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.

Pulmonary cyst newly formed after lobectomy in various underlying lung conditions.

BACKGROUND: It has been recently recognized that pulmonary cyst may develop after pulmonary resection, causing various symptoms. Most previously reported cases were after upper lobectomy in patients with chronic obstructive lung disease (COPD). CASE PRESENTATION: Case 1 was a man in his 70 s with interstitial pneumonia (IP). Right lower lobectomy was performed for metastatic lung tumor using video-assisted thoracoscopic surgery (VATS). On postoperative day (POD) 19, computed tomography (CT) revealed a large cyst at the upper interlobular surface of the middle lobe, with pneumoderma and pneumomediastinum. The cyst was incised, polyglycolic acid (PGA) sheet and fibrin glue were applied, and the cyst was sutured. The sutured line was covered again with PGA sheet and fibrin glue. Case 2 was a man in his 70 s with COPD. Right upper lobectomy for primary lung cancer was performed using VATS. On POD 17, CT revealed a large pulmonary cyst at the apex of S6 and massive air leakage was observed. The same surgical procedure as that used in case 1 was performed. Cases 3 and 4 were healthy donors for living-donor lung transplantation. Two months after the right lower lobectomy in Case 3 and 3 months after the left lower lobectomy in Case 4, the patients had respiratory symptoms such as dyspnea and hemosputum. CT revealed a large cyst on the diaphragmatic surface of the right middle lobe in Case 3 and on the posterior mediastinal surface of the left upper lobe in Case 4. Cyst incision, soft coagulation, and application of PGA sheet with fibrin glue were performed in both cases. CT performed 1 year after surgery showed no development of a pulmonary cyst or air space in these four cases. CONCLUSIONS: Pulmonary cysts newly formed after lobectomy can develop not only in COPD or IP but also in healthy lungs. Our findings suggest that incision of the cyst and application of fibrin glue and PGA sheet with or without suturing the cyst wall is effective for management.

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.

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.

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.

M2-like tumor-associated macrophages promote epithelial-mesenchymal transition through the transforming growth factor ß/Smad/zinc finger e-box binding homeobox pathway with increased metastatic potential and tumor cell proliferation in lung squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.

Dedifferentiated liposarcoma lung metastases with different FDG-PET/CT findings.

BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is a rare tumor and generally shows poor prognosis with the lung frequent metastatic site. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is used for staging or metastatic evaluation of this disease. We report a case of bilateral lung metastases of DDLPS showing uncommon imaging on FDG-PET/CT with completely different FDG uptake, which made preoperative diagnosis difficult. CASE PRESENTATION: The patient was a male in his 60 s and bilateral lung nodules were noted after proton beam therapy for retroperitoneal DDLPS. FDG-PET/CT showed high FDG uptake in the left S3 15-mm nodule but no uptake in the right S8 10-mm nodule. Thoracoscopic wedge resection for the left nodule was performed, and the pathology revealed metastasis of dedifferentiated liposarcoma. After resection of the left nodule, the right S8 nodule enlarged without FDG uptake. Thoracoscopic right S8 segmentectomy was performed, and metastasis of dedifferentiated liposarcoma was diagnosed. The 2 tumors showed completely different appearances on FDG-PET/CT with similar histopathological findings. CONCLUSIONS: We encountered a case of multiple pulmonary metastases of DDLPS which did not follow the same imaging appearance on FDG-PET/CT. Appropriate timing of surgical resection for pathological diagnosis should be determined carefully.

The first successful case of ABO-incompatible living-donor lobar lung transplantation following desensitization therapy.

ABO-incompatible (ABO-I) living-donor lobar lung transplantation (LDLLT) was successfully performed in a 14-year-old girl who suffered from bronchiolitis obliterans due to graft-versus-host disease following hematopoietic stem cell transplantation. In the ABO-I LDLLT procedure, the blood type O patient received a right lower lobe donated from her blood type B father and a left lower lobe donated from her blood type O mother. Desensitization therapy, using rituximab, immunosuppressants, and plasmapheresis, was implemented for 3 weeks prior to transplantation to reduce the production of anti-B antibodies in the recipient and prevent acute antibody-mediated rejection after ABO-I LDLLT.

