Resection of the irradiated esophagus: the impact of lymph node yield on survival.

There is debate surrounding the appropriate threshold for lymph node harvest during esophagectomy in patients with esophageal cancer, specifically for those receiving preoperative radiation. The purpose of this study was to determine the impact of lymph node yield on survival in patients receiving preoperative chemoradiation for esophageal cancer. The National Cancer Database (NCDB) was utilized to identify patients with esophageal cancer that received preoperative radiation. The cohort was divided into patients undergoing minimal (<9) or extensive (≥9) lymph node yield. Demographic, operative, and postoperative outcomes were compared between the groups. Kaplan-Meier analysis with the log rank test was used to compare survival between the yield groups. Cox proportional hazards model was used to determine the association between lymph node yield and survival. In total, 886 cases were included: 349 (39%) belonging to the minimal node group and 537 (61%) to the extensive group. Unadjusted 5-year survival was similar between the minimal and extensive groups, respectively (37.3% vs. 38.8%; P > 0.05). After adjustment using Cox regression, extensive lymph node yield was associated with survival (hazard ratio 0.80, confidence interval 0.66-0.98, P = 0.03). This study suggests that extensive lymph node yield is advantageous for patients with esophageal cancer undergoing esophagectomy following induction therapy. This most likely reflects improved diagnosis and staging with extensive yield.

Immunophenotyping of cerebrospinal fluid cells in ischaemic stroke.

BACKGROUND AND PURPOSE: Post-ischaemic immune cell invasion into the brain is well characterized in animal stroke models and contributes to neuronal damage. Therefore, it represents a promising therapeutic target. Cerebrospinal fluid (CSF) is easily accessible and may reflect cellular events within the parenchyma. However, comprehensive studies on CSF immune cells in patients with stroke are lacking. METHODS: In a retrospective cohort study, we performed extensive immune-cell profiling in CSF and peripheral blood of patients with acute ischaemic stroke and healthy controls. In patients with stroke, infarct size was quantified on follow-up imaging. RESULTS: Overall, 90 patients with ischaemic stroke and 22 controls were included in our study. After stroke, the total protein was increased (537.3 vs. 353.2 mg/L, P = 0.008) and the mean total white cell count was slightly but non-significantly elevated (1.76 vs. 0.50 cells/µL, P = 0.059). Proportions of CSF lymphocytes, monocytes and granulocytes and their respective subsets did not differ between patients with stroke and controls. In addition, there were no associations between proportions of major leukocyte subsets in CSF and the time from symptom onset to CSF sampling, infarct size or infarct localization. CONCLUSIONS: Ischaemic stroke induces only a very slight increase of CSF immune cells without changes in the composition of immune cell subsets, thus indicating that parenchymal inflammation is not sufficiently reflected in the CSF. Our findings suggest that CSF is not a major invasion route for immune cells and that CSF cell analyses are not suitable as biomarkers to guide future immune therapies for stroke.

Gastroesophageal reflux symptoms are not sufficient to guide esophageal function testing in lung transplant candidates.

Gastroesophageal reflux disease and esophageal dysmotility are prevalent in patients with advanced lung disease and are associated with graft dysfunction following lung transplantation. As a result, many transplant centers perform esophageal function testing as part of the wait-listing process but guidelines for testing in this population are lacking. The aim of this study is to describe whether symptoms of gastroesophageal reflux correlate with abnormal results on pH-metry and high-resolution manometry and can be used to identify those who require testing. We performed a retrospective cohort study of 226 lung transplant candidates referred for high-resolution manometry and pH-metry over a 12-month period in 2015. Demographic data, results of a standard symptom questionnaire and details of esophageal function testing were obtained. Associations between the presence of symptoms and test results were analyzed using Fisher's exact tests and multivariable logistic regression. The most common lung disease diagnosis was interstitial lung disease (N = 131, 58%). Abnormal pH-metry was seen in 116 (51%) patients and the presence of symptoms was significantly associated with an abnormal study (p < 0.01). Dysmotility was found in 98 (43%) patients, with major peristaltic or esophageal outflow disorders in 45 (20%) patients. Symptoms were not correlated with findings on esophageal high-resolution manometry. Fifteen of 25 (60%) asymptomatic patients had an abnormal manometry or pH-metry. These results demonstrate that in patients with advanced lung disease, symptoms of gastroesophageal reflux increase the likelihood of elevated acid exposure on pH-metry but were not associated with dysmotility. Given the proportion of asymptomatic patients with abnormal studies and associated post-transplant risks, a practice of universal high-resolution manometry and pH-metry testing in this population is justifiable.

