Search

Robotic thymectomy is an emerging treatment for myasthenia gravis. However, the Myasthenia Gravis Foundation of America clinical research standards have been infrequently adopted in the surgical literature.Twenty-six patients underwent robotic thymectomy for myasthenia gravis between 2003 and 2008, performed by a single surgeon using the da Vinci system (Intuitive Surgical; Sunnyvale, CA) through a four-port right-sided approach.Mean operative times were 68+/-25 minutes of robotic system activation and 127+/-35 minutes from incision to closure. There were no intraoperative or postoperative mortalities; the most common intraoperative complication was desaturation after single-lung ventilation, for which four procedures were converted to open. On histologic examination, there were five thymomas. The average follow-up after surgery was 26 months. Median preoperative and postoperative Myasthenia Gravis Foundation of America disease classifications were 2 and 0, respectively, reflecting a statistically significant decrease in symptoms (p0.01). Additionally, the average daily dose of cholinesterase inhibitor decreased by 63% postoperatively. Overall, 82% of patients improved and 18% were unchanged; no worsening disease was observed.Robotic thymectomy is a safe and efficacious treatment option for myasthenia gravis. There were no notable differences in patient demographics compared with previously published reports of open thymectomies. Furthermore, surgical and neurologic outcomes in this series compare favorably with conventional approaches in the literature. Of those with follow-up greater than 6 months, 82% of patients undergoing robotic thymectomy demonstrated significant clinical improvement postoperatively, indicating that this approach in concert with optimized medical management is an effective treatment for myasthenia gravis.

Oxidative stress is increased in the myocardium following infarction and plays a significant role in death of cardiac myocytes, leading to cardiac dysfunction. Levels of the endogenous antioxidant Cu/Zn-superoxide dismutase (SOD1) decrease following myocardial infarction. While SOD1 gene therapy studies show promise, trials with SOD1 protein have had little success due to poor pharmacokinetics and thus new delivery vehicles are needed. In this work, polyketal particles, a recently developed delivery vehicle, were used to make SOD1-encapsulated-microparticles (PKSOD). Our studies with cultured macrophages demonstrated that PKSOD treatment scavenges both intracellular and extracellular superoxide, suggesting efficient delivery of SOD1 protein to the inside of cells. In a rat model of ischemia/reperfusion (IR) injury, injection of PKSOD, and not free SOD1 or empty particles was able to scavenge IR-induced excess superoxide 3 days following infarction. In addition, only PKSOD treatment significantly reduced myocyte apoptosis. Further, PKSOD treatment was able to improve cardiac function as measured by acute changes in fractional shortening from baseline echocardiography, suggesting that sustained delivery of SOD1 is critical during the early phase of cardiac repair. These data demonstrate that delivery of SOD1 with polyketals is superior to free SOD1 protein therapy and may have potential clinical implications.

Objective We hypothesized that most relapses in patients with esophageal cancer having neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields. Methods Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who had esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years. Results Of 267 patients, 82 (30.7%) showed complete response to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) showing partial response or no response, respectively. Recurrence developed in 84 patients (patients with complete response 18/82, 21.4%; patients with partial response 39/108, 36.1%; patients with no response 27/77, 35.1%; P = .055, respectively). Most patients had recurrences at distant sites (65/84;77.4%) regardless of pathologic response, and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for patients with partial response or no response, but was longer for patients with complete response with distant recurrence, whose median disease-free survival was 27.3 months (P = .008). By multivariate analysis, no other factor except for pathologic response to neoadjuvant therapy was associated with disease recurrence or death. Patients with partial response or no response were 1.97 and 2.23 times more likely to have recurrence than patients with complete response (P = .024 and P = .012, respectively). Conclusions Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathologic response. Fewer patients achieving complete response had recurrences, and distant recurrences in these patients manifest later than in patients showing partial response and those showing no response. Only pathologic response is significantly associated with disease recurrence, suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-beta, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-beta is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-beta induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-beta may be involved in the development of scleroderma-associated pulmonary hypertension.

New adjuvants and delivery strategies are needed to optimize the ability of protein-based vaccines to elicit CD8(+) T cell responses. We have developed a model vaccine formulation containing ovalbumin (OVA) and the double-stranded RNA analog poly(inosinic acid)-poly(cytidylic acid) (poly(I:C)), a TLR3 agonist. OVA and poly(I:C) were each ion-paired to cetyltrimethylammonium bromide (CTAB) to produce hydrophobic complexes, which were co-encapsulated in pH-sensitive polyketal (PK3) microparticles (1-3 microm) using a single emulsion method. Loading levels ranged from 13.6 to 18.8 microg/mg OVA and 4.8 to 10.3 microg/mg poly(I:C). Murine splenic dendritic cells (DCs) pulsed with PK3-OVA-poly(I:C) microparticles, at antigen doses of 0.01 and 0.1 microg/mL, induced a higher percentage of IFNgamma-producing CD8(+) T cells than DCs treated with PK3-OVA particles or soluble OVA/poly(I:C). A higher antigen dose (1 microg/mL) was less effective, which can be attributed to CTAB toxicity. At the lowest antigen dose (0.01 microg/mL), PK3-OVA-poly(I:C) microparticles also enhanced TNF-alpha and IL-2 production in CD8(+) T cells. These data demonstrate the potential of polyketal microparticles in formulating effective CD8(+) T cell-inducing vaccines comprising protein antigens and dsRNA adjuvants.