[Anti-MDA5 antibody-positive rapidly progressive interstitial lung disease after allogeneic hematopoietic cell transplantation successfully treated with triple immunosuppressive therapy].

A 34-year-old man with KMT2A-MLLT1 acute myeloid leukemia in first complete remission underwent allogeneic peripheral blood stem cell transplantation from his HLA-matched sister after conditioning with busulfan/cyclophosphamide. He did not have severe graft-versus-host disease, but he developed interstitial pneumonia six months after transplantation when his oral cyclosporine A (CsA) dose was reduced to 10 mg/day. He was given prednisolone (PSL), which temporarily improved his respiratory condition, but he quickly deteriorated when PSL was reduced. Anti-MDA5 antibody was found to be positive after additional testing, and a three-drug combination of intravenous cyclophosphamide+PSL+CsA was initiated for anti-MDA5 antibody positive rapidly progressive interstitial lung disease, which was effective for interstitial pneumonia. He received a successful living-donor lung transplant from his younger brother and sister. We present a case of rapidly progressive anti-MDA5 antibody positive interstitial lung disease in which the patient's respiratory condition improved after triple therapy and subsequent living-donor lung transplantation.

A case of vasculogenic mesenchymal tumor in the mediastinum: whole-exome sequencing reveals origin from pre-existing germ cell tumor.

Vasculogenic mesenchymal tumor (VMT), a primitive mesenchymal neoplasm enriched by various-sized atypical vessels, is a new entity that develops in mediastinal germ cell tumors (GCTs) with yolk sac tumor (YST) components after chemotherapy. Notably, patients with VMT in the residual GCT have increased risk of developing sarcomas or hematopoietic malignancies. Here, we report a late-teenage male patient with residual teratoma and high-grade VMT after chemotherapy for a mediastinal mixed GCT, including YST. Whole-exome sequencing revealed biallelic inactivation of TP53 and extensive copy number alterations that suggested whole-genome doubling. The biopsy tissue of the mixed GCT before chemotherapy exhibited overlapping genetic alterations to those in the VMT. Immunohistochemical analyses of the VMT showed that the abnormal vessels were positive for cytokeratin, glypican 3, EZH2, and IMP3. The findings that VMT inherits the genetic alterations of pre-existing mixed GCT and exhibits a partly YST-like immunophenotype might contribute to its clinical aggressiveness.

Comparison of living-donor lobar lung transplantation and cadaveric lung transplantation for pulmonary hypertension.

OBJECTIVES: Living-donor lobar lung transplantation (LDLLT) is a life-saving procedure for critically ill patients with various lung diseases, including pulmonary hypertension (PH). However, there are concerns regarding the development of heart failure with pulmonary oedema after LDLLT in which only 1 or 2 lobes are implanted. This study aimed to compare the preoperative conditions and postoperative outcomes of LDLLT with those of cadaveric lung transplantation (CLT) in PH patients. METHODS: Between 2008 and 2021, 34 lung transplants for PH, including 12 LDLLTs (5 single and 7 bilateral) and 22 bilateral CLTs, were performed. Preoperative variables and postoperative outcomes were retrospectively compared between the 2 procedures. RESULTS: Based on the preoperative variables of less ambulatory ability (41.7% vs 100%, P < 0.001), a higher proportion of World Health Organization class 4 (83.3% vs 18.2%, P < 0.001) and higher mean pulmonary artery pressure (74.4 vs 57.3 mmHg, P = 0.040), LDLLT patients were more debilitated than CLT patients. Nevertheless, hospital death was similar between the 2 groups (8.3% vs 9.1%, P > 0.99, respectively). Furthermore, the 5-year overall survival rate was similar between the 2 groups (90.0% vs 76.3%, P = 0.489). CONCLUSIONS: Although LDLLT patients with PH had worse preoperative conditions and received smaller grafts than CLT patients, LDLLT patients demonstrated similar perioperative outcomes and prognoses as CLT patients. LDLLT is a viable treatment option for patients with PH.

