Ten-Year Trends of Clinicopathologic Features and Surgical Treatment of Lung Cancer in China.

BACKGROUND: Lung cancer has changed significantly during the past 2 decades in its epidemiology and treatment. This retrospective analysis used data from 7 major areas of China over 10 years to evaluate clinicopathologic and surgical treatment trends of lung cancer in China during the past decade. METHODS: Data from 7184 patients with primary lung cancer who were treated between 2005 and 2014 in 8 provinces of China were retrospectively collected. Their clinicopathologic features and surgical treatment information were recorded. Simple linear regression models and the Cochrane-Armitage trend test were used to assess temporal trends. RESULTS: The proportion of female patients (from 57.4% to 59.6%; P < .001) and nonsmoking patients (from 37.1% to 48.9%; P < .001) and of patients with a family history of malignant tumors (from 7.0% to 11.5%; P < .001) increased significantly. The percentage of adenocarcinomas increased significantly (from 36.4% to 53.5%; P < .001), with a decrease in squamous cell carcinomas (from 45.4% to 34.4%; P < .001). After 2008, the application of minimally invasive surgery significantly increased in China (from 2.4% in 2008 to 34.4% in 2014; P < .001), with a decline in the rate of conversion to open operation (from 14.3% in 2008 to 4.8% in 2014; P = .146) and an increase in the proportion of systematic mediastinal lymph node dissection (from 50.0% in 2008 to 84.1% in 2014; P = .001). CONCLUSIONS: This study investigated recent 10-year trends in the clinicopathologic features and surgical treatment of lung cancer in China and found significant important changes. These findings provide valuable information and evidence for the future control of the disease in China.

Palliative esophagectomy in unexpected metastatic disease: sense or nonsense?

Background Despite integrated positron emission tomography and computed tomography screening before and after neoadjuvant treatment in patients with locally advanced esophageal cancer, unexpected metastatic disease is still found in some patients during surgery. Should then esophagectomy be aborted or is there a place for palliative resection? Methods Between 2002 and 2015, 681 patients with potentially resectable esophageal cancer were sheduled for neoadjuvant therapy and subsequent esophagectomy. In 552 patients, a potentially curative esophagectomy was performed. In 12 patients, unexpected disease was discovered during surgery but esophagectomy was performed with synchronous resection of metastases; 10 of them had oligometastatic disease (≤4 single-organ metastases). Esophagectomy was not performed in 117 patients (because of disease progression in 50); 14 were also single-organ oligometastatic. Data of 10 single-organ oligometastatic patients who underwent esophageal resection (group 1) were compared those of 10 non-resected but treated counterparts (group 2) and with 228 patients who underwent potentially curative esophagectomy with persistent pathological lymph nodes (group 3). Results Five oligometastatic esophagectomy patients had lung metastases: 1 peritoneal, 2 adrenal, 1 pleural, and 1 pancreatic. Two oligometastatic non-resected patients had lung, 5 liver, and 3 brain metastases. Median overall survival was 21.4, 12.1, and 20.2 months in the respective groups (group 1 vs. group 2 p = 0.042; group 2 vs. group 3 p = 0.002; group 1 vs. group 3 p = 0.88). Conclusions Survival is longer in patients undergoing palliative esophagectomy with unexpected single-organ oligometastatic disease and comparable to survival in patients with persistent pathological lymph nodes. Palliative resection in these patients seems to be justified.

Impact of Extracapsular Lymph Node Involvement After Neoadjuvant Chemoradiation Therapy Followed by Surgery in Carcinoma of the Esophagus: A Multicenter Study.

OBJECTIVES: The current study aims to examine the impact of extracapsular lymph node involvement (EC-LNI) on survival for both esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC) treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery. BACKGROUND: Studies have demonstrated the negative prognostic value of EC-LNI in primary surgery, but its impact after nCRT remains unclear. METHODS: From the databases of 6 European high-volume centers 1505 patients with R0 resections were withheld. Oncologic variables, including ypT, ypN, number of positive lymph nodes, and lymph node capsular status: EC-LNI and intracapsular lymph node involvement (IC-LNI), were examined. Statistical analysis was performed by Cox proportional hazards modeling. RESULTS: In SCC 182 patients (31.6%) had positive lymph nodes, of whom 60 (33.0%) showed EC-LNI. In AC 391 patients (42.1%) had positive lymph nodes, of whom 147 (37.6%) showed EC-LNI. Overall 5-year survival (O5YS) in SCC was 42.0%. Presence of EC-LNI meant a significantly worse O5YS than IC-LNI or pN0 (10.6%, 39.5%, and 47.4%, respectively; P < 0.05). O5YS in AC was 41.2%. No significant difference was observed between EC-LNI and IC-LNI (P = 0.322). In the multivariate analysis, among the examined possible prognosticators, presence of EC-LNI showed the highest hazard ratio (2.29, confidence interval: 1.52-3.47) as an independent prognosticator for overall survival in SCC, but it was not in AC. CONCLUSIONS: Based on this international multicenter study, the presence of EC-LNI after nCRT is at least as important as N-stage for survival and EC-LNI is the strongest prognosticator for overall survival in SCC but not in AC.

