Restrictive allograft dysfunction rather than bronchiolitis obliterans syndrome had a major impact on the overall survival after living-donor lobar lung transplantation.

PURPOSE: Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). METHODS: We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. RESULTS: Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CONCLUSIONS: CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restriction on PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

Elderly lung transplant recipients show acceptable long-term outcomes for lung transplantation: A propensity score-matched analysis.

PURPOSE: Although the performance lung transplantation (LTx) in the elderly (≥ 60 years) has increased globally, the situation in Japan remains quite different, because the age limit at registration for cadaveric transplantation is 60 years. We investigated the long-term outcomes of LTx in the elderly in Japan. METHODS: This was a single-center retrospective study. We divided the patients into two groups according to age: the younger group (< 60 years; Y group; n = 194) and the elderly group (≥ 60 years; E group; n = 10). We performed three-to-one propensity score matching to compare the long-term survival between the E and Y groups. RESULTS: In the E group, the survival rate was significantly worse (p = 0.003), and single-LTx was more frequent (p = 0.036). There was a significant difference in the indications for LTx between the two groups (p < 0.001). The 5-year survival rate after single-LTx in the E group was significantly lower than that in the Y group (p = 0.006). After propensity score matching, the 5-year survival rates of the two groups were comparable (p = 0.55). However, the 5-year survival rate after single-LTx in the E group was significantly lower than that in the Y group (p = 0.007). CONCLUSION: Elderly patients showed acceptable long-term survival after LTx.

Effect of preoperative long-term use of corticosteroids on the development of post-transplant lymphoproliferative disorders after lung transplantation: a single-center experience in Japan.

PURPOSE: Post-transplant lymphoproliferative disorder (PTLD) is a major complication of lung transplantation (LTx). However, few studies on PTLD in Asian populations have been reported. We explored the characteristics of Japanese PTLD cases after LTx. METHODS: We retrospectively reviewed 195 cases of LTx at our institute. We summarized the clinical experiences of 7 PTLD cases and analyzed the patient characteristics and survival outcomes of patients with (n = 7) and without (n = 188) PTLD. RESULTS: All PTLD patients were taking corticosteroids preoperatively (p = 0.0030), and the duration of preoperative corticosteroid therapy was significantly longer in the PTLD group (p = 0.0064) than in the non-PTLD group. The overall survival after LTx was significantly worse in the PTLD group (p = 0.027) than in the non-PLTD group. Among the three patients who died within 1 year after the PTLD onset, two died of opportunistic infections without residual PTLD lesions. Chronic lung allograft dysfunction (CLAD) or bronchiolitis obliterans at an autopsy were diagnosed after PTLD treatment in four cases. CONCLUSIONS: Long-term preoperative corticosteroid therapy may be a risk factor for PTLD after LTx. Opportunistic infections are lethal complications of PTLD, regardless of the effectiveness of PTLD treatment. CLAD occurs at a high rate after PTLD treatment, and close monitoring is required.

Emphysematous changes and lower levels of plasma irisin are associated with bronchiolitis obliterans syndrome after bilateral living-donor lobar lung transplantation.

PURPOSE: Decreased irisin levels may be associated with the development of emphysema. Similarly, emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT). We investigated the severity of emphysematous changes and the relationship between irisin levels and CLAD after bilateral LDLLT and cadaveric lung transplantation (CLT). METHODS: The subjects of this retrospective study were 59 recipients of bilateral LDLLT (n = 31) or CLT (n = 28), divided into a non-CLAD group (n = 41), a LDLLT-CLAD group (n = 11), and a CLT-CLAD group (n = 7). We compared the severity of emphysematous changes, the skeletal muscle mass, and the plasma irisin levels among the groups. RESULTS: The emphysematous changes were significantly more severe in the LDLLT-CLAD and CLT-CLAD groups (p = 0.046 and 0.036), especially in patients with bronchiolitis obliterans syndrome (BOS), than in the non-CLAD group. Although the skeletal muscle mass was similar in all the groups, the plasma irisin levels were significantly lower in the LDLLT-CLAD group (p = 0.022), especially in the patients with BOS after LDLLT, than in the non-CLAD group. CONCLUSION: Emphysematous changes and lower levels of plasma irisin were associated with CLAD, especially in patients with BOS, after bilateral LDLLT.

