Efficacy and safety of add-on mirogabalin to conventional therapy for the treatment of peripheral neuropathic pain after thoracic surgery: the multicenter, randomized, open-label ADMIT-NeP study.

BACKGROUND: For chronic pain after thoracic surgery, optimal timing of its diagnosis and effective treatment remains unresolved, although several treatment options are currently available. We examined the efficacy and safety of mirogabalin, in combination with conventional pain therapy (nonsteroidal anti-inflammatory drugs and/or acetaminophen), for treating peripheral neuropathic pain (NeP) after thoracic surgery. METHODS: In this multicenter, randomized, open-label, parallel-group study, patients with peripheral NeP were randomly assigned 1:1 to mirogabalin as add-on to conventional therapy or conventional treatment alone. RESULTS: Of 131 patients of consent obtained, 128 were randomized (mirogabalin add-on group, 63 patients; conventional treatment group, 65 patients). The least squares mean changes (95% confidence interval [CI]) in Visual Analogue Scale (VAS) score for pain intensity at rest from baseline to Week 8 (primary endpoint) were - 51.3 (- 54.9, - 47.7) mm in the mirogabalin add-on group and - 47.7 (- 51.2, - 44.2) mm in the conventional group (between-group difference: - 3.6 [95% CI: - 8.7, 1.5], P = 0.161). However, in patients with Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) score (used for the screening of NeP) ≥ 12 at baseline, the greater the S-LANSS score at baseline, the greater the decrease in VAS score in the mirogabalin add-on group, while no such trend was observed in the conventional treatment group (post hoc analysis). This between-group difference in trends was statistically significant (interaction P value = 0.014). Chronic pain was recorded in 7.9% vs. 16.9% of patients (P = 0.171) at Week 12 in the mirogabalin add-on vs. conventional treatment groups, respectively. Regarding activities of daily living (ADL) and quality of life (QOL), changes in Pain Disability Assessment Scale score and the EQ-5D-5L index value from baseline to Week 8 showed significant improvement in the mirogabalin add-on group vs. conventional treatment group (P < 0.001). The most common adverse events (AEs) in the mirogabalin add-on group were dizziness (12.7%), somnolence (7.9%), and urticaria (3.2%). Most AEs were mild or moderate in severity. CONCLUSIONS: Addition of mirogabalin to conventional therapy did not result in significant improvement in pain intensity based on VAS scores, but did result in significant improvement in ADL and QOL in patients with peripheral NeP after thoracic surgery. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071200053 (registered 17/11/2020).

Prevalence of coronary calcification on preoperative computed tomography and its management in thoracic surgery.

PURPOSE: We investigated the preoperative assessment of coronary artery calcification using computed tomography for appropriate intraoperative management to reduce the risk of perioperative cardiac complications during pulmonary resection. METHODS: Patients (n = 665) who underwent anatomical lung resection were examined. The extent of preoperative asymptomatic coronary artery stenosis or cardiac complications in patients with coronary artery calcification was assessed. In addition, the risk factors for perioperative cardiac complications were determined. RESULTS: Coronary artery calcification was detected in 233 (35.0%) asymptomatic patients. Nineteen (8.2%) patients with coronary artery calcification had coronary artery stenosis ≥ 75%. Percutaneous coronary intervention was performed preoperatively (n = 3) and postoperatively (n = 10), and preoperative drug intervention was performed in 10 cases. One case of severe postoperative cardiac complications and 20 cases of mild postoperative cardiac complications, including those without coronary artery calcification, occurred. Patients with calcified coronary arteries were at risk of cardiovascular complications in the perioperative period. However, patients with coronary artery calcification who underwent preoperative cardiology intervention had no significant perioperative cardiovascular complications. CONCLUSIONS: Coronary artery calcification detected on preoperative computed tomography is a risk factor for perioperative cardiovascular complications. Early intervention may reduce the risk of such complications.

Adipose-derived mesenchymal stem cells attenuate rejection in a rat lung transplantation model.

