Allograft dysfunction after lung transplantation for COPA syndrome: A case report and literature review.

Coatomer subunit alpha (COPA) syndrome is an autoinflammatory disease with autoimmune and autoinflammatory manifestations affecting lungs, joints, and kidneys. COPA syndrome is caused by heterozygous loss-of-function mutations in COPA gene, encoding α subunit of coatmer protein complex I (COP-I) coated vesicles. Mutant COPA induces constitutive activation of stimulator of interferon genes, leading to systemic inflammation and elevated type I interferon response. We have previously reported a Japanese family of COPA syndrome with a novel V242G mutation. Two out of four patients required lung transplantation due to intractable interstitial lung disease and respiratory failure. Both of them deceased after lung transplantation, one due to sepsis and the other due to allograft dysfunction possibly caused by the reccurent interstitial lung disease. The literature review indentified unfavorable outcome of the solid organ transplant in COPA syndrome and its related disease, however, precise clinico-pathological description of these cases has been scarce. Here, we report in detail the clinical course of our cases to clarify the pathophysiology of allograft dysfunction in COPA syndrome and propose potential therapeutic approaches to improve post-transplant graft survival.

Lung Autotransplantation for Bulky Superior Sulcus Tumor With Hilar Involvement.

Lung autotransplantation with ex vivo bench surgery is a useful surgical technique for centrally located and locally advanced lung cancer to spare lung parenchyma by avoiding pneumonectomy. Here, we present a patient with a bulky superior sulcus tumor with hilar involvement for which lung-sparing complete resection was achieved with autotransplantation. After concurrent chemoradiotherapy, en bloc resection, consisting left pneumonectomy combined with apical chest wall resection (1-4 ribs), back-table extended double-sleeve resection after lung preservation, and reimplantation of basal segment was performed. The postoperative course was uneventful, and the patient is alive without tumor recurrence at 18 months after surgery.

Characterization of localized macrophages in bronchiolitis obliterans after allogeneic hematopoietic cell transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains one of the most devastating manifestations of chronic graft-versus-host disease in hematopoietic cell transplantation (HCT). Recent findings of BOS after lung transplantation indicate that donor (lung)-derived lung-resident macrophages contribute to BOS, suggesting that differences in the origin of immune cells and localized antigen-presenting cells cause the onset of BOS. METHODS: We identified the phenotype and origin of infiltrating macrophages using immunohistochemistry and fluorescence in situ hybridization in eight sex-mismatched HCT recipients who underwent lung transplantation for BOS after HCT. RESULTS: Most of the infiltrating macrophages appeared to be derived from donor (hematopoietic) cells in patients who developed BOS following HCT. Macrophages observed in the early-stage region of BOS were positive for cluster of differentiation (CD)68 and inducible nitric oxide synthase (iNOS) and negative for CD163 and CD206, suggesting an M1 phenotype. In the late-stage region, macrophages were negative for CD68 and iNOS in all patients, but also positive for CD163 and CD206 in some patients. CONCLUSIONS: Donor-derived M1-macrophages may be involved in the pathogenesis of the early-stage region of BOS. In addition, some macrophages in the late-stage region showed M2 polarization that might be involved in fibrosis.

"Hybrid Lung Transplantation" Combining Living Donor and Cadaveric Lung Transplants: Report of 2 Cases.

We present 2 cases of "hybrid lung transplant," which included sequentially implanting a living lobar graft to 1 side and a cadaveric graft to the other side. This procedure was approved by the institutional review board at Okayama University Hospital. The 2 recipients were diagnosed with severe idiopathic pulmonary fibrosis, and living donor lobar lung transplant was considered; however, 2 appropriate donors were not available. Therefore, we accepted extended criteria donor lungs with a partial pressure of oxygen/fraction of inspired oxygen ratio of <251 mm Hg. However, 1 of the 2 patients developed grade 2 primary graft dysfunction. The living donor lobar lung had a low volume but was in good condition, which contributed to the patient's recovery after primary graft dysfunction during the perioperative period. The other patient's status of bronchiolitis obliterans syndrome had gradually progressed to grade 3, and only the living donor lung was functioning at that time. However, both patients are alive 5.5 and 4.2 years after lung transplant, respectively. Hybrid lung transplantation may increase patients' chances of receiving transplants because patients are not likely to survive while waiting for ideal donor lungs to become available.

Patient-reported dyspnea and health predict waitlist mortality in patients waiting for lung transplantation in Japan.

