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.

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.

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.

[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.

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.

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.

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.

Expanded indications for lung transplantation for pulmonary complications after hematopoietic stem cell transplantation.

OBJECTIVES: Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are associated with poor survival and can be treated by lung transplantation (LT). However, the indications for LT in patients with pulmonary complications after HSCT remain unclear due to low number of cases. HSCT is frequently conducted for hematologic malignancies, which have different recurrence patterns from solid-organ malignancies. Some patients also experience ABO blood type changes post-HSCT. This study aimed to reassess the indication of LT for pulmonary complications post-HSCT, focusing on disease-free interval (DFI) and ABO-incompatibility. METHODS: Retrospective chart reviews were performed in patients who underwent LT for post-HSCT pulmonary complications. In patients with previous hematologic malignancy, indication was based on estimated recurrence rate instead of DFI. Donors were selected based on the recipient anti-A/B antibody profile rather than ABO type. Post-LT survival and complication rates were examined. RESULTS: Forty consecutive patients undergoing LT after HSCT (including 31 with previous hematologic malignancy) were analyzed. The median DFI between HSCT and LT was 64.5 months. Thirteen patients with previous hematologic malignancy had DFI <5 years but none experienced recurrence. There was no significant difference in 5-year post-LT survival between patients undergoing (74.7%) and not undergoing HSCT (68.4%). There was no significant difference in survival between patients with DFI ≥5 years (63.8%) and patients with DFI <5 years (83.3%). Five patients underwent LTs from major ABO-incompatible donors, but none developed incompatibility-related complications. CONCLUSIONS: Indications based on estimated recurrence rates and recipients' anti-A/B antibody profiles may increase the use of LT for patients after HSCT.

Protective effect of necrosulfonamide on rat pulmonary ischemia-reperfusion injury via inhibition of necroptosis.

BACKGROUND: Necroptosis plays an important role in cell death during pulmonary ischemia-reperfusion injury (IRI). We hypothesized that therapy with necrosulfonamide (NSA), a mixed-lineage kinase domain-like protein inhibitor, would attenuate lung IRI. METHODS: Rats were assigned at random into the sham operation group (n = 6), vehicle group (n = 8), or NSA group (n = 8). In the NSA and vehicle groups, the animals were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes, followed by reperfusion for 120 minutes. NSA (0.5 mg/body) and a solvent were administered i.p. in the NSA group and the vehicle group, respectively. The sham group underwent 210 minutes of perfusion without ischemia. After reperfusion, arterial blood gas analysis, physiologic data, lung wet-to-dry weight ratio, histologic changes, and cytokine levels were assessed. Fluorescence double immunostaining was performed to evaluate necroptosis and apoptosis. RESULTS: Arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) was better, dynamic compliance was higher, and mean airway pressure and lung edema were lower in the NSA group compared with the vehicle group. Moreover, in the NSA group, lung injury was significantly alleviated, and the mean number of necroptotic cells (55.3 ± 4.06 vs 78.2 ± 6.87; P = .024), but not of apoptotic cells (P = .084), was significantly reduced compared with the vehicle group. Interleukin (IL)-1ß and IL-6 levels were significantly lower with NSA administration. CONCLUSIONS: In a rat model, our results suggest that NSA may have a potential protective role in lung IRI through the inhibition of necroptosis.

Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).

Changes in the health-related quality of life and social reintegration status after lung transplantation following hematopoietic stem cell transplantation.

PURPOSE: Late-onset non-infectious pulmonary complications (LONIPCs) after allogeneic hematopoietic stem cell transplantation are fatal; however, lung transplantation might achieve good survival. Nevertheless, improving the health-related quality of life (HRQoL) is still a major concern. This study aimed to investigate, in detail, the recovery in HRQoL and social reintegration status after lung transplantation in patients with LONIPC after allo-HSCT. METHODS: This prospective cohort study involving 18 patients examined changes in the health and social reintegration status after lung transplantation following LONIPC. RESULTS: Physical function and HRQoL were lowest before lung transplantation. Two years after lung transplantation, the dyspnea scores and performance status improved. Most patients had made a successful return to society, and patients who achieved social reintegration were significantly younger and had a good performance status. However, their Physical Functioning score and Physical Component Summary did not show significant improvement after lung transplantation. Moreover, recipients who were unemployed before lung transplantation were likely to remain unemployed and continued to show poor HRQoL. CONCLUSIONS: These results showed poor recovery of HRQoL, especially in terms of physical function, and the likelihood of failure to reintegrate into society within 2 years after lung transplantation. It is necessary to consider long-term follow-up and physical training to improve social reintegration and HRQoL.

Pleural Invasion Depth of Disseminated Nodules in Patients with Stage IVa or Recurrent Thymoma: Assessment, Curative Impact, and Surgical Outcomes.

BACKGROUND: Thymoma patients with pleural dissemination are difficult to manage, and their treatment strategy remains undefined. This study aimed to investigate the clinicopathologic features of these patients, focusing on the association between the depth of pleural invasion and prognosis. METHODS: Between 2003 and 2019, the study identified 120 disseminated lesions in 20 thymoma patients. Seven patients had de novo stage IVa thymoma and 13 were recurrent cases. Extrapleural pneumonectomy was performed for 8 patients and debulking surgery for 12 patients. Invasion depth of pleural tumors was classified into two groups: when the disseminated tumors invaded the pleura beneath the elastic layer, the tumor was diagnosed as Da, and when the disseminated tumors invaded the pleura beyond the elastic layer, the tumor was diagnosed as Db. RESULTS: Of 120 nodules, 31 (26%), found in eight patients with recurrent malignancies, were classified as Db. The pathologic status of the surgical margin (PSM) was positive in eight patients, seven of whom had Db nodules. The 5-year overall survival (OS) rate was 100% in the Da group and 75% in the Db group (P = 0.02). The 5-year progression-free survival (PFS) rate was 66.7% in the Da group and 25% in the Db group (P = 0.02). Cox univariate analysis showed that PFS was significantly influenced by the depth of invasion (P = 0.04) and PSM (P = 0.03). CONCLUSION: Depth of pleural invasion may influence survival outcomes for thymoma patients with pleural dissemination. The patients in this study with Da-disseminated nodules had an increased probability of a longer OS and PFS and tended to achieve negative PSM compared with the patients with Db.