Circulating microRNA Panel for Prediction of Recurrence and Survival in Early-Stage Lung Adenocarcinoma.

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

The efficacy of pulmonary rehabilitation training program for patients after lung transplantation.

Background: Pulmonary rehabilitation is recognized widely as one of the most effective measures to promote postoperative recovery of lung transplant recipients (LTRs), and it has positive effects on both short- and long-term quality of life (QoL) and survival outcomes. However, no standardized pulmonary rehabilitation training programs exist specifically for LTRs. The pulmonary rehabilitation programs widely used in clinical practice focus mainly on exercise or respiratory training, to some extent neglecting other therapeutic methods that could promote patient health, such as nutrition support, pain control, spiritual comfort, and so on. This study aimed to develop a postoperative pulmonary rehabilitation training program for LTRs and evaluate its effectiveness. Methods: Using convenience sampling, all patients who underwent lung transplantation (LTx) at Shanghai Pulmonary Hospital from January 2021 to December 2022 were screened for inclusion and exclusion criteria, and a total of 68 patients were finally included in this study. A non-synchronous quasi-experimental design was used, with patients who underwent LTx in 2021 as the control group and patients who underwent LTx in 2022 as the experimental group. The control group received routine treatment, health education, and rehabilitation guidance when patients determined the date of surgery. In addition to this, the experimental group received pulmonary rehabilitation training. The incidence of postoperative pulmonary complications (pulmonary infections), duration of chest tube drainage, intensive care unit (ICU) length of stay, postoperative pain scores, postoperative QoL, pulmonary function, oxygenation index, and the distance in the 6-minute walking test (6MWD) were compared between the two groups. Results: The length of ICU stay and duration of chest tube drainage in the experimental group were lower than those in the control group, and the results of oxygenation index, 6MWD, and St. George's Respiratory Questionnaire (reflecting the QoL) were better than those of the control group (P<0.05). There was no significant difference in the pain of the two groups 1 week after surgery and 3 months after surgery, and the pain score of the experimental group was lower than that of the control group at 1 month after surgery (P<0.05). There was no significant difference in the incidence of complications between the two groups (P>0.05). Conclusions: The postoperative pulmonary rehabilitation training program for LTRs is safe and effective. It can shorten both the duration of chest tube drainage and ICU stay, it can also improve patients' exercise capacity and pulmonary function while also promote safety outcomes of LTRs, and improve QoL scores.

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.

Perioperative changes in radiographic density in erector spinae muscle and mortality after lung transplantation.

RATIONALE: The radiographic density of the erector spinae muscle (ESM) is often decreased early after lung transplantation (LTx). The prognostic impact of this change has not been elucidated. OBJECTIVE: To investigate whether the decrease in the radiographic density of ESMs early after LTx is associated with a poor prognosis. METHODS: This study is a single center retrospective cohort study. Routine follow-up chest computed tomography scan data just before and 12 weeks after LTx were retrospectively retrieved for adult patients who underwent primary LTx at Kyoto University Hospital. The radiographic density of ESM was quantitatively evaluated as the mean attenuation of the ESM (ESMct), and the impact of the decreased ESMct during the 12 weeks after LTx on overall survival (OS) was examined by Cox proportional hazard regression. RESULTS: A total of 151 recipients (94 cadaveric LTx, 57 living-donor lobar LTx) were included in this study. The median duration of postoperative observation was 4.4 years, during which time 39 recipients (26%) died. Decreased postoperative ESMct was significantly associated with poor OS (HR, 1.64; 95% CI, 1.14-2.35, P = 0.008 per 1 Z score decrease) in the multivariate model adjusted for age, sex, episodes of acute rejection, and preoperative ESMct. Similar results were obtained when the subjects were limited to those with cadaveric LTx. CONCLUSION: A decreased perioperative ESMct was strongly associated with a poor prognosis after LTx in addition to low preoperative ESMct. Maintaining postoperative muscle radiographic density, which reflects muscle quality, may be important for a better prognosis after LTx.

[Postoperative Complications of Open Window Thoracostomy:Report of a Case].

While open window thoracostomy is used to treat empyema with a high rate of infection control, it is an invasive procedure that leads to a decline in the quality of life. An 80-year-old man who had undergone wedge resection for pulmonary nodules subsequently developed postoperative empyema and underwent open window thoracostomy. After thoracostomy, the patient developed several complications, including bleeding from the lung surface and air leakage. Window closure was planned at this time;however, the plan was scuttled due to his low nutritional status and pulmonary air leakage. After the patient's condition improved with persistent conservative treatment, window closure was performed, and he overcame his complications. Patients with postoperative empyema requiring thoracostomy are at a high risk of developing postoperative complications. Therefore, it is important to manage the patients' condition persistently so that they can receive window closure at an appropriate time.

