Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCsIL-10). Pig lungs were placed on EVLP for 6 h and randomized to control (n = 7), intravascular delivery of 20 × 106 (n = 5, low dose) or 40 × 106 human MSCs IL-10 (n = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSCIL-10 therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSCIL-10 delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSCIL-10 dose resulting in inflammation and cytotoxic CD8+ T cell activation. MSCIL-10 therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.

Pirfenidone alleviates lung ischemia-reperfusion injury in a rat model.

OBJECTIVE: Lung ischemia-reperfusion injury is among the complications seen after lung transplantation, resulting in morbidity and mortality. Pirfenidone, an antifibrotic agent for the treatment of idiopathic pulmonary fibrosis, is reported to have cytoprotective properties in various disease models. The purpose of this study was to investigate the effect of pirfenidone on lung ischemia-reperfusion injury. METHODS: Male Lewis rats (260-290 g) were divided into 3 groups: sham group (n = 5), warm ischemia (WI) group (n = 10), and WI plus pirfenidone (WI+PFD) group (n = 10). The sham group underwent 210 minutes of perfusion without ischemia. The WI and WI+PFD groups underwent 90 minutes of warm ischemia and 120 minutes of reperfusion. In the WI+PFD group, pirfenidone (300 mg/kg) was administered orally by gavage 30 minutes before ischemia. After reperfusion, arterial blood gas analysis, lung mechanics, lung wet-to-dry weight ratio, and histologic findings were obtained. The gene expressions of proinflammatory cytokines in lung tissue were measured by quantitative reverse transcription polymerase chain reaction. RESULTS: Compared with the WI group, the WI+PFD group had significantly better dynamic pulmonary compliance (P < .01) and oxygenation levels (P < .05). The wet-to-dry ratio was lower in the WI+PFD group (P < .05). Histologic analysis showed that the WI+PFD group had reduced perivascular edema and neutrophil infiltration. The expression of tumor necrosis factor-α messenger RNA was decreased in the WI+PFD group (P < .05). CONCLUSIONS: Our results revealed that in a rat hilar clamp model, pirfenidone alleviated lung ischemia-reperfusion through anti-inflammatory effects.

Native upper lobe-sparing living-donor lobar lung transplantation maximizes respiratory function of the donor graft.

BACKGROUND: We have developed a novel method for native upper lobe-sparing living-donor lobar lung transplantation (LDLLT) to overcome a small-for-size graft in standard LDLLT with acceptable results. We hypothesized that grafts implanted with this procedure might work more efficiently than those in standard lobe transplantation. METHODS: Bilateral LDLLT was performed in 31 patients with a functional graft matching of less than 60% at our institution between August 2008 and December 2015. Of these, 22 patients were available for evaluation of pulmonary function more than 1 year later: 15 undergoing standard LDLLT with less than 60% functional matching and 7 undergoing native upper lobe-sparing LDLLT. RESULTS: Overall survival at 2 years was 87.5% in the lobe-sparing LDLLT patients and 79.0% in the standard LDLLT patients (p = 0.401). The median forced vital capacity size-matching levels were 50.7% ± 1.6% in the standard LDLLT and 45.2% ± 2.3% in the sparing LDLLT group (p = 0.074). The 1-year and 2-year post-operative volume ratios of inspiration to expiration were significantly different between the 2 groups, at 1.76 and 1.45 after standard LDLLT (p = 0.019) vs 2.41 and 2.23 after lobe-sparing LDLLT (p = 0.015). CONCLUSIONS: The grafts in lobe-sparing LDLLT functioned more effectively than those in standard LDLLT. This advantage was associated with the improvement of pulmonary functions.

Anterior mediastinal tissue volume is correlated with antiacetylcholine receptor antibody level in myasthenia gravis.