Paediatric lung transplantation: the impact of age on the survival.

OBJECTIVES: We herein review the outcomes of paediatric lung transplantation (LTx) and analyse subgroups divided by age. METHODS: We retrospectively reviewed 43 consecutive paediatric LTx recipients (< 18 years old: cadaveric LTx [n = 9], living-donor lobar LTx [n = 34]). We also analysed subgroups of patients 1-6 years old (n = 10) and 7-17 years old (n = 33). RESULTS: The 1-, 5- and 10-year overall survival (OS) rates in paediatric recipients were 93%, 82% and 67%, respectively. The 1-, 5- and 10-year graft dysfunction (GD)-free survival rates in paediatric recipients were 85%, 59% and 31%, respectively. The 1- and 5-year OS in the 1- to 6-year-old vs. 7- to 17-year-old groups were 70% vs. 100% and 48% vs. 93%, respectively (p < 0.0001). The 1- and 5-year GD-free survival rates in the 1- to 6-year-old vs. 7- to 17-year-old groups were 60% vs. 93% and 24% vs. 69%, respectively (p = 0.024). The 1- to 6-year-old group showed higher rates of non-standard LTx (p = 0.0001), interstitial pneumonia (p = 0.004) and ventilator dependency (p = 0.007) than the 7- to 17-year-old group. CONCLUSION: Paediatric recipients under 7 years old seemed to have a higher risk of mortality and GD than those 7 years old and older.

A Simple Prognostic Benefit Scoring System for Sarcoma Patients with Pulmonary Metastases: Sarcoma Lung Metastasis Score.

BACKGROUND: Pulmonary metastasectomy could be considered one of the treatment options for disease control in sarcoma patients with pulmonary metastases; however, there is little consensus regarding the suitable criteria for predicting the likely outcomes in these patients. The aim of this study was to establish a prognostic benefit scoring system based on preoperatively examined prognostic factors for sarcoma patients with pulmonary metastases. METHODS: This was a single-center, retrospective cohort study conducted in a cohort of 135 sarcoma patients who underwent a first pulmonary metastasectomy at Okayama University Hospital between January 2006 and December 2015. Based on the results of a multivariable logistic regression analysis performed to determine the factors influencing 3-year mortality, a Sarcoma Lung Metastasis Score was created and its correlation with 3-year survival was analyzed. RESULTS: The results of the multivariate analysis revealed significant differences in the disease-free interval (< 2 years vs. ≥ 2 years; odds ratio (OR) 4.22, 95% confidence interval (CI) 1.67-10.70), maximum tumor diameter (≥ 15 mm vs. < 15 mm; OR 3.86, 95% CI 1.75-8.52), and number of pulmonary metastases (≥ 6 vs. < 6; OR 2.65, 95% CI 1.06-6.620). The Sarcoma Lung Metastasis Score, which was defined as the total score of these three factors, reliably predicted 3-year survival (score: 0, 89.5%; 1, 63.2%; 2, 39.0%; 3, 10.5%). CONCLUSIONS: Our newly proposed simple Sarcoma Lung Metastasis Score appears to be a useful prognostic predictor for sarcoma patients with pulmonary metastases, in that it could be helpful for the selection of appropriate treatments for these patients.

The prognostic nutritional index is correlated negatively with the lung allocation score and predicts survival after both cadaveric and living-donor lobar lung transplantation.