Novel intrathoracic irrigation using ultrafine ozone bubbles in a rat empyema model.

Dissolved ozone is generally used for sanitization, but it has not been used for thoracic cavity sanitization because of its short half-life (< 20 min) and possible toxicity. We developed a novel solution containing ultrafine ozone bubbles (ozone-UFB) with a fivefold longer half-life than non-UFB ozone. Using an in vitro model, Staphylococcus aureus colonies were counted after exposure to ozone-UFB or non-UFB ozone at the same ozone concentration (0.4 mg/L). The colony count was significantly lower in the ozone-UFB group than in the non-UFB ozone group (p = 0.034). The effect of repeated pleural irrigation using ozone-UFB and saline was compared in a rat empyema model of S. aureus infection. The bacterial count in the pleural effusion was decreased by at least fivefold following intrathoracic lavage with ozone-UFB (3 mg/L). To examine the safety of ozone-UFB for intrathoracic use, ozone-UFB with a higher ozone concentration (10 mg/L) was injected into the thoracic cavities of normal rats. The treatment did not result in any specific pleural damage or elevated serum interleukin-6 concentrations. The findings highlighted the efficacy and safety of ozone-UFB for intrathoracic sanitization, but further studies are needed to determine the optimal therapeutic ozone concentration with appropriate safety margins.

ABO blood type incompatible lung transplantation.

ABO-incompatible transplantation has been successfully performed in the kidney and liver. However, lungs are subject to strong rejection and are vulnerable to infection because they are directly exposed to air. Therefore, lung transplantation from organs with incompatible blood types has been considered a significant challenge. Due to the severe shortage of donors, ABO-incompatible lung transplantation might be a viable method to save critically ill patients with end-stage respiratory diseases. Herein, we review the worldwide published reports about both minor and major ABO-incompatible lung transplantations. In North America, major ABO-incompatible lung transplants have been performed in cases with clerical errors in blood typing. But they were successful with additional treatments following the protocol for ABO-incompatible transplants in other organs (multiple plasma exchanges and additional immunosuppressive therapy such as anti-thymocyte globulin administration). In Japan, major ABO-incompatible living-donor lobar lung transplantations have also been performed successfully when the recipient does not have an ABO antibody against the donor. This unique situation sometimes occurs when the recipient undergoes hematopoietic stem cell transplantation before lung transplantation, in which the recipient's blood type changes after hematopoietic stem cell transplantation. One infant and one adult had successful intentional major ABO-incompatible lung transplantation with both induction therapy and aggressive maintenance antibody-depletion therapy. Furthermore, an experimental antibody-depletion study has also been conducted to overcome ABO incompatibility. Even though intentional major ABO-incompatible lung transplantation has rarely been performed, several significant pieces of evidence have been accumulated to prepare for ABO-incompatible lung transplantation in selected cases. In the future, this challenge can potentially expand the donor organ pool and lead to improvements in the fairness of organ allocation.

[Robot-assisted Extended Thymectomy via a Bilateral Approach for Patients with Myasthenia Gravis].

Extended thymectomy is a procedure to remove the thymus gland and surrounding adipose tissue, while the traditional approach via a median sternotomy, minimally invasive approaches such as video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracoscopic surgery (RATS) have been adopted. This report described the technique of bilateral approach for extended thymectomy in patients with myasthenia gravis (MG) by robot-assisted thoracoscopic surgery, and also showed the perioperative outcomes and postoperative exacerbation rates of 11 patients. In most patients, score of MG symptom were reduced and levels of anti-acetylcholine receptor antibodies declined postoperatively. In a small number of cases, the safety and efficacy of a RATS bilateral approach for extended thymectomy were confirmed.

Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database.

PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART). METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors. RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases. CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.

Robotic resection of ectopic mediastinal parathyroid adenoma in multiple endocrine neoplasia 1.

