.2 vs. 13.8%, p < 0.01). The median waiting time for BDLT was significantly reduced (708 days vs. 1163 days, p < 0.01) and the mortality rate while waiting for BDLT improved significantly after the law amendment (33.1 vs. 42.6%, p < 0.01). In the post-revision group, 18 pediatric patients underwent BDLT. The 5-year survival rates after BDLT were comparable between the groups (73.5% in the pre-revision group vs. 73.2% in the post-revision group, p = 0.32). CONCLUSIONS: The organ transplant law revision shortened the waiting time for BDLT significantly and decreased the mortality rate while waiting for BDLT. The posttransplant outcomes in Japan remained favorable throughout the study period.

A Deep Learning-Based Assay for Programmed Death Ligand 1 Immunohistochemistry Scoring in Non-Small Cell Lung Carcinoma: Does it Help Pathologists Score?

Several studies have developed various artificial intelligence (AI) models for immunohistochemical analysis of programmed death ligand 1 (PD-L1) in patients with non-small cell lung carcinoma; however, none have focused on specific ways by which AI-assisted systems could help pathologists determine the tumor proportion score (TPS). In this study, we developed an AI model to calculate the TPS of the PD-L1 22C3 assay and evaluated whether and how this AI-assisted system could help pathologists determine the TPS and analyze how AI-assisted systems could affect pathologists' assessment accuracy. We assessed the 4 methods of the AI-assisted system: (1 and 2) pathologists first assessed and then referred to automated AI scoring results (1, positive tumor cell percentage; 2, positive tumor cell percentage and visualized overlay image) for final confirmation, and (3 and 4) pathologists referred to the automated AI scoring results (3, positive tumor cell percentage; 4, positive tumor cell percentage and visualized overlay image) while determining TPS. Mixed-model analysis was used to calculate the odds ratios (ORs) with 95% CI for AI-assisted TPS methods 1 to 4 compared with pathologists' scoring. For all 584 samples of the tissue microarray, the OR for AI-assisted TPS methods 1 to 4 was 0.94 to 1.07 and not statistically significant. Of them, we found 332 discordant cases, on which the pathologists' judgments were inconsistent; the ORs for AI-assisted TPS methods 1, 2, 3, and 4 were 1.28 (1.06-1.54; P = .012), 1.29 (1.06-1.55; P = .010), 1.28 (1.06-1.54; P = .012), and 1.29 (1.06-1.55; P = .010), respectively, which were statistically significant. For discordant cases, the OR for each AI-assisted TPS method compared with the others was 0.99 to 1.01 and not statistically significant. This study emphasized the usefulness of the AI-assisted system for cases in which pathologists had difficulty determining the PD-L1 TPS.

Practical guide for the diagnosis and management of primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients. METHODS: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology. RESULTS: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells. CONCLUSION: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan.

Pulmonary metastasectomy after immune checkpoint inhibitors in malignant melanoma.

The management of malignant melanoma with pulmonary metastases is controversial and occasionally requires multimodality management, including pulmonary metastasectomy after immune checkpoint inhibitors (ICIs). However, limited data are available on these patients. We described a case series of three consecutive patients who underwent pulmonary metastasectomy after ICIs for malignant melanoma and discussed the important characteristics of these patients. After pulmonary metastasectomy, none of the patients had recurrent pulmonary metastases, although extrapulmonary metastases were developed. Our case series suggests that pulmonary metastasectomy after ICIs may control pulmonary metastases in carefully selected patients with malignant melanoma.

Japanese guidelines for the treatment of idiopathic pulmonary fibrosis 2023:Revised edition.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an unknown cause that generally progresses to pulmonary fibrosis and leads to irreversible tissue alteration. The "Guidelines for the treatment of idiopathic pulmonary fibrosis 2017," specializing in the treatment of IPF for the first time in Japan and presenting evidence-based standard treatment methods suited to the state of affairs in Japan, was published in 2017, in line with the 2014 version of "Formulation procedure for Minds Clinical Practice Guidelines." Because new evidence had accumulated, we formulated the "Guidelines for the treatment of Idiopathic Pulmonary Fibrosis 2023 (revised 2nd edition)." While keeping the revision consistent with the ATS/ERS/JRS/ALAT IPF treatment guidelines, new clinical questions (CQs) on pulmonary hypertension were added to the chronic stage, in addition to acute exacerbation and comorbid lung cancer, which greatly affect the prognosis but are not described in the ATS/ERS/JRS/ALAT IPF guidelines. Regarding the advanced stages, we additionally created expert consensus-based advice for palliative care and lung transplantation. The number of CQs increased from 17 in the first edition to 24. It is important that these guidelines be used not only by respiratory specialists but also by general practitioners, patients, and their families; therefore, we plan to revise them appropriately in line with ever-advancing medical progress.

