B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling.

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.

Validation of a novel donor lung scoring system based on the updated lung Composite Allocation Score.

Lung transplantation (LTx) continues to have lower rates of long-term graft survival compared with other organs. Additionally, lung utilization rates from brain-dead donors remain substantially lower compared with other solid organs, despite a growing need for LTx and the significant risk of waitlist mortality. This study aims to examine the effects of using a combination of the recently described novel lung donor (LUNDON) acceptability score and the newly adopted recipient lung Composite Allocation Score (CAS) to guide transplantation. We performed a review of nearly 18 000 adult primary lung transplants from 2015-2022 across the US with retroactive calculations of the CAS value. The medium-CAS group (29.6-34.5) had superior 1-year posttransplant survival. Importantly, the combination of high-CAS (> 34.5) recipients with low LUNDON score (≤ 40) donors had the worst survival at 1 year compared with any other combination. Additionally, we constructed a model that predicts 1-year and 3-year survival using the LUNDON acceptability score and CAS values. These results suggest that caution should be exercised when using marginally acceptable donor lungs in high-priority recipients. The use of the LUNDON score with CAS value can potentially guide clinical decision-making for optimal donor-recipient matches for LTx.

Lobe-specific lymph node sampling is associated with lower risk of cancer recurrence.

Objective: Adequate intraoperative lymph node (LN) assessment is a critical component of early-stage non-small cell lung cancer (NSCLC) resection. The National Comprehensive Cancer Network and the American College of Surgeons Commission on Cancer (CoC) recommend station-based sampling minimums agnostic to tumor location. Other institutions advocate for lobe-specific LN sampling strategies that consider the anatomic likelihood of LN metastases. We examined the relationship between lobe-specific LN assessment and long-term outcomes using a robust, highly curated cohort of stage I NSCLC patients. Methods: We performed a cohort study using a uniquely compiled dataset from the Veterans Health Administration and manually abstracted data from operative and pathology reports for patients with clinical stage I NSCLC (2006-2016). For simplicity in comparison, we included patients who had right upper lobe (RUL) or left upper lobe (LUL) tumors. Based on modified European Society of Thoracic Surgeons guidelines, lobe-specific sampling was defined for RUL tumors (stations 2, 4, 7, and 10 or 11) and LUL tumors (stations 5 or 6, 7, and 10 or 11). Our primary outcome was the risk of cancer recurrence, as assessed by Fine and Gray competing risks modeling. Secondary outcomes included overall survival (OS) and pathologic upstaging. Analyses were adjusted for relevant patient, disease, and treatment variables. Results: Our study included 3534 patients with RUL tumors and 2667 patients with LUL tumors. Of these, 277 patients (7.8%) with RUL tumors and 621 patients (23.2%) with LUL tumors met lobe-specific assessment criteria. Comparatively, 34.7% of patients met the criteria for count-based assessment, and 25.8% met the criteria for station-based sampling (ie, any 3 N2 stations and 1 N1 station). Adherence to lobe-specific assessment was associated with lower cumulative incidence of recurrence (adjusted hazard ratio [aHR], 0.83; 95% confidence interval [CI], 0.70-0.98) and a higher likelihood of pathologic upstaging (aHR, 1.49; 95% CI, 1.20-1.86). Lobe-specific assessment was not associated with OS. Conclusions: Adherence to intraoperative LN sampling guidelines is low. Lobe-specific assessment is associated with superior outcomes in early-stage NSCLC. Quality metrics that assess adherence to intraoperative LN sampling, such as the CoC Operative Standards manual, also should consider lobe-specific criteria.

"Horses for courses" computed tomography or predicted total lung capacity for size matching in lung transplantation.