OBJECTIVES: Extended thymectomy is a treatment option for myasthenia gravis (MG), but the surgical indications are controversial. Pathologic features of the thymus can be used to predict surgical outcomes, but there is no reliable method for evaluating these characteristics preoperatively. The purpose of this study was to determine whether anterior mediastinal tissue volume, as measured via 3-dimensional computed tomography (3DCT) volumetry, correlates with serum anti-acetylcholine receptor antibody (AChRAb) levels in patients undergoing thymectomy for myasthenia gravis. Therefore, we investigated the relationships among anterior mediastinal tissue volume determined by 3DCT volumetry and AChRAb levels. METHODS: The subjects were 28 patients who underwent extended thymectomy and were enrolled retrospectively. We measured volume of the anterior mediastinum and calculated the volumes of more than -30 Hounsfield units (V-30) by using 3DCT volumetry and compared them with perioperative AChRAb levels. The significance of their volumes in MG was examined by comparison with 53 patients without MG. RESULTS: V-30 values were related to age and were significantly greater in patients with MG than in patients without MG (P < .001). V-30 values were correlated positively with preoperative AChRAb levels (ρ = 0.505, P = .006) and inversely with the post/preoperative AChRAb ratio (ρ = -0.453, P = .018). The histologic nonadipose tissue ratio was correlated with the V-30/volume of the anterior mediastinum (ρ = 0.700, P < .001). CONCLUSIONS: This method for evaluation of the anterior mediastinal tissue volume and AChRAb production may be helpful in establishing a treatment plan for MG.

Pulmonary Function and Exercise Capacity in Patients With Flat Chests After Lung Transplantation.

BACKGROUND: Severe chest wall deformation is generally a contraindication for lung transplantation; however, it is not known whether patients with flat chests have reduced postoperative exercise capacity and pulmonary function. This study's purpose was to investigate the relationship between preoperative thoracic shape and postoperative exercise capacity and pulmonary function in patients undergoing lung transplantation. METHODS: Twenty recipients who underwent successful bilateral living-donor lobar lung transplantation were evaluated. To analyze postoperative graft function in relation to preoperative thoracic shape, 40 donor grafts implanted into 20 recipients were divided into two groups: flat chest group and normal chest group. Flat chest is diagnosed when the thoracic anteroposterior diameter to transverse diameter ratio is 1:3 or less. RESULTS: The ratio of the postoperative forced vital capacity to the preoperatively estimated forced vital capacity was significantly lower in the flat chest group than in the normal chest group 1 year after lung transplantation (p = 0.002). However, there were no significant differences in postoperative 6-minute walk distances between the two groups. Furthermore, the thoracic anteroposterior diameter to transverse diameter ratio in the flat chest group significantly increased after lung transplantation (p = 0.02). CONCLUSIONS: Although postoperative pulmonary function was significantly poorer for patients with flat chests than for patients with normal chests, their postoperative exercise capacity was equivalent. We also found that flat chest severity significantly improved after lung transplantation. Our study, the first investigating postoperative functional status in patients with flat chests, clearly shows that it is possible to perform lung transplantation in such patients with acceptable outcomes.

A case of multiple pleural cryptococcosis without pleural effusion.

Pulmonary cryptococcosis is most likely to occur in immunocompromised patients. The radiological manifestations generally include pulmonary parenchymal lesions, namely, pulmonary nodules, cavitary lesions, and consolidation; thus, multiple pleural nodules are unusual presentation. Here, we report a woman who presented with multiple pleural cryptococcosis without pleural effusion. The patient had previously undergone surgery for stage II rectal cancer. In addition, she received 6 cycles of chemotherapy for follicular lymphoma. Computed tomography (CT) revealed multiple small nodules involving the pleura without pleural effusion, which suggested possible recurrence of rectal cancer or malignant lymphoma as pleural dissemination. Thoracoscopic examination was performed, and pleural cryptococcosis was diagnosed. Although pleural cryptococcosis without pleural effusion is extremely rare presentation, clinicians should consider it when an immunocompromised patient presents with multiple pleural nodules. Thoracoscopic exploration should be the best procedure for the definitive diagnosis of multiple pleural nodules.

Postoperative pulmonary function and complications in living-donor lobectomy.

