Ischemia-reperfusion (I/R)-induced lung injury undermines lung transplantation (LTx) outcomes by predisposing lung grafts to primary graft dysfunction (PGD). Necrosis is a feature of I/R lung injury. ...However, regulated necrosis (RN) with specific signaling pathways has not been explored in an LTx setting. In this study, we investigated the role of RN in I/R-induced lung injury. To study I/R-induced cell death, we simulated an LTx procedure using our cell culture model with human lung epithelial (BEAS-2B) cells. After 18 h of cold ischemic time (CIT) followed by reperfusion, caspase-independent cell death, mitochondrial reactive oxygen species production, and mitochondrial membrane permeability were significantly increased. N-acetyl-Leu-Leu-norleucinal (ALLN) (calpain inhibitor) or necrostatin-1 (Nec-1) receptor interacting serine/threonine kinase 1 (RIPK1) inhibitor reduced these changes. ALLN altered RIPK1/RIPK3 expression and mixed lineage kinase domain-like (MLKL) phosphorylation, whereas Nec-1 did not change calpain/calpastatin expression. Furthermore, signal transducer and activator of transcription 3 (STAT3) was demonstrated to be downstream of calpain and regulate RIPK3 expression and MLKL phosphorylation during I/R. This calpain-STAT3-RIPK axis induces endoplasmic reticulum stress and mitochondrial calcium dysregulation. LTx patients' samples demonstrate that RIPK1, MLKL, and STAT3 mRNA expression increased from CIT to reperfusion. Moreover, the expressions of the key proteins are higher in PGD samples than in non-PGD samples. Cell death associated with prolonged lung preservation is mediated by the calpain-STAT3-RIPK axis. Inhibition of RIPK and/or calpain pathways could be an effective therapy in LTx.
A 60-year-old previously healthy man was admitted to hospital with COVID-19 pneumonia that was treated initially with noninvasive ventilation, steroids and antibiotics. Six weeks after admission, the ...patient remained dependent on oxygen, using a high-flow nasal cannula combined with a nonrebreather mask. Physical examination found proximal muscle wasting due to the long hospital stay. Computed tomography of his chest showed bilateral dense consolidations with superimposed interstitial and fibrotic changes. Because we thought the fibrosis was unlikely to resolve, we discussed the option of lung transplantation with him and his family, both of whom were interested in the procedure. An acute clinical deterioration subsequently led to his intubation, transfer to our extracorporeal life support centre and placement on veno-venous extracorporeal membrane oxygenation (V-V ECMO) as a bridge to transplantation. Seventeen days after ECMO cannulation, the patient underwent successful double lung transplantation with removal of the V-V ECMO immediately after transplant.
Extracorporeal life support (ECLS) is increasingly used to bridge deteriorating patients awaiting lung transplantation (LTx), however, few systematic descriptions of this practice exist. We therefore ...aimed to review our institutional experience over the past 10 years.
In this case series, we included all adults who received ECLS with the intent to bridge to LTx. Data were retrieved from patient charts and our institutional ECLS and transplant databases.
Between January 2006 and September 2016, 1111 LTx were performed in our institution. ECLS was used in 71 adults with the intention to bridge to LTx; of these, 11 (16%) were bridged to retransplantation. The median duration of ECLS before LTx was 10 days (range, 0-95). We used a single dual-lumen venous cannula in 23 patients (32%). Nine of 13 patients (69%) with pulmonary hypertension were bridged by central pulmonary artery to left atrium Novalung. Twenty-five patients (35%) were extubated while on ECLS and 26 patients (37%) were mobilized. Sixty-three patients (89%) survived to LTx. Survival by intention to treat was 66% (1 year), 58% (3 years) and 48% (5 years). Survival was significantly shorter in patients undergoing ECLS bridge to retransplantation compared with first LTx (median survival, 15 months (95% CI, 0-31) versus 60 months (95% CI, 37-83); P = .041).
In our center experience, ECLS bridge to first lung transplant leads to good short-term and long-term outcomes in carefully selected patients. In contrast, our data suggest that ECLS as a bridge to retransplantation should be used with caution.