Acute inflammatory diseases are a major cause of death in the world, and effective treatments are greatly needed. Macrophages play a central role in causing acute inflammatory diseases, and there is currently great interest in developing drug delivery vehicles that can target therapeutics to macrophages. Microparticles formulated from aliphatic polyketals have great potential to enhance the treatment of acute inflammatory diseases, due to their ability to passively target therapeutics to macrophages, their acid sensitivity, and their biocompatible degradation products. However, existing aliphatic polyketals are unsuitable for treating acute inflammatory diseases because they require weeks to hydrolyze, and strategies for accelerating their hydrolysis kinetics are greatly needed. In this report, we demonstrate that the hydrolysis kinetics of aliphatic polyketals can be accelerated by increasing their hydrophilic/hydrophobic balance. Aliphatic polyketals of varying hydrophobicity were synthesized, via the acetal exchange reaction, and their hydrolysis kinetics were investigated at the pH values of 4.5 and 7.4. A polyketal termed PK3 was developed, which had the hydrolysis kinetics suitable for treating acute inflammatory diseases. PK3 has a hydrolysis half-life of 2 days at pH 4.5, but requires several weeks to hydrolyze at pH 7.4. Microparticles were formulated with PK3, which encapsulated the anti-inflammatory drug, imatinib. In vivo experiments demonstrated that PK3 microparticles were able to significantly improve the efficacy of imatinib in treating acute liver failure. We anticipate that aliphatic polyketals will have numerous applications for the treatment of acute inflammatory diseases, given their pH sensitivity, tunable hydrolysis kinetics, and biocompatible degradation products.

Background: Despite optimal and early surgical treatment of non-small-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor. Methods: Fifty-one patients with stage I NSCLC who underwent curative resection but who had a recurrence within 40 months after resection (case patients) were matched on the basis of age, NSCLC stage, sex, and date of surgery to 116 patients with stage I NSCLC who underwent curative resection but who did not have a recurrence within 40 months after resection (controls). We investigated whether the methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence. Results: In a multivariate model, promoter methylation of the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of p16 and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an odds ratio of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC. Conclusions: Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence. Copyright © 2008 Massachusetts Medical Society.

Complex esophageal reconstruction (CER) is defined as restoring esophageal continuity in a previously operated field, using a nongastric conduit, or after esophageal diversion. This study compares the outcomes of CER with non-CER (NCER), which uses an undisturbed stomach for reconstruction.This single-institution retrospective cohort study compares 75 CERs with 75 NCERs from 1995 to 2014 that were matched for cancer versus benign disease. Distributions of demographic characteristics, comorbidities, and complications were compared between CER and NCER. Odds of mortality at 30 and 90 days were calculated with logistic regression. Overall survival was illustrated with Kaplan-Meier method and Cox proportional hazards regression.Although patients were similar in age, sex, and preoperative comorbidities, more non-white patients underwent CER (p = 0.04). Most NCER patients had adenocarcinoma (44%) or Barrett's high-grade dysplasia (39%); most CER patients had other benign disease (44%) or squamous cell carcinoma (24%, p0.01). CER had statistically significantly higher rates of reoperation, pneumonia, infection, and gastrointestinal complications, and longer median length of stay than NCER. Odds of mortality for CER and NCER at 30 days (odds ratio [OR] 1.0, 95% CI: 0.1 to 16.3), 90 days (OR 2.6, 95% CI: 0.5 to 13.9) and overall (adjusted hazard ratio 1.56, 95% CI: 0.9 to 2.7) were not statistically significantly different.Compared with NCER, CER patients had higher rates of return to the operating room, more postoperative infections and gastrointestinal complications, and longer length of stay. However, 30-day, 90-day, and overall survival were similar. CER should be offered to patients with acceptable risks and anticipated long-term survival.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

There is currently great interest in developing microparticles that can enhance the delivery of proteins to macrophages. In this communication, we present a new acid-sensitive polymer for drug delivery, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK). PCADK is designed to hydrolyze, after phagocytosis by macrophages, in the acidic environment of the phagosome and enhance the intracellular delivery of phagocytosed therapeutics. Other key attributes of PCADK for drug delivery are its well-characterized degradation products and straightforward synthesis. PCADK hydrolyzes into 1,4-cyclohexanedimethanol, a compound used in food packaging, and acetone, a compound on the FDA GRAS list. PCADK was synthesized using the acetal exchange reaction between 1,4-cyclohexanedimethanol and 2,2-dimethoxypropane, and could be obtained on a multigram scale in one step. The hydrolysis kinetics of the ketal linkages in PCADK were measured by 1H NMR and were determined to be pH-sensitive, having a half-life of 24.1 days at pH 4.5 and over 4 years at pH 7.4. The therapeutic enzyme superoxide dismutase (SOD), which scavenges reactive oxygen species, was encapsulated into PCADK-based microparticles using a double emulsion procedure. Cell culture experiments demonstrated that PCADK-based microparticles dramatically improved the ability of SOD to scavenge reactive oxygen species produced by macrophages. We anticipate numerous applications of PCADK in drug delivery, based on its acid sensitivity, well-characterized degradation products, and straightforward synthesis.

