Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts.

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-ß-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.

Low-Dose CT Screening of Persistent Subsolid Lung Nodules: First-Order Features in Radiomics.

BACKGROUND: Nondisappearing subsolid nodules requiring follow-up are often detected during lung cancer screening, but changes in their invasiveness can be overlooked owing to slow growth. We aimed to develop a method for automatic identification of invasive tumors among subsolid nodules during multiple health checkups using radiomics technology based on low-dose computed tomography (LD-CT) and examine its effectiveness. METHODS: We examined patients who underwent LD-CT screening from 2014 to 2019 and had lung adenocarcinomas resected after 5-year follow-ups. They were categorized into the invasive or less-invasive group; the annual growth/change rate (Δ) of the nodule voxel histogram using three-dimensional CT (e.g., tumor volume, solid volume percentage, mean CT value, variance, kurtosis, skewness, and entropy) was assessed. A discriminant model was designed through multivariate regression analysis with internal validation to compare its efficacy with that of a volume doubling time of < 400 days. RESULTS: The study included 47 tumors (23 invasive, 24 less invasive), with no significant difference in the initial tumor volumes. Δskewness was identified as an independent predictor of invasiveness (adjusted odds ratio, 0.021; p = 0.043), and when combined with Δvariance, it yielded high accuracy in detecting invasive lesions (88% true-positive, 80% false-positive). The detection model indicated surgery 2 years earlier than the volume doubling time, maintaining accuracy (median 3 years vs.1 year before actual surgery, p = 0.011). CONCLUSION: LD-CT radiomics showed promising potential in ensuring timely detection and monitoring of subsolid nodules that warrant follow-up over time.

Thoracic mediastinal-occupying ratio predicts recovery and prognosis after lung transplantation.

OBJECTIVES: Even after transplantation of favourable donor lungs, some recipients require prolonged weaning from mechanical ventilation, indicating a poor prognosis. We investigated the effects of prolonged mechanical ventilation (PMV) for >14 days on the recovery and survival of patients who underwent cadaveric lung transplantation in relation to their physical traits. METHODS: We retrospectively reviewed patients who underwent cadaveric lung transplantation (age ≥15 years) at a single centre between April 2015 and December 2020 and classified them into PMV and non-PMV groups (>14 and ≤14 days of mechanical ventilation postoperatively, respectively). The factors predicting PMV comprised clinical factors (e.g. marginal donor) and physical features, namely flat chest, narrow fourth intercostal space (length, <5 mm), mediastinal shift, thoracic mediastinal-occupying ratio (TMOR) >40% and sarcopenia, according to the logistic regression analysis. The log-rank test was used to examine the association between TMOR >40% and 3-year prognosis. RESULTS: The PMV group comprised 17 (33%) of 51 recipients. Multivariable logistic analysis showed that the TMOR >40% (odds ratio, 7.3; 95% confidence interval, 1.3-40.1; P = 0.023) was an independent preoperative predictive factor for PMV postoperatively. Stepwise analysis revealed intraoperative extracorporeal membrane oxygenation and reoperation as postoperative predictive factors in addition to TMOR >40%. Recipients with TMOR >40% had significantly worse 3-year survival than other recipients (71.2% vs 100.0%, respectively; P = 0.008). CONCLUSIONS: Recipients with a TMOR >40% may be long-term ventilator dependent and have a poor prognosis.

Effect of intraoperative needle biopsy on the survival of nonsmall cell lung cancer patients: a propensity score matching analysis.

PURPOSE: It is unknown whether intraoperative needle biopsy (INB) predisposes to the postoperative recurrence of lung cancer and compromises the prognosis of these patients. We conducted this study to identify the effect of INB before lobectomy on the postoperative recurrence rate and prognosis of patients with nonsmall cell lung cancer (NSCLC). METHODS: The subjects of this retrospective study were 953 patients with pathological stage I-III NSCLC who underwent lobectomy between 2001 and 2016. The patients were divided into two groups: the INB group (n = 94) and the non-INB group (n = 859). After propensity score matching (PSM), we compared the postoperative cumulative recurrence rate, recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) between the two groups. RESULTS: After PSM, 94 patient pairs were matched. The cumulative recurrence rate was significantly higher in the INB group than in the non-INB group (P = 0.01). The 5-year RFS rate was significantly lower in the INB group than in non-INB group (48% vs 68%), as were the 5-year DSS (76% vs 92%) and 5-year OS rates (67% vs 84%) (all P < 0.05). CONCLUSIONS: The findings of this analysis suggest that INB before lobectomy may increase the cumulative recurrence rate and worsen the prognosis of patients with resectable NSCLC. Thus, we believe that INB should be avoided unless a lung lesion cannot be diagnosed by another type of biopsy.