BACKGROUND: Waitlist mortality due to donor shortage for lung transplantation is a serious problem worldwide. Currently, the selection of recipients in Japan is mainly based on the registration order. Hence, scientific evidence for risk stratification regarding waitlist mortality is urgently needed. We hypothesized that patient-reported dyspnea and health would predict mortality in patients waitlisted for lung transplantation. METHODS: We analyzed factors related to waitlist mortality using data of 203 patients who were registered as candidates for lung transplantation from deceased donors. Dyspnea was evaluated using the modified Medical Research Council (mMRC) dyspnea scale, and the health status was determined with St. George's Respiratory Questionnaire (SGRQ). RESULTS: Among 197 patients who met the inclusion criteria, the main underlying disease was interstitial lung disease (99 patients). During the median follow-up period of 572 days, 72 patients died and 96 received lung transplantation (69 from deceased donors). Univariable competing risk analyses revealed that both mMRC dyspnea and SGRQ Total score were significantly associated with waitlist mortality (p = 0.003 and p < 0.001, respectively) as well as age, interstitial lung disease, arterial partial pressure of carbon dioxide, and forced vital capacity. Multivariable competing risk analyses revealed that the mMRC and SGRQ score were associated with waitlist mortality in addition to age and interstitial lung disease. CONCLUSIONS: Both mMRC dyspnea and SGRQ score were significantly associated with waitlist mortality, in addition to other clinical variables such as patients' background, underlying disease, and pulmonary function. Patient-reported dyspnea and health may be measured through multi-dimensional analysis (including subjective perceptions) and for risk stratification regarding waitlist mortality.

Outcomes of lung transplantation for idiopathic pleuroparenchymal fibroelastosis.

PURPOSE: This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF). METHODS: We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018. RESULTS: There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/m2, respectively; P < 0.01). However, Kaplan-Meier survival curves showed no significant difference in overall survival between the groups. The BMI did not increase in patients with IPPFE, even 1 year after LT (pretransplant, 16.5 ± 3.2 kg/m2 vs. 1 year post-transplant, 15.6 ± 2.5 kg/m2; P = 0.08). The percent predicted forced vital capacity (%FVC) 1 year after LT was significantly lower in the IPPFE group than in the IPF group (48.4% ± 19.5% vs. 68.6% ± 15.5%, respectively; P < 0.01). CONCLUSIONS: Despite extrapulmonary problems such as a flat chest, low BMI, and associated restrictive impairment persisting in patients with IPPFE, patient survival after LT for IPPFE or IPF was equivalent.

Photocatalytic hydrogenation of nitrobenzene to aniline over titanium(iv) oxide using various saccharides instead of hydrogen gas.

Bare TiO2 photocatalyst almost quantitatively converted nitrobenzene to aniline with various saccharides without the use of hydrogen gas. Although aniline was formed when any saccharide was used, the use of disaccharides (lactose, maltose, and sucrose) decreased the reaction rate. The rate of photocatalytic hydrogenation of nitrobenzene using saccharides is determined by the degradation rate of saccharides at positive holes. When glucose was used, formic acid, arabinose, glyceraldehyde and lactic acid were obtained, which are products that are consistent with the product of the photocatalytic oxidation of glucose.

Effectiveness of scheduled intravenous acetaminophen in the postoperative pain management of video-assisted thoracic surgery.

PURPOSE: The scheduled administration of intravenous acetaminophen (scheduled-IV-AcA) is one of the more effective multimodal analgesic approaches for postoperative pain in abdominal/orthopedic surgeries. However, there is little evidence concerning scheduled-IV-AcA after general thoracic surgery, especially when limited to video-assisted thoracoscopic surgery (VATS). We investigated the efficacy of scheduled-IV-AcA administration in patients after undergoing VATS. METHODS: Ninety-nine patients who underwent VATS lobectomy or segmentectomy via an 8-cm access window and 1 camera port were retrospectively reviewed by categorizing them into groups either with scheduled-IV-AcA (Group AcA: n = 29) or without it (Group non-AcA: n = 70). Group AcA received 1 g of IV-AcA every 6 h from the end of the operation until the end of POD2. Postoperative pain was measured using a numeric rating scale (NRS) three times per day until discharge. RESULTS: NRS scores were significantly lower in Group AcA with motion (on POD1 to the first point of POD2) than in Group non-AcA. Group non-AcA was also more likely to use additional analgesics than Group AcA (39% vs. 17%, p = 0.058). CONCLUSIONS: Scheduled-IV-AcA administration is a safe and effective multimodal analgesic approach in patients undergoing VATS pulmonary resection via an 8-cm access window.

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.

Sleep quality and its association with health-related quality of life of patients on lung transplantation waitlist in Japan.