Effect of epoprostenol-induced thrombocytopaenia on lung transplantation for pulmonary arterial hypertension.

OBJECTIVES: Preoperative intravenous epoprostenol therapy can cause thrombocytopaenia, which may increase the risk of perioperative bleeding during lung transplantation. This study aimed to determine whether lung transplantation can be safely performed in patients with epoprostenol-induced thrombocytopaenia. METHODS: From June 2008 to July 2022, we performed 37 lung transplants in patients with pulmonary arterial hypertension (PAH), including idiopathic PAH (n = 26), congenital heart disease-associated PAH (n = 7), pulmonary veno-occlusive disease (n = 3) and peripheral pulmonary artery stenosis (n = 1) at our institution. Of these, 26 patients received intravenous epoprostenol therapy (EPO group), whereas 11 patients were treated with no epoprostenol (no-EPO group). We retrospectively analysed the preoperative and postoperative platelet counts and post-transplant outcomes in each group. RESULTS: Preoperative platelet counts were relatively lower in the EPO group than in the no-EPO group (median EPO: 127 000 vs no-EPO: 176 000/µl). However, blood loss during surgery was similar between the 2 groups (EPO: 2473 ml vs no-EPO: 2615 ml). The platelet counts significantly increased over 1 month after surgery, and both groups showed similar platelet counts (EPO: 298 000 vs no-EPO: 284 000/µl). In-hospital mortality (EPO: 3.9% vs no-EPO: 18.2%) and the 3-year survival rate (EPO: 91.4% vs no-EPO: 80.8%) were similar between the 2 groups. CONCLUSIONS: Patients with PAH treated with intravenous epoprostenol showed relatively lower platelet counts, which improved after lung transplantation with good post-transplant outcomes.

Immune checkpoint inhibitors in patients with lung cancer having chronic interstitial pneumonia.

Background: In interstitial pneumonia (IP)-associated lung cancer, immune checkpoint inhibitor pneumonitis (ICIP) is common with immune checkpoint inhibitor (ICI) treatment. The purpose of the present study was to clarify the safety and efficacy of ICI treatment for patients with lung cancer with IP. Methods: This multicentre retrospective observational study was conducted from June 2016 to December 2020 in patients with primary lung cancer with IP who received ICI treatment. Results: A total of 200 patients (median age 70 years; male/female, 176/24) were enrolled from 27 institutions. ICIP occurred in 61 patients (30.5%), pneumonitis grades 3-5 in 32 patients (15.5%) and death in nine patients (4.5%). The common computed tomography pattern of ICIP was organising pneumonia in 29 patients (47.5%). Subsequently, diffuse alveolar damage (DAD) pattern was observed in 19 patients (31.1%) who had a significantly worse prognosis than those with a non-DAD pattern (median progression-free survival (PFS) 115 days versus 226 days, p=0.042; median overall survival (OS) 334 days versus 1316 days, p<0.001). Immune-related adverse events (irAEs) occurred in approximately 50% of patients. Patients with irAEs (n=100) had a better prognosis than those without irAEs (n=100) (median PFS 200 days versus 77 days, p<0.001; median OS 597 days versus 390 days p=0.0074). The objective response rate and disease control rate were 41.3% and 68.5%, respectively. Conclusions: Although ICI treatment was effective for patients with lung cancer with IP, ICIP developed in approximately 30% of patients. Patients with irAEs had a significantly better PFS and OS than those without irAEs.

Efficacy of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Metastatic Non-Small Cell Lung Cancer Patients with Poor Performance Status and Epidermal Growth Factor Receptor Mutations: Findings from the Japanese Lung Cancer Registry Database.