Reduction of donor mononuclear phagocytes with clodronate-liposome during ex vivo lung perfusion attenuates ischemia-reperfusion injury.

OBJECTIVES: Clodronate-liposome is used for depleting mononuclear phagocytes associated with ischemia-reperfusion injury. We hypothesized that administration of clodronate-liposome into the perfusate during ex vivo lung perfusion could reduce mononuclear phagocytes and attenuate ischemia-reperfusion injury. METHODS: First, the number of mononuclear phagocytes in flushed grafts (minimum cold ischemic time, 6-hour cold ischemic time, 15-hour cold ischemic time, and 18-hour cold ischemic time; n = 6 each) was determined using flow cytometry. Second, grafts (15-hour cold ischemic time) were allocated to control or clodronate (n = 5 each). In the clodronate group, clodronate-liposome is administered into the perfusate. After 4 hours of ex vivo lung perfusion, the number of mononuclear phagocytes in the perfusate and lung tissues was measured. Third, grafts (15-hour cold ischemic time) were allocated to control or clodronate (n = 6 each). After 4 hours of ex vivo lung perfusion, the left lungs were transplanted and reperfused for 2 hours. Lung function was evaluated, and samples were analyzed. RESULTS: First, mononuclear phagocytes remain in flushed grafts after prolonged cold ischemia. Second, the number of mononuclear phagocytes in lung tissues after ex vivo lung perfusion was significantly reduced in the clodronate group (P = .008). Third, lung compliance and vascular resistance during ex vivo lung perfusion were significantly improved in the clodronate group (P < .001 for both). Blood oxygenation and pulmonary edema were significantly improved in the clodronate group after 2 hours of reperfusion (P = .015 and P = .026, respectively). Histological findings showed reduced lung injury in the clodronate group (P = .013). CONCLUSIONS: Administration of clodronate-liposome into the perfusate during ex vivo lung perfusion resulted in a significant reduction of mononuclear phagocytes in donor lungs, leading to attenuation of ischemia-reperfusion injury.

Efficacy and safety of the SARS-CoV-2 mRNA vaccine in lung transplant recipients: a possible trigger of rejection.

OBJECTIVE: Solid organ transplant recipients have an increased risk of developing severe coronavirus disease 2019 (COVID-19). Although SARS-CoV-2 mRNA vaccination has been strongly recommended for solid organ transplant recipients, its efficacy and safety have remained unknown. METHODS: We performed an observational prospective cohort study in 18 lung transplant recipients who received two doses of SARS-CoV-2 mRNA vaccine, including BNT162b2 (n = 17) or mRNA-1273 (n = 1), between June and October 2021. The titers of IgG antibodies against the SARS-CoV-2 spike protein (S-IgG) were measured in serum samples collected before the prime dose, three weeks after the prime dose, and four weeks after the booster dose. Reactogenicity and adverse events were evaluated after vaccination. RESULTS: There were no recipients with previous SARS-CoV-2 infection prior to vaccination. S-IgG levels were elevated in 2/18 (11.1%) recipients after the prime dose and in 5/18 recipients (27.8%) after the booster dose (31.7 ± 30.6 U/ml). The time from transplantation to vaccination tended to be longer in the seropositive group than the seronegative group [7.5 (3.9-10.2) vs 2.8 (1.9-4.0) years, p = 0.059]. Maintenance dose of mycophenolate mofetil tended to be lower in the seropositive group than in the seronegative group [500 (250-500) vs 1000 (1000-1000) mg/day, p = 0.088]. Regarding the adverse events after vaccination, the development of chronic lung allograft dysfunction (CLAD) or antibody-mediated rejection (AMR) were observed in two seropositive patients. CONCLUSIONS: The antibody response to the SARS-CoV-2 mRNA vaccine was quite poor in lung transplant recipients. We experienced cases that developed clinical CLAD or AMR that was likely related to SARS-CoV-2 vaccination.