Lung Transplant Center Volume Ameliorates Adverse Influence of Prolonged Ischemic Time on Mortality.

The influence of prolonged ischemic time on outcomes after lung transplant is controversial, but no research has investigated ischemic time in the context of center volume. We used data from the United Network for Organ Sharing to estimate the influence of ischemic time on patient survival conditional on center volume in the post-lung allocation score era (2005-2015). The analytic sample included 14 877 adult lung transplant recipients, of whom 12 447 were included in multivariable survival analysis. Patient survival was improved in high-volume centers compared with low-volume centers (log-rank test p = 0.001), although mean ischemic times were longer at high-volume centers (5.16 ± 1.70 h vs. 4.83 ± 1.63 h, p < 0.001). Multivariable Cox proportional hazards regression stratified by transplant center found an adverse influence of longer ischemic time at low-volume centers but not at high-volume centers. At centers performing 50 transplants in the period 2005-2015, for example, 8 versus 6 h of ischemia were associated with an 18.9% (95% confidence interval 6.5-32.7%; p < 0.001) greater mortality hazard, whereas at centers performing 350 transplants in this period, no differences in survival by ischemic time were predicted. Despite longer mean ischemic time at high-volume transplant centers, these centers had favorable patient outcomes and no adverse survival implications of prolonged ischemia.

Staging of Bilateral Lung Transplantation for High-Risk Patients With Interstitial Lung Disease: One Lung at a Time.

The choice of a single or bilateral lung transplant for interstitial lung disease (ILD) is controversial, as surgical risk, long-term survival and organ allocation are competing factors. In an effort to balance risk and benefit, our center adopted a staged bilateral lung transplant approach for higher surgical risk ILD patients where the patient has a single lung transplant followed by a second single transplant at a later date. We sought to understand the surgical risk, organ allocation and early outcomes of these staged bilateral recipients as a group and in comparison to matched single and bilateral recipients. Our analysis demonstrates that staged bilateral lung transplant recipients (n = 12) have a higher lung allocation score (LAS), lower pulmonary function tests and a lower glomerular filtration rate prior to the first transplant compared to the second (p < 0.01). There was a shorter length of hospital stay for the second transplant (p = 0.02). The staged bilateral compared to the single and bilateral case-matched controls had comparable short-term survival (p = 0.20) and pulmonary function tests at 1 year. There was a higher incidence of renal injury in the conventional bilateral group compared to the single and staged bilateral groups. The staged bilateral procedure is a viable option in select ILD patients.

Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

Induction chemoradiation therapy prior to esophagectomy is associated with superior long-term survival for esophageal cancer.