Size-matching donors to recipients in lung transplantation continues to be a clinical challenge. Predicted total lung capacity equations, or more simply, donor and recipient heights, while widely used, are imprecise and may not be representative of the pool of donors and recipients. These inherent limitations may result in size discrepancies. The advent of easily accessible software and the widespread availability of computed tomography (CT) imaging in donor assessments have made it possible to directly measure lung volumes in donors and recipients. As a result, there is a growing interest in adopting personalized CT volumetry as an alternative. This article explores both methods and underscores the potential benefits and precision offered by CT.

A Pilot Randomized Controlled Trial of De Novo Belatacept-based Immunosuppression After Lung Transplantation.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. The development of donor-specific antibodies (DSA) is a recognized risk factor for CLAD. Based on experience in kidney transplantation, we hypothesized that belatacept, a selective T-cell costimulatory blocker, would reduce the incidence of DSA after lung transplantation, which may ameliorate the risk of CLAD. METHODS: We conducted a pilot randomized controlled trial (RCT) at 2 sites to assess the feasibility and inform the design of a large-scale RCT. All participants were treated with rabbit antithymocyte globulin for induction immunosuppression. Participants in the control arm were treated with tacrolimus, mycophenolate mofetil, and prednisone, and participants in the belatacept arm were treated with tacrolimus, belatacept, and prednisone through day 89 after transplant then converted to belatacept, mycophenolate mofetil, and prednisone for the remainder of year 1. RESULTS: After randomizing 27 participants, 3 in the belatacept arm died compared with none in the control arm. As a result, we stopped enrollment and treatment with belatacept, and all participants were treated with standard-of-care immunosuppression. Overall, 6 participants in the belatacept arm died compared with none in the control arm (log rank P = 0.008). We did not observe any differences in the incidence of DSA, acute cellular rejection, antibody-mediated rejection, CLAD, or infections between the 2 groups. CONCLUSIONS: We conclude that the investigational regimen used in this pilot RCT is associated with increased mortality after lung transplantation.

Smoking exposure-induced bronchus-associated lymphoid tissue in donor lungs does not prevent tolerance induction after transplantation.

The presence of bronchus-associated lymphoid tissue (BALT) in donor lungs has been suggested to accelerate graft rejection after lung transplantation. Although chronic smoke exposure can induce BALT formation, the impact of donor cigarette use on alloimmune responses after lung transplantation is not well understood. Here, we show that smoking-induced BALT in mouse donor lungs contains Foxp3+ T cells and undergoes dynamic restructuring after transplantation, including recruitment of recipient-derived leukocytes to areas of pre-existing lymphoid follicles and replacement of graft-resident donor cells. Our findings from mouse and human lung transplant data support the notion that a donor's smoking history does not predispose to acute cellular rejection or prevent the establishment of allograft acceptance with comparable outcomes to nonsmoking donors. Thus, our work indicates that BALT in donor lungs is plastic in nature and may have important implications for modulating proinflammatory or tolerogenic immune responses following transplantation.

Developing machine learning models to predict primary graft dysfunction after lung transplantation.

Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality in the first 30 days after lung transplantation. Risk factors for the development of PGD include donor and recipient characteristics, but how multiple variables interact to impact the development of PGD and how clinicians should consider these in making decisions about donor acceptance remain unclear. This was a single-center retrospective cohort study to develop and evaluate machine learning pipelines to predict the development of PGD grade 3 within the first 72 hours of transplantation using donor and recipient variables that are known at the time of donor offer acceptance. Among 576 bilateral lung recipients, 173 (30%) developed PGD grade 3. The cohort underwent a 75% to 25% train-test split, and lasso regression was used to identify 11 variables for model development. A K-nearest neighbor's model showing the best calibration and performance with relatively small confidence intervals was selected as the final predictive model with an area under the receiver operating characteristics curve of 0.65. Machine learning models can predict the risk for development of PGD grade 3 based on data available at the time of donor offer acceptance. This may improve donor-recipient matching and donor utilization in the future.

Exposure to Agent Orange is associated with increased recurrence after surgical treatment of stage I non-small cell lung cancer.