A novel cell-based assay for the high-throughput screening of epithelial-mesenchymal transition inhibitors: Identification of approved and investigational drugs that inhibit epithelial-mesenchymal transition.

OBJECTIVES: Lung cancer with distant metastases is associated with a very poor prognosis, and epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Therefore, elucidation and inhibition of EMT signaling in lung cancer may be a new therapeutic strategy for improving the prognosis of patients. We constructed a high-throughput screening system for EMT inhibitors. Using this system, we aimed to identify compounds that indeed inhibit EMT. MATERIALS AND METHODS: We generated a luciferase reporter cell line using A549 human lung cancer cells and E-cadherin or vimentin as EMT markers. EMT was induced by transforming growth factor ß1 (TGF-ß1), and candidate EMT inhibitors were screened from a library of 2,350 compounds. The selected compounds were further tested using secondary assays to verify the inhibition of EMT and invasive capacity of cells. RESULTS: Values obtained by the assay were adjusted for the number of viable cells and scored by determining the difference between mean values of the positive and negative control groups. Four compounds were identified as novel candidate drugs. Among those, one (avagacestat) and two compounds (GDC-0879 and levothyroxine) improved the expression of E-cadherin and vimentin, respectively, in epithelial cells. GDC-0879 and levothyroxine also significantly inhibited the invasive capacity of cells. CONCLUSION: We systematically screened approved, investigational, and druggable compounds with inhibitory effects using a reporter assay, and identified candidate drugs for EMT inhibition.

Living-donor segmental lung transplantation for pediatric patients.

OBJECTIVE: The preset study evaluated the outcome of living-donor segmental lung transplantation for pediatric patients. METHODS: Between August 2009 and May 2021, we performed living-donor segmental lung transplantation in 6 critically ill pediatric patients, including 1 patient on a ventilator alone and another patient on a ventilator and extracorporeal membrane oxygenation (ECMO). There were 4 male and 2 female patients, with a median age of 7 years (range, 4-15 years) and a median height of 112.7 cm (range, 95-125.2 cm). The diagnoses included complications of allogeneic hematopoietic stem cell transplantation (n = 4) and pulmonary fibrosis (n = 2). All patients received bilateral lung transplantation under cardiopulmonary bypass. A basal segment and a lower lobe were implanted in 3 patients, and a basal segment and an S6 segment were implanted in the other 3 patients. In 2 patients, the right S6 segmental graft was horizontally rotated 180° and implanted as the left lung. RESULTS: Among the 9 segmental grafts implanted, 7 functioned well after reperfusion. Two rotated S6 segmental grafts became congestive, with 1 requiring graft extraction and the other venous repair, which was successful. There was 1 hospital death (14 days) due to sepsis and 1 late death (9 years) due to leukoencephalopathy. The remaining 4 patients are currently alive at 9 months, 10 months, 1.3 years, and 1.9 years. CONCLUSIONS: Living-donor segmental lung transplantation was a technically difficult but feasible procedure with acceptable outcomes for small pediatric patients with chest cavities that were too small for adult lower lobe implantation.

Assessment of listing criteria for lung transplant candidates with interstitial lung disease.