Purpose: This randomized phase II, parallel-design study evaluated preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients with resectable adenocarcinoma of the esophagus that were stage II or greater. The objectives of the trial were to determine pathologic complete response rate (pCR), overall response rate, progression-free survival, pattern of disease relapse, and two-year and overall survival. Patients and Methods: Preoperative staging included computed tomography, endoscopic ultrasound, and, when feasible, laparoscopy. Eligible patients were randomized to preoperative prinomastat or placebo, plus continuous infusion 5-FU, cisplatin, paclitaxel, and concurrent radiotherapy. Esophagectomy was performed on day 71. Adjuvant paclitaxel and prinomastat were available to all study patients. Results: Between August 2000 and June 2001, 15 of a planned 78 patients were randomized into the trial. One patient after randomization withdrew consent. Fourteen patients, 7 in each arm, completed preoperative treatment and surgery. pCR was achieved in 5 patients; 1/ 7 prinomastat and 4/ 7 placebo. Disease improvement was achieved in 7 patients; 5 /7 prinomastat and 2 /7 placebo. At a median follow-up of 28 months, 7 patients (2 prinomastat, 5 placebo) are alive with no evidence of disease. The primary prinomastat related toxicity was moderate to severe musculoskeletal toxicity interfering with daily function. This toxicity was managed with treatment rest, dose reduction, or discontinuation. Five patients (3 prinomastat and 2 placebo) had life-threatening thrombo-embolic events, which led to early evaluation of safety and efficacy, and subsequent termination of the study. Conclusions: All patients, regardless of treatment arm, were able to successfully undergo neoadjuvant combined modality therapy and esophagectomy. However, early closure of the study due to unexpected thrombo-embolic events precluded any conclusions regarding clinical activity of prinomastat in locally advanced esophageal cancer patients.

Objective Lung transplantation is a viable, life-saving intervention for several primary pulmonary disorders complicated by severe lung dysfunction. This study was undertaken to evaluate whether patients with systemic sclerosis (scleroderma), a systemic autoimmune rheumatic disorder, would receive similar benefit from this intervention. Methods Survival following lung transplantation was examined at 2 university medical centers among 29 patients with scleroderma as compared with 70 patients with idiopathic pulmonary fibrosis (IPF) and 38 with idiopathic pulmonary arterial hypertension (IPAH), the latter groups representing pathologically related primary pulmonary disorders. The end point was death from any cause. Risk of mortality in patients with scleroderma was compared with that in patients with IPF or IPAH, with adjustment for demographic and clinical parameters. Results During 2 years of followup, 11 patients with scleroderma (38%), 23 with IPF (33%), and 14 with IPAH (37%) died. Cumulative survival at 6 months posttransplantation was 69% in the scleroderma group compared with 80% in the IPF group (log-rank P = 0.21) and 79% in the IPAH group (P = 0.38). The estimated risk of mortality at 6 months was increased in patients with scleroderma compared with those with IPF (relative risk [RR] 1.70, 95% confidence interval [95% CI] 0.74–3.93) and those with IPAH (RR 1.52, 95% CI 0.59–3.96), but the differences were not statistically significant. Over the following 18 months, there was convergence in the survival rates such that cumulative survival at 2 years was comparable, at ∼64%, among all 3 groups. Conclusion Patients with scleroderma who are recipients of lung transplantation experience similar rates of survival 2 years after the procedure compared with those with IPF or IPAH. Lung transplantation may represent a viable therapeutic option to consider for patients with end-stage lung disease due to scleroderma.

Purpose: Histologically positive bronchial margins after resection for non-small cell lung cancer are associated with shortened patient survival due to local recurrence. We hypothesized that DNA promoter hypermethylation changes at bronchial margins could be detected in patients with no histological evidence of malignancy and that they would reflect epigenetic events in the primary tumor. Experimental Design: Bronchial margins, primary tumor, bronchoalveolar fluid, and paired nonmalignant lung were obtained from 20 non-small cell lung cancer patients who underwent a lobectomy or greater resection. Disease-specific recurrence was the primary end point. The methylation status of p16, MGMT, DAPK, SOCS1, RASSF1A, COX2, and RARβ was examined using methylation-specific polymerase chain reaction. Results: All malignancies had methylation in at least one locus. Concordance of one gene with an identical epigenetic change in the tumor or bronchial margin was observed in 85% of patients. Only one patient had methylation at the bronchial margin for a gene that was not methylated in the corresponding tumor. Median time to recurrence was 37 months (range, 5–71 months). There were two local recurrences and five metastases. There were no significant correlations between DNA methylation in tumor, margins, or bronchoalveolar fluid specimens and either regional recurrence or distant metastases. Conclusions: Histologically negative bronchial margins of resected non-small cell lung cancer exhibit frequent hypermethylation changes in multiple genes. These hyper-methylation abnormalities are also present in the primary tumor and thus may represent a field defect of preneoplastic changes that occurs early in carcinogenesis.

Background This study was performed to test the hypothesis that a history of other primary neoplasms before a lung cancer diagnosis increases the risk of subsequent malignancy. Methods Of 8363 lung cancer patients seen from 1978 to 2002, 881 (11%) had at least 1 previous nonlung primary malignancy. Charts were analyzed for the occurrence of subsequent malignancies. Results Lung cancer diagnosis in 881 patients consisted of 75% non–small cell, 12% small cell, and 13% other histologies. The median age was 66 years, with 56% male, 76% white, and 86% smokers. Of the 881 patients, 92% had no subsequent cancer (group 1), and 8% went on to experience the development of a new primary neoplasm (including lung) after their lung cancer (group 2). After adequate follow-up, the cumulative probability of developing a subsequent cancer did not differ markedly between those with and without a prior non–lung cancer diagnosis at 2 years (12% vs 10%) or 5 years (16% vs 15%). Group 1 patients had a significantly lower 1- and 5-year survival than group 2 patients (59% vs 48% and 29% vs 17%, respectively; P = .008). Although multivariate analysis suggested that stage, history of tobacco-associated neoplasm, and history of definitive surgical resection were important determinants in predicting long-term survival, a prior malignancy was not an independent risk factor in the development of subsequent malignancy. Conclusions The risk of developing a subsequent malignancy is very high in lung cancer patients with prior primary malignancies, but it is not markedly different from the risks experienced by patients with no prior malignancies.