BACKGROUND: Immunosuppression following lung transplantation is a key aspect to the graft's survival. However, the well-known complications that are caused by immunosuppressive regimens present an opportunity to study ways to minimize the usage of these drugs. Recently, a promising discovery has been made pertaining to the immunomodulatory effects of adipose tissue-derived mesenchymal stem cells (ADMSCs) through their secretion of hepatocyte growth factor. In the hopes of mitigating the adverse effects of standard immunosuppressive regimens, our study aims to investigate the effects of ADMSCs on the immune response utilizing a rat lung transplantation model. METHODS: Each rat's own ADMSCs were intravenously administered immediately after orthotopic left lung transplantation. The experimental subjects were divided into four groups: 1) control group (group C) was administered no treatment following transplantation; 2) ADMSC group (group A), administered a single intravenous injection of ADMSCs following transplantation; 3) tacrolimus group (group T), administered tacrolimus (0.5 mg/kg) every 24 h following transplantation; and 4) ADMSC and tacrolimus group (AT group) administered a single intravenous injection of ADMSCs in combination with tacrolimus every 24 h following transplantation. RESULTS: The histologically proven rejection grade in group AT was significantly lower than that in group T. The serum levels of hepatocyte growth factor and the expression of cMet in group AT accompanied by low CD40 expression were also significantly higher than those of the lung grafts of group T. CONCLUSIONS: These results suggest that co-administration of ADMSCs with tacrolimus is a beneficial therapeutic approach in lung transplantation.

Balloon-Based Organ Retractor With Increased Safety and Reduced Invasiveness During Video-Assisted Thoracoscopic Surgery.

OBJECTIVES: In recent years, video-assisted thoracoscopic surgery (VATS) has increasingly become the preferred technique for thoracic surgery. However, the inherent characteristics of the lungs as large, soft, slippery, and delicate creates difficulties for pulmonary surgery. In this article, we outline the development and assessment of a balloon-based organ retractor for VATS via collaboration between medical and engineering personnel. METHODS: A dry lab trial and accompanying questionnaire assessment were performed by a group of thoracic surgeons. Objective pressure measurements were obtained, and animal experiment on pigs was performed. RESULTS: In the dry lab trial, use of the developed organ retractor required significantly less time and resulted in fewer difficulties than using a Cherry Dissector. The measured pressure per mm2 of the developed retractor was clearly lower than that for the Cherry Dissector. The questionnaire completed by the surgeons following the dry lab and animal experiments showed that most of the surgeons (7 surgeons out of 9) were satisfied with the quality of the balloon-based retractor based on a score of 3.13 ± 0.28 (mean ± standard deviation) out of 4.0. During the animal experiment, the balloon-based retractor provided stable and clear viewing with minimal need for adjustment. CONCLUSION: This balloon-based retractor could contribute to increased safety and less-invasive VATS.

Lymphoid follicular hyperplasia arising from the chest wall presenting as a substantial mass.

Lymphoid follicular hyperplasia (LFH) is a benign lymphoproliferative disease. Although it can occur within the thoracic cavity, LFH originating from the chest wall has not been reported. A 79-year-old woman was incidentally found to have a well-defined mass on the left posterior chest wall during a preoperative examination for aortic valve replacement. The mass had slowly grown over 6 years. Thoracoscopic surgical resection was performed without complications. Pathological examination ruled out lymphoproliferative diseases, such as Castleman disease or malignant lymphoma, and a diagnosis of LFH was made. Although LFH generally has a good prognosis, surgical resection is recommended for diagnostic and therapeutic purposes owing to the possibility of malignancy masquerading as a reactive lesion. This is the first report of an LFH arising from the chest wall with imaging findings similar to other benign tumours. Its potential as a differential diagnosis for tumours with similar imaging findings is highlighted.

Predictive factors of early autologous blood pleurodesis for postoperative air leak.