BACKGROUND: Hyperparathyroidism in patients with multiple endocrine neoplasia 1 is attributed to the excessive secretion of parathyroid hormone (PTH) from multiple parathyroid glands. This can be successfully treated through complete resection of the parathyroid glands; however, subsequent surgery is often required because of the presence of supernumerary or ectopic parathyroid glands. Therefore, identifying the locations of all functional glands is crucial for precise resection. Here, we report a case of ectopic mediastinal parathyroid adenoma that was successfully resected using robot-assisted thoracoscopic surgery. CASE PRESENTATION: A 53-year-old woman underwent a total parathyroidectomy with autotransplantation for multiple endocrine neoplasia 1-associated primary hyperparathyroidism. The patient previously underwent laparoscopic distal pancreatectomy for a pancreatic neuroendocrine tumor. She also presented with a mediastinal tumor and nonfunctional pituitary adenoma that could be followed up. Blood tests before total parathyroidectomy showed high levels of intact PTH (183 pg/mL) and calcium (Ca; 10.3 mg/dL); however, postoperative blood tests still revealed high levels of intact PTH (103 pg/mL) and Ca (11.4 mg/dL). Computed tomography and magnetic resonance imaging revealed a 45-mm-sized mass in the right upper mediastinum as a well-defined solid and cystic lesion, whereas 99mTc-methoxyisobutylisonitrile scintigraphy indicated a strong accumulation of tracers, suggesting an ectopic lesion in the mediastinum. Persistent hyperparathyroidism after total parathyroidectomy via neck incision was attributed to an ectopic parathyroid tumor in the mediastinum. Thus, we decided to resect the tumor using robot-assisted thoracoscopic surgery to perform the procedure gently and carefully. During surgery, a mediastinal tumor was identified as it was detected radiographically. Because it did not invade the surrounding tissues, it could be completely resected without injuring the capsule. The patient was discharged without complications. Postoperatively, Ca and intact PTH levels decreased back to normal. The final pathological diagnosis confirmed that the mass was an ectopic mediastinal parathyroid adenoma. CONCLUSIONS: Minimally invasive surgical resection of a remnant ectopic lesion was successfully performed in a patient with multiple endocrine neoplasia 1 using robot-assisted thoracoscopic surgery.

One-year change in the health status predicts the subsequent hospitalization and mortality in patients waitlisted for lung transplantation in Japan.

BACKGROUND: Poor health-related quality of life (HRQL) at the registration for lung transplantation is related to waitlist mortality. We investigated the relationship between 1-year change in HRQL and subsequent outcomes in patients waitlisted for lung transplantation. METHODS: In a 5-year longitudinal study, we analyzed the factors related to waitlist mortality in 197 lung transplant patients registered on the Japan Organ Transplant Network. HRQL was assessed using St. George's Respiratory Questionnaire (SGRQ), and factors related to changes in SGRQ scores were evaluated after 1 year. We assessed the relationship between the 1-year change in SGRQ score and subsequent mortality or hospitalization. RESULTS: Among 197 patients, 108 remained waitlisted during the first-year assessment. During the median follow-up period of 469 d, 28 patients died, and 54 underwent lung transplantation. Univariate Cox proportional hazards analysis revealed that the changes in all components and total score of the SGRQ after 1 year were associated with waitlist mortality (p < 0.05). Stepwise multivariate analysis revealed that the 1-year changes in SGRQ scores were significantly related to waitlist mortality. Forty-three patients with worsened HRQL after 1 year had higher likelihoods of hospitalization (p = 0.038) and mortality (p = 0.026) after 1 and 4 years of follow-up, respectively, than 61 patients without worsened HRQL. CONCLUSIONS: Patients with worsened health status during the first year after registration had higher likelihoods of hospitalization and mortality after 1 and 4 years of follow-up, respectively, than those without worsened HRQL. Strategies to improve health status while waiting are needed to reduce waitlist hospitalization or mortality.

Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.

Patients with pulmonary graft-versus-host disease (pGVHD) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, pGVHD pathogenesis is not fully elucidated in humans, and currently available immunosuppressants are inadequately effective. We performed pathologic evaluation of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation. Patient pathology was characterized by bronchiolitis and subpleural perivascular inflammation, with B-cell, monocyte, and T-cell accumulation around bronchioles. Bronchiolitis, perivascular inflammation, and peribronchial macrophage aggregation were also identified in a murine pGVHD model after transplant of bone marrow cells and splenocytes from C57BL/6 to B10.BR mice. Among mitogen-activated protein kinase kinase (MEK) inhibitors, cobimetinib, but not trametinib, improved survival rates. Cobimetinib attenuated bronchiolitis, improved airway resistance and lung compliance in the mice, and suppressed activation of B cells and tumor necrosis factor α production by monocytes in vitro; these features were not suppressed by trametinib or tacrolimus. Furthermore, cobimetinib suppressed activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling, resulting in B-cell and monocyte suppression. Dual inhibition of the MEK/extracellular signal-regulated kinase (ERK) and PI3K/AKT pathways using a combination of trametinib and the PI3K inhibitor taselisib strongly suppressed B-cell activation in vitro and improved mouse survival rates compared with vehicle or monotherapy with trametinib or taselisib. Imaging mass cytometry of human pGVHD revealed that T cells around bronchioles were positive for phosphorylated ERK, whereas B cells were positive for phosphorylated AKT. Thus, perivascular inflammation and bronchiolitis mediated by activation of the MEK/ERK and PI3K/AKT pathways are essential for pGVHD and represent a potential novel therapeutic target in humans.