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by α- and β-adrenoceptor antagonists. HSC from dopamine β-hydroxylase deficient (Dbh−/−) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh−/− mice, as evidenced by reduced hepatic accumulation of α-smooth muscle actin+ve HSC and decreased induction of transforming growth factor β1 (TGF-β1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-β1 and collagen, and increased liver fibrosis. Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.

From the Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md. Disclosures: Author has nothing to disclose with regard to commercial support. Received for publication Feb 26, 2016; accepted for publication Feb 27, 2016. Address for reprints: Stephen C. Yang, MD, Department of Surgery, The Johns Hopkins Medical Institutions, 600 N Wolfe St, Blalock 240, Baltimore, MD 21287 (E-mail: syang@jhmi.edu). J Thorac Cardiovasc Surg 2016;151:1559-60 0022-5223/$36.00 Copyright 2016 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2016.02.060

Background The morbidity of lung transplantation is higher than other solid organ transplants. Little is known about the outcomes of patients who require pulmonary resection following lung transplantation. We reviewed our experience to evaluate and discern any variables affecting outcome of pulmonary resections performed following lung transplantation. Methods A retrospective review of the lung transplant database was performed. Data are presented as mean ± standard error (median). Results A total of 136 lung transplants (80 single lung transplants [SLT], 55 bilateral lung transplants [BLT], and 3 heart-lung transplants [HLT]) were performed from August 1995 to February 2002. Twelve pulmonary resections, 7 lobectomies, and 5 wedge resections were performed on 11 patients. The indication for lobectomy was infection in 5 of 7 lobectomies (3 fungal, 2 bacterial), mass in 1 of 7, and infarction in 1 of 7. The indication for wedge resection was native lung hyperinflation in 4 of 5 wedge resections and mass in 1 of 5. The native lung was resected in 3 of 7 lobectomies and 4 of 5 wedge resections. An allograft lobectomy was performed following 1 SLT and 3 BLT and a wedge resection was performed after 1 SLT. The mean time to pulmonary resection was 12.4 ± 3.9 (9.1) months. Survival postresection was 17.2 ± 5.8 (8.3) months and 5 of 11 patients are still alive. There were no bronchial stump leaks following lobectomy. Conclusions Major pulmonary resections can safely be performed following lung transplant. We recommend early intervention to optimize outcomes.

The effect of tracheostomy on patients receiving lung transplantation is unknown. We reviewed our experience by performing a retrospective analysis on all lung transplant recipients at our institution. Patients were assigned to each study group based on whether or not they received a tracheostomy in the acute postoperative period. One hundred and fourteen lung transplants were performed, and 16 of those patients received a tracheostomy. In the tracheostomy group, more patients had undergone bilateral-lung transplantation (81% vs. 34%, p = 0.001), more required cardiopulmonary bypass (75% vs. 38%, p = 0.005), more acquired postoperative pneumonia (88% vs. 30%, p0.001), had greater reperfusion injury at 48 h (PaO2/FiO2 of 233 vs. 345, p = 0.047), had longer initial periods on the ventilator (21 +/- 7 vs. 2 +/- 0.5 days, p0.001), more required re-intubation (56% vs. 18%, p = 0.001), spent longer times in the intensive care unit (30 +/- 7 vs. 5.5 +/- 0.9 days, p0.001), and had longer lengths of stay (67 +/- 10 vs. 22 +/- 2 days, p0.001). Despite these differences between the two groups, a significant difference in survival at 180 days (75 vs. 81%) did not exist (p = 0.89). Although tracheostomy is more likely in sicker patients, it is not associated with poor long-term outcomes.

Bronchiolitis obliterans syndrome remains the leading cause of morbidity and mortality in the pulmonary transplant population. Previous studies show that macrolide antibiotics may be efficacious in the treatment of panbronchiolitis and cystic fibrosis. In the latter, azithromycin decreases the number of respiratory exacerbations, improves FEV1, and improves quality of life. We hypothesized that oral azithromycin therapy may improve lung function in patients with bronchiolitis obliterans syndrome. To test this hypothesis, we conducted an open-label pilot trial using maintenance azithromycin therapy in six lung transplant recipients (250 mg orally three times per week for a mean of 13.7 weeks). In this study, five of these six individuals demonstrated significant improvement in pulmonary function, as assessed by FEV1, as compared with their baseline values at the start of azithromycin therapy. The mean increase in the percentage of predicted FEV1 values in these individuals was 17.1% (p/= 0.05). In addition, the absolute FEV1 increased by 0.50 L (range -0.18 to 1.36 L). These data suggest a potential role for maintenance macrolide therapy in the treatment of bronchiolitis obliterans syndrome in lung transplant recipients.

Pulmonary eosinophilia is an uncommon problem in lung transplant recipients. We report the unique occurrence of two cases of pulmonary eosinophilia in pulmonary allografts for sarcoidosis. Both patients rapidly acquired bronchiolitis obliterans syndrome (BOS) after resolution of pulmonary eosinophilia. It is known that peripheral eosinophilia is a marker for pulmonary allograft rejection, but its potential in the pathogenesis of BOS is unclear.