BACKGROUND: The usefulness of autologous blood pleurodesis for air leak after pulmonary resection is well known; however, factors predicting the therapeutic efficacy are poorly understood. Herein, we aimed to examine the predictors of early autologous blood pleurodesis for air leak following pulmonary resection. METHODS: Patients who underwent pulmonary resection and autologous blood pleurodesis with thrombin for postoperative air leak between January 2016 and October 2022 were retrospectively analyzed. Patients received 50-100 mL of autologous blood and 20,000 units of thrombin on postoperative days 1-4. If necessary, the same procedure or pleurodesis with other chemical agents was repeated until the air leak stopped. Patients were divided into single-dose and multiple-dose groups based on the number of times pleurodesis had occurred before the air leak stopped and were statistically analyzed. Logistic regression analysis was performed to identify predictors of treatment efficacy. RESULTS: Of the 922 patients who underwent pulmonary resection, 57 patients (6.2%) were included and divided into single-dose (n = 38) and multiple-dose (n = 19) groups. The amount of air leaks was identified as a significant predictor of multiple dosing, with a cutoff of 60 mL/min, in multivariate logistic regression analyses (odds ratio 1.13, 95% CI 1.03-1.24, p = 0.0065). The multiple-dose group showed a significantly higher recurrence of air leak (p = 0.0417). CONCLUSIONS: The amount of air leaks after pulmonary resection is the only significant factor predicting whether multiple autologous blood pleurodesis is required, and the recurrence rate of pneumothorax is significantly higher in such cases.

Timing of Mesenchymal Stromal Cell Therapy Defines its Immunosuppressive Effects in a Rat Lung Transplantation Model.

Cell therapy using mesenchymal stromal cells (MSCs) is being studied for its immunosuppressive effects. In organ transplantation, the amount of MSCs that accumulate in transplanted organs and other organs may differ depending on administration timing, which may impact their immunosuppressive effects. In vitro, adipose-derived mesenchymal stem cells (ADMSCs) suppress lymphocyte activation under cell-to-cell contact conditions. However, in vivo, it is controversial whether ADMSCs are more effective in accumulating in transplanted organs or in secondary lymphoid organs. Herein, we aimed to investigate whether the timing of ADMSC administration affects its immunosuppression ability in a rat lung transplantation model. In the transplantation study, rats were intramuscularly administered half the usual dose of tacrolimus (0.5 mg/kg) every 24 h after lung transplantation. ADMSCs (1 × 106) were administered via the jugular vein before (PreTx) or after (PostTx) transplantation. Cell tracking using quantum dots was performed. ADMSCs accumulated predominantly in the lung and liver; fewer ADMSCs were distributed in the grafted lung in the PreTx group than in the PostTx group. The rejection rate was remarkably low in the ADMSC-administered groups, particularly in the PostTx group. Serum tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin (IL)-6 levels showed a greater tendency to decrease in the PreTx group than in the PostTx group. The proportion of regulatory T cells in the grafted lung 10 days after transplantation was higher in the PostTx group than in the PreTx group. PostTx administration suppresses rejection better than PreTx administration, possibly due to regulatory T cell induction by ADMSCs accumulated in the transplanted lungs, suggesting a mechanism different from that in heart or kidney transplantation that PreTx administration is more effective than PostTx administration. These results could help establish cell therapy using MSCs in lung transplantation.

Adipose-Derived Mesenchymal Stem Cells Attenuate Immune Reactions Against Pig Decellularized Bronchi Engrafted into Rat Tracheal Defects.

Decellularized scaffolds are promising biomaterials for tissue and organ reconstruction; however, strategies to effectively suppress the host immune responses toward these implants, particularly those without chemical crosslinking, remain warranted. Administration of mesenchymal stem cells is effective against immune-mediated inflammatory disorders. Herein, we investigated the effect of isogeneic abdominal adipose-derived mesenchymal stem/stromal cells (ADMSCs) on xenogeneic biomaterial-induced immunoreactions. Peripheral bronchi from pigs, decellularized using a detergent enzymatic method, were engrafted onto tracheal defects of Brown Norway (BN) rats. BN rats were implanted with native pig bronchi (Xenograft group), decellularized pig bronchi (Decellularized Xenograft), or Decellularized Xenograft and ADMSCs (Decellularized Xenograft+ADMSC group). In the latter group, ADMSCs were injected intravenously immediately post implantation. Harvested graft implants were assessed histologically and immunohistochemically. We found that acute rejections were milder in the Decellularized Xenograft and Decellularized Xenograft+ADMSC groups than in the Xenograft group. Mild inflammatory cell infiltration and reduced collagen deposition were observed in the Decellularized Xenograft+ADMSC group. Additionally, ADMSC administration decreased CD8+ lymphocyte counts but increased CD163+ cell counts. In the Decellularized Xenograft+ADMSC group, serum levels of vascular endothelial growth factor and IL-10 were elevated and tissue deposition of IgM and IgG was low. The significant immunosuppressive effects of ADMSCs illustrate their potential use as immunosuppressive agents for xenogeneic biomaterial-based implants.