OBJECTIVE: Approximately 3 million Americans served in the armed forces during the Vietnam War. Veterans have a higher incidence rate of lung cancer compared with the general population, which may be related to exposures sustained during service. Agent Orange, one of the tactical herbicides used by the armed forces as a means of destroying crops and clearing vegetation, has been linked to the development of several cancers including non-small cell lung cancer. However, traditional risk models of lung cancer survival and recurrence often do not include such exposures. We aimed to examine the relationship between Agent Orange exposure and overall survival and disease recurrence for surgically treated stage I non-small cell lung cancer. METHODS: We performed a retrospective cohort study using a uniquely compiled dataset of US Veterans with pathologic I non-small cell lung cancer. We included adult patients who served in the Vietnam War and underwent surgical resection between 2010 and 2016. Our 2 comparison groups included those with identified Agent Orange exposure and those who were unexposed. We used multivariable Cox proportional hazards and Fine and Gray competing risk analyses to examine overall survival and disease recurrence for patients with pathologic stage I disease, respectively. RESULTS: A total of 3958 Vietnam Veterans with pathologic stage I disease were identified (994 who had Agent Orange exposure and 2964 who were unexposed). Those who had Agent Orange exposure were more likely to be male, to be White, and to live a further distance from their treatment facility (P < .05). Tumor size distribution, grade, and histology were similar between cohorts. Multivariable Cox proportional hazards modeling identified similar overall survival between cohorts (Agent Orange exposure hazard ratio, 0.97; 95% CI, 0.86-1.09). Patients who had Agent Orange exposure had a 19% increased risk of disease recurrence (hazard ratio, 1.19; 95% CI, 1.02-1.40). CONCLUSIONS: Veterans with known Agent Orange exposure who undergo surgical treatment for stage I non-small cell lung cancer have an approximately 20% increased risk of disease recurrence compared with their nonexposed counterparts. Agent Orange exposure should be taken into consideration when determining treatment and surveillance regimens for Veteran patients.

SPOT: Scanning plant IoT facility for high-throughput plant phenotyping.

Many plant phenotyping platforms have been kept out of the reach of smaller labs and institutions due to high cost and proprietary software. The Scanning Plant IoT (SPOT) Facility, located at the University of Florida, is a mobile, laboratory-based platform that facilitates open-source collection of high-quality, interoperable plant phenotypic data. It consists of three main sensors: a hyperspectral sensor, a thermal camera, and a LiDAR camera. Real-time data from the sensors can be collected in its 10 ft. × 10 ft. scanning region. The mobility of the device allows its use in large growth chambers, environmentally controlled rooms, or greenhouses. Sensors are oriented nadir and positioned via computer numerical control of stepper motors. In a preliminary experiment, data gathered from SPOT was used to autonomously and nondestructively differentiate between cultivars.

Tocilizumab for antibody-mediated rejection treatment in lung transplantation.

Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR.

Utilizing computed tomography volumetry for size matching prior to lung transplantation: a case series.

Background: Appropriate size matching between donor and recipient is critical for successful pulmonary transplantation. Although surrogate measurements such as height and gender are often utilized to approximate predicted lung volume, these methods provide only a gross estimation with wide variability and poor predictive value. Case Description: A single center exploratory study was conducted in which four patients underwent lung transplantation (LT) with pre-operative computed tomography (CT) volumetry obtained in both the donor and recipient to facilitate decision making regarding organ size and suitability. In four cases in which CT volumetry was used, the lung volumes calculated using surrogate measurements significantly overestimated both donor and recipient lung volumes quantified by CT volumetric analysis. All recipients underwent successful LT without necessary graft downsizing. Conclusions: This is an initial report of prospectively utilizing CT volumetry as an adjunct to decision-making regarding suitability of donor lungs. In these cases, CT volumetry facilitated the confident acceptance of donor lungs that were initially predicted to be oversized based on other clinical measures.

Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer.