BACKGROUND: In advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations, those with impaired performance status (PS) treated with EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated comparable activities to good-PS patients. Due to the limited sample size and inclusion of older adult patients with good PS, these findings may not accurately depict the efficacy of EGFR-TKI in poor-PS patients. We investigated the benefit of EGFR-TKIs in this population and identified relevant prognostic factors. PATIENTS AND METHODS: This nationwide prospective registry study included 9872 patients with local or advanced NSCLC. Outcomes were compared between poor- and good-PS patients treated with EGFR-mutated lung cancer therapies. RESULTS: Of 9872 NSCLC patients, 1965 (19.9%) had EGFR mutations, with 1846 (93.9%) presenting common EGFR mutations. Poor PS (PS score ≥ 3) was noted in 171 patients (8.7%) and identified as an independent prognostic factor; those with poor PS had a significantly lower 1-year survival rate. The median overall survival (OS) for EGFR-TKI-treated good-PS patients was 31.5 (95% confidence interval, 29.6-33.4) months. Among poor-PS patients with EGFR mutations, 135 (78.9%) of whom were treated with EGFR-TKI had an OS of 15.5 (12.7-18.3) months, while those receiving only supportive care had an OS of 2.5 (1.4-3.6) months (P < .001). Hypoalbuminemia (< 3.5 g/dL), liver metastasis, and uncommon EGFR mutations were associated with poor prognosis. CONCLUSION: Poor PS at diagnosis was rare and associated with limited EGFR-TKI efficacy and a dismal prognosis. Liver metastasis and hypoalbuminemia may reduce EGFR-TKI efficacy in these patients.

The impact of vascular division sequence and epithelial-mesenchymal transition status on postoperative recurrence in lung adenocarcinoma.

BACKGROUND: The vascular division sequence in video-assisted thoracic surgery (VATS) lung resection is usually determined by the handling difficulty due to the limited surgical view through the scope. However, upfront pulmonary vein division is theoretically desirable to avoid tumor cells spreading by surgical manipulation. Epithelial-mesenchymal transition (EMT) is associated with poor prognosis and an increased number of circulating tumor cells. The purpose of this study is to evaluate the effect of vascular division sequence and EMT on postoperative recurrence. METHODS: We retrospectively investigated tissue microarrays of 282 lung adenocarcinomas surgically resected between 2001 and 2007. We excluded the cases with segmentectomy, wedge resection, dissemination, insufficient material for staining, or lack of medical records. The effect of vascular division sequence and clinicopathologic factors on recurrence was evaluated in 195 cases. RESULTS: The upfront pulmonary vein division (V-first) was performed in 60 patients, and the upfront pulmonary artery division (A-first) was performed in 135 patients. The recurrence was observed in 67 patients (13 in V-first and 54 in A-first). Epithelial-mesenchymal transition activation was observed in 104 patients. Multivariable analysis with 195 patients revealed that lymph node metastasis and pleural invasion were risk factors for the recurrence. The stratified multivariable analysis showed that vascular division sequence (A-first) was a risk factor only in the EMT-negative group (91 patients). In the EMT-negative subset, the 5-year relapse-free survival rate was significantly lower in the A-first group than the V-first group (72.6% vs. 92.2%, p = 0.0136). CONCLUSIONS: The upfront pulmonary artery division might be a risk factor in patients without EMT activation.

Various combinations of living and deceased donors for lung retransplantation-a single institutional retrospective study.

OBJECTIVES: Lung retransplantation has been performed as a treatment option mainly for chronic lung allograft dysfunction; however, the outcomes of lung retransplantation have been reported to be worse than those of primary lung transplantation. Because of the scarcity of deceased donors in our country, our lung transplant experience includes both living and deceased donors. Therefore, we have experienced lung retransplantation cases with various combinations of living and deceased donors. The aim of this study was to explore technical pitfalls and outcomes of lung retransplantation in this unique environment. METHODS: We performed 311 lung transplantation procedures between April 2002 and October 2022. Eight lung retransplantation cases (2.6%) were analysed retrospectively. RESULTS: At lung retransplantation, the age of the recipient patients ranged from 11 to 61 years (median, 33 years). The combinations of donor sources (primary lung transplantation/lung retransplantation) were as follows: 2 living/living, 2 deceased/living, 3 living/deceased and 1 deceased/deceased. Seven of 8 patients received lung retransplantation for chronic lung allograft dysfunction. Hospital death occurred in 2 patients (25.0%). The 1-, 3- and 5-year survival rates after lung retransplantation (n = 8) were 75.0%, 75.0% and 75.0%, respectively, while those after primary lung transplantation (n = 303) were 92.8%, 83.4% and 76.4%, respectively (P = 0.162). CONCLUSIONS: Lung retransplantation with various combinations of living and deceased donors is a technically difficult but feasible procedure with acceptable outcomes.

Thoracoscopic precision excision technique for small lung lesions using radiofrequency identification marking.