Virtual-assisted lung mapping in sublobar resection of small pulmonary nodules, long-term results.

OBJECTIVES: The short-term efficacy of virtual-assisted lung mapping (VAL-MAP), a preoperative bronchoscopic multi-spot lung-marking technique, has been confirmed in 2 prospective multicentre studies. The objectives of this study were to analyse the local recurrence and survival of patients enrolled in these studies, long-term. METHODS: Of the 663 patients enrolled in the 2 studies, 559 patients' follow-up data were collected. After excluding those who did not undergo VAL-MAP, whose resection was not for curative intent, who underwent concurrent resection without VAL-MAP, or who eventually underwent lobectomy instead of sublobar resection (i.e. wedge resection or segmentectomy), 422 patients were further analysed. RESULTS: Among 264 patients with primary lung cancer, the 5-year local recurrence-free rate was 98.4%, and the 5-year overall survival (OS) rate was 94.5%. Limited to stage IA2 or less (≤2 cm in diameter; n = 238, 90.1%), the 5-year local recurrence-free and OS rates were 98.7% and 94.8%, respectively. Among 102 patients with metastatic lung tumours, the 5-year local recurrence-free rate was 93.8% and the 5-year OS rate was 81.8%. Limited to the most common (colorectal) cancer (n = 53), the 5-year local recurrence-free and OS rates were 94.9% and 82.3%, respectively. CONCLUSIONS: VAL-MAP, which is beneficial in localizing small barely palpable pulmonary lesions and determining the appropriate resection lines, was associated with reasonable long-term outcomes. SUBJ COLLECTION: 152, 1542.

Risk Factors for Invisible Intraoperative Markings After Virtual-Assisted Lung Mapping.

BACKGROUND: Virtual-assisted lung mapping (VAL-MAP) is a preoperative bronchoscopic multispot dye-marking technique that can be combined with bronchoscopic placement of a microcoil (VAL-MAP 2.0). VAL-MAP can identify unpalpable pulmonary lesions; however, the markings are occasionally deemed invisible intraoperatively. We investigated preoperative risk factors for invisible markings after VAL-MAP. METHODS: We prospectively performed preoperative VAL-MAP in patients at the University of Tokyo between January 2014 and June 2020. Data of 219 patients (257 lesions) and 857 markings were retrospectively reviewed. Dye markings were categorized as grade 0 (invisible) or 1-5 (visible). The risk factors for grade 0 markings were assessed using multiple logistic regression analysis. Subsegments of the bronchus showing grade 0 markings were also evaluated for 133 lesions and 504 markings without missing data for the target segment. RESULTS: Sixty-one of the 257 lesions (24%) displayed ≥1 grade 0 markings. Seventy-six (8.9%) of the 857 markings were grade 0 intraoperatively. VAL-MAP 1.0 was performed for 202 (79%) and 25 lesions (10%) without and with electromagnetic navigation bronchoscopy, and VAL-MAP 2.0 with a microcoil was performed for 30 lesions (11%). Upper lobe markings were associated with a significantly increased risk of invisible markings. There was no significant difference in the frequency of grade 0 markings among the VAL-MAP methods. Among all bronchi subsegments, left B1+2c exhibited the highest rate of grade 0 markings. CONCLUSIONS: Markings placed using VAL-MAP are more likely to be invisible for upper lobe pulmonary lesions. Injecting markings for lesions in the left S1+2c thus require caution.

Efficacy of the Segment-Counting Method in Predicting Lung Function and Volume Following Stapler-Based Thoracoscopic Segmentectomy.