International Consensus on Standardization of Data Collection for Complications Associated With Esophagectomy: Esophagectomy Complications Consensus Group (ECCG).

INTRODUCTION: Perioperative complications influence long- and short-term outcomes after esophagectomy. The absence of a standardized system for defining and recording complications and quality measures after esophageal resection has meant that there is wide variation in evaluating their impact on these outcomes. METHODS: The Esophageal Complications Consensus Group comprised 21 high-volume esophageal surgeons from 14 countries, supported by all the major thoracic and upper gastrointestinal professional societies. Delphi surveys and group meetings were used to achieve a consensus on standardized methods for defining complications and quality measures that could be collected in institutional databases and national audits. RESULTS: A standardized list of complications was created to provide a template for recording individual complications associated with esophagectomy. Where possible, these were linked to preexisting international definitions. A Delphi survey facilitated production of specific definitions for anastomotic leak, conduit necrosis, chyle leak, and recurrent nerve palsy. An additional Delphi survey documented consensus regarding critical quality parameters recommended for routine inclusion in databases. These quality parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion, grading of complication severity, changes in level of care, discharge location, and readmission rates. CONCLUSIONS: The proposed system for defining and recording perioperative complications associated with esophagectomy provides an infrastructure to standardize international data collection and facilitate future comparative studies and quality improvement projects.

Signet ring cells in esophageal and gastroesophageal junction carcinomas have a more aggressive biological behavior.

OBJECTIVE: To clarify the biologic behavior of esophageal signet ring cell (SRC) carcinomas of the esophagus and gastroesophageal junction (GEJ). To evaluate the accuracy of pretreatment biopsies in diagnosing true SRC carcinoma. BACKGROUND: In contrast with gastric cancer, little is known about the biologic behavior and prognosis of SRC. METHODS: All adenocarcinomas (ADC) of the esophagus and GEJ-patients undergoing primary resection between 1990 and 2009 were included (n = 920). Specimens containing SRCs (n = 114) were classified according to World Health Organization criteria (>50% SRC or <50% SRC). RESULTS: Thirty-two patients showed more than 50% SRC and 71 patients showed less than 50% SRC. Overall cancer-specific 5-year survival was worse for SRC (22.4%, P < 0.0001) and for SRC > 50% (13.6%, P = 0.0001) compared with ADC. Complete resection was achieved in 86.5% of patients (n = 697) in ADC, 69.5% (n = 57) in SRC < 50%, and 78.1% (n = 25) in SRC > 50% (vs ADC, respectively, P < 0.0001 and P = 0.1801). In 379 pN + R0 patients, the median number of positive lymph nodes was comparable between ADC and SRC < 50% (4 vs 5, P = 0.207) or SRC > 50% (4 vs 8, P = 0.077). Compared with ADC, SRC > 50% showed more pN3's (30% vs 61%, P = 0.006), higher recurrence (56% vs 42% for ADC, P = 0.003), and local-regional recurrences (29% vs 16%, P = 0.002). Pretreatment biopsies were unreliable to define the presence of SRC > 50% (sensitivity = 56.3%, positive predictive value = 43.9%). CONCLUSIONS: SRCs are aggressive neoplasms associated with poorer prognosis than other ADCs after primary esophagectomy. Because our data suggest that pretreatment biopsies failed to reliably define presence of SRC > 50%, presence of SRCs in pretreatment biopsies seems to be of no use to define treatment strategy or prognosis.

A porcine model to study ex vivo reconditioning of injured donor lungs.