With the introduction of multi-detector computed tomography (CT), the number of incidentally detected small lung nodules has dramatically increased. Determination of lung nodule malignancy is crucial, and an early diagnosis of these indeterminate lesions can lead to subsequent potentially curative treatment. However, there are some limitations to excising these nodules with sublobar resection in a minimally invasive thoracoscopic setting. Under thoracoscopy, although stapler-based wedge resection seems to be the preferred technique, particularly in patients whose lesions are located far from the edge of the lobe, the stapler can unexpectedly sacrifice normal pulmonary parenchyma. To overcome this issue, we have developed a wireless excision precision technique using cone-beam CT-guided electromagnetic navigation bronchoscopy in a minimally invasive thoracoscopic setting. Our technique is implemented in a hybrid operating room, and small tumors can be removed using a radiofrequency identification microchip without intraoperative fluoroscopy and do not require lung palpation under thoracoscopy.

Impact of perioperative airway pathogens on living-donor lobar lung transplantation outcomes.

PURPOSE: To elucidate the clinical impact of pathogenic organism (PO) positivity early after transplantation, we evaluated the impact of perioperative airway POs on outcomes after living-donor lobar lung transplantation (LDLLT), where the graft airway is supposed to be sterile from a healthy donor. METHOD: A retrospective review of 67 adult LDLLT procedures involving 132 living donors was performed. Presence of POs in the recipients' airways was evaluated preoperatively and postoperatively in intensive-care units. RESULTS: POs were detected preoperatively in 13 (19.4%) recipients. No POs were isolated from the donor airways at transplantation. POs were detected in 39 (58.2%) recipients postoperatively; most were different from the POs isolated preoperatively. Postoperative PO isolation was not associated with short-term outcomes other than prolonged postoperative ventilation. The 5-year overall survival was significantly better in the PO-negative group than in the PO-positive group (89.1% vs. 63.7%, P = 0.014). In the multivariate analysis, advanced age (hazard ratio [HR]: 1.041 per 1-year increase, P = 0.033) and posttransplant PO positivity in the airway (HR: 3.684, P = 0.019) significantly affected the survival. CONCLUSIONS: The airways of the living-donor grafts were microbiologically sterile. PO positivity in the airway early after transplantation negatively impacted long-term outcomes.

Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis.

BACKGROUND: We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. METHODS: We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. RESULTS: Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. CONCLUSIONS: Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.

Intermittent Ex Vivo Lung Perfusion in a Porcine Model for Prolonged Lung Preservation.

BACKGROUND: Ex vivo lung perfusion expands the lung transplant donor pool and extends preservation time beyond cold static preservation. We hypothesized that repeated regular ex vivo lung perfusion would better maintain lung grafts. METHODS: Ten pig lungs were randomized into 2 groups. The control underwent 16 h of cold ischemic time and 2 h of cellular ex vivo lung perfusion. The intermittent ex vivo lung perfusion group underwent cold ischemic time for 4 h, ex vivo lung perfusion (first) for 2 h, cold ischemic time for 10 h, and 2 h of ex vivo lung perfusion (second). Lungs were assessed, and transplant suitability was determined after 2 h of ex vivo lung perfusion. RESULTS: The second ex vivo lung perfusion was significantly associated with better oxygenation, limited extravascular water, higher adenosine triphosphate, reduced intraalveolar edema, and well-preserved mitochondria compared with the control, despite proinflammatory cytokine elevation. No significant difference was observed in the first and second perfusion regarding oxygenation and adenosine triphosphate, whereas the second was associated with lower dynamic compliance and higher extravascular lung water than the first. Transplant suitability was 100% for the first and 60% for the second ex vivo lung perfusion, and 0% for the control. CONCLUSIONS: The second ex vivo lung perfusion had a slight deterioration in graft function compared to the first. Intermittent ex vivo lung perfusion created a better condition for lung grafts than cold static preservation, despite cytokine elevation. These results suggested that intermittent ex vivo lung perfusion may help prolong lung preservation.

Benefit of Adjuvant Chemotherapy for Patients Older Than 75 Years With Completely Resected p-Stage II-IIIA Non-Small-Cell Lung Cancer: A Retrospective Cohort Study Using Japanese Nationwide Real-World Data.

