Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation.

BACKGROUND: The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. METHODS: The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. RESULTS: The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3 ± 6.5, 36.8 ± 10.7, and 20.6 ± 9.6 µg·h/mL, respectively (P = .0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8 µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P = .0050). CONCLUSIONS: The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.

Hyperinflation With Pulmonary Dysfunction in Donor Lungs With Smoking History During Lung Perfusion.

BACKGROUND: Donor lungs with smoking history are perfused in ex vivo lung perfusion (EVLP) to expand donor lung pool. However, the impact of hyperinflation of perfused lungs in EVLP remains unknown. The aim of this study was to investigate the significance of hyperinflation, using an ex vivo measurement delta VT, during EVLP in smoker's lungs. MATERIALS AND METHODS: Seventeen rejected donor lungs with smoking history of median 10 pack-years were perfused for 2 h in cellular EVLP. Hyperinflation was evaluated by measuring delta VT = inspiratory - expiratory tidal volume (VT) difference at 1 h. All lungs were divided into two groups; negative delta VT (n = 11, no air-trapping pattern) and positive delta VT (n = 6, air-trapping pattern). Transplant suitability was judged at 2 h. By using lung tissue, linear intercept analysis was performed to evaluate the degree of hyperinflation. RESULTS: The positive delta VT group had significantly lower transplant suitability than the negative delta VT group (16 versus 81%, P = 0.035). The positive delta VT group was significantly associated with lower partial pressure of oxygen/fraction of inspired oxygen ratio ratio (278 versus 356 mm Hg, P = 0.049), higher static compliance (119 versus 98 mL/cm H2O, P = 0.050), higher lung weight ratio (1.10 versus 0.96, P = 0.014), and higher linear intercept ratio (1.52 versus 0.93, P = 0.005) than the negative delta VT group. CONCLUSIONS: Positive delta VT appears as an ex vivo marker of ventilator-associated lung hyperinflation of smoker's lungs during EVLP.

Resecting a giant malignant lung tumor in a patient with unilateral acute interstitial pneumonitis.

Acute interstitial pneumonia is a rare and fulminant form of idiopathic interstitial lung disease. Here, we report a case of a giant malignant sarcomatoid tumor of the left lung with unilateral lung infiltration. The tumor was resected under venovenous extracorporeal membrane oxygenation support. Right middle lung lobe biopsy revealed alveolar epithelial hyperplasia, mild interstitial fibrosis, and interstitial edema. The patient was diagnosed with acute interstitial pneumonitis, and effectively treated with steroid pulse therapy followed by prednisolone. In this case, the contralateral lung expansion accomplished with tumor resection, definitive diagnosis based on lung biopsy, and corticosteroid treatment possibly improved the outcome.

Chest wall/parietal pleural invasions worsen prognosis in T4 non-small cell lung cancer patients after resection.

OBJECTIVES: Appropriate selection for surgery is particularly important in T4 non-small cell lung cancer patients. In clinical settings, patients those who are positive for T4 criteria occasionally are also positive for T3 factors which are independently defined from original T4 or even have multiple T4 factors. Significance of these factors on prognosis is still unknown. METHODS: We retrospectively reviewed clinicopathorogical data of 113 patients with T4 non-small cell lung cancer those who underwent surgery between 1990 and 2015 in Tohoku University Hospital. Significance on prognosis of single or multiple T4 factors and with or without independent T3 factors were statistically analyzed. RESULTS: No significant difference was seen in the 5-year survival rate between patients with single (35.6%) and multiple (31.4%) T4 factors (P = 0.94), but the rate was significantly lower when patients also had independent T3 factors (19.6%) compared with when they did not (42.5%) (P = 0.011). The 5-year survival rate was particularly lower among patients with invasion of the chest wall or parietal pleura (8.1%) than in those without (40.6%) (P = 0.0052). CONCLUSIONS: Invasion of the chest wall or parietal pleura is poor prognostic factors in T4 non-small cell lung cancer patients.

Muse Cells and Ischemia-Reperfusion Lung Injury.