Fibrous dysplasia causing thoracic outlet syndrome is rare. A 41-year-old woman presented with neurogenic thoracic outlet syndrome with imaging that demonstrated a large tumor of her proximal left first rib. Transaxillary excision was unsuccessful due to involvement of the subclavian vasculature and brachial plexus. Subsequent posterolateral thoracotomy and resection of her first rib revealed fibrous dysplasia. Thoracotomy should be considered in these cases for optimal vascular control and identification of thoracic outlet anatomy.

Severe reflux-induced esophagitis is a condition characterized by esophageal inflammation caused by acid and biliary reflux. The process leads to different degrees of esophageal damage with respective clinical presentations, which range from acute pain and severe debilitating dysphagia to life-threatening adenocarcinoma. Early intervention is essential in order to avoid irreversible damage, and since symptoms alone are not always reliable to identify progression of disease, it is important to monitor patients with predisposing risk factors. Depending on the severity of the disease, several options for treatment are available, ranging from medication to endoscopic and surgical therapy.

Purpose: Neoplastic polyps are common in the colon, but not elsewhere in the gastrointestinal tract. They are rare at the gastroesophageal junction, especially associated with Barrett’s dysplasia or adenocarcinoma. We identify a subset of early esophageal adenocarcinomas that present as symptomatic polyps with gastrointestinal bleeding, reflux, and even dysphagia. Because little is known about polypoid esophageal adenocarcinomas, we examine the clinical presentation, pathological features, and postoperative outcomes of these lesions. Methods: We defined esophageal polyps as macroscopic, well-demarcated projections above the mucosa that project the greater percentage of their mass into the lumen without central ulceration. From a consecutive series of 400 patients who underwent esophagectomies for adenocarcinoma (1988 to 2000), 14 (4%) had polyps on presentation. Clinical records, pathology reports, photographs, and original slides of these resected specimens were reviewed. Results: All patients with polyps had early staged esophageal adenocarcinomas. Lymph node involvement was found in only 4 patients, and no patients with distant metastases were found. All but 1 patient (13 of 14; 93%) were symptomatic at diagnosis. Most presented either with gastrointestinal bleeding or gastroesophageal reflux (11 of 14; 79%). Only 2 patients complained of mild dysphagia, and mean weight loss of the series was minimal at 1.3 ± 4.0 kg (range, 0 to 15 kg). Barrett’s was present in 10 patients (71%), and in 80% of these cases, high-grade dysplasia was found. The polyps were small 3.4 ± 1.1 cm, and most contained poorly differentiated adenocarcinomas. No postoperative mortalities occurred, and follow-up was complete at 100%. Actuarial 2-year survival was 88%, with a mean survival of 61.3 months. Recurrent disease was identified in 4 patients. Conclusions: Polypoid adenocarcinomas of the distal esophagus are a subset of esophageal cancer that produce clear symptoms at an early tumor stage, which allows prompt detection and favorable prognosis. Their pathological features and demographics suggest an origin via the Barrett’s esophagus-dysplasia-carcinoma sequence.

8508 Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24-63%) had a major pathologic response ( < 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT02259621.

Background Medical student exposure to cardiothoracic surgery has been facilitated by many scholarship opportunities. This study reviews the long-term interest of students at our institution who have received such support. Methods After the first or second year of medical school, participants were selected to receive scholarships for clinical or research activities in cardiothoracic surgery ranging from 4 to 8 weeks in duration. These were funded by the American Association for Thoracic Surgery, Society of Thoracic Surgeons, Southern Thoracic Surgical Association, or a private family donor. Over time, each student's scholarship type, current interest in cardiothoracic surgery, and current education or career status was prospectively monitored in an institutional database. Results Since 1999, 45 students received scholarships. Eight (18%) were funded by the American Association for Thoracic Surgery, two (4%) by The Society of Thoracic Surgeons one (2%) by the Southern Thoracic Surgical Association, and 34 (76%) by private donors. The median follow-up of graduated students is 7 years. Of the 20 (44%) with an active current interest in cardiothoracic surgery, 2 are faculty, 1 is a fellow, 1 is in an integrated 6-year program, 11 are in general surgery residency and are planning to apply to cardiothoracic surgery fellowship, and the remaining 5 are in medical school and planning a cardiothoracic surgery career. Of all former medical students who received cardiothoracic surgery research scholarships and who have now made a career choice, 17.4% chose cardiothoracic surgery. Conclusions More than one-third of medical students who received scholarships in cardiothoracic surgery maintained their interest over time, and more than half maintained interest in a surgical field. Although long-term data are scarce, it remains critical to foster mentoring relationships with students over time to guide their career choices.

Objective Readmission after surgery is an unwanted adverse event that is costly to the healthcare system. We sought to evaluate factors associated with increased risk of readmission and to characterize the nature of these readmissions in patients who have esophageal cancer. Methods A retrospective cohort study was performed in 306 patients with esophageal carcinoma who underwent neoadjuvant chemoradiation followed by esophagectomy at Johns Hopkins Hospital between 1993 and 2011. Logistic regression was used to identify factors associated with 30-day readmission. Readmissions were defined as inpatient admissions to our institution within 30 days of discharge. Results The median age at surgery was 61 years; the median postoperative length of stay was 9 days; and 48% of patients had ≥1 postoperative complication (POC). The 30-day readmission rate was 13.7% (42 of 306). In univariate analysis, length of stay and having ≥1 POC were significantly associated with readmission. In multivariate analysis, having ≥1 POC was significantly associated with a >2-fold increase in risk for 30-day readmission (odds ratio 2.35, with 95% confidence interval [1.08-5.09], P = .031) when controlling for age at diagnosis and length of stay. Of the 42 patients who were readmitted, 67% experienced POCs after surgery; 50% of patients who experienced POCs were readmitted for reasons related to their postoperative complication. The most common reasons for readmission were pulmonary issues (29%), anastomotic complications (20%), gastrointestinal concerns (17%), and venous thromboembolism (14%). Conclusions Complications not adequately managed before discharge may lead to readmission. Quality improvement efforts surrounding venous thromboembolism prophylaxis, and discharging patients nothing-by-mouth, may be warranted.