OBJECTIVES: Lung transplantation (LT) is an effective treatment for patients with interstitial lung disease (ILD) refractory to medical treatment. Although the cases of cadaveric LT (CLT) have increased, the donor shortage in Japan has remained severe. This study aimed to evaluate the International Society of Heart and Lung Transplantation (ISHLT) listing criteria for LT in patients with ILD by predicting outcomes during the waiting time for CLT. METHODS: We retrospectively identified 166 patients with fibrotic ILDs who were evaluated and registered for CLT at Kyoto Universal Hospital from April 1, 2008, to December 31, 2017. We examined the correlation between individual parameters of the ISHLT listing criteria and patient outcomes. RESULTS: Among 166 patients, 57 (34.3%) underwent CLT, whereas 83 (50.0%) died before CLT. The median survival time from the date of registration was 22.5 months. The 2-year survival rate was 47.8%. On multivariate Cox proportional hazards analysis, relative decline of percent predicted forced vital capacity (%FVC) in 6 months ≥ 10% (hazard ratio [HR]: 1.72; 95% confidence interval [95%CI]: 1.03-2.87, p = 0.04) and 6-min walking distance (6MWD) < 250 m (HR: 2.77; 95%CI: 1.64-4.69, p < 0.001) were independently associated with worse outcome (i.e., death or living-donor lobar LT). CONCLUSIONS: The 2014 ISHLT criteria could appropriately identify patients with ILD who have a potentially poor prognosis. In particular, 6-month decline in %FVC and shorter 6 min walk distance may be useful for selecting patients with higher risks of mortality.

Nrf2/p­Fyn/ABCB1 axis accompanied by p­Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non­small cell lung cancer.

Adjuvant cisplatin­vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP­binding cassette (ABC) sub­family B member 1 (ABCB1) and phosphorylated Fyn (p­Fyn) overexpression. However, the underlying mechanisms remain unclear. NF­E2­related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p­Fyn/ABCB1 axis in vinorelbine­resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH­DA assay. The total and subcellular expression of Nrf2, ABCB1 and p­Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p­Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin­vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p­Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease­free survival, and p­Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p­Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non­small cell lung cancer.

Perioperative diabetes mellitus affects the outcomes of lung transplant recipients.

OBJECTIVES: Identifying the risks for chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx) is beneficial to the patient. We hypothesized that diabetes mellitus (DM) is relevant to CLAD development. Our study aimed to clarify if DM is a risk for poor post-LTx outcomes. METHODS: The records of patients first undergoing LTx in our institution between 2010 and 2018 were reviewed retrospectively. Patient characteristics and postoperative outcomes were analysed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and CLAD development. To identify perioperative DM, we evaluated the patient for DM at 6 months post-LTx. RESULTS: A total of 172 patients were investigated. DM and CLAD occurred in 76 and 39 patients, respectively, and 40 died. At 6 months post-LTx, the unadjusted and adjusted hazard ratios of DM for OS were 3.36 [95% confidence interval (CI) = 1.67-6.73] and 2.78 (95% CI = 1.35-5.75), respectively. The unadjusted and adjusted hazard ratios of DM for CLAD-free survival were 2.20 (95% CI = 1.27-3.80) and 2.15 (95% CI = 1.24-3.74). The patients with DM were older and had a higher body mass index and more incidents of post-LTx malignant disease than the non-DM patients. The 5-year OS and CLAD-free survival rates of the patients with or without DM were 57.2% vs 86.5% and 50.1% vs 72.9%, respectively. CONCLUSIONS: Perioperative DM was identified as an independent adverse factor for OS and CLAD-free survival. Perioperative management of DM should be emphasized in the clinical setting of LTx.

Fissure-last technique for left upper lobe lung cancer with interlobar invasion: how to do it?

The fissure-last technique is used to minimize postoperative air leak after anatomical lung resection when the interlobar pulmonary artery is inaccessible through the fused fissure. After first dividing the hilar bronchovascular structures, the incomplete fissure is divided using staplers. This technique can be applied for lobectomy combined with segmentectomy in lung cancer with interlobar invasion. We performed this thoracoscopic fissure-last technique in a lung cancer patient in the left upper lobe with invasion to the superior segment (S6) in the left lower lobe.