Ischemia-reperfusion injury (IRI) is one of the main causes of primary graft dysfunction that accounts for 25% of mortality after lung transplantation. Disruption of blood supply and subsequent reperfusion result in organ damage with activating innate and adaptive immune response, leading to inflammatory insults. The IRI after lung transplantation is primarily manifested by permeability pulmonary edema on the basis of pulmonary vascular endothelial cell injury as seen in acute respiratory distress syndrome (ARDS). Stem cells have potent anti-inflammatory and immunomodulatory properties through local paracrine mechanisms. The application of mesenchymal stem cells (MSCs) for ARDS as well as IRI in various organs, therefore, has been interested and extensively investigated in animal models with promising results. Furthermore, two recent clinical randomized, placebo-controlled pilot studies demonstrated that treatment of ARDS with MSCs appears to be safe and feasible.Muse cells are stress-tolerant and non-tumorigenic endogenous pluripotent-like stem cells. They comprise small proportions of cultured fibroblasts and MSCs and can be isolated from these populations. Muse cells are known to migrate to the damaged tissue after local or systemic administration, spontaneously differentiate into the tissue-compatible cells, and also secrete factors related to immunomodulation and tissue repair. We have recently shown the effect of Muse cells on ameliorating lung IRI in a rat model. With 2 h of warm ischemia and subsequent reperfusion on the left lung, the lung showed severe pulmonary edema. Administration of Muse cell through the left pulmonary artery immediately after reperfusion more significantly improved lung oxygenation capacity, compliance, and histological damage on days 1 and 3 after reperfusion compared with MSCs, and this was associated with higher expression levels of proteins related with anti-inflammation and tissue repair in the lung. Encouraging results of this study advocate further investigation of the ability of Muse cells to prevent and treat IRI after lung transplantation.

Resection of primary malignant lung melanoma: a case report.

A 74-year-old man presented with chest pain and high-grade fever. Chest radiography revealed a consolidation in the right lower lung lobe, and computed tomography demonstrated atelectasis and infiltration of the right lower lobe, with pleural effusion. Bronchoscopy revealed a tumor occluding the inlet of the lateral/posterior basal segmental bronchus of the right lung, but bronchoscopic biopsy did not lead to a definitive diagnosis. Considering the possibility of obstructive pneumonia and pleuritis, we performed a right lower lobectomy, decortication, and pleuroclysis. Pathological examination revealed a malignant melanoma. The clinical and pathological findings suggested primary malignant melanoma of the lung.

Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia-Reperfusion Injury in a Rat Model.

Posttransplantation lung ischemia-reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin-eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.

High preoperative plasma vasohibin-1 concentration predicts better prognosis in patients with non-small cell lung carcinoma.

BACKGROUND AND AIM: Vasohibin-1 (VASH1) is an angiogenesis inhibitor synthesized and secreted by endothelial cells, whose expression is induced by angiogenic stimuli such as vascular endothelial growth factor. We have previously demonstrated that VASH1 is immunohistochemically evident in endothelial cells in the tumor microenvironment of patients with non-small cell lung cancer (NSCLC) and is positively correlated with that of vascular endothelial growth factor in cancer cells. Here, we determined the preoperative plasma concentration of VASH1 in patients with NSCLC and evaluated the association between the preoperative VASH1 levels and certain outcomes. METHODS: We analyzed presurgical plasma VASH1 concentrations in a total of 79 lung cancer patients (51 males and 28 females; 34-83 y of age; 46 adenocarcinomas, 27 squamous cell carcinomas, and 6 other types) who underwent lung resection. The impact of preoperative VASH1 level was analyzed using clinical characteristics and prognosis. RESULTS: Plasma VASH1 concentration ranged from 34.1 to 1190.4 fmol/mL. We divided the patients into 3 groups according to plasma VASH1 level for this assessment: low VASH1 group (n = 26), medium VASH1 group (n = 27), and high VASH1 group (n = 26). The death and recurrence rates of the high, medium, and low VASH1 groups were 5.5, 16.2, and 12.7 per 100 person-years, respectively. Multivariate adjusted hazard ratio of death and recurrence of the high VASH1 group was lower than that of the low VASH1 group (hazard ratio 0.42; 95% CI 0.17-0.99). CONCLUSION: The present analysis suggests that high preoperative plasma VASH1 concentration is associated with better prognosis in patients with NSCLC. We propose preoperative VASH1 level as a biomarker for the prognosis of patients with non-small cell lung carcinoma.

Influences of environmental noise level and respiration rate on the accuracy of acoustic respiration rate monitoring.

We tested the hypothesis that the environmental noise generated by a forced-air warming system reduces the monitoring accuracy of acoustic respiration rate (RRa). Noise levels were adjusted to 45-55, 56-65, 66-75, and 76-85 dB. Healthy participants breathed at set respiration rates (RRset) of 6, 12, and 30/min. Under each noise level at each RRset, the respiration rates by manual counting (RRm) and RRa were recorded. Any appearance of the alarm display on the RRa monitor was also recorded. Each RRm of all participants agreed with each RRset at each noise level. At 45-55 dB noise, the RRa of 13, 17, and 17 participants agreed with RRset of 6, 12, and 30/min, respectively. The RRa of 14, 17, and 16 participants at 56-65 dB noise, agreed with RRset of 6, 12, and 30/min, respectively. At 66-75 dB noise, the RRa of 9, 15, and 16 participants agreed with RRset of 6, 12, and 30/min, respectively. The RRa of one, nine, and nine participants at 76-85 dB noise agreed with RRset of 6, 12, and 30/min, respectively, which was significantly less than the other noise levels (P < 0.05). Overall, 72.9% of alarm displays highlighted incorrect values of RRa. In a noisy situation involving the operation of a forced-air warming system, the acoustic respiration monitoring should be used carefully especially in patients with a low respiration rate.

