Fengshi Chen

Normothermic Ex Vivo Lung Perfusion in Clinical Lung Transplantation

BACKGROUND More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. METHODS In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital. RESULTS During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP. CONCLUSIONS Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).

Salvage Lung Resection for Non-small Cell Lung Cancer After Stereotactic Body Radiotherapy in Initially Operable Patients

Background: Stereotactic body radiotherapy (SBRT) has emerged as a curative treatment for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC). Since NSCLC recurs locally in 10% of the patients treated with SBRT, salvage lung resection after SBRT may be considered in these cases. To further understand the indications for salvage surgery and the pathogenesis of tumor recurrence in these patients, we retrospectively reviewed cases treated at our institution. Methods: SBRT has been performed in patients with early-stage NSCLC at Kyoto University Hospital. We encountered 5 patients who underwent salvage lung resection for NSCLC after SBRT. Results: All the patients were initially operable, but they chose SBRT. After SBRT, the tumors shrank initially in all patients, but increased in size within 18 months of SBRT in the case of 4 patients. During surgical extirpation, we did not find any significant SBRT-related adhesions in any of the patients. Conclusions: We have successfully treated 5 patients who underwent salvage lung resection for early-stage NSCLC after SBRT. We found that surgical resection was feasible after SBRT.

Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage i non-small-cell lung cancer in patients at high risk for lobectomy: A propensity score matching analysis

BACKGROUND The aim of this study was to perform a survival comparison between stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small-cell lung cancer (NSCLC) at high risk for lobectomy. METHODS All patients who underwent SBRT or SLR because of medical comorbidities for clinical stage I NSCLC were reviewed retrospectively. Propensity score matching (PSM) was performed to reduce selection bias between SLR and SBRT patients based on age, gender, performance status, tumour diameter, forced expiratory volume in 1 second (FEV1) and Charlson comorbidity index (CCI). RESULTS One hundred and fifteen patients who underwent SBRT and 65 SLR were enrolled. The median potential follow-up periods for SBRT and SLR were 6.7 and 5.3 years, respectively. No treatment-related deaths were observed. Before PSM, the 5-year overall survival (OS) was 40.3% and 60.5% for SBRT and SLR, respectively (P=0.008). PSM identified 53 patients from each treatment group with similar characteristics: a median age of 76 years, a performance status of 0-1, a median tumour diameter of ∼20 mm, a median FEV1 of ∼1.8L and a median CCI of 1. The difference in OS became insignificant between the matched pairs (40.4% and 55.6% at 5 years with SBRT and SLR; P=0.124). The cumulative incidence of cause-specific death was comparable between groups (35.3% and 30.3% at 5 years, P=0.427). CONCLUSION SBRT can be an alternative treatment option to SLR for patients who cannot tolerate lobectomy because of medical comorbidities.

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.

Comparison of pulmonary function test and computed tomography volumetry in living lung donors.

BACKGROUND We previously proposed calculating forced vital capacity (FVC) by the number of segments for size matching in living-donor lobar lung transplantation (LDLLT). The primary purpose of this study was to compare spirometry-obtained calculations of lower lobe volumes with three-dimensional (3D) computed tomography (CT) volumetric images. Our second goal was to compare the data of pulmonary function tests with CT volumetry in living lung donors. METHODS Pulmonary function test, including FVC and total lung capacity (TLC), and 3D CT volumetry were performed pre-operatively in 21 healthy donor candidates for LDLLT. The relationship of 3D CT volumetric data and calculated volume of lower lobes by the number of segments was investigated. Also studied were 3D CT volumetric data in relation to FVC and TLC. Various pre-operative variables were analyzed retrospectively. RESULTS According to 3D CT volumetry, the right and left lower lobe volume was 26.3% ± 2.9% and 22.6% ± 3.1% of the total lung volume, respectively. We found a significant, strong correlation between each lower lobe volume and the total lung volume. Because the calculated volumes of right and left lower lobes by the number of segments were 26.3% and 21.1%, respectively, our results implied that the volume of both lower lobes was accurately described by the number of segments. FVC was significantly associated with TLC and the total lung volume. CONCLUSIONS We confirmed that it would be justified to estimate graft FVC by the number of segments according to the CT volumetric data in LDLLT.