BACKGROUND: Brain death rapidly results in lung injury making many cadaveric donors unsuitable for lung transplantation. The aim of this study was to develop a porcine model of lung injury as a first step to study mechanisms to ameliorate the pretransplant graft quality during ex vivo perfusion. MATERIALS AND METHODS: Male pigs (47 ± 8 kg) were divided into three groups: LPS-group [LPS] (n = 6) [instillation of lipopolysaccharides (15 mg/lung)]; saline-group [SAL] (n = 5) (50 mL saline/lung); and sham-group [SHAM] (n = 5). CT scans of the lungs were taken 17h before (T-17) and 31h after (T31) instillation. Broncho-alveolar lavage (BAL) was performed, and blood gases, hemodynamic, and aerodynamic parameters were measured at T 0 and T 50. Blood samples and temperature were taken at all time points. Pigs were sacrificed during cold pulmoplegia (T 50), and tissue samples were collected for histology. Wet lung weight was measured. RESULTS: Wet lung weight/body weight was higher in [LPS] versus [SAL] (P < 0.05). Total BAL cells were higher in [LPS] versus [SAL] and [SHAM] at T 50 (left: P < 0.001 and P < 0.01; right: P < 0.01 and P < 0.001). More neutrophils were present in BAL of [LPS] at T 50 versus T 0 (left: P < 0.001; right: P < 0.01). [LPS] demonstrated more ground glass opacities (GGO) on CT at T 31 compared with [SAL] and [SHAM] (P < 0.05). Histologically, more interstitial hemorrhage was observed in [LPS] versus [SAL] and [SHAM](P < 0.01). Neutrophils in blood increased and lymphocytes decreased in [LPS] versus [SAL] (P < 0.05). No differences were observed in hemodynamic and aerodynamic parameters and in saturation between groups at T 50. CONCLUSIONS: LPS instillation caused inflammation with more cells in BAL, changes on CT, and histology. However, no physiologic changes occurred.

Optimum lymphadenectomy for esophageal cancer.

OBJECTIVE: Using Worldwide Esophageal Cancer Collaboration data, we sought to (1) characterize the relationship between survival and extent of lymphadenectomy, and (2) from this, define optimum lymphadenectomy. SUMMARY BACKGROUND DATA: What constitutes optimum lymphadenectomy to maximize survival is controversial because of variable goals, analytic methodology, and generalizability of the underpinning data. METHODS: A total of 4627 patients who had esophagectomy alone for esophageal cancer were identified from the Worldwide Esophageal Cancer Collaboration database. Patient-specific risk-adjusted survival was estimated using random survival forests. Risk-adjusted 5-year survival was averaged for each number of lymph nodes resected and its relation to cancer characteristics explored. Optimum number of nodes that should be resected to maximize 5-year survival was determined by random forest multivariable regression. RESULTS: For pN0M0 moderately and poorly differentiated cancers, and all node-positive (pN+) cancers, 5-year survival improved with increasing extent of lymphadenectomy. In pN0M0 cancers, no optimum lymphadenectomy was defined for pTis; optimum lymphadenectomy was 10 to 12 nodes for pT1, 15 to 22 for pT2, and 31 to 42 for pT3/T4, depending on histopathologic cell type. In pN+M0 cancers and 1 to 6 nodes positive, optimum lymphadenectomy was 10 for pT1, 15 for pT2, and 29 to 50 for pT3/T4. CONCLUSIONS: Greater extent of lymphadenectomy was associated with increased survival for all patients with esophageal cancer except at the extremes (TisN0M0 and >or=7 regional lymph nodes positive for cancer) and well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 for pT2, and >or=30 for pT3/T4 is recommended.

The mode of death in the non-heart-beating donor has an impact on lung graft quality.

OBJECTIVE: We hypothesised that the agonal phase prior to cardiac death may negatively influence the quality of the pulmonary graft recovered from non-heart-beating donors (NHBDs). Different modes of death were compared in an experimental model. METHODS: Non-heparinised pigs were divided into three groups (n=6 per group). Animals in group I [FIB] were sacrificed by ventricular fibrillation resulting in immediate circulatory arrest. In group II [EXS], animals were exsanguinated (45+/-11 min). In group III [HYP], hypoxic cardiac arrest (13+/-3 min) was induced by disconnecting the animal from the ventilator. Blood samples were taken pre-mortem in HYP and EXS for measurement of catecholamine levels. After 1 h of in situ warm ischaemia, unflushed lungs were explanted and stored for 3 h (4 degrees C). Left lung performance was then tested during 60 min in our ex vivo reperfusion model. Total protein concentration in bronchial lavage fluid was measured at the end of reperfusion. RESULTS: Pre-mortem noradrenalin (mcg l(-1)) concentration (baseline: 0.03+/-0) increased to a higher level in HYP (50+/-8) vs EXS (15+/-3); p=0.0074. PO(2) (mmHg) at 60 min of reperfusion was significantly worse in HYP compared to FIB (445+/-64 vs 621+/-25; p<0.05), but not to EXS (563+/-51). Pulmonary vascular resistance (dynes s cm(-5)) was initially higher in EXS (p<0.001) and HYP (NS) vs FIB (15824+/-5052 and 8557+/-4933 vs 1482+/-61, respectively) but normalised thereafter. Wet-to-dry weight ratio was higher in HYP compared to FIB (5.2+/-0.3 vs 4.7+/-0.2, p=0.041), but not to EXS (4.9+/-0.2). Total protein (g l(-1)) concentration was higher, although not significant in HYP and EXS vs FIB (18+/-6 and 13+/-4 vs 4.5+/-1.3, respectively). CONCLUSION: Pre-mortem agonal phase in the NHBD induces a sympathetic storm leading to capillary leak with pulmonary oedema and reduced oxygenation upon reperfusion. Graft quality appears inferior in NHBD lungs when recovered in controlled (HYP) vs uncontrolled (EXS and FIB) setting.