The objective of this study was to review the international experience in lung transplantation using lung donation after circulatory death (DCD).
In this retrospective study, data from the ...International Society for Heart and Lung Transplantation (ISHLT) DCD Registry were analyzed. The study cohort included DCD lung transplants performed between January 2003 and June 2013, and reported to the ISHLT DCD Registry as of April 2014. The participating institutions included 10 centers in North America, Europe and Australia. The control group was a cohort of lung recipients transplanted using brain-dead donors (DBDs) during the same study period. The primary end-point was survival after lung transplantation.
There were 306 transplants performed using DCD donors and 3,992 transplants using DBD donors during the study period. Of the DCD transplants, 94.8% were Maastricht Category III, whereas 4% were Category IV and 1.2% Category V (euthanasia). Heparin was given in 54% of the cases, donor extubation occurred in 90% of the cases, and normothermic ex vivo lung perfusion (EVLP) was used in 12%. The median time from withdrawal of life support therapy (WLST) to cardiac arrest was 15 minutes (5th to 95th percentiles of 5 to 55 minutes), and from WLST to cold flush was 33 minutes (5th to 95th percentiles of 19.5 to 79.5 minutes). Recipient age and medical diagnosis were similar in DCD and DBD groups (p = not significant NS). Median hospital length of stay was 18 days in DCD lung transplants and 16 days in DBD transplants (p = 0.016). Thirty-day survival was 96% in the DCD group and 97% in the DBD group. One-year survival was 89% in the DCD group and 88% in the DBD group (p = NS). Five-year survival was 61% in both groups (p = NS). The mechanism of donor death within the DCD group seemed to influence recipient early survival. The survival rates through 30 days were significantly different by donor mechanism of death (p = 0.0152). There was no significant correlation between the interval of WLST to pulmonary flush with survival (p = 0.11).
This large study of international, multi-center experience demonstrates excellent survival after lung transplantation using DCD donors. It should be further evaluated whether the mechanism of donor death influences survival after DCD transplant.
Abstract Objective(s) Localization and resection of non-visible, non-palpable pulmonary nodules during video-assisted thoracoscopic surgery (VATS) is challenging. Our study was to determine the ...feasibility and safety of indocyanine green (ICG) fluorescence localization and resection of small nodules using a near-infrared (NIR) fluorescence thoracoscope. Methods Twenty patients with undiagnosed peripheral nodules smaller than 3cm scheduled for CT-guided microcoil placement followed by VATS wedge resection were enrolled. After microcoil deployment, 100-150 μl of diluted ICG was injected percutaneously near the nodule. The nodule was initially localized solely by using the NIR thoracoscope to visualize ICG fluorescence. Thoracoscopic instruments were used to determine the staple line. Wedge resection was performed after confirmation of the location of the microcoil using fluoroscopy. Results Twenty patients underwent NIR image-guided VATS resection. The median CT tumor size was 1.2 cm. The median depth from the pleural surface was 1.4 cm (range: 0.2-4.8). The median CT-guided intervention time was 35 min and VATS procedural time was 54 min. ICG fluorescence was clearly identified in 18 of 20 cases (90%). The surgical margins were all negative on final pathology without the need of additional resection. The final diagnoses included 18 primary lung cancer, 1 metastatic lung cancer, and 1 benign lung tumor. Conclusions CT-guided percutaneous ICG injection and intraoperative NIR localization of small nodules is safe and feasible. It offers surgeons the ease of localization through direct ICG fluorescence imaging without the use of fluoroscopy and may be a complementary technique to preoperative microcoil placement for non-visible, non-palpable intrapulmonary nodules.