To move toward a competency-based residency curriculum, the Accreditation Council for Graduate Medical Education (ACGME) Outcome Project will use educational Milestones to assess residents' acquisition of competence for unsupervised practice, and will require measures of educational program effectiveness by assessing whether residents achieve certain specialty-specific Milestones in the 6 ACGME competencies. In January 2012, the American Board of Thoracic Surgery (ABTS) and the ACGME jointly formed a working group and charged it with developing the Thoracic Surgery Milestones. The development of the Milestones come at an important time, as the curricular and training paradigms in cardiothoracic surgery (CTS) have changed in recent years, and the Milestones will also be used to assess the success of these important changes.

Liposarcomas of the esophagus are rare with only 19 cases reported in the English literature. We present a giant, well-differentiated liposarcoma of the esophagus with multiple pedunculated polypoid-like growths, which made it radiographically and pathologically noncharacteristic. We discuss the diagnostic dilemmas, clinical and pathologic findings, and surgical treatment.

Background: Diagnostic laparoscopy has been used to determine resectability and to prevent unnecessary laparotomy in patients with advanced esophageal cancer. The objective of this prospective study was to evaluate the role of laparoscopy in conjunction with computed tomography (CT) scan in staging patients with esophageal cancer. Methods: From March 1995 to October 1998, 59 patients with biopsy-proven esophageal cancer underwent diagnostic laparoscopy with concurrent vascular access device and feeding jejunostomy tube placement. Results: Laparoscopy changed the treatment plan in 10 of 59 patients (17%). Of the patients with normal-appearing regional or celiac nodes, 78% were confirmed by biopsy to be tumor free, whereas 76% of patients with abnormal-appearing nodes were confirmed by biopsy to have node-positive disease. Conclusions: Diagnostic laparoscopy is useful for detecting and confirming nodal involvement and distant metastatic disease that potentially would alter treatment and prognosis in patients with esophageal cancer.

Inactivation of the P16 (INK4A)/retinoblastoma (RB) or TP53 biochemical pathway is frequent event in most human cancers. Recent evidence has shown that P14ARF binds to MDM2 leading to an increased availability of wild type TP53 protein. Functional studies also support a putative tumor suppressor gene function for p14ARF suggesting that p14ARF or p53 inactivation may be functionally equivalent in tumorigenesis. To study the relative contribution of each pathway in tumorigenesis, we analysed and compared alterations of the p16, p14ARF and p53 genes in 38 primary non-small cell lung cancers (NSCLCs) (19 adenocarcinomas and 19 squamous carcinoma). The p16 tumor suppressor gene was inactivated in 22 of 38 (58%) tumors. Twelve of these samples (31%) had homozygous deletions by microsatellite analysis; eight of them (21%) had p16 promoter hypermethylation detected by Methylation Specific PCR (MSP) and the remaining two (5%) harbored a point mutation in exon 2 by sequence analysis. The absence of P16 protein in every case was confirmed by immunohistochemistry. Fourteen of the 22 tumors with p16 inactivation also inactivated the p14ARF gene (12 with homozygous deletions extending into INK4a/ARF and two with exon 2 mutations). Mutations of p53 were found in 18 (47%) of the tumors and nine of them (50%) harbored p14ARF inactivation. Thus, an inverse correlation was not found between p14ARF and p53 genetic alterations (P=0.18; Fisher Exact Test). Our data confirm that the p16 gene is frequently inactivated in NSCLC. Assuming that 9p deletion occurs first, the common occurrence of p53 and p14ARF alterations suggests that p14ARF inactivation is not functionally equivalent to abrogation of the TP53 pathway by p53 mutation.

The p53 gene was sequenced in 100 primary human lung cancers by using direct dideoxynucleotide cycle sequencing and compared with sequence analysis by using the p53 GeneChip assay. Differences in sequence analysis between the two techniques were further evaluated to determine the accuracy and limitations of each method. p53 mutations were either detected by using both techniques or, if only detected by one technique, were confirmed by using mutation-specific oligonucleotide hybridization. Dideoxynucleotide sequencing of the conserved regions of the p53 gene (exons 5–9) detected 76% of the mutations within this region of the gene. The GeneChip p53 assay detected 81% of all (exons 2–11) mutations, including 80% of the mutations within the conserved regions of the gene. The GeneChip assay detected 46 of 52 missense mutations (88%), but 0 of 5 frameshift mutations. The specificity of direct sequencing and of the p53 GeneChip assay at detecting p53 mutations were 100% and 98%, respectively. The GeneChip p53 assay is a rapid and reasonably accurate approach for detecting p53 mutations; however, neither direct sequencing nor the p53 GeneChip are infallible at p53 mutation detection.