BACKGROUND: The efficacy of adjuvant chemotherapy (ACT) in elderly patients with completely resected p-stage II-IIIA non-small-cell lung cancer (NSCLC) remains unclear because all previous randomized controlled trials on ACT have been conducted among patients aged <75 years. Thus, this study aimed to evaluate the effectiveness of ACT in elderly patients with completely resected NSCLC. PATIENTS: We extracted the nationwide data of 812 patients aged ≥75 years who underwent lobectomy with mediastinal nodal dissection in 2010 and were diagnosed with p-stage II-IIIA NSCLC, from nationwide registry data accumulated in 2016. METHODS: We classified the 812 patients into 2 groups based on the ACT administration status and analyzed the differences in their postoperative overall survival (OS). RESULTS: Overall, 295 patients received ACT (36.3%; group A), whereas 517 patients did not (63.70%; group N). Group A showed significantly better OS as a whole (hazard ratio [HR]: 0.650 [95% confidence interval {CI}: 0.526-0.804]), in the p-stage II subset (HR: 0.688 [95% CI: 0.513-0.925]), and p-stage IIIA subset (HR: 0.547 [95% CI: 0.402-0.743]) than group N. Even after propensity score matching, group A showed significantly better OS as a whole (HR: 0.626 [95% CI: 0.495-0.792]), in the p-stage II subset (HR: 0.690 [95% CI: 0.493-0.964]), and p-stage IIIA subset (HR: 0.554 [95% CI: 0.398-0.772]) than group N. CONCLUSION: ACT is recommended even in elderly patients with completely resected p-stage II-IIIA NSCLC. Hence, physicians should not avoid ACT in patients with completely resected NSCLC based solely on age.

Evaluation of Bone Mineral Density in Lung Transplant Recipients by Chest Computed Tomography.

INTRODUCTION: Lung transplantation (LT) recipients are at risk of bone mineral density (BMD) loss. Pre- and post-LT BMD loss has been reported in some cross-sectional studies; however, there are limited studies regarding the serial BMD change in LT recipients. The aim of this study was to investigate the serial BMD changes and the clinical characteristics associated with BMD decline. METHODS: This was a single-center, retrospective observational study. BMD was serially measured in thoracic vertebral bodies (Th4, 7, 10) using computed tomography (CT) before and 3 and 12 months after LT. The frequency of osteoporosis and factors associated with pre-LT osteoporosis and post-LT BMD loss were evaluated. The frequency of post-LT compression fracture and its associated factors were also analyzed. RESULTS: This study included 128 adult LT recipients. LT recipients had decreased BMD (151.8 ± 42.2 mg/mL) before LT compared with age-, sex-, and smoking index-matched controls (176.2 ± 35.7 mg/mL). The diagnosis of COPD was associated with pre-LT osteoporosis. LT recipients experience further BMD decline after transplantation, and the percentage of recipients classified as exhibiting osteoporosis increased from 20% at baseline to 43% at 12 months. Recipients who had been taking no or small doses of glucocorticoids before LT had rapid BMD loss after LT. Early bisphosphonate use (within 3 months) after LT attenuated BMD loss and decreased new-onset compression fracture. CONCLUSION: LT recipients are at high risk for BMD loss and compression fracture after LT. Early bisphosphonate use may decrease BMD loss and compression fracture.

Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation-positive Lung Cancer.

EGFR-tyrosine kinase inhibitors (TKI) are the first-line therapies for EGFR mutation-positive lung cancer. EGFR-TKIs have favorable therapeutic effects. However, a large proportion of patients with EGFR mutation-positive lung cancer subsequently relapse. Some cancer cells survive the initial treatment with EGFR-TKIs, and this initial survival may be associated with subsequent recurrence. Therefore, we aimed to overcome the initial survival against EGFR-TKIs. We hypothesized that yes-associated protein 1 (YAP1) is involved in the initial survival against EGFR-TKIs, and we confirmed the combined effect of EGFR-TKIs and a YAP1-TEAD pathway inhibitor. The KTOR27 (EGFR kinase domain duplication) lung cancer cell lines established from a patient with EGFR mutation-positive lung cancer and commercially available PC-9 and HCC827 (EGFR exon 19 deletions) lung cancer cell lines were used. These cells were used to evaluate the in vitro and in vivo effects of VT104, a TEAD inhibitor. In addition, YAP1 involvement was investigated in pathologic specimens. YAP1 was activated by short-term EGFR-TKI treatment in EGFR mutation-positive lung cancer cells. In addition, inhibiting YAP1 function using siRNA increased the sensitivity to EGFR-TKIs. Combination therapy with VT104 and EGFR-TKIs showed better tumor-suppressive effects than EGFR-TKIs alone, in vitro and in vivo. Moreover, the combined effect of VT104 and EGFR-TKIs was observed regardless of the localization status of YAP1 before EGFR-TKI exposure. These results suggest that combination therapy with the TEAD inhibitor and EGFR-TKIs may improve the prognosis of patients with EGFR mutation-positive lung cancer.