Preoperative inhalation therapy for patients with chronic obstructive pulmonary disease undergoing lung surgery: a retrospective study.

BACKGROUND: Research shows that even the short-term administration of inhaled drugs immediately before surgery can improve respiratory function in surgical candidates with chronic obstructive pulmonary disease (COPD). However, the long-term efficacies of different types of long-acting inhaled agents when used during a short preoperative period remain unclear. Therefore, we evaluated the efficacies of short-term, preoperative long-acting muscarinic antagonists (LAMAs), inhaled corticosteroids with long-acting ß2-agonists (ICSs/LABAs), and long-acting muscarinic antagonists with long-acting ß2-agonists (LAMAs/LABAs) in patients with COPD after lung resection. METHODS: Patients who underwent anatomical lung resections between April 2010 and March 2020 were divided into the non-COPD (193 patients) and COPD (241 patients) groups. The COPD group underwent preoperative treatment with either a LAMA (51 patients), an ICS/LABA (112 patients), or a LAMA/LABA (78 patients) for almost 1 month, with pulmonary function tests performed initially, just before surgery, and at 1 and 6 months after surgery. Improvement in preoperative respiratory function by inhalation therapy and the maintenance of improvement in respiratory function after surgery were examined in each group. RESULTS: The COPD group had significantly higher proportions of men, older patients, smokers, and histopathologic types except for adenocarcinoma than the non-COPD group; however, there were neither differences in sex, age, percentage of smokers, or histopathologic type among the inhalant groups within the COPD group nor were there differences in percentage of GOLD stage, preoperative inhalation period, or percentage of resected lobes in lobectomy. Preoperative increases in forced expiratory volume in 1.0 s (FEV1.0) were significantly higher in the COPD group (129.07 ± 11.29 mL) than in the non-COPD group (-2.32 ± 12.93 mL) (p < 0.0001). At 6 months, there was no significant difference in residual FEV1.0 between the COPD-LAMA/LABA (2017.46 ± 62.43 mL) and non-COPD groups (2046.93 ± 40.53 mL). The FEV1.0 reduction rate was more suppressed in the COPD-LAMA/LABA group than in the non-COPD group at 1 and 6 months after surgery. CONCLUSIONS: Short-term, preoperative, inhaled pharmacotherapies, particularly LAMAs/LABAs, were effective at improving respiratory function in patients with COPD; thus, these agents are recommended for use in this population.

Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation.

BACKGROUND: Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. METHODS: Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. RESULTS: Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. CONCLUSIONS: Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.

Replacement of Rat Tracheas by Layered, Trachea-Like, Scaffold-Free Structures of Human Cells Using a Bio-3D Printing System.

Current scaffold-based tissue engineering approaches are subject to several limitations, such as design inflexibility, poor cytocompatibility, toxicity, and post-transplant degradation. Thus, scaffold-free tissue-engineered structures can be a promising solution to overcome the issues associated with classical scaffold-based materials in clinical transplantation. The present study seeks to optimize the culture conditions and cell combinations used to generate scaffold-free structures using a Bio-3D printing system. Human cartilage cells, human fibroblasts, human umbilical vein endothelial cells, and human mesenchymal stem cells from bone marrow are aggregated into spheroids and placed into a Bio-3D printing system with dedicated needles positioned according to 3D configuration data, to develop scaffold-free trachea-like tubes. Culturing the Bio-3D-printed structures with proper flow of specific medium in a bioreactor facilitates the rearrangement and self-organization of cells, improving physical strength and tissue function. The Bio-3D-printed tissue forms small-diameter trachea-like tubes that are implanted into rats with the support of catheters. It is confirmed that the tubes are viable in vivo and that the tracheal epithelium and capillaries proliferate. This tissue-engineered, scaffold-free, tubular structure can represent a significant step toward clinical application of bioengineered organs.