PURPOSE: The prognostic nutritional index (PNI), calculated based on the serum albumin levels and the total lymphocyte count, has been identified as a predictor of clinical outcomes in various fields of surgery. In this study, we investigated the relationship between the PNI and the lung allocation score (LAS) as well as the impact of the PNI on the outcomes of both cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: We reviewed retrospective data for 127 recipients of lung transplantation (LT), including 71 recipients of CLT and 56 recipients of LDLLT. RESULTS: The PNI was correlated significantly and negatively with the LAS (r = - 0.40, P = 0.0000037). Multivariate analysis revealed that age (P = 0.00093), BMI (P = 0.00087), and PNI (P = 0.0046) were independent prognostic factors of a worse outcome after LT. In a subgroup analysis, survival after both CLT (P = 0.015) and LDLLT (P = 0.041) was significantly worse in the low PNI group than in the high PNI group. CONCLUSION: Preoperative nutritional evaluations using the PNI can assist with the assessment of disease severity in LT recipients and may predict survival after both CLT and LDLLT.

The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas.

PURPOSE: Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. METHODS: The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan-Meier method and prognostic factors were evaluated by multivariate analysis. RESULTS: Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. CONCLUSION: The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy.

Right single lung transplantation using an inverted left donor lung: interposition of pericardial conduit for pulmonary venous anastomosis - a case report.

BACKGROUND: Lung transplantation (LTx) is still limited by the shortage of suitable donor lungs. Developing flexible surgical procedures can help to increase the chances of LTx by unfolding recipient-to-donor matching options based on the pre-existing organ allocation concept. We report a case in which a successful left-to-right inverted LTx was completed using the interposition of a pericardial conduit for pulmonary venous anastomosis. CASE PRESENTATION: A left lung graft was offered to a 59-year-old male who had idiopathic pulmonary fibrosis with predominant damage in the right lung. He had been prescribed bed rest with constant oxygen inhalation through an oxymizer pendant and had been on the waiting list for 20 months. Considering the condition of the patient (LAS 34.3) and the scarcity of domestic organ offers, the patient was highly likely to be incapable of tolerating any additional waiting time for another donor organ if he was unable to accept the presently reported offer of a left lung. Eventually, we decided to transplant the left donor lung into the right thorax of the recipient. Because of the anterior-posterior position gap of the hilar structures, the cuff lengths of the pulmonary veins had to be adjusted. The patient did not develop any anastomotic complications after the transplantation. CONCLUSIONS: A left-to-right inverted LTx is technically feasible using an autologous pericardial conduit for pulmonary venous anastomosis in selected cases. This technique provides the potential benefit of resolving challenging situations in which surgeons must deal with a patient's urgency and the logistical limitations of organ allocation.

Impact of chronic lung allograft dysfunction, especially restrictive allograft syndrome, on the survival after living-donor lobar lung transplantation compared with cadaveric lung transplantation in adults: a single-center experience.

PURPOSE: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT. METHODS: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT. RESULTS: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083). CONCLUSION: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

A single-nucleotide polymorphism in a gene modulating glucocorticoid sensitivity is associated with the decline in total lung capacity after lung transplantation.

PURPOSE: Glucocorticoids are used to prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). Our study was aimed at assessing the association between the glucocorticoid-induced transcript 1 gene (GLCCI1) variant, which modulates glucocorticoid sensitivity, and the postoperative lung function and development of CLAD after LT. METHODS: A total of 71 recipients of LT were genotyped for the GLCCI1 variant (rs37972) and divided into three groups: the homozygous mutant allele (TT) group, the heterozygous mutant allele (CT) group, and the wild-type allele (CC) group. The results of pulmonary function tests were compared with the postoperative baseline values. RESULTS: The total lung capacity (TLC) in the TT group was significantly lower than that in the CC group at 3 years after LT (P = 0.029). In the recipients of cadaveric LT, the TLC and forced expiratory volume in 1 s in the TT group were significantly lower than those in the CC groups, resulting in a significant worse CLAD-free survival at 3 years after LT (P = 0.016). CONCLUSION: The GLCCI1 variant was associated with a significant decrease of the TLC at 3 years after LT and the development of CLAD at 3 years, especially in patients undergoing cadaveric LT.