BACKGROUND: Risk factors contributing to more than 10-fold increase in esophageal cancer in the last 50 years remain underexplored. We aim to examine the associations of sleep behaviors with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). METHODS: We prospectively assessed the associations between sleep behaviors (chronotype, duration, daytime napping, daytime sleepiness, snoring, and insomnia) and EAC and ESCC risk in 393,114 participants in the UK Biobank (2006-2016). Participants with 0, 1, and ≥2 unhealthy behaviors, including sleep <6 or >9 h/d, daytime napping, and usual daytime sleepiness were classified as having a good, intermediate, and poor sleep. For EAC, we also examined interactions with polygenic risk score (PRS). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We documented 294 incident EAC and 95 ESCC. Sleep >9 h/d (HR, 2.05; 95% CI, 1.18-3.57) and sometimes daytime napping (HR, 1.36; 95% CI, 1.06-1.75) were individually associated with increased EAC risk. Compared with individuals with good sleep, those with intermediate sleep had a 47% (HR, 1.47; 95% CI, 1.13-1.91) increased EAC risk, and those with poor sleep showed an 87% (HR, 1.87; 95% CI, 1.24-2.82) higher risk (Ptrend < 0.001). The elevated risks for EAC were similar within strata of PRS (Pinteraction = 0.884). Evening chronotype was associated with elevated risk of ESCC diagnosed after 2 years of enrollment (HR, 2.79; 95% CI, 1.32-5.88). CONCLUSIONS: Unhealthy sleep behaviors were associated with an increased risk of EAC, independent of genetic risk. IMPACT: Sleep behaviors may serve as modifiable factors for the prevention of EAC.

Potential Role of Computed Tomography Volumetry in Size Matching in Lung Transplantation.

BACKGROUND: Accumulated knowledge on the outcomes related to size mismatch in lung transplantation derives from predicted total lung capacity equations rather than individualized measurements of donors and recipients. The increasing availability of computed tomography (CT) makes it possible to measure the lung volumes of donors and recipients before transplantation. We hypothesize that CT-derived lung volumes predict a need for surgical graft reduction and primary graft dysfunction. METHODS: Donors from the local organ procurement organization and recipients from our hospital from 2012 to 2018 were included if their CT exams were available. The CT lung volumes and plethysmography total lung capacity were measured and compared with predicted total lung capacity using Bland Altman methods. We used logistic regression to predict the need for surgical graft reduction and ordinal logistic regression to stratify the risk for primary graft dysfunction. RESULTS: A total of 315 transplant candidates with 575 CT scans and 379 donors with 379 CT scans were included. The CT lung volumes closely approximated plethysmography lung volumes and differed from the predicted total lung capacity in transplant candidates. In donors, CT lung volumes systematically underestimated predicted total lung capacity. Ninety-four donors and recipients were matched and transplanted locally. Larger donor and smaller recipient lung volumes estimated by CT predicted a need for surgical graft reduction and were associated with higher primary graft dysfunction grade. CONCLUSION: The CT lung volumes predicted the need for surgical graft reduction and primary graft dysfunction grade. Adding CT-derived lung volumes to the donor-recipient matching process may improve recipients' outcomes.

Characteristics of donor lungs declined on site and impact of lung allocation policy change.