PURPOSE: To investigate the accuracy of a segment-counting method in predicting lung function and volume after stapler-based thoracoscopic segmentectomy in comparison with lobectomy. METHODS: Between 2014 and 2018, patients who underwent these procedures were retrospectively reviewed. Thoracic computed tomography and spirometry data before and 1 year after the surgery were assessed. We evaluated the differences between the predicted values using a segment-counting method and the actual postoperative values for lung function and volume in each group. Sub-analyses were also performed to assess the impact of the number of staples and resected segments in predicting patient outcomes. RESULTS: We included 116 patients (segmentectomy, 69; lobectomy, 47). Actual postoperative lung function and volume values matched the predicted values in the stapler-based segmentectomy group, and significantly exceeded the predictions in the lobectomy group (P <0.01). Sub-analyses revealed lower postoperative lung function values than predicted existed after single segmentectomy, with an odds ratio of 3.29 (95% confidence interval: 1.02-10.70, P = 0.04) in a multivariable analysis. The degree of predicted error regarding lung function was negligible. CONCLUSIONS: The segment-counting method was useful in predicting lung function after stapler-based thoracoscopic segmentectomy. Segmentectomy rarely yielded lower-than-predicted lung function and volume values.

Lung transplant after long-term veno-venous extracorporeal membrane oxygenation: a case report.

BACKGROUND: Although the number of patients who undergo extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is increasing worldwide, there are few reports on lung transplantation after long-term ECMO (more than 1 month). We report a rare case of successful bilateral lung transplantation in a Japanese patient after 5 months of veno-venous (VV)-ECMO support. CASE PRESENTATION: A 27-year-old man who underwent bone marrow transplantation (BMTx) with fully matched human leukocyte antigen typing was diagnosed with bronchiolitis obliterans caused by chronic graft-versus-host disease 3 years after the BMTx. One year later, his respiratory condition had exacerbated, with carbon dioxide retention that required conventional mechanical ventilation. He was then deemed a suitable candidate for lung transplantation by a multidisciplinary transplantation selection committee. While waiting for donor lungs, his hypercapnia and acidosis became barely manageable under care with mechanical ventilation and ultimately he was switched to VV-ECMO. He remained on VV-ECMO for the next 5 months, during which period the circuit was switched nine times. In addition, sophisticated intensive care was required to manage multiple episodes of sepsis and coagulopathy. A suitable donor was identified 5 months later, and bilateral lung transplantation was initiated with continuous VV-ECMO. The procedure itself was extremely challenging owing to severe adhesions resulting from previous thoracotomy, inflammation, infection, and intrapulmonary hemorrhage. The operative time for the transplantation was about 19 h. Currently, at 2 years 8 months postoperatively, the patient is alive and well. CONCLUSION: Transplant surgery in this patient was extremely challenging because of the presence of severe pleural adhesions and stiff native lungs secondary to hemorrhagic complications due to the prolonged ECMO support. Surgeons must recognize that lung transplantation after long-term ECMO bridging can be technically more complicated and challenging than shorter-term ECMO.

Pediatric living-donor lobar lung transplantation in postpneumonectomy-like anatomy caused by pulmonary hypoplasia with congenital diaphragmatic hernia.

When performing living-donor lobar lung transplantation on small children of height 100 cm or under, accommodation of an oversized adult lobar graft is problematic, sometimes necessitating single lobar transplantation in combination with contralateral pneumonectomy. We here report a unique case of living-donor lobar lung transplantation in a 9-year-old boy with congenital pulmonary hypoplasia. Although he was 104 cm tall, and the available adult lower lobe graft appeared to be oversized, his right lung was hypoplastic, resulting in his mediastinum being shifted to the right and thus already showing "postpneumonectomy-like" anatomy. His father's left lower lobe was successfully transplanted into the left thorax without performing a contralateral pneumonectomy. Three-dimensional reconstruction of computed tomography images and computed tomography volumetry were extremely helpful in matching the size of the graft and planning this unique surgery.

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: a nationwide survey.

OBJECTIVES: Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. METHODS: Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. RESULTS: During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20 ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4 days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18 years. CONCLUSIONS: Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended.

Familial Interstitial Pneumonia Revealed After Living-Donor Lobar Lung Transplantation.

Living-donor lobar lung transplantation is often indicated for acute exacerbation of idiopathic interstitial pneumonia because of the long waiting time for cadaveric lung transplantation in Japan. Donors without major underlying diseases are selected after medical screening. A 44-year-old man donated his right lower lobe to his sibling with idiopathic interstitial pneumonia. Although he was free of any major medical problems before transplantation, fibrotic changes appeared in both the donated lung and the donor's remaining lungs in a case of familial interstitial pneumonia. For living-donor lobar lung transplantation for idiopathic interstitial pneumonia, donor candidates should be informed of the potential issue of a familial disease.

