Nobuharu Hanaoka

Clinical Significance of p21 Expression in Non–Small-Cell Lung Cancer

PURPOSE The clinical significance of p21 expression remains unclear, whereas many experimental studies have demonstrated that p21, the product of the WAF1/CIP1/SDI1 gene, plays an important role in regulation of the cell cycle as an inhibitor of cyclin-dependent kinases. The purpose of this study was to clarify the clinical significance in resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A total of 233 consecutive patients with completely resected pathologic stage I to IIIA NSCLC were retrospectively reviewed. Expression of p21 and the status of p53 were examined immunohistochemically. Proliferative activity was also evaluated immunohistochemically. The incidence of apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining. RESULTS Expression of p21 was positive in 120 patients (51.5%). The 5-year survival rate of p21-positive patients was 73.8%, significantly higher than that of p21-negative patients (60.7%; P =.006). Aberrant expression of p53 was positive in 98 patients (42.1%). When combined with p53 status, the prognostic value of p21 status was enhanced: the 5-year survival rate of p21-positive and p53-negative patients was 80.7%, markedly higher than that of p21-negative and p53-positive patients (50.0% for both; P =.001). Multivariate analysis confirmed that positive expression of p21 was a significant factor for predicting a favorable prognosis. There was no significant correlation between p21 expression and p53 status, proliferative activity, or incidence of apoptosis. CONCLUSION p21 expression was shown to be an independent prognostic factor in NSCLC.

Isoflurane inhalation after circulatory arrest protects against warm ischemia reperfusion injury of the lungs

Background. Non-heart-beating donors are expected to ameliorate shortages of donors for organ transplantation. The issue of preventing warm ischemic injury after circulatory arrest must be investigated. In the current study, we investigated whether isoflurane inhalation during warm ischemia could attenuate ischemia reperfusion injury (IRI) of the lung. Methods. An isolated perfused rat lung model was used. The rats were allocated into four groups: the no ischemia group; the ischemia-1 minimum alveolar concentration (MAC) iso group (ventilation with air and 1.38% isoflurane); the Ischemia-3MAC iso group (ventilation with air and 4.2% isoflurane); and the Ischemia-no treatment group (ventilation with only air). Lungs were subjected to 50 min of ischemia at 37°C. Physiological lung functions were measured after reperfusion in experiment one. Mitochondrial control ratio (RCR), cytochrome-c release from mitochondria, and caspase activities just after warm ischemia were measured in experiment two. Results. Pulmonary functions in the Ischemia-1MAC iso group were significantly greater than those in the Ischemia-no treatment group for experiment one. There were no dose-dependent effects between 1MAC and 3MAC isoflurane. In experiment two, RCR in the Ischemia-1MAC iso group was significantly greater than that in the Ischemia-no treatment group. Cytochrome-c release and caspase-9 activity in the Ischemia-1MAC iso group were significantly decreased compared to those in the Ischemia-no treatment group. Conclusions. Isoflurane inhalation attenuates warm IRI with the protection of mitochondria. Our results suggest that isoflurane inhalation after circulatory arrest can be a simple and effective method to protect the lung against warm ischemia.

Primary lung carcinoma arising from emphysematous bullae

To clarify clinical characteristics and biological features of primary lung carcinoma arising from emphysematous bullae (EB), a total of 50 patients (49 males and one female) among all 1478 patients who underwent operation for primary lung carcinoma cases were reviewed; biological features were examined in 31 patients whose resected specimens were available for immunohistochemical staining (IHS). Thirty-one patients (62.0%) had pathologic stage I disease, and 30 cases (60.0%) had poorly differentiated tumor, demonstrating earlier pathologic stages and poorer cell differentiation of lung carcinoma with EB as compared with that without EB. The mean proliferative index (PI) for carcinoma with EB was 64.0%, which was significantly higher than that for carcinoma without EB (47.2%, P = 0.001); no significant difference in Apoptotic index (AI) was demonstrated. Aberrant p53 expression was less frequent in carcinoma with EB (29.0%) than in carcinoma without EB (47.9%, P = 0.043). Five-year survival rates for carcinoma with and that without EB were 50.3 and 46.9%, respectively, showing no significant difference. Multivariate analysis did not demonstrate that association of EB was a significant prognostic factor. In conclusion, although with the poorer cell differentiation and accelerated proliferative activity of lung carcinoma arising from EB, this does not have a significantly different prognosis than primary lung carcinoma not associated with bullae.

Application of ET-Kyoto solution in clinical lung transplantation

We have developed a new organ preservation solution called extracellular-type trehalose-containing Kyoto (ET-Kyoto) solution. ET-Kyoto solution has been applied in clinical lung transplantation. The patient was a 49-year-old woman with diffuse panbronchiolitis. She underwent bilateral lobar lung transplantation from living donors. Each lobe was flushed with ET-Kyoto solution. After reperfusion, PaO(2) with inhalation of 100% oxygen was more than 500 Torr. Posttransplantation course was uneventful. Despite the relatively short ischemic time of this case report, ET-Kyoto solution may be feasible and safely applied in clinical lung transplantation.