Retrograde flush following warm ischemia in the non-heart-beating donor results in superior graft performance at reperfusion.

BACKGROUND: The use of non-heart-beating donors (NHBD) has been propagated as an alternative to overcome the scarcity of pulmonary grafts. The presence of postmortem thrombi, however, is a concern for the development of primary graft dysfunction. In this isolated lung reperfusion study, we looked at the need and the best route of preharvest pulmonary flush. METHODS: Domestic pigs were sacrificed by ventricular fibrillation and divided in 3 groups (n = 6 per group). After 1 h of in situ warm ischemia, lungs in group I were retrieved unflushed (NF). In group II, lungs were explanted after an anterograde flush (AF) through the pulmonary artery. Finally, in group III, lungs were explanted after a retrograde flush (RF) via the left atrium. After 3 h of cold storage, the left lung was assessed for 60 min in our ex vivo reperfusion model. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. RESULTS: Pulmonary vascular resistance (dynes x sec x cm(-5)) was 1145 +/- 56 (RF) versus 1560 +/- 123 (AF) and 1435 +/- 95 (NF) at 60 min of reperfusion (P < 0.05). Oxygenation and compliance were higher and plateau airway pressure was lower in RF versus AF and NF, although the difference did not reach statistical significance. No differences in W/D were observed between groups after reperfusion. Histological examination revealed fewer microthrombi in the left lung in RF compared with AF and NF. CONCLUSION: RF of lungs from NHBD improves graft function by elimination of microthrombi from the pulmonary vasculature, resulting in lower pulmonary vascular resistance upon reperfusion.

N-acetyl cysteine attenuates the inflammatory response in warm ischemic pig lungs.

BACKGROUND: Lungs donated after cardiac death (DCD) may significantly reduce current organ shortage. However, the warm ischemic period following circulatory arrest may enhance ischemia-reperfusion injury (IRI). We investigated the possible therapeutic effect of N-acetyl cysteine (NAC), a potent anti-oxidative agent on IRI in a porcine ex vivo lung reperfusion model. MATERIALS AND METHODS: NAC (50 mg/kg) was nebulized to pigs (n = 6/group) prior to sacrifice (NAC-DCD). In DCD-NAC, animals received NAC 15 min after death. Control animals did not receive an aerosol (DCD). Interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-8, lactate dehydrogenase activity and thiobarbituric acid reactive substances were measured and cells were counted in broncho-alveolar lavage from the right lung after a 3-h warm plus 1-h cold ischemic interval. RESULTS: There were no differences in cells between groups, however cell death was lower in NAC-DCD (10.3 +/- 1.5%) and DCD-NAC (7.83 +/- 1.8%) compared to DCD (18.0 +/- 3.8%). IL-1beta levels (111.5 +/- 28.8 pg/mL and 92.2 +/- 51.0 pg/mL versus 250.3 +/- 56.6 pg/mL) and lactate dehydrogenase activity (1258.0 +/- 440.9 U/L and 1606.0 +/- 289.0 U/L versus 2848.0 +/- 760.9 U/L) were significantly lower in NAC-DCD and DCD-NAC compared with DCD, respectively. These postischemic inflammatory markers correlated with functional parameters upon reperfusion of the left lung, reported in a previous study. CONCLUSIONS: Administration of NAC prior to or shortly after circulatory arrest results in a marked reduction of inflammation during the warm ischemic phase.

Retrograde flush following topical cooling is superior to preserve the non-heart-beating donor lung.