Video-assisted thoracoscopic surgery for pleuroperitoneal communication.

Here we report the cases of five patients on continuous ambulatory peritoneal dialysis (CAPD) who developed hydrothorax because of pleuroperitoneal communication. Preoperative computed tomography (CT) peritoneography revealed penetrated sites on the diaphragm in all patients. All patients underwent video-assisted thoracoscopic surgery (VATS), and a dialysate containing indigo carmine was injected intraperitoneally through a CAPD catheter to confirm the fistula. In all patients, a thinned bleb was found at the center of the diaphragmatic tendon consistent with that noted on preoperative CT peritoneography. The bleb was resected using a surgical stapler in four patients, and the pleuroperitoneal communication did not recur. However, in one patient, the bleb was only covered with reinforcement agents and the hydrothorax recurred after CAPD. This study demonstrates that VATS treatment for pleuroperitoneal communication is safe and effective but that lesion resection would be more useful for preventing hydrothorax recurrence in patients undergoing CAPD.

Impact of inspiratory muscle strength on exercise capacity after lung transplantation.

BACKGROUND AND PURPOSE: Though inspiratory muscle strength is essential for patients with respiratory disease, it is unclear whether the recovery of inspiratory muscle strength contributes to an exemplary achievement of exercise tolerance after lung transplantation (LTx). We aimed to elucidate the inspiratory muscle strength affects the recovery of exercise capacity after LTx. METHODS: Recipients who underwent LTx between June 2017 and September 2018 were enrolled, and 6-min walking distance (6MWD), quadriceps force, inspiratory muscle strength (maximal inspiratory pressure [MIP]), and spirometry were evaluated at 3, 6, and 12 months after LTx. The relationships between inspiratory muscle strength and changes in physical performance were analyzed. RESULTS: Nineteen recipients (mean age: 44.8 years, male: 32%) who completed all follow-ups were analyzed. At 3 months after LTx, mean MIP (88.4% predicted) and vital capacity (60.9% predicted), quadriceps force (QF; 2.1 N*m/kg), and 6MWD (504 m) were lower than normal values. After LTx, 6MWD significantly improved up to 12 months. From 3 to 6 months after LTx, changes in MIP were significantly associated with increases in 6MWD by univariate (r = 0.55, p = 0.02) and multivariate (ß = 0.59, p = 0.01) regression analyses, whereas changes of QF in place of MIP were significantly associated with the recoveries of 6MWD from 6 to 12 months. DISCUSSION: Improvements in MIP may impact the recovery of exercise capacity in the early phase after LTx. Factors that determine the improvement in exercise capacity following LTx may vary with postoperative time.

Radiologic evaluation of compensatory lung growth using computed tomography by comparison with histological data from a large animal model.

Non-invasive analysis using computed tomography (CT) data may be a promising candidate to evaluate neo-alveolarization in adult lungs following lung resection. This study evaluates and compares the validity of CT analysis with histologic morphometry for compensatory lung growth in a large animal model. We calculated the radiologic tissue volume and the radiologic lung weight from CT data taken at 1, 3, and 6 months post-surgery on 15 male beagle dogs that had a right thoractotomy, bilobectomy, or pneumonectomy (n = 5 in each group). Results were analyzed using one-way ANOVA and were subsequently compared to histologic findings of tissue samples at 6 months post-surgery using Pearson's correlation. An increase in radiologic tissue volume and radiologic lung weight was identified, which was positively correlated with histologic lung parenchymal amounts (correlation coefficient = 0.955 and 0.934, respectively, p < 0.001). Histology of lung specimens at 6 months post-surgery revealed an increase in the tissue amount in both Bilobectomy and Peumonectomy groups, which was consistent with compensatory lung growth. Radiologic tissue volume and radiologic lung weight reflected compensatory lung growth following lung resection. Radiologic assessment using CT data can be a promising clinical modality to evaluate postoperative lung growth.

Successful lung transplant cases with ex vivo lung perfusion assessment of extended criteria donor lungs.

We report our successful experience in two lung transplant cases in which ex vivo lung perfusion (EVLP) was used to evaluate the function of injured brain-dead donor lungs that were otherwise initially unacceptable. After the donor's lungs were declined for transplantation by all other transplant centers, the lungs were offered to the patients listed for lung transplantation in our hospital. The donor lung function was considered acceptable for transplantation after the 3-h EVLP assessment. In the first case, a 32-year-old man with bronchiolitis obliterans after hematopoietic stem cell transplantation underwent hybrid lung transplantation, that was right brain-dead donor lung transplantation, combined with native-upper lobe sparing living-donor lobar lung transplantation on the left side. In the second case, a 61-year-old woman received the right single lung transplantation for idiopathic pulmonary fibrosis. Both patients are doing well at one and a half years after lung transplantation.