BACKGROUND: Successful living-donor lobar lung transplantation largely depends on the donor's outcome. Because surgical skills and peri-operative management have evolved over time, this study evaluated the recent outcomes of donor lobectomies. METHODS: Between 2008 and 2014, 48 consecutive living-donor lobar lung transplantations with 85 donor lobectomies were performed at Kyoto University. All donors were prospectively followed up regularly until 1 year after surgery. RESULTS: Right and left lower lobectomies were performed in 49 and 36 donors, respectively. Pulmonary arterial branches were sacrificed at equal frequency in both lobectomies, whereas pulmonary arterioplasty was only performed in left lower lobectomy (n = 9). All donors were discharged after the lobectomies, and none died during follow-up. Post-operative complications occurred in 24 donors (28%) overall, without a significant difference between donor sides. Intraoperative complications were found in 2 donors. Early and late post-operative complications were noted in 17 and 6 donors, respectively. Pneumothorax, pleuritis, and pleural effusion were the most frequent. Post-operative pulmonary function sequentially recovered more than expected and was not significantly affected by the sacrifice of pulmonary arterial branches during lobectomy. By contrast, pulmonary function at 1 year after donor lobectomy in the donors who had peri-operative complications was significantly lower than that in the donors who did not, although even post-operative pulmonary function in the donors with peri-operative complications still recovered more than expected. CONCLUSIONS: Living-donor lobectomies have been safely performed in recent decades with low morbidities and without mortality.

Prognostic impact of lymphovascular invasion compared with that of visceral pleural invasion in patients with pN0 non-small-cell lung cancer and a tumor diameter of 2 cm or smaller.

BACKGROUND: Both visceral pleural invasion (VPI) and lymphovascular invasion (LVI) have been shown to be adverse prognostic factors for early-stage non-small-cell lung cancer (NSCLC). Positive VPI upstages the T category of tumors ≤ 2 cm (T1a) to T2a, whereas LVI is not adapted as a descriptor for the Tumor, Node, Metastasis classification system. This study was conducted to evaluate the prognostic impacts of VPI and LVI in patients with pN0 NSCLC and a tumor diameter of ≤ 2 cm. METHODS: We reviewed records of a total of 142 patients with pN0 NSCLC and a tumor diameter of ≤ 2 cm, who underwent lobectomy with hilar and mediastinal lymph node dissection between January 2001 and December 2009. We conducted univariate and multivariate analyses to evaluate the impact of VPI, LVI, and other clinicopathologic factors on survival. RESULTS: Visceral pleural invasion and LVI were diagnosed as positive in 18 (12.7%) and 22 (15.5%) patients, respectively. Male sex, squamous cell carcinoma, positive VPI, and positive LVI were risk factors for overall survival. Squamous cell carcinoma, positive VPI, and positive LVI were risk factors for relapse-free survival. In multivariate analysis, squamous cell carcinoma and positive LVI were independent risk factors for overall survival, and positive LVI was an independent risk factor for relapse-free survival. CONCLUSIONS: Positive LVI was more important than VPI as a prognostic factor in patients with pN0 NSCLC and a tumor diameter of ≤ 2 cm. Adjuvant chemotherapy should be considered for such patients, to improve the treatment outcomes.

[Pulmonary abscess caused by fish bone].

We describe an extremely rare case of pulmonary abscess caused by fish bone which stabbed the lung from transesophageal route. A 60-year-old woman referred to our hospital complaining of fever. Three days before, she had swallowing pain while eating the bony parts of a fish. An examination on admission showed that C-reactive protein (CRP) is 9.70 mg/dl. Chest computed tomography (CT)revealed, 4 cm mass shadow in the right upper lobe and fish bone material in the mass shadow. Esophagography showed no abnormal findings. Right upper lobectomy was performed under the diagnosis of pulmonary abscess by fish bone. Post operative course was uneventful. The cause was suspected of migration of a fish bone into the right upper lobe via mediasinum and thoracic cavity from esophagus.