OBJECTIVE: The use of non-heart-beating donors (NHBD) has been propagated as an alternative to overcome the scarcity of pulmonary grafts. Formation of microthrombi after circulatory arrest, however, is a major concern for the development of reperfusion injury. We looked at the effect and the best route of pulmonary flush following topical cooling in NHBD. METHODS: Non-heparinized pigs were sacrificed by ventricular fibrillation and divided into three groups (n=6 per group). After 1h of in situ warm ischaemia and 2.5h of topical cooling, lungs in group I were retrieved unflushed (NF). In group II, lungs were explanted following an anterograde flush (AF) through the pulmonary artery with 50 ml/kg Perfadex (6 degrees C). Finally, in group III, lungs were retrieved after an identical but retrograde flush (RF) via the left atrium. Flush effluent was sampled at intervals to measure haemoglobin concentration. Performance of the left lung was assessed during 60 min in our ex vivo reperfusion model. Wet-to-dry weight ratio (W/D) of both lungs was calculated as an index of pulmonary oedema. IL-1beta and TNF-alpha protein levels in bronchial lavage fluid from both lungs were compared between groups. RESULTS: Haemoglobin concentration (g/dl) was higher in the first effluent in RF versus AF (3.4+/-1.1 vs 0.6+/-0.1; p<0.05). Pulmonary vascular resistance (dynes x s x cm(-5)) was 975+/-85 RF versus 1567+/-98 AF and 1576+/-88 NF at 60 min of reperfusion (p<0.001). Oxygenation (mmHg) and compliance (ml/cmH(2)O) were higher (491+/-44 vs 472+/-61 and 430+/-33 NS, 22+/-3 vs 19+/-3 and 14+/-1 NS, respectively) and plateau airway pressure (cmH(2)O) was lower (11+/-1 vs 13+/-1 and 13+/-1 NS) after RF versus AF and NF, respectively. No differences in cytokine levels or in W/D ratios were observed between groups after reperfusion. Histology demonstrated microthrombi more often present after AF and NF compared to RF. CONCLUSION: Retrograde flush of the lung following topical cooling in the NHBD results in a better washout of residual blood and microthrombi and subsequent reduced pulmonary vascular resistance upon reperfusion.

Comparative study of donor lung injury in heart-beating versus non-heart-beating donors.

OBJECTIVE: The use of non-heart-beating donors (NHBD) has been advocated as an alternative to overcome the critical organ shortage in lung transplantation despite the warm ischemic period that may result in primary graft dysfunction. On the contrary, brain death in the heart-beating donor (HBD) may be an underestimated risk factor for donor lung injury. We postulated that 60 min of warm ischemia in the NHBD is less detrimental to the lung than the pathophysiological changes after brain death in the HBD. In this study we compared the quality of lungs from HBD versus NHBD in an isolated reperfusion model. METHODS: Pigs (n=10 per group) were divided into three groups. In group I (HBD), brain death was induced by acute inflation of an intracranial epidural balloon catheter. In group II (CONTROL), the balloon was not inflated. In group III (NHBD), cardiac arrest was induced by myocardial fibrillation. After 5 h of in situ mechanical ventilation, lungs in HBD and CONTROL were preserved with a cold antegrade flush. In NHBD, unflushed grafts were explanted after 1 h of warm ischemia and 4 h of topical cooling in the cadaver. Graft performance was evaluated during 1 h in an isolated ventilation and reperfusion model. Extravascular lung water content (EVLW) was calculated. All data are reported as mean+/-SEM. RESULTS: A significant autonomic storm was observed in HBD following balloon inflation. During ex vivo assessment, pulmonary vascular resistance (PVR) at 60 min in HBD (2634+/-371 dynes cm(-5)) was significantly higher as compared with that of CONTROL and NHBD (1894+/-137 dynes s cm(-5) and 1268+/-111 dynes s cm(-5), respectively; p<0.05). Plateau airway pressure (Plateau AwP) was also higher in HBD (17+/-1cmH2O) compared with that of CONTROL (12+/-1 cmH2O; p<0.05) and NHBD (14+/-1 cmH2O; not significant). No significant differences were observed between HBD, CONTROL and NHBD in EVLW (79+/-1%, 79+/-0% and 78+/-1%, respectively), and in PO2/FiO2 (564+/-58 mmHg, 622+/-14 mmHg and 578+/-26 mmHg, respectively). CONCLUSIONS: These data indicate that 1-h warm ischemic lungs in our model are less susceptible to ischemia-reperfusion injury than lungs retrieved 5 h after brain death. This study further supports the use of lungs from NHBD for pulmonary transplantation.

Impact of warm ischemia on different leukocytes in bronchoalveolar lavage from mouse lung: possible new targets to condition the pulmonary graft from the non-heart-beating donor.