[The role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) in liposarcoma of the chest wall].

18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT)imaging is valuable in biopsy guidance, response assessment, grading, follow-up and prognostication for soft-tissue sarcoma. In liposarcoma, the maximum standardized uptake value (SUVmax) on PET/CT scan is correlated with the histological subtypes. We briefly review the role of FDG PET/CT in liposarcoma, and describe a case of chest wall liposarcoma treated based on the assessment with PET/CT. A 76-year-old man, with a 10-cm tumor at the thoracic outlet of the right chest wall, underwent the complete resection of the tumor according to the assessment with PET/CT that showed high FDG uptakeonly in the central area of the tumor with SUVmax of 5.89, but low uptake in the peripheral area. In accordance with the PET/CT findings, pathological examination revealed dedifferentiated liposarcoma in the central area and well-differentiated liposarcoma in the peripheral area. Pretherapy PET/CT should be performed for the appropriate treatment of liposarcoma.

In vivo lung perfusion for prompt recovery from primary graft dysfunction after lung transplantation.

BACKGROUND: No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here, we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP vs conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. METHODS: After 1.5-hour warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into 3 groups (n = 5 each): control (no intervention), ECMO, and IVLP. After 2 hours of treatment, a 4-hour functional assessment was conducted, and samples were obtained. RESULTS: Significantly better oxygenation was achieved in the IVLP group (p ≤ 0.001). Recovery was confirmed immediately and maintained during the following 4-hour observation. The IVLP group also demonstrated better lung compliance than the control group (p = 0.045). A histologic evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. CONCLUSIONS: A 2-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management.

CRISPR-Cas Genome Editing in Ex Vivo Human Lungs to Rewire the Translational Path of Genome-Targeting Therapeutics.

The ongoing advancements in CRISPR-Cas technologies can significantly accelerate the preclinical development of both in vivo and ex vivo organ genome-editing therapeutics. One of the promising applications is to genetically modify donor organs prior to implantation. The implantation of optimized donor organs with long-lasting immunomodulatory capacity holds promise for reducing the need for lifelong potent whole-body immunosuppression in recipients. However, assessing genome-targeting interventions in a clinically relevant manner prior to clinical trials remains a major challenge owing to the limited modalities available. This study introduces a novel platform for testing genome editing in human lungs ex vivo, effectively simulating preimplantation genetic engineering of donor organs. We identified gene regulatory elements whose disruption via Cas nucleases led to the upregulation of the immunomodulatory gene interleukin 10 (IL-10). We combined this approach with adenoviral vector-mediated IL-10 delivery to create favorable kinetics for early (immediate postimplantation) graft immunomodulation. Using ex vivo organ machine perfusion and precision-cut tissue slice technology, we demonstrated the feasibility of evaluating CRISPR genome editing in human lungs. To overcome the assessment limitations in ex vivo perfused human organs, we conducted an in vivo rodent study and demonstrated both early gene induction and sustained editing of the lung. Collectively, our findings lay the groundwork for a first-in-human-organ study to overcome the current translational barriers of genome-targeting therapeutics.

The impact of prognostic nutrition index on the waitlist mortality of lung transplantation.

OBJECTIVE: The prognostic nutrition index (PNI), calculated using serum albumin and total lymphocyte count, is a recent topical index related to inflammation. Preoperative PNI is regarded as a new preoperative prognostic score in lung transplantation (LTx). This study aimed to investigate the impact of PNI at the time of registration as a prognostic parameter of mortality on the waiting list for LTx. METHODS: A retrospective review was conducted on the data of 132 adult patients registered for LTx in our department between January 2013 and June 2020. Patients who finally received LTx were analyzed as censored data. The overall survival was evaluated using the Kaplan-Meier method for pre-registered clinical factors including the PNI at the time of registration. Overall survival was calculated from the date of listing to the Japan Organ Transplant Network to the date of death. RESULTS: The low-PNI group had a significantly worse prognosis. Multivariate analysis demonstrated that age (p = 0.023), idiopathic interstitial pneumonia (p < 0.001), lung allocation score (LAS) (p < 0.001), and PNI (p < 0.001) were independent prognostic factors for waitlist mortality. CONCLUSIONS: PNI at the time of registration can be an independent prognostic parameter in registered candidates for LTx.