Optimal alveolar oxygen concentration for cold storage of the lung

Background. Ischemia of the lung is different from that of solid organs because the lung contains gas in the alveoli. However, the optimal gas composition in the alveoli during cold storage remains uncertain. We investigated the relationship between the alveolar oxygen concentration and reperfusion injury. Methods. The lungs inflated with 0% O2, 5% O2, room air, 50% O2, or 100% O2 were reperfused after 8 hR storage at 4°C and pulmonary functions were measured for 120 min using an ex vivo rat lung model. The levels of high-energy phosphate and lipid peroxidation of the lung were analyzed after a PA flush, preservation, and reperfusion. Additionally, respiration of the mitochondria in the lungs was measured after preservation. Results. The pulmonary functions were significantly superior in the 5% O2 group than those in the 0% O2, 50% O2, and 100% O2 groups. Pulmonary edema developed in the 0% O2, 50% O2, and 100% O2 groups, but not in the 5% O2 group. After preservation, the energy level in the lungs decreased only in the 0% O2 group. Although lipid peroxidation of the lungs did not increase in any group after preservation, significant increases were observed in the room air, 50% O2 and 100% O2 groups after reperfusion. State 3 and 4 ratios of the mitochondrial respiration significantly decreased in the lungs of the room air, 50% O2 and 100% O2 groups. Conclusions. Although the cold-preserved lungs require oxygen, hyperoxygenation induced mitochondrial dysfunction and increased lipid peroxidation and led to deleterious lung function after reperfusion. Therefore, hypoxic conditions that can maintain the energy level of the lung during cold storage would be optimal.

Balloon angioplasty for pulmonary artery stenosis after lung transplantation

We report here a successful case of balloon angioplasty for a stenosis of the pulmonary artery after lung transplantation. A 49-year-old patient with end stage diffuse bronchiectasis with sinusitis underwent bilateral living donor lobar lung transplantation. After treatment of postoperative right pneumothorax, a perfusion lung scan revealed deficient perfusion in the left lung. Pulmonary angiography showed a severe stenosis in the left pulmonary artery just distal to the anastomosis. Percutaneous balloon angioplasty improved both pulmonary perfusion and respiratory function.

Inflammatory endobronchial stenosis

We encountered a 71-year-old woman with inoperable bronchial stenosis of the right main bronchus, which was caused by inflammatory granulation infected with Pseudomonas aeruginosa in posttuberculous bronchiectasis. Two months after placement of self-expanding nitinol stents, fiberoptic bronchoscopic examination to investigate hemosputum revealed endobronchial granuloma formation. Endobronchial granulation has disappeared with long-term oral administration of tranilast.

Recurrence of bilateral diffuse bronchiectasis after bilateral lung transplantation.

Abstract:  We report two cases of bilateral diffuse bronchiectasis in which early recurrence of the original lung disease occurred after bilateral lung transplantation (LT). Patient 1 underwent cadaveric LT. Recurrent bronchiectasis occurred 4 months later, and he died 6 years after LT. Patient 2 underwent living‐related lobar LT, bronchiectasis relapsed 4 months later, and he died 13 months after LT. Both cases were finally diagnosed as bilateral diffuse bronchiectasis by the pathological features of the explanted lungs: infiltration of inflammatory cells predominantly in the conducting airways with dilation of the bronchi of bilateral lungs and scarcity of foamy macrophages in the wall of the respiratory bronchioles. Similar pathological features were seen in autopsy specimens from patient 1 and a transbronchial biopsy specimen from patient 2. LT should be carried out with caution in patients with bilateral diffuse bronchiectasis. When performing LT in such patients, it is suggested that sinusitis should be controlled perioperatively.

Combined lipiodol marking and video-assisted thoracoscopic surgery in a hybrid operating room

Background The development of diagnostic technology has led to detection of an increasing number of small pulmonary nodules (SPNs), which can be difficult to locate intraoperatively. Here, we report our experience performing single-stage lipiodol localization and surgical resection in a hybrid operating room (OR). Methods Between June 2016 and August 2017, 30 patients with 32 SPNs underwent sliding gantry-based multidetector computed tomography (MDCT)-guided lipiodol marking followed by video-assisted thoracoscopic surgery (VATS) in a hybrid OR. After induction of general anesthesia, all nodules were marked with 0.2 mL lipiodol under MDCT fluoroscopic guidance, followed by immediate VATS. Results The mean SPN diameter and distance from the pleural surface were 10.7±4.5 mm (range, 5.0-21.0 mm) and 18.0±9.0 mm (range, 2.8-32.0 mm) respectively. The MDCT-guided localization procedure required 15.8±6.0 min (range, 8.0-32.0 min). All the nodules were marked with lipiodol and detected during fluoroscopy as a clear spot. The median deviation between the radio-opaque nodule and the target nodule was 7.8±3.6 mm (range, 3.0-20.0 mm). In two cases, MDCT scans performed after completion of marking revealed mild pneumothorax, which did not need further intervention. VATS resection was converted to thoracotomy in two patients because of strong pleural adhesions and intraoperative bleeding from the pulmonary vein. No other complications occurred during the combined approach, and there was no intra- or post-operative mortality or morbidity. Conclusions These results suggest that a combined approach using MDCT-guided lipiodol marking followed by VATS is feasible and has acceptable accuracy in resection of SPNs.