The purpose of this study was to examine the role of induction chemoradiation in the treatment of potentially resectable locally advanced (T2-3N0 and T1-3N+) esophageal cancer utilizing a large national database. The National Cancer Data Base (NCDB) was queried for all patients undergoing esophagectomy for clinical T2-3N0 and T1-3N+ esophageal cancer of the mid- or lower esophagus. Patients were stratified by the use of induction chemoradiation therapy versus surgery-first. Trends were assessed with the Cochran-Armitage test. Predictors of receiving induction therapy were evaluated with multivariable logistic regression. A propensity-matched analysis was conducted to compare outcomes between groups, and the Kaplan-Meier method was used to estimate long-term survival. Within the NCDB, 7921 patients were identified, of which 6103 (77.0%) were treated with chemoradiation prior to esophagectomy, while the remaining 1818 (23.0%) were managed with surgery-first. Use of induction therapy increased over time, with an absolute increase of 11.8% from 2003-2011 (P < 0.001). As revealed by the propensity model, induction therapy was associated with higher rates of negative margins and shorter hospital length of stay, but no differences in unplanned readmission and 30-day mortality rates. In unadjusted survival analysis, induction therapy was associated with better long-term survival compared to a strategy of surgery-first, with 5-year survival rates of 37.2% versus 28.6%, P < 0.001. Following propensity score matching analysis, the use of induction therapy maintained a significant survival advantage over surgery-first (5-year survival: 37.9% vs. 28.7%, P < 0.001). Treatment with induction chemoradiation therapy prior to surgical resection is associated with significant improvement in long-term survival, even after adjusting for confounders with a propensity model. Induction therapy should be considered in all medically appropriate patients with resectable cT2-3N0 and cT1-3N+ esophageal cancer, prior to esophagectomy.

Antibody desensitization therapy in highly sensitized lung transplant candidates.

As HLAs antibody detection technology has evolved, there is now detailed HLA antibody information available on prospective transplant recipients. Determining single antigen antibody specificity allows for a calculated panel reactive antibodies (cPRA) value, providing an estimate of the effective donor pool. For broadly sensitized lung transplant candidates (cPRA ≥ 80%), our center adopted a pretransplant multi-modal desensitization protocol in an effort to decrease the cPRA and expand the donor pool. This desensitization protocol included plasmapheresis, solumedrol, bortezomib and rituximab given in combination over 19 days followed by intravenous immunoglobulin. Eight of 18 candidates completed therapy with the primary reasons for early discontinuation being transplant (by avoiding unacceptable antigens) or thrombocytopenia. In a mixed-model analysis, there were no significant changes in PRA or cPRA changes over time with the protocol. A sub-analysis of the median fluorescence intensity (MFI) change indicated a small decline that was significant in antibodies with MFI 5000-10,000. Nine of 18 candidates subsequently had a transplant. Posttransplant survival in these nine recipients was comparable to other pretransplant-sensitized recipients who did not receive therapy. In summary, an aggressive multi-modal desensitization protocol does not significantly reduce pretransplant HLA antibodies in a broadly sensitized lung transplant candidate cohort.

Significance of and risk factors for the development of central airway stenosis after lung transplantation.

Central airways stenosis (CAS) after lung transplant is a poorly understood complication. Objectives of this study were to determine if CAS was associated with chronic rejection or worse survival after transplant as well as to identify factors associated with CAS in a large cohort of lung transplant recipients. Lung transplant recipients transplanted at a single center were retrospectively reviewed for the development of CAS requiring airway dilation. A total of 467 subjects met inclusion criteria with 60 (13%) of these developing CAS requiring intervention. Of these 60 recipients, 22 (37%) had resolution of CAS with bronchoplasty alone, while 32 (53%) ultimately required stent placement. CAS that required intervention was not a risk factor for the development of bronchiolitis obliterans syndrome or worse overall survival. Significant risk factors for the subsequent development of CAS in a time-dependant multivariable model were pulmonary fungal infections and the need for postoperative tracheostomy. While CAS was not associated with BOS or worse survival, it remains an important complication after lung transplant with potentially preventable risk factors.

Coronary revascularization in lung transplant recipients with concomitant coronary artery disease.