Less Maintenance Immunosuppression in Lung Transplantation Following Hematopoietic Stem Cell Transplantation From the Same Living Donor

Living‐donor lobar lung transplantation (LDLLT) is one of the final options for saving patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). We retrospectively investigated 19 patients who had undergone LDLLT after HSCT in Japan. Eight patients underwent LDLLT after HSCT in which one of the donors was the same living donor as in HSCT (SD group), while 11 received LDLLT from relatives who were not the HSCT donors (non‐SD group). In the SD group, three patients underwent single LDLLT. The 5‐year survival rate was 100% and 58% in the SD and non‐SD groups, respectively. In the SD group, postoperative immunosuppression was significantly lower than in the non‐SD group. Two patients died of infection and one died of post‐transplant lymphoproliferative disease (PTLD) in the non‐SD group, while only one patient died of PTLD 7 years after LDLLT in the SD group. Hematologic malignancy relapsed in two patients in the non‐SD group. For the three single LDLLTs in the SD group, immunosuppression was carefully tapered. In our study, LDLLT involving the same donor as for HSCT appeared to have advantages related to lower immunosuppression compared to LDLLT from relatives who were not the HSCT donors.

Reconditioning of lungs donated after circulatory death with normothermic ex vivo lung perfusion

BACKGROUND The use of donation-after-circulatory-death (DCD) donors for lung transplantation has come into practice. In this study we investigated whether DCD lungs can be resuscitated after warm ischemia with normothermic ex vivo lung perfusion (EVLP). METHODS Four hours after cardiac arrest, beagle dogs were divided into two groups (n = 6 each): those with static cold storage (SCS group) and those with normothermic EVLP (EVLP group), for 3.5 hours. Physiologic lung functions were evaluated during EVLP. In both groups, the left lungs were then transplanted and reperfused for 4 hours to evaluate post-transplant lung functions. Lung tissue adenosine triphosphate (ATP) levels were measured at given time-points. RESULTS Lung oxygenation was significantly improved with EVLP (p < 0.01), and lung oxygenation at the end of EVLP significantly reflected post-transplant lung oxygenation (r = 0.99, p < 0.01). Post-transplant lung oxygenation was significantly better in the EVLP group than in the SCS group (p < 0.05). Both dynamic pulmonary compliance and wet-to-dry lung weight ratio 4 hours after transplantation were also significantly better in the EVLP group than in the SCS group (p < 0.05). Microthrombi in the donor lungs before transplantation were microscopically detected more often in the SCS group. The lung tissue ATP levels 4 hours after transplantation were significantly higher in the EVLP group compared with the SCS group (p = 0.03). CONCLUSIONS Normothermic ex vivo lung perfusion could resuscitate DCD lungs injured by warm ischemia, and may ameliorate ischemia-reperfusion injury.

Living-donor lobar lung transplantation provides similar survival to cadaveric lung transplantation even for very ill patients †