Management of Partial Anomalous Pulmonary Venous Return In Lung Transplantation.

This report describes the case of a patient who underwent bilateral lung transplantation for idiopathic pulmonary arterial hypertension with coexisting partial anomalous pulmonary venous return and tracheal bronchus. The hypoplastic and low-positioned left atrial orifice caused by abnormal reflux of the right upper pulmonary vein and high-positioned right upper lobe bronchus made right anastomosis challenging. To prevent excessive tension on left atrial anastomosis, the donor's right main bronchus was anastomosed to the recipient's bronchus intermedius, a maneuver that resulted in successful anastomosis and an uneventful postoperative course.

Radiomics technology for identifying early-stage lung adenocarcinomas suitable for sublobar resection.

OBJECTIVE: Early-stage lung adenocarcinomas that are suitable for limited resection to preserve lung function are difficult to identify. Using a radiomics approach, we investigated the efficiency of voxel-based histogram analysis of 3-dimensional computed tomography images for detecting less-invasive lesions suitable for sublobar resection. METHODS: We retrospectively reviewed the medical records of 197 patients with pathological stage 0 or IA adenocarcinomas who underwent lung resection for primary lung cancer at our institution between January 2014 and June 2018. The lesions were categorized as either less invasive or invasive. We evaluated tumor volumes, solid volume percentages, mean computed tomography values, and variance, kurtosis, skewness, and entropy levels. We analyzed the relationships between these variables and pathologically less-invasive lesions and designed an optimal model for detecting less-invasive adenocarcinomas. RESULTS: Univariate analysis revealed seven variables that differed significantly between less invasive (n = 71) and invasive (n = 141) lesions. A multivariate analysis revealed odds ratios for tumor volumes (0.64; 95% confidence interval (CI), 0.46-0.89; P = .008), solid volume percentages (0.96; 95% CI, 0.93-0.99; P = .024), skewness (3.45; 95% CI, 1.38-8.65; P = .008), and entropy levels (0.21; 95% CI, 0.07-0.58; P = .003). The area under the receiver operating characteristic curve was 0.90 (95% CI, 0.85-0.94) for the optimal model containing these 4 variables, with 85% sensitivity and 79% specificity. CONCLUSIONS: Voxel-based histogram analysis of 3-dimensional computed tomography images accurately detected early-stage lung adenocarcinomas suitable for sublobar resection.

Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome.

Chronic lung allograft dysfunction (CLAD) following lung transplantation limits long-term survival considerably. The main reason for this is a lack of knowledge regarding the pathological condition and the establishment of treatment. The consensus statement from the International Society for Heart and Lung Transplantation on CLAD in 2019 classified CLAD into two main phenotypes: Bronchiolitis obliterans syndrome and restrictive allograft syndrome. Along with this clear classification, further exploration of the mechanisms and the development of appropriate prevention and treatment strategies for each phenotype are desired. In this review, we summarize the new definition of CLAD and update and summarize the existing knowledge on the underlying mechanisms of bronchiolitis obliterans syndrome and restrictive allograft syndrome, which have been elucidated from clinicopathological observations and animal experiments worldwide.

Early postoperative inflammatory response by procedure types: stapler-based segmentectomy versus lobectomy.

OBJECTIVE: Perioperative C-reactive protein (CRP) levels have become a contentious topic on the surgical outcome of lung cancer, but the influence of the procedure types has not been precisely investigated. From this viewpoint, we compared two types of thoracoscopic anatomical lung resection: segmentectomy and lobectomy. METHODS: This was a retrospective study involving patients who underwent standardized anatomical lung resection at a single institute from 2014 to 2017; CRP levels were routinely measured on postoperative days 1, 3, and 5. Changes in the CRP levels from the preoperative period were calculated (ΔCRP), and factors associated with a higher ΔCRP value were analyzed. RESULTS: Among 186 patients included, 91 (48.9%) patients underwent stapler-based segmentectomy and 95 (51.1%) patients underwent lobectomy. The segmentectomy group showed significantly higher ΔCRP values on every measurement day than the lobectomy group, in spite of shorter operation time, smaller blood loss, shorter drainage periods, shorter dissection time, and limited lymph node dissection. The number of stapler cartridges for the lung parenchyma was significantly larger in the segmentectomy group. Regression analyses indicated that procedure type and smoking history were associated with a higher ΔCRP value, whereas no significant difference was indicated in the smoking history between the groups. CONCLUSION: In our cohort, stapler-based thoracoscopic segmentectomy was associated with an increase in acute inflammatory response despite favorable perioperative outcome compared to lobectomy. Local surgical stress and damage in the remaining segments might play a key role and warrants further investigation.