PURPOSE: Poor quality of sleep is a common feature in patients with various lung diseases and affects their health-related quality of life (HRQL). We evaluated sleep quality and HRQL in patients on the waitlist for lung transplantation in Japan. METHODS: In this prospective study, patient-reported and physiological data were collected from patients newly registered on the waitlist for lung transplantation in Japan. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) and HRQL using the St. George's Respiratory Questionnaire (SGRQ). The frequency of poor sleep quality, correlations between sleep quality and various clinical parameters, and predictive factors of sleep quality were examined. RESULTS: Of 193 patients, the three most-frequent indications for lung transplantation were interstitial pneumonia (n = 96), pulmonary complications of hematopoietic stem cell transplantation (n = 25), and pulmonary hypertension (n = 17). Poor sleep quality (PSQI > 5) was observed in 102 patients (53%) and was significantly associated with worse Hospital Anxiety and Depression Score (HADS), worse SGRQ score, worse modified Medical Research Council Dyspnea score, and shorter 6-min walk distance. However, it was not associated with sex, pulmonary function, interstitial pneumonia, or arterial blood gas. Stepwise multiple regression analysis indicated that poor sleep quality was explained significantly by HADS anxiety (23%) and SGRQ Symptoms (10%). CONCLUSION: Poor sleep quality was found to be common among patients on the lung transplantation waitlist in Japan. The two most significant factors responsible for impaired sleep quality were anxiety and respiratory symptoms. Additional care should be taken to ensuring a better quality of sleep for such patients.

Severe thrombocytopenia in patients with idiopathic pulmonary arterial hypertension provided several strategies for lung transplantation.

While the prognosis of idiopathic pulmonary arterial hypertension has improved significantly due to newer medications, lung transplantation remains a critical therapeutic option for severe pulmonary arterial hypertension. Hence, it is essential for patients awaiting lung transplantation to avoid complications, including thrombocytopenia, which may affect their surgical outcomes. Herein we present the case of a 21-year-old woman diagnosed with idiopathic pulmonary arterial hypertension at the age of 15. She developed thrombocytopenia while awaiting lung transplantation. Her medication was switched from epoprostenol to treprostinil, suspecting possible drug-induced thrombocytopenia. Furthermore, she was administered thrombopoietin receptor agonists in view of the possibility of idiopathic thrombocytopenic purpura, along with maximum support for right heart failure. Subsequently, her platelet count increased to >70,000/µL, enabling her to successfully undergo bilateral lung transplantation. Post-bilateral lung transplantation, pulmonary arterial hypertension as well as thrombocytopenia appeared to have resolved. In this case, we suspected that thrombocytopenia could have resulted owing to a combination of pulmonary arterial hypertension, right heart failure, drug interactions, and idiopathic thrombocytopenic purpura. Thrombocytopenia is a very critical condition in patients with pulmonary arterial hypertension, especially those awaiting lung transplantation. Several approaches are known to improve intractable thrombocytopenia in patients with pulmonary arterial hypertension.

Allogeneic hematopoietic stem cell transplantation in a prior lung transplant recipient.

Hematological diseases after solid organ transplant (SOT) are an emerging issue as the number of long-term SOT survivors increases. Expertise in managing patients requiring allogeneic hematopoietic stem cell transplantation (HSCT) after SOT from independent donors is needed; however, clinical reports of HSCT after SOT are limited, and the feasibility and risk are not well understood. In particular, HSCT in prior lung transplant recipients is thought to be complicated as the lung is immunologically distinct and is constantly exposed to the surrounding environment. Herein, we describe a case of successful HSCT in a patient with myelodysplastic syndromes who had previously received a lung transplant from a deceased donor for bronchiolitis obliterans syndrome. Reports about cases of HSCT after lung transplant are quite rare; thus, we discuss the mechanisms of immune tolerance through the clinical course of our case. This case suggests that HSCT after SOT can be considered a therapeutic option in cases where the transplanted organ is functionally retained and the hematological disease is in remission.

Lung perfusion scintigraphy to detect chronic lung allograft dysfunction after living-donor lobar lung transplantation.

Because chronic lung allograft dysfunction (CLAD) develops predominantly on one side after bilateral living-donor lobar lung transplantation (LDLLT), lung perfusion scintigraphy (Q-scinti) was expected to show a perfusion shift to the contralateral unaffected lung with the development of CLAD. Our study examined the potential usefulness of Q-scinti in the diagnosis of CLAD after bilateral LDLLT. We conducted a single-center retrospective cohort study of 58 recipients of bilateral LDLLT. The unilateral shift values on Q-scinti were calculated and compared between the CLAD group (N = 27) and the non-CLAD group (N = 31) from 5 years before to 5 years after the diagnosis of CLAD. The unilateral shift values in Q-scinti were significantly higher in the CLAD group than in the non-CLAD group from 5 years before the diagnosis of CLAD to 5 years after the diagnosis (P < 0.05). The unilateral shift values in Q-scinti were significantly correlated with the percent baseline values of the forced expiratory volume in 1 s (P = 0.0037), the total lung capacity (P = 0.0028), and the forced vital capacity (P = 0.00024) at the diagnosis of CLAD. In patients developing unilateral CLAD after bilateral LDLLT, Q-scinti showed a unilateral perfusion shift to the contralateral unaffected lung. Thus, Q-scinti appears to have the potential to predict unilateral CLAD after bilateral LDLLT.