Coronary artery disease (CAD) is not uncommon among lung transplant candidates. Several small, single-center series have suggested that short-term outcomes are acceptable in selected patients who undergo coronary revascularization prior to, or concomitant with, lung transplantation. Our objective was to evaluate perioperative and intermediate-term outcomes in this patient population at our institution. We performed a retrospective, observational cohort analysis of 898 lung transplant recipients between 1997 and 2010. Pediatric, multivisceral, lobar or repeat transplantations were excluded, resulting in 791 patients for comparative analysis, of which 49 (median age 62, 79.6% bilateral transplant) underwent concurrent coronary artery bypass and 38 (median age 64, 63.2% bilateral transplant) received preoperative percutaneous coronary intervention (PCI). Perioperative mortality, overall unadjusted survival and adjusted hazard ratio for cumulative risk of death were similar among both revascularization groups as well as controls. The rate of postoperative major adverse cardiac events was also similar among groups; however, concurrent coronary artery bypass was associated with longer postoperative length of stay, more time in the intensive care unit and more postoperative days requiring ventilator support. These results suggest that patients with CAD need not be excluded from lung transplantation. Preferential consideration should be given to preoperative PCI when feasible.

A call to action in thoracic transplant surgical training.

Thoracic organ recovery and implantation is increasing in complexity. Simultaneously the logistic burden and associated cost is rising. An electronic survey distributed to the surgical directors of thoracic transplant programs in the United States indicated dissatisfaction amongst 72% of respondents with current procurement training and 85% of respondents favored a process for certification in thoracic organ transplantation. These responses highlight concerns for the current paradigm of training in thoracic transplantation. We discuss the implications of advancements in organ retrieval and implant for surgical training and propose that the thoracic transplant community might address the need through formalized training in procurement and certification in thoracic transplantation.

In the face of chronic aspiration, prolonged ischemic time exacerbates obliterative bronchiolitis in rat pulmonary allografts.

Aspiration of gastric fluid into the lung mediates the development of obliterative bronchiolitis (OB) in orthotopic WKY-to-F344 rat pulmonary transplants that have been subjected to immunosuppression with cyclosporine. However, the contribution of ischemic time to this process remains unknown. In this study, the effect of long (n = 16) and short (n = 12) ischemic times (average of 6 h and of 73 min, respectively) on rat lung transplants receiving aspiration of gastric fluid was assessed. Long ischemic times (LIT) led to significantly (p < 0.05) greater development of OB (ratio of OB lesions/total airways = 0.45 ± 0.07, mean ± standard error) compared to short ischemic times (ratio = 0.19 ± 0.05). However, the development of OB was dependent on aspiration, as controls receiving aspiration with normal saline showed little development of OB, regardless of ischemic time (p < 0.05). These data suggest that LIT, while insufficient by itself to lead to OB, works synergistically with aspiration of gastric fluid to exacerbate the development of OB.

Anticoagulation Strategies in the Perioperative Period for Lung Transplant.

Patients who are undergoing lung transplantation may require systemic anticoagulation in the perioperative period for various indications at the time of the procedure. Four-factor prothrombin complex concentrate has been approved in the United States to reverse the effects of warfarin for patients requiring urgent surgery. We describe a perioperative anticoagulation strategy with warfarin that is reversed before incision using 4-factor complex concentrate for off-pump lung transplant recipients.

Chronic aspiration of gastric fluid induces the development of obliterative bronchiolitis in rat lung transplants.

Long-term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY-to-F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha and TGF-beta in BAL and of IL-1 alpha, IL-4 and GM-CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration-related injuries might improve outcomes in clinical lung transplantation.

Robot-assisted repair of diaphragmatic hernias following ventricular assist device implantation.

Use of ventricular assist devices (VADs) is increasingly common, as is the need for surgeons to be familiar with the management of common complications in this population. Nonetheless, repair of diaphragmatic hernias which commonly develop following VAD implantation remains technically challenging due to intra-abdominal adhesions and the proximity of vital structures. Despite the potential benefits of improved dexterity and visualization, robotic approaches have thus far not been used to address this. We present the first two described cases of robot-assisted repair of diaphragmatic hernias in the setting of prior or current VAD placement.

Maintenance immunotherapy by repetitive low-dose donor lymphocytes infusions in a child with relapse state aml after allogeneic stem cell transplantation.