Serum ß-hCG as an Indicator of Recurrence After the Complete Resection of a Malignant Solitary Fibrous Tumor of the Pleura.

In solitary fibrous tumors (SFTs) of the pleura, malignant SFTs are uncommon. Although SFTs are known to cause paraneoplastic syndromes through the production of insulin-like growth factor, to the best of our knowledge, the production of beta-human chorionic gonadotropin (ß-hCG) has been reported only in 1 case involving a patient with a benign SFT. We herein report the first case of the elevation of ß-hCG serum levels associated with a malignant SFT in which the ß-hCG serum level became a useful indicator of recurrence after the complete resection of the primary mediastinal lesion.

[Heparin-induced thrombocytopenia developed during the acute phase after left upper lobectomy for lung cancer].

Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin administration. This must not be rarely encountered but is not often reported in Japan compared to Western countries. A 68-year-old woman underwent left upper lobectomy for lung cancer. Low-dose unfractionated heparin was administrated to prevent thromboembolism after the operation. Two days later, sudden dyspnea appeared and ultracardiosonography showing an extensive thromboembolus from the main trunk to both main branches of pulmonary artery indicated pulmonary embolization. After the establishment of percutaneous cardiopulmonary support (PCPS) support, the embolus was removed by emergent open heart surgery. However, despite further unfractionated heparin administration following embolization surgery, other thrombus was identified in both the bi-lateral internal jagular veins and inferior vena cava by ultrasonography and contrast computed tomography( CT). Her platelet count was decreased gradually despite platelet transfusion. Plate factor 4( PF4) antibody against heparin in her blood examination was found, and HIT II was diagnosed. Discontinuation of unfractionated heparin and administration of antithrombin agent improved platelet count, and no additional embolization was identified.

[Anomalous systemic arterial supply to left basal lung with anomalous return of V6].

The patient was 52-year-old woman. Her chief compliant was bloody sputum. The computed tomography revealed an anomalous artery from descending aorta running into left lung basal segment and anomalous left V6 return to superior pulmonary vein. The bronchoscopic examination showed normal bronchial branches. Under the diagnosis of anomalous systemic arterial supply to left basal lung without sequestration, left lower lobectomy was performed. Microscopically, the pulmonary artery showed intimal thickening and alveolar collapse with interstitial fibrosis were seen. The postoperative course was uneventful and she discharged at 6th postoperative day.

[Primary malignant peripheral nerve sheath tumor of the lung; report of a case].

We report a patient with primary malignant peripheral nerve sheath tumor (MPNST) of the lung. A 84-year-old man was referred to our hospital because of an abnormal shadow on chest X-ray. The computed tomography( CT) of the chest revealed a 6 cm tumor close to the posterior chest wall in the left thorax. He was followed-up because a benign tumor from posterior mediastinum was suspected. But the CT after 17 months showed the tumor enlargement. We performed complete resection under video-assisted thoracic surgery. It arose from the left lower lobe and was diagnosed as primary MPNST of the lung by immuno-histopathological examination. MPNSTs have a poor prognosis with tendency to recur. Although there is no sign of recurrence a year after surgery, we should follow-up carefully.

[Empyema that was diagnosed as primary ciliary dyskinesia by electron microscopical image of nasal mucosa].

A patient was 17-year-old. She had a history of repeated pneumonia and sinusitis. She was admitted to our hospital with the diagnosis of pneumonia. Although she was prescribed a course of antibiotics, chest roentgenogram and computed tomography showed increased and capselized pleural effusion, suggesting the development of acute empyema. Capsulized effusion and pus in thorax were removed by surgery. A part of lingular segment was raptured necessitating the partial resection of lingular segment. Her postoperative course was well. Her history of repeated pneumonia and sinusitis indicated the existence of primary ciliary dyskinesia, and the biopsy of nasal mucosa was done. The electron microscopical image of nasal mucosa showed defect of inner dynein arm. We made a diagnosis of primary ciliary dyskinesia based on her previous history and electron microscopical image.

[The influence of difference of surgical procedure for the young spontaneous pneumothorax to the recurrence rate after surgery].