Diagnostic value of circulating microRNA-21 in chronic lung allograft dysfunction after bilateral cadaveric and living-donor lobar lung transplantation.

Background: MicroRNAs (miRNAs) involved in the pathogenesis of pulmonary fibrosis have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). We investigated the role of circulating miRNAs in the diagnosis of CLAD after bilateral LT, including cadaveric LT (CLT) and living-donor lobar LT (LDLLT). Methods: The subjects of this retrospective study were 37 recipients of bilateral CLT (n = 23) and LDLLT (n = 14), and they were divided into a non-CLAD group (n = 24) and a CLAD group (n = 13). The plasma miRNA levels of the two groups were compared, and correlations between their miRNAs levels and percent baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) values were calculated from one year before to one year after the diagnosis of CLAD. Results: The plasma levels of both miR-21 and miR-155 at the time of the diagnosis of CLAD were significantly higher in the CLAD group than in the non-CLAD group (miR-21, P = 0.0013; miR-155, P = 0.042). The miR-21 levels were significantly correlated with the percent baseline FEV1, FVC, and TLC value of one year before and at the time of diagnosis of CLAD (P < 0.05). A receiver operating characteristic curve analysis of the performance of miR-21 levels in the diagnosis of CLAD yielded an area under the curve of 0.89. Conclusion: Circulating miR-21 appears to be of potential value in diagnosing CLAD after bilateral LT.

Identification of genetic loci associated with renal dysfunction after lung transplantation using an ethnic-specific single-nucleotide polymorphism array.

Renal dysfunction is a long-term complication associated with an increased mortality after lung transplantation (LT). We investigated the association of single-nucleotide polymorphisms (SNPs) with the development of renal dysfunction after LT using a Japanese-specific SNP array. First, eligible samples of 34 LT recipients were genotyped using the SNP array and divided into two groups, according to the presence of homozygous and heterozygous combinations of mutant alleles of the 162 renal-related SNPs. To identify candidate SNPs, the renal function tests were compared between the two groups for each SNP. Next, we investigated the association between the candidate SNPs and the time course of changes of the estimated glomerular filtration rate (eGFR) in the 99 recipients until 10 years after the LT. ΔeGFR was defined as the difference between the postoperative and preoperative eGFR values. Eight SNPs were identified as the candidate SNPs in the 34 recipients. Validation analysis of these 8 candidate SNPs in all the 99 recipients showed that three SNPs, namely, rs10277115, rs4690095, and rs792064, were associated with significant changes of the ΔeGFR. Pre-transplant identification of high-risk patients for the development of renal dysfunction after LT based on the presence of these SNPs might contribute to providing personalized medicine.

Lung Transplantation for Bronchiectasis Due to Hyperimmunoglobulin E Syndrome.

Hyperimmunoglobulin E syndrome (HIES) is one of the primary immunodeficiencies characterized by recurrent staphylococcal skin and lung infections that result in lung destruction and critically diminished pulmonary function. Despite the lack of definitive treatment, there have been no reports of successful lung transplantation for HIES patients. We report the case of a 42-year-old woman with HIES with progressive bronchiectasis whose pulmonary infection was controlled before transplantation, and subsequent lung transplantation was uneventful. Lung transplantation may be feasible in HIES if the patient is immunologically stable preoperatively and perioperative infections, especially Aspergillus infections, are well controlled.