BACKGROUND: The use of non-heart-beating donors (NHBDs) for lung transplantation is a possible alternative for increasing the number of organs available. The warm ischemic period after circulatory arrest may contribute to a higher degree of primary graft dysfunction, resulting from ischemia-reperfusion injury (IRI). A better understanding of the role of inflammatory cells during the warm ischemic interval may be useful for developing new therapeutic strategies against IRI. METHODS: Mice were divided in 7 groups (n = 6/group). In 3 groups, ischemia was induced by clamping the hilum of the left lung for 30, 60 or 90 minutes (Groups [30I], [60I] or [90I], respectively). In 3 more groups, the lung was reperfused for 4 hours after identical ischemic intervals (Groups [30I+R], [60I+R] or [90I+R], respectively). Surgical impact was evaluated in a sham group ([sham]). Total and differential cell counts and interleukin-1beta (IL-1beta) protein levels in bronchoalveolar lavage (BAL) were determined and their correlations were investigated. RESULTS: Total cell, macrophage and lymphocyte numbers and IL-1beta protein levels increased progressively with longer ischemic intervals. A significant rise in BAL macrophages and lymphocytes was observed between [60I] and [90I] (p < 0.01 and p < 0.001, respectively). BAL neutrophils only increased after reperfusion with longer ischemic intervals. A positive correlation was found in the ischemic groups between IL-1beta levels and the number of macrophages (r = 0.62; p = 0.0012) and the number of lymphocytes (r = 0.68; p = 0.0002). A positive correlation was found in the reperfusion groups between IL-1beta levels and the number of neutrophils (r = 0.48; p = 0.044). CONCLUSIONS: This study demonstrates for the first time that BAL macrophages and lymphocytes increase significantly during warm ischemia and correlate with IL-1beta levels.

Nebulized N-acetyl cysteine protects the pulmonary graft inside the non-heart-beating donor.

BACKGROUND: The use of lungs from non-heart-beating donors (NHBD) might significantly alleviate the organ shortage. The tolerable warm ischemic period after cardiac arrest, however, is limited to approximately 1 hour. If the lung could be safely protected inside the cadaver, this time period may be prolonged. This would help to obtain family consent and to organize organ retrieval. METHODS: Pigs (30.8 +/- 0.6 kg) were killed, left untouched for 3 hours, and divided into 3 groups. Nebulized N-acetyl cysteine (NAC) (300 mg), a precursor of the antioxidant agent glutathione, was administered during 10 minutes before death in Group I (NAC-NHBD, n = 6) and 15 minutes after death in Group II (NHBD-NAC, n = 6). In the control group, no aerosol was administered (NHBD, n = 6). After a warm ischemic interval of 3 hours, both lungs in all groups were topically cooled for 1 hour. Thereafter, the left lung was prepared for evaluation in an isolated reperfusion circuit. Hemodynamic, aerodynamic, and oxygenation parameters were measured. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. The right lung was used to measure reduced glutathione (GSH) and oxidized glutathione (GSSG) levels (micromol/g) in lung homogenates and total protein levels in bronchial lavage fluid. RESULTS: Pulmonary vascular resistance, mean airway pressure, and W/D were significantly decreased in NAC-NHBD (1930 +/- 144 Dynes x sec x cm(-5), 14.2 +/- 0.5 cm H2O, and 7.4 +/- 0.4; p < 0.01, 0.01, and 0.05, respectively) and NHBD-NAC (1837 +/- 180 Dynes x sec x cm(-5), 13.3 +/- 1.2 cm H2O, and 7.3 +/- 0.3; p < 0.01, 0.05, and 0.05, respectively) when compared with the control group (5051 +/- 530 Dynes x sec x cm(-5), 17 +/- 0.4 cm H2O, 8.5 +/- 0.1, respectively). GSH/GSSG ratio was significantly higher and protein levels were significantly lower in NAC-NHBD (1.7 +/- 0.1 and 1315 +/- 60 microg/ml; p < 0.05 and 0.05, respectively) and NHBD-NAC (1.7 +/- 0.2 and 1475 +/- 159 microg/ml; p < 0.05 and 0.05, respectively) when compared with the control group (1.2 +/- 0.1 and 2150 +/- 200 microg/ml). CONCLUSIONS: Nebulized NAC administered before or shortly after death attenuates early ischemia reperfusion injury via upregulation of glutathione. NAC might be a promising tool to protect the pulmonary graft from both controlled and uncontrolled NHBD.

IL-1beta in bronchial lavage fluid is a non-invasive marker that predicts the viability of the pulmonary graft from the non-heart-beating donor.