INTRODUCTION: In spontaneous pneumothorax (SP) in patients under the age of 30, we studied the postoperative recurrence rate due to differences in the surgical procedures and the patient's age. MATERIALS AND METHODS: Between October 2003 and September 2012, 351 operations were performed for the young(30 years or younger)SP in our hospital. The recurrence rate was calculated in 2 age groups( under 20 or older) with different surgical procedures which were classified into 5 groups on the basis of the combination of the covering site with the polyglycol acid (PGA) seat and the presence or absence of ligation at both ends of staple-line. RESULTS: The mean age of all patients was 21.0±4.4, 320 were male. The recurrence rate of all was 8.8%.The group 20 years or younger in comparison with the group 21 years or older had significantly high recurrence rate after surgery(11.9% v.s. 5.1%;p=0.034).However, covering the staple-line with ligation of both ends and covering the staple-line and the bullae common site were both significantly lower recurrence rate compared with the group with covering only to the staple-line in 20 years or younger group(0% v.s. 23.8%;p=0.041, 4.9% v.s. 23.8%;p=0.041). CONCLUSION: The results suggest that we need to choose the appropriate procedure of the surgery for SP considering the patient's age. The recurrence rate in the patient 20 years or younger can be reduced by covering the bullae common site and/or the ligating both ends of staple-line in addition to covering the staple-line.

[Primary pulmonary malignant melanoma].

The patients was 63-year-old man. He had a chest abnormally shadow pointed out in examination of March, 2012 and referred to our hospital for a close inspection. The chest computed tomography(CT)revealed a mass shadow of 60 mm in left lung. Bronchoscopic examination was done and it was diagnosed as non-small-cell lung cancer by cytology. The clinical stage was cT2bN1M0 and video-assistedthoracic surgery (VATS) left pneumonectomy with mediastinal lymph node dissection was performed. A lot of neoplastic cells which contained melanin in cytoplasm were recognized by pathology and the diagnosis of malignant melanoma was comfirmed. Lymph node metastasis were recognized in #10, #11, #12 and the pathological stage of a disease was pT2bN1M0, pStage IIB. Further examination to find another lesion after surgery was in vain suggesting primary site to be left lung. A adjuvant chemotherapy has not been done. Surgical resection of primary pulmonary malignant melanoma is reported with reference to literatures.

[Mixed squamous and glandular papilloma].

The patient was a 64-year-old man. He had a smoking history for 43 years (20 cigarettes per day). Being pointed out a mass shadow in the left lower lung field on chest X-ray in a regular checkup, he was referred to our hospital. The chest computed tomography (CT) revealed a tumor shadow of 30 mm diameter in the left S8. Blood tests showed that carcinoembryonic antigen (CEA) and squamous cell carcinoma-related antigen (SCC) were elevated. Accumulation of standardized uptake value (SUV) max 9.78/15.17 match the tumor shadow in fluorodeoxyglucose positron emission tomography (FDGPET),suspected of malignancy. As a result of bronchoscopy, squamous cell carcinoma was suspected by cytology, and he was introduced to us for surgery. Video-assisted thoracic surgery (VATS)-left lower lobectomy and lymph node dissection was performed. By pathology, the tumor showed papillary growth in peripheral bronchus, with squamous cell and high columnar epithelial cell components. The tumor was diagnosed as mixed squamous and glandulas papilloma. In addition, a part of the squamous cells was considered to be atypical, indicating squamous cell carcinoma in situ in a mixed epithelial and glandular papilloma.

[Re-operation for recurrent pulmonary metastases].

Fifty two patients with metastatic lung tumors were treated surgically in our hospital. Second pulmonary resections were performed in 6 patients. They consist of 1 male and 5 females, their age ranged from 59 to 80 years old( average 66 years old). Tumors originate from laryngeal cancer, colorectal cancer in 2 cases respectively, lung cancer and hepatic cancer in 1 case respectively. Three-year and 5-year survival was seen in 75% and 75% of patients, respectively.

[Treament using a free omental flap for pulmonary Aspergillosis with chronic methicillin-resistant Staphylococcus aureus( MRSA) empyema after fenestration].

A case is 48-year-old man who had a history of Blalock-Taussig shunt and the radical operation for Fallot's tetralogy, had been performed cavernostomy and fenestration operation for aspergilloma of left upper lobe in the previous hospital due to control blood spitting. Although the contents of the abscess cavity were removed, the opened cavity was again infected by methicillin-resistant Staphylococcus aureus (MRSA) and he was referred to our hospital. The plombage of free omental flap with vascular anastomosis was performed. He has been well without any symptoms or recurrence of empyema for 6 years after surgery.