Objective To determine the response rate, toxicity, and rate of complete resection after induction chemoradiotherapy for locally advanced thymic tumors, which were defined by specific radiographic ...criteria. Methods A single-arm, pilot trial was conducted at 4 institutions. Patients with thymoma or thymic carcinoma who met specific criteria on computed tomography were accrued. Induction therapy consisted of 2 cycles of cisplatin and etoposide combined with 45 Gy of thoracic radiotherapy. Patients underwent computed tomography and positron emission tomography before and after induction therapy and then resection was attempted. Postoperative chemoradiotherapy was administered in selected patients. The primary endpoint was the pathologic response to induction therapy. The secondary endpoints were toxicity, surgical complications, radiographic response, and the rate of R0 resection. Results A total of 22 patients were accrued during a 5-year period (1 patient withdrew before starting induction therapy). Of the 22 patients, 21 completed induction therapy, and 9 (41%) experienced grade 3 or 4 toxicity. A total of 10 patients had a partial radiographic response and 11 had stable disease. Of the 21 patients, 17 (77%) underwent an R0 resection, 3 (14%) an R1 resection, and 1 (5%) underwent debulking. Eight patients sustained surgical complications (36%), and two patients (9%) died postoperatively. Of the 21 patients, 13 (62%) had either thymic carcinoma or B3 thymoma and 15 (71%) had either Masaoka stage III or IV disease. No patient had a complete pathologic response, but 5 specimens (24%) had <10% viable tumor. Conclusions The present induction chemoradiotherapy protocol, which used specific computed tomography inclusion criteria to successfully select locally advanced thymic tumors, appeared to be tolerable and resulted in a high rate of complete surgical resection.
Many donor lungs do not meet current criteria for transplantation. In this study, ex vivo lung perfusion and ventilation allowed the successful transplantation of lungs that might otherwise have been ...considered unsuitable as transplants.
Lung transplantation is lifesaving for patients with end-stage lung diseases. However, the number of patients waiting for a lung transplant greatly exceeds the number of available donors. On average, only 15% of lungs from multiorgan donors are used for transplantation
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; the rest are considered unsuitable owing to the lung injury that occurs after brain death and to complications associated with treatment in the intensive care unit (ICU) (e.g., barotrauma and pulmonary edema). Although nonstandard donor lungs (i.e., lungs with suboptimal gas-exchange function or infiltrates visible on chest radiographs)
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have been used successfully,
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,
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increased primary graft dysfunction — an . . .
Ex-vivo lung perfusion (EVLP) can be used to extend overall lung preservation time by splitting one long cold ischaemic time into two shorter ones and interposing an additional EVLP time. We assessed ...the outcomes after clinical transplantation of lungs with more than 12 h of preservation time.
For this retrospective study, we searched the Toronto Lung Transplant Program database for patients who had received at least one lung transplant between Jan 1, 2006, and April 30, 2015, at a single hospital in Toronto, Canada. We split the identified patients into those with a total preservation time of more than 12 h and those with a total preservation time of less than 12 h to act as the control group. Total preservation time was defined as the sum of first cold ischaemic time, EVLP time, and second cold ischaemic time. We excluded patients if they had received a heart-lung transplant or were younger than 18 years. In bilateral lung transplantations, we used the longer preservation time of the two lungs for analysis. Lung preservation was done according to present standards of care and EVLP was done according to the Toronto EVLP technique. The primary outcomes were survival and International Society for Heart and Lung Transplantation Primary Graft Dysfunction (PGD) grade at 72 h post-transplantation. We compared outcomes with our control group using univariable and multivariable models.
We identified 906 patients who met eligibility criteria and had sufficient data for analysis (<12 h group n=809; mean lung preservation time 400·8 min SD 121·8 vs >12 h group n=97; 875·7 min 109·0). Median hospital and intensive-care unit length of stay were similar between the less than 12 h group and the more than 12 h group (hospital stay: 23 days 16-42 vs 25·5 days 17-50·25, p=0·60; intensive-care unit stay: 4 days 2-14 vs 4 days 2-16, p=0·53). PGD grade was also not different between the two groups at 72 h post-transplantation (p=0·85). There was also no difference in survival between the two groups as shown on Kaplan-Meier survival curves (p=0·61). Multivariable survival analysis using Cox's model showed increasing recipient age to be a significant variable affecting survival.
Extension of graft preservation time beyond 12 h with EVLP does not negatively affect early lung transplantation outcomes. Extension of clinical lung preservation times might allow for more transplantations to be done as a result of improved facilitation and increased flexibility around timing of lung transplantation operations.
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