The treatment of a child with a relapsed state acute leukemia after allogeneic stem cell transplantation (allo-SCT) is a challenge. The authors report about a child with an acute myelogenous leukemia (AML), which relapsed after allo-SCT despite immunological intervention. It was further treated with a second line chemotherapy followed by an infusion of stem cells and donor lymphocytes. Because of an immense risk for a further relapse, an immunological maintenance therapy was also performed, consisting of repetitive infusions of low doses of donor lymphocytes combined with low-dose chemotherapy. Presently, the child is in continuous complete remission and has a good quality of life.

Reliability and validity of cardiovascular and vasomotor autonomic function tests.

OBJECTIVE: To determine the reliability and validity of autonomic function tests (AFTs) as clinical tools for diagnosing diabetic autonomic dysfunction. RESEARCH DESIGN AND METHODS: Twenty-one healthy control subjects and 21 insulin-dependent diabetes mellitus (IDDM) patients (11 with no symptomatology and 10 with symptomatic diabetic autonomic neuropathy [DAN]) were matched for age, and administered three standard cardiovascular tests and two new vasomotor tests of autonomic function. Each of the cardiovascular tests (change in heart rate [delta bpm], Valsalva ratio [VR], change in systolic blood pressure [delta sBP]) and vasomotor tests (total pulse amplitude [TPA] and percent vasoconstriction [%VC]) were repeated within 1 week. Infrared photoplethysmography measured sympathetic-mediated vasomotor function. Reliability was determined by intraclass correlation coefficients. Validity was determined by analysis of variance procedures to test for differences between known groups and by computing sensitivity, specificity, and positive and negative predictive values. RESULTS: All AFTs were reliable, with %VC having highest reproducibility (r = 0.90). AFT scores were not different from time 1 to time 2. After controlling for age, two cardiovascular tests had significantly different values for control subjects and asymptomatic diabetic patients. AFTs, except delta sBP, were significantly different between symptomatic diabetic patients and asymptomatic diabetic patients after controlling for age and duration of disease simultaneously. Sensitivity, specificity, and predictive values for %VC were comparable to the values for delta bpm and VR. TPA indexes were lower but clinically acceptable. CONCLUSIONS: AFTs were found to be reliable and valid tests for detecting DAN. TPA and %VC are important because they measure an aspect of sympathetic function not assessed by standard cardiovascular AFTs, and they do not depend on the patient's cooperation or ability to exert effort.

Immune control of mammalian aging: a T-cell model.

A competent immune response appears to play an important role in retarding aging. On the other hand, the aged immune system is assumed to accelerate the general aging process. In order to approach the underlying mechanism of this paradoxical immune response, the process of clonal deletion in the thymus is addressed under the aspect of aging. It is assumed that T-cell deletion in the thymus brings about a control of cell differentiation in the organism. For proper functioning, this control is suggested to be directed, in the sense of a feedback mechanism, primarily to thymic stromal cells involved in the process of clonal deletion. At the expense of a thymus atrophy, the control system can retard aging up into the reproductive period of life. With the progress of thymic involution, however, the control is predetermined to undergo a breakdown and, in consequence, through loss of self-tolerance it speeds up the whole aging process.

On a causal mechanism of chronic thymic involution in man.

The age-associated chronic thymus involution is interpreted to occur due to cytolytic depletion of thymic stromal tissue whose cells present altered self-peptides. Using simplified assumptions and based on morphometric data on thymic involution in man, the chance for a single protein to be altered is estimated to be in the range of 2-4 x 10(-6) per year. The corresponding mutation rate is compatible with that derived from both evolutionary and direct studies, thus supporting the proposed model.

Age-related changes of DNA winding and repair in human peripheral lymphocytes.

Superhelical density and incision capacity for UV light-induced damage have been studied in nuclear DNA of human peripheral lymphocytes as a function of donor age. With advancing age between 20 and 90 years the content of negative superhelical turns increases, whereas the ability to incise UV lesions is impaired. These data may be suggestive of an immature lymphoid cell state arising in aging.