The impact of surgical chest wall damage caused by classic thoracotomy on pulmonary function and morphology.

OBJECTIVES: Postoperative changes in pulmonary function (PF) and morphology due to surgical chest wall damage by thoracotomy with rib resection are unclear. Therefore, we evaluated the effects of surgical damage on PF and morphology at > 6 months postoperatively by comparing different lung lobectomy approaches. METHODS: A total of 140 patients who underwent lobectomy for lung diseases between January 2006 and March 2016 were analyzed. Patients who underwent PF tests and computed tomography (CT) scans preoperatively and postoperatively were divided into posterolateral thoracotomy with one rib resection (PT) group and video-assisted thoracoscopic surgery (VATS) group. A 1:1 propensity score-matched (PSM) analysis was used to balance clinically important confounders between the groups. Regarding morphology, lung volume was measured semi-automatically using image analysis software and reconstructed three-dimensional (3D) images. RESULTS: After PSM, 31 patients in each group were compared. Perioperative reduction ratios in forced vital capacity (FVC) (- 23% vs. - 13%; P = 0.006) and forced expiratory volume in 1 s (FEV1) (- 19% vs. - 12%; P = 0.02) were significantly larger for the PT group. No significant differences in lung volume values based on 3D CT volumetry (PT vs. VATS; total lung volume: - 7.9% vs. - 7.2%, P = 0.82; non-resected ipsilateral lung volume: + 36% vs. + 40%, P = 0.69; contralateral lung volume: + 9.3% vs. + 9.4%, P = 0.98) were found in either group. CONCLUSIONS: Among the patients underwent lobectomy, classic thoracotomy decreased PF by an additional FVC loss of 10% and FEV1 loss of 7% compared with VATS, without affecting residual lung volume.

[Thoracic Incisions for Open Chest Surgery;Posterolateral Thoracotomy, Anterolateral Thoracotomy, Axillary Thoracotomy, and Muscle Sparing Thoracotomy].

Lung disease requiring surgical treatment has shifted from pulmonary tuberculosis that was prevalent in the 1940s during wartime to lung cancer in the last half century. The surgical approach for pulmonary tuberculosis was open chest surgery. Likewise for lung cancer, a thoracotomy approach had initially been used for a while. Thoracoscopic minimally invasive surgery became more widely used around 1990 and was shown to improve the patient's quality of life (QOL). Currently, thoracoscopic surgery and robotic surgery are the mainstream procedures for patients with lung cancer, and thoracotomy procedures have fallen out of favor. However, in some cases of unexpected bleeding from the pulmonary artery or tumor infiltration into the pulmonary artery, appropriate thoracotomy must be performed. In this volume, 4 representative methods of performing thoracotomy are described with some tips in Japanese.

Lifesaving surgery for a ruptured invasive thymoma using the hemi-clamshell approach: a case report.

BACKGROUND: Among anterior mediastinal tumors, a teratoma is known to rupture with growth, but there have been few previous reports about thymoma rupture. We here report a rare case of an invasive thymoma with intrapulmonary and intrathoracic rupture requiring emergency life-saving surgery. To our knowledge, this is the first such case in the literature. CASE PRESENTATION: A 56-year-old woman suddenly experienced right precordial pain and hemoptysis. Enhanced computed tomography revealed a large mediastinal tumor pressing against the pulmonary hilar vascularity, with extravasation of blood into the right lung. Tumor rupture into the lungs was suspected. Given the deterioration of her respiratory status and hemodynamics, thymomectomy with removal of the involved tissues was urgently performed using the hemi-clamshell approach and intrapericardial dissection, with veno-arterial extracorporeal membrane oxygenation on standby. She survived, and no recurrence has been noted for 2 years postoperatively. CONCLUSIONS: A large thymoma can suddenly rupture into the thorax, similar to the rupture of a teratoma. Additionally, in cases with hemoptysis, an appropriate procedure should be selected to reach both the pulmonary hilum and thorax for complete resection, as hemoptysis might suggest tumor invasion into the lungs.