Analysis of Optimal Health-Related Quality of Life Measures in Patients Waitlisted for Lung Transplantation.

Background: Improving health-related quality of life (HRQL) is an important goal of lung transplantation, and St. George's Respiratory Questionnaire (SGRQ) is frequently used for assessing HRQL in patients waitlisted for lung transplantation. We hypothesized that chronic respiratory failure (CRF)-specific HRQL measures would be more suitable than the SGRQ, considering the underlying disease and its severity in these patients. Methods: We prospectively collected physiological and patient-reported data (HRQL, dyspnea, and psychological status) of 199 patients newly registered in the waiting list of lung transplantation. CRF-specific HRQL measures of the Maugeri Respiratory Failure Questionnaire (MRF) and Severe Respiratory Insufficiency Questionnaire (SRI) were assessed in addition to the SGRQ. Results: Compared to the MRF-26 and SRI, the score distribution of the SGRQ was skewed toward the worse ends of the scale. All domains of the MRF-26 and SRI were significantly correlated with the SGRQ. Multiple regression analyses to investigate factors predicting each HRQL score indicated that dyspnea and psychological status accounted for 12% to 28% of the variance more significantly than physiological measures did. The MRF-26 Total and SRI Summary significantly worsened from the baseline to 1 year (p < 0.001 and p < 0.001 and p < 0.001 and. Conclusions: The MRF-26 and SRI are valid, discriminative, and responsive in patients waitlisted for lung transplantation. In terms of the score distribution and responsiveness, CRF-specific measures may function better in their HRQL assessment than the currently used measures do.

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.

Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy.

PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment. METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018. RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59). CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

Prolonged warm ischemia exacerbated acute rejection after lung transplantation from donation after cardiac death in a mouse.

OBJECTIVE: In lung transplantation (LTx) from donation after cardiac death (DCD), the donor lungs are inevitably exposed to warm ischemic time (WIT) between the cardiac arrest and the initiation of cold preservation. We conducted this study to examine the effect of prolonged WIT on lung allograft rejection in a murine model of LTx from DCD. METHODS: Allogeneic BALB/c → B6 LTx from DCD was performed with a WIT of 15 min (WIT15 group, n = 5) or 60 min (WIT60 group, n = 5). Recipients were immunosuppressed by perioperative costimulatory blockade. The lung allografts were analyzed by histology and flow cytometry on day 7 after the LTx. RESULTS: Histologically, the rejection grade in the WIT60 group was significantly higher than that in the WIT15 group (3.4 ± 0.4 vs. 2.2 ± 0.2, P = 0.0278). Moreover, the intragraft CD8+ to CD4+ T cell ratio in the WIT60 group was significantly higher than that in the WIT15 group (2.3 ± 0.12 vs. 1.2 ± 0.11, P < 0.0001). CONCLUSIONS: Prolonged WIT could exacerbate the severity of lung allograft rejection after LTx from DCD. Minimization of the WIT could improve the outcomes after LTx from DCD.

Favorable survival even with high disease-specific complication rates in lymphangioleiomyomatosis after lung transplantation-long-term follow-up of a Japanese center.

BACKGROUND: Lung transplantation (LT) is a reliable therapeutic option for end-stage pulmonary lymphangioleiomyomatosis (LAM). Long-term outcome of LAM recipients after LT remains unknown. The aim of this study was to describe the outcomes of LT for LAM with a long-term follow-up, comparing those for other diseases in the same period. METHODS: We retrospectively reviewed consecutive 145 LT recipients between 1998 and 2015 at Okayama University Hospital with minimum 3-year follow-up. RESULTS: Twelve LAM recipients including nine sporadic-LAM and three tuberous sclerosis complex -LAM were identified. Nine of 12 underwent bilateral LT including four living-donor lobar LT. There was no significant difference in overall survival between the two groups. (P = 0.15). Chronic lung allograft dysfunction free survival rate in LAM compared with other diseases tended to be better (P = 0.058). However, the rate of requiring hemodialysis was significantly higher in LAM recipients than in the recipients of other diseases (P = 0.047). Notably, 8 of 12 (67%) LAM patients encountered LAM-related complication including chylothorax and pneumothorax, seven (58%) had proliferative diseases consisting of renal angiomyolipoma and recurrent LAM. Nine patients required mTOR inhibitors for LAM-related problems, contributing to improved control of LAM-related problems. While all nine recipients of bilateral LT have still survived, two patients died of diseases in their native lungs and one required re-LT among three recipients of single LT. CONCLUSION: Although the rates of LAM-related complications were unexpectedly high in the long term, LT is a feasible therapeutic option for patients with advanced pulmonary LAM.