BACKGROUND: Viability testing of the pulmonary graft retrieved from the non-heart-beating donor (NHBD) is mandatory for successful outcome after lung transplantation. Functional assessment by ex vivo reperfusion, however, remains a cumbersome procedure. In this study, therefore, we wanted to investigate the possible value of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) measured in bronchial lavage fluid (BLF) in predicting functional outcome of the pulmonary graft after reperfusion. METHODS: Domestic pigs (29.9 +/- 0.56 kg) were sacrificed and divided in 5 groups (n = 5/group). In the non-ischemic group (NHBD-0), the heart-lung block was explanted immediately. In the other groups the animals were left untouched with increasing time intervals (1 hour = NHBD-1; 2 hours = NHBD-2; 3 hours = NHBD-3). Thereafter both lungs were cooled topically via chest drains up to a total ischemic interval of 4 hours. Finally, in the heart-beating donor group lungs were flushed and stored for 4 hours (4 degrees C) [HBD]. BLF samples were taken from the right lung in all groups after explantation for measurement of IL-1beta and TNF-alpha and the left lung was prepared for evaluation in an isolated reperfusion circuit. Haemodynamic, aerodynamic and oxygenation parameters were measured. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. RESULTS: Graft function deteriorated with increasing time intervals after death. A strong correlation was found between the increase of IL-1beta concentration measured in BLF and the increase in pulmonary vascular resistance (r = 0.80), mean airway pressure (r = 0.74) and wet-to dry weight ratio (r = 0.78); (p < 0.0001, for all parameters). No significant differences in TNF-alpha levels in BLF were observed amongst groups (p = 0.933). CONCLUSIONS: IL-1beta in BLF prior to reperfusion correlated well with graft function and may therefore be a useful, non-invasive marker that can predict the viability of the pulmonary graft from the NHBD.

How long can we preserve the pulmonary graft inside the nonheart-beating donor?

BACKGROUND: The use of lungs from nonheart-beating donors (NHBD) might significantly alleviate the organ shortage. Extending the preharvest interval in NHBD would facilitate distant organ retrieval. We hypothesized that prolonged topical cooling inside NHBD after 60 minutes of initial warm ischemia would not affect the pulmonary graft. METHODS: Domestic pigs were anesthetized and divided into three groups (n = 6 in each group). In the control group (HBD), lungs were flushed, explanted, and further stored in low potassium dextran solution (4 degrees C) for 4 hours. In the two study groups pigs were sacrificed by myocardial fibrillation and left untouched for 1 hour. Chest drains were then inserted for topical lung cooling (6 degrees C) for 3 hours (NHBD-TC3) or 6 hours (NHBD-TC6). The left lung in all groups was then prepared for evaluation. In an isolated circuit lungs were ventilated and reperfused through the pulmonary artery. Hemodynamic, aerodynamic, and oxygenation variables were measured 35 minutes after onset of controlled reperfusion. Wet-to-dry weight ratio was calculated. RESULTS: No significant differences were observed among the three groups in pulmonary vascular resistance (p = 0.38), mean airway pressure (p = 0.39), oxygenation index (p = 0.62), and wet-to-dry weight ratio (p = 0.09). CONCLUSIONS: These data confirm that 1 hour of warm ischemia does not affect the pulmonary graft from NHBD compared with HBD. The preharvest interval can be safely extended up to 7 hours postmortem by additional topical cooling of the graft inside the cadaver. This technique may facilitate distant organ retrieval in NHBD.

Non-heart-beating donors.

The widespread application of lung transplantation is limited by the shortage of suitable donor organs resulting in longer waiting times for listed patients with a substantial risk of dying before transplantation. To overcome this critical organ shortage, some transplant programs have now begun to explore the use of lungs from circulation-arrested donors, so called non-heart-beating donors (NHBDs). This review outlines the different categories of NHBDs, the relevant published experimental data that support the use of lungs coming from these donors and the clinical experience worldwide so far. Techniques for NHBD lung preservation and pretransplant functional assessment are reviewed. Ethical issues involved in transplanting lungs from asystolic donors are discussed.

Long-term preservation with interim evaluation of lungs from a non-heart-beating donor after a warm ischemic interval of 90 minutes.