Objective: The objective was to determine the course of the long thoracic nerve relative to the scapula as an aid to the prevention of proximal long thoracic nerve injuries. Methods: Eighteen fresh cadavers (7 male, 11 female) were studied. Each was sequentially placed in the transaxillary and posterolateral thoracotomy positions, and the distance of the long thoracic nerve from the scapular tip and anterior scapular border was measured. The measurements were made bilaterally; the mean, standard deviation, and 99% confidence interval were calculated for each position by gender. Results: Distances from the scapular tip to the long thoracic nerve are listed as mean/outer range: transaxillary thoracotomy, male 4.9/7.0 cm left, 5.2/7.5 cm right; female 4.3/5.0 cm left, 4.7/6.0 cm right; posterolateral thoracotomy, male 3.1/6.0 cm left, 4.5/5.1 cm right; female 3.2/4.5 cm left, 3.8/5.5 cm right. In all instances, the long thoracic nerve was furthest from the scapula at its tip. Conclusion: For patients positioned for a transaxillary thoracotomy, incision sites should be at least 7.5 and 6.0 cm anterior to the scapular tip for male and female patients, respectively. For patients in posterolateral thoracotomy positioning, incisions should be 6.0 and 5.5 cm anterior to the scapular tip for male and female patients, respectively. By using these anatomic guidelines, we believe that the incidence of iatrogenic proximal long thoracic nerve injury can be minimized. (J Thorac Cardiovasc Surg 1998;116:960-4)

u B o s s p e t r a a a a s t c a ver the last few years, there have been a number of articles about the problems facing our specialty, articularly with regard to attracting the best individuals nto our cardiothoracic training programs. In an excellent rticle entitled Why Become a Cardiothoracic Surgeon [1], icholas Kouchoukos commences the paper with: These are trying times for the specialty of cardiothoracic urgery.” He goes on to enumerate some of the factors ontributing to these difficult times: six to nine years of urgical training after medical school; difficulty in finding uitable jobs at the completion of training and then the ual factors of increased malpractice payments in comination with diminishing annual incomes. Several thoacic society presidential addresses in the last two years ave also presented the foregoing problems related to ttracting “the best and brightest” medical students to ur specialty. The supply/demand issue in our specialty as a major topic considered in the 2003 Society of horacic Surgeons’ presidential address by one of us WAB) [2]. We pointed out that the current semi-crisis in he cardiothoracic job market appears to be transient and e could be facing a shortage of cardiothoracic surgeons n 10 to 12 years. This prediction is based on a 2002 ardiothoracic Manpower Study reported by Dr Richard hemin that indicates that one-half of the current cardiohoracic surgeons will be retired in 13 years; this correponds to a median calendar year of 2011 [3]. More recently, Irving Kron discussed the current suply/demand issue in cardiothoracic surgery in his presiential address at the Southern Thoracic Surgical Assoiation meeting in November 2005 [4]. In his insightful resentation, Dr Kron indicated that because of our aging aby-boomer population, the US Medicare population ill double between 2000 and 2030, and this dramatic ncrease in our aged population will no doubt provide any new patients who will require surgical procedures or ventricular dysfunction, valvular pathology, and cornary and pulmonary disease processes. Dr Kron also redicted a shortage of cardiothoracic surgeons within he next 5 to 10 years. Certainly a shortage of cardiothoacic surgeons, even in the next 10 years, makes it mperative that we try to attract at this time, a large umber of highly qualified medical (and premedical) tudents to our specialty. Those of us in the Divisions of Cardiac and Thoracic

Background Cardiothoracic surgical education faces numerous challenges, including reduced duty hours and diminishing prioritization of teaching, in the setting of rapidly advancing knowledge, skills, and case complexity. Pass rates on the American Board of Thoracic Surgery exam remain suboptimal, and new training formats are being evaluated. We hypothesize that Internet-based courses can be developed and implemented to supplement learning of basic topics in cardiothoracic surgery. Methods After a needs assessment, 4 online self-study courses were developed by content experts using a Moodle [modular object-oriented dynamic learning environment] platform. As a pilot cohort, students from 4 thoracic surgery training programs participated, accessing courses at their own pace. Each course included general and detailed readings, multimedia content, discussion forum, and a question-bank supported quiz (90% required to pass, multiple attempts allowed). Utilization and exam data were tracked electronically. The t tests were used to compare first versus final-year traditional track trainees. Post-course surveys collected data on trainee attitudes. Results Nineteen students completed 4 courses on tracheal disease. Mean time spent per course and quiz attempts to pass were 1.35 hours and 2.86, respectively. Scores improved with successive attempts. Senior trainees showed a trend toward less time per course and fewer quiz attempts. Post-course surveys uniformly demonstrated perceived benefits from the content and quizzes in an easy-to-navigate format. Conclusions Online courses can be developed and integrated within cardiothoracic training programs. This pilot demonstrates evidence of active learning as shown through the embedded assessments. Internet-based courses may serve as a means of supplementing modern thoracic surgical training. Further development and evaluation are warranted.

Background A dramatic transformation of cardiothoracic surgical education has evolved over the past few decades. Methods We begin by presenting recognized catalysts of this change, organized by whom they primarily affect: the trainees, the trainers, and the profession as a whole. Our trainees' prior training is different, and their current demographics and priorities have changed. There is less incentive to teach, with time-honored traditions of education inadequate to meet the needs of trainees. Concurrently, our profession has to adjust to new regulations, increasing financial constraints, and an expanding body of knowledge and technology. To address these issues requires developing new models of education and assessment that can thrive in today's environment. We discuss efforts in the United States and abroad, including new training paradigms ranging from restructuring existing models to novel approaches (eg, competency-based training). Training tools are being developed, such as online instruction, simulation-based learning, and regular student-centered assessments. Finally, models that recognize and reward teaching as a scholarly activity are being implemented. Conclusions Like the radical advances we have witnessed in surgical therapy, surgical education requires creative and perhaps disruptive changes if we are to continue to produce well-trained additions to our professional ranks.