OBJECTIVES Living-donor lobar lung transplantation (LDLLT) has been performed as a life-saving procedure for critically ill patients who are unlikely to survive the long wait for cadaveric lungs. The purpose of this study was to compare the preoperative condition and outcome of LDLLT patients with those of conventional cadaveric lung transplantation (CLT) patients. METHODS A new lung transplant programme was established in 2008 at Kyoto University. Between June 2008 and January 2014, we performed 79 lung transplants, including 42 LDLLTs (10 single, 32 bilateral) and 37 CLTs (22 single, 15 bilateral). Data collected included pre- and perioperative variables and mid-term survival. All data were analysed retrospectively as of January 2014. RESULTS The majority of patients were female (57.1%) in the LDLLT group and male (64.9%) in the CLT group. The average age was similar (36.6 ± 20.7 vs 39.7 ± 12.6 years, P = 0.42) between the two groups. Preoperatively, interstitial lung disease was more common in LDLLT patients than in CLT patients (47.6 vs 24.3%, P = 0.048); prior haematopoietic stem cell transplantation was performed more often in LDLLT patients than in CLT patients (33.3 vs 13.5%, P = 0.040) and there were more steroid-dependent LDLLT patients than CLT patients (64.3 vs 29.7%, P = 0.0022). Based on preoperative criteria of lower body mass index (17.2 ± 4.0 vs 19.3 ± 3.3 kg/m(2), P = 0.013), less ambulatory ability (42.9 vs 86.5%, P = 0.0001) and more ventilator dependence (11.9 vs 2.7%, P = 0.12), LDLLT patients were more debilitated than CLT patients. LDLLT patients required longer postoperative mechanical ventilation than CLT patients (15.6 ± 16.2 vs 8.5 ± 8.1 days, P = 0.025). However, 1- and 3-year survival rates were similar between the two groups (89.7 and 86.1% vs 88.3 and 83.1%, P = 0.55). All living donors returned to their previous lifestyles without restriction. CONCLUSIONS Although LDLLT patients were in a worse preoperative condition than CLT patients, LDLLT patients demonstrated survival rates similar to CLT patients. LDLLT is a viable option for patients too ill to survive a long waiting time for cadaveric donors.

Pulmonary resection for metastasis from renal cell carcinoma

The treatment of metastatic renal cell carcinoma still represents a widely debated issue due to the introduction of several immunotherapies. To confirm again a role for resection of pulmonary metastases for such tumors, we reviewed our institutional experience. Between 1992 and 2007, eight patients with pulmonary metastases from renal cell carcinoma underwent complete pulmonary resection. All patients had undergone curative resection of their primary renal cell carcinomas and also had obtained or had obtainable locoregional control of their primaries. Various perioperative variables were investigated retrospectively. Disease-free interval varied from 25 to 156 months, with a median of 73 months. In three patients, lung metastases were found to be unilateral and solitary. Four patients presented two metastases in the unilateral lungs. One patient showed five metastases in the bilateral lungs. Six patients underwent wedge resection or segmentectomy, while two patients underwent more than lobectomy. Five patients showed recurrence after pulmonary metastasectomy. Five-year and 10-year overall survival rate was 83.3% and 41.7%, respectively, while 3-year and 5-year disease-free survival rate was 35.0% and 17.5%, respectively. Our study suggested that pulmonary metastasectomy for renal cell carcinoma might be well justified.

Pulmonary resection for metastasis from esophageal carcinoma

Pulmonary metastasectomy has become the standard therapy for various metastatic malignancies to the lungs; however, few data have been available regarding lung metastasectomy for esophageal carcinoma. To confirm a role for resection of pulmonary metastases for such tumors, we reviewed our institutional experience. Between 2001 and 2007, five patients with pulmonary metastases from esophageal carcinoma underwent complete pulmonary resection. All patients had undergone curative resection of their primary esophageal carcinomas and also had obtained locoregional control of their primaries. Disease-free interval varied from 13 to 56 months, with a median of 21 months. In three patients, lung metastases were found to be unilateral and solitary. The other two patients presented several metastases in the unilateral or bilateral lungs. All patients underwent wedge resection or segmentectomy. Currently, four patients are alive without evidence of disease and one patient has died of disease. All patients undertook or were going to undertake chemotherapy after the pulmonary metastasectomy. Three patients with solitary metastasis are all alive without disease 13, 48, and 90 months after the first pulmonary metastasectomy, respectively. Pulmonary metastasectomy for esophageal carcinoma with postoperative chemotherapy was seemingly justified. Solitary pulmonary metastasis might be a good candidate for favorable prognostic factor.