OBJECTIVE: To investigate the value of in situ preservation and ex vivo evaluation of lungs from a non-heart-beating donor (NHBD) prior to long-term cold storage. SUMMARY BACKGROUND DATA: The use of pulmonary grafts from NHBD might alleviate the organ shortage. However, viability testing of these grafts is mandatory to transplant only those lungs with excellent function. METHODS: Pigs were divided into two groups. In the control group, lungs were flushed, explanted, and stored for 4 hours (4 degrees C). In the study group, pigs were killed and left untouched for 90 minutes. Thereafter, the lungs were cooled for 150 minutes via chest drains. Graft function of the left lung in both groups was assessed in an isolated ventilation and reperfusion circuit 4 hours after death. The lung was then cooled and stored. Twenty-four hours after death, the pulmonary graft was reassessed in the same model. RESULTS: We did not observe a statistical significant difference between the two groups in pulmonary vascular resistance, mean airway pressure, and partial oxygen tension at each time point. There was also no statistical significant difference in wet-to-dry weight ratio. Finally, no statistical difference was found within both groups comparing the assessment at 24 hours with the interim evaluation at 4 hours. CONCLUSIONS: These data demonstrate that: 1) 90 minutes of warm ischemia and 150 minutes of intrapleural cooling do not affect pulmonary graft function; and 2) NHBD lungs can be safely preserved up to 24 hours. Finally, we have demonstrated that interim ex vivo evaluation of NHBD lungs is a valid and safe method to assess graft function.

Should we ventilate or cool the pulmonary graft inside the non-heart-beating donor?

BACKGROUND: The ideal preservation method during the warm ischemic period in the non-heart-beating donor (NHBD) remains unclear. In this study we compare the protective effect of ventilation vs cooling of the non-perfused pulmonary graft. METHODS: Domestic pigs (30.8 +/- 0.35 kg) were divided into 3 groups. In Group I, lungs were flushed with cold Perfadex solution, explanted and stored in saline (4 degrees C) for 4 hours (HBD, n = 5). Pigs in the 2 study groups were killed by myocardial fibrillation and left untouched for 1 hour. Lungs in Group II were ventilated (NHBD-V, n = 5) for 3 hours. Lungs in Group III were topically cooled (NHBD-TC, n = 5) in situ for 3 hours with saline (6 degrees C) infused via intra-pleural drains. Thereafter, the left lungs from all groups were prepared for evaluation. In an isolated circuit the left lungs were ventilated and reperfused via the pulmonary artery (PA) with autologous, hemodiluted, deoxygenated blood. Hemodynamic, aerodynamic and oxygenation parameters were measured at 37.5 degrees C and a PA pressure of 20 mm Hg. The wet:dry weight ratio (W/D) was calculated after reperfusion. RESULTS: Pulmonary vascular resistance, oxygenation index and W/D weight ratio were significantly worse in NHBD-V (3,774 +/- 629 dyn sec cm(-5), 3.43 +/- 0.5, 6.98 +/- 0.42, respectively) compared with NHBD-TC (1,334 +/- 140 dyn sec cm(-5), 2.47 +/- 0.14, 5.72 +/- 0.24, respectively; p < 0.01, p < 0.05 and p < 0.05, respectively) and HBD (1,130 +/- 91 dyn sec cm(-5), 2.25 +/- 0.09, 5.23 +/- 0.49, respectively; p < 0.01, p < 0.01 and p < 0.05, respectively groups). No significant differences were observed, however, in any of these parameters between NHBD-TC and HBD (p = 0.46, p = 0.35 and p = 0.12, respectively). CONCLUSION: These results indicate that cooling of the pulmonary graft inside the cadaver is the preferred method in an NHBD protocol. It is also confirmed that 1 hour of warm ischemia does not diminish graft function upon reperfusion.

The role of leukocyte depletion in ex vivo evaluation of pulmonary grafts from (non-)heart-beating donors.

If lungs could be retrieved for transplantation after circulatory arrest, the shortage of donors might be significantly alleviated. An important issue in using lungs from these so-called non-heart-beating donors is the development of a technique to assess their quality prior to transplantation without jeopardizing the life of the recipient. In our laboratory we tested the reliability of an ex vivo model for such an evaluation. We used pig lungs from optimal control animals, in casu heart-beating donors. This model enabled us to preserve and evaluate lungs with perfect function up to 24 hours after death. The intermediate assessment is performed in an isolated circuit where the lungs are being ventilated and reperfused via the pulmonary artery (PA) with autologous and haemodiluted blood. Haemodynamic, aerodynamic and oxygenation parameters are measured at 37.5 degrees C and a maximum PA pressure of 20 mmHg. These data were correlated with premortem values. During this ex vivo evaluation, leukocyte depletion plays an important role since neutrophils have been recognized as critical components in the inflammatory cascade, which is responsible for graft dysfunction soon and long after transplantation.