OBJECTIVE: National and institutional data suggest an increase in organ discard rate (donor lungs procured but not implanted) after a new lung allocation policy was introduced in 2017. However, this measure does not include on-site decline rate (donor lungs declined intraoperatively). The objective of this study is to examine the impact of the allocation policy change on on-site decline. METHODS: We used a Washington University (WU) and our local organ procurement organization (Mid-America Transplant [MTS]) database to abstract data on all accepted lung offers from 2014 to 2021. An on-site decline was defined as an event in which the procuring team declined the organs intraoperatively, and the lungs were not procured. Logistic regression models were used to investigate potentially modifiable reasons for decline. RESULTS: The overall study cohort comprised 876 accepted lung offers, of which 471 donors were at MTS with WU or others as the accepting center and 405 at other organ procurement organizations with WU as the accepting center. At MTS, the on-site decline rate increased from 4.6% to 10.8% (P = .01) after the policy change. Given the greater likelihood of non-local organ placement and longer travel distance after policy change, the estimated cost of each on-site decline increased from $5727 to $9700. In the overall group, latest partial pressure of oxygen (odds ratio [OR], 0.993; 95% confidence interval [CI], 0.989-0.997), chest trauma (OR, 2.474; CI, 1.018-6.010), chest radiograph abnormality (OR, 2.902; CI, 1.289-6.532), and bronchoscopy abnormality (OR, 3.654; CI, 1.813-7.365) were associated with on-site decline, although lung allocation policy era was unassociated (P = .22). CONCLUSIONS: We found that nearly 8% of accepted lungs are declined on site. Several donor factors were associated with on-site decline, although lung allocation policy change did not have a consistent impact on on-site decline.

Development and validation of the lung donor (LUNDON) acceptability score for pulmonary transplantation.

There is a chronic shortage of donor lungs for pulmonary transplantation due, in part, to low lung utilization rates in the United States. We performed a retrospective cohort study using data from the Scientific Registry of Transplant Recipients database (2006-2019) and developed the lung donor (LUNDON) acceptability score. A total of 83 219 brain-dead donors were included and were randomly divided into derivation (n = 58 314, 70%) and validation (n = 24 905, 30%) cohorts. The overall lung acceptance was 27.3% (n = 22 767). Donor factors associated with the lung acceptance were age, maximum creatinine, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen, mechanism of death by asphyxiation or drowning, history of cigarette use (≥20 pack-years), history of myocardial infarction, chest x-ray appearance, bloodstream infection, and the occurrence of cardiac arrest after brain death. The prediction model had high discriminatory power (C statistic, 0.891; 95% confidence interval, 0.886-0.895) in the validation cohort. We developed a web-based, user-friendly tool (available at https://sites.wustl.edu/lundon) that provides the predicted probability of donor lung acceptance. LUNDON score was also associated with recipient survival in patients with high lung allocation scores. In conclusion, the multivariable LUNDON score uses readily available donor characteristics to reliably predict lung acceptability. Widespread adoption of this model may standardize lung donor evaluation and improve lung utilization rates.

Pulmonary Carcinoid Tumorlet in the Explanted Lungs for Lung Transplantation: A Case Series of 15 Patients.

BACKGROUND: Pulmonary carcinoid tumorlet (PCT) is defined as small proliferation of neuroendocrine cells that invade the adjacent basement membrane. It is often associated with chronic pulmonary inflammatory processes. However, the characteristics of PCT in end-stage lung diseases remain unclear. METHODS: We conducted a retrospective cohort study of the explanted lungs after transplantation at our institution between January 1999 and October 2020. Patients who underwent re-transplantation were excluded. RESULTS: Pulmonary carcinoid tumorlet was incidentally discovered in the explanted lungs from 15 patients (1.1%) out of 1367 lung transplants performed during the study period. Nine patients (60.0 %) were women, with a median age of 59 years (IQR: 57-62) at transplant. Underlying pulmonary indications for lung transplantation were chronic obstructive pulmonary disease (9/15, 60.0%), interstitial lung disease (2/15, 13.0%), pulmonary vascular disease (2/15, 13.0%), alpha-1 antitrypsin deficiency (1/15, 7.0%), and bronchiectasis (1/15, 7.0%). Of the patients who underwent bilateral lung transplantation (13/15, 86.7%), PCT was found in the right lung in 10 patients (10/13, 76.9%). Thirteen patients had one lesion, 1 patient had 2 lesions and 1 patient had multiple lesions. CONCLUSION: Our study shows that PCT is generally uncommon, but when it occurs, it occurs more frequently on the right side and in female patients with end-stage pulmonary disease. Chronic obstructive pulmonary disease may be a predisposing factor for developing PCT.