Objectives Simulation may reduce the risks associated with the complex operations of cardiothoracic surgery and help create a more efficient, thorough, and uniform curriculum for cardiothoracic surgery fellowship. Here, we review the current status of simulation in cardiothoracic surgical training and provide an overview of all simulation models applicable to cardiothoracic surgery that have been published to date. Methods We completed a comprehensive search of all publications pertaining to simulation of cardiothoracic surgical procedures by using PubMed. Results Numerous cardiothoracic surgical simulators at various stages of development, assessment, and commercial manufacturing have been published to date. There is currently a predominance of models simulating coronary artery bypass grafting and bronchoscopy and a relative paucity of simulators of open pulmonary and esophageal procedures. Despite the wide range of simulators available, few models have been formally assessed for validity and educational value. Conclusions Surgical simulation is becoming an increasingly important educational tool in training cardiothoracic surgeons. Our next steps forward will be to develop an objective, standardized way to assess surgical simulation training compared with the current apprenticeship model.

We describe 2 patients with neurofibromatosis type 1 (NF1) who underwent lung transplantation. Case 1 reports a patient with NF1 with no complications 5 years after bilateral lung transplantation. Case 2 details a patient with NF1 diagnosed with both post-transplant lymphoproliferative disorder (PTLD) and massive intra-abdominal sarcoma consistent with a malignant nerve sheath tumor 9 months after lung transplantation. There was no clinical evidence of sarcoma preceding or immediately following lung transplant as demonstrated by a normal abdominal sonogram 3 months post-transplantation. Although an increased risk for cancer has been documented in NF1, the rapid malignant degeneration of a neurofibroma following transplantation raises concern about immunosuppression and transplantation candidacy among individuals with NF1.

Background Simulation can enhance learning effectiveness, efficiency, and patient safety and is engaging for learners. Methods A survey was conducted of surgical clerkship directors nationally and medical students at 5 medical schools to rank and stratify simulation-based educational topics. Students applying to surgery were compared with others using Wilcoxon's rank-sum tests. Results Seventy-three of 163 clerkship directors (45%) and 231 of 872 students (26.5%) completed the survey. Of students, 28.6% were applying for surgical residency training. Clerkship directors and students generally agreed on the importance and timing of specific educational topics. Clerkship directors tended to rank basic skills, such as examination skills, higher than medical students. Students ranked procedural skills, such as lumbar puncture, more highly than clerkship directors. Conclusions Surgery clerkship directors and 4th-year medical students agree substantially about the content of a simulation-based curriculum, although 4th-year medical students recommended that some topics be taught earlier than the clerkship directors recommended. Students planning to apply to surgical residencies did not differ significantly in their scoring from students pursuing nonsurgical specialties.

As a surgeon, the requirement for academic clinical practice is completion of an accredited residency program with or without a fellowship, followed by appropriate board certification. It was classically assumed that those who complete this rigorous training process in an academic setting naturally developed the teaching skills necessary to teach the next generation of academic surgeons. To date, no specific training paradigm has been defined for individuals desiring to become surgical educators. Historically, volunteer academic faculty have shouldered the responsibility of teaching medical students and residents with little to no additional insights beyond what they were exposed to during their own curriculum. Unfortunately, their teaching commitments were sometimes viewed as a distraction from the tasks of grant application and publication of research efforts. With the added pressures of research and clinical productivity, the ability and the time dedicated to teaching have been placed low on the prioritization of academic tasks. The “student” generational gap has changed since most of us have trained, as educational technology and techniques have evolved to capture the attention of our trainees.

e20005Background: Nivolumab is an anti-PD1 immune checkpoint blocker which has demonstrated durable responses and improved survival vs. second-line chemotherapy in metastatic non-small-cell lung ca...

Surgeons are faced with increasingly complex and larger chest wall defects as a result of a variety of pathologies, the majority of which are oncologic. Skeletal reconstruction of these resulting defects and subsequent soft-tissue coverage remain a challenge for thoracic and plastic and reconstructive surgeons. A variety of techniques and grafts have been utilized to support the thoracic cage. This review focuses on the use of acellular dermal matrices in thoracic skeletal reconstruction, with a focus on the indications, published data, and surgical techniques for utilizing acellular dermal matrices in chest wall reconstruction.

Inflammatory bowel diseases are characterized by epithelial barrier disruption and alterations in immune regulation. Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but the underlying mechanisms need to be defined. Herein, SPAK knockout (KO) C57BL/6 mice exhibited significant increases in intestinal transepithelial resistance, a marked decrease in paracellular permeability to fluorescence isothiocyanate–dextran, and altered apical side tight junction sodium ion selectivity, compared with wild-type mice. Furthermore, the expression of junction protein, claudin-2, decreased. In contrast, expressions of occludin, E-cadherin, β-catenin, and claudin-5 increased significantly, whereas no obvious change of claudin-1, claudin-4, zonula occludens protein 1, and zonula occludens protein 2 expressions was observed. In murine models of colitis induced by dextran sulfate sodium and trinitrobenzene sulfuric acid, KO mice were more tolerant than wild-type mice, as demonstrated by colonoscopy features, histological characteristics, and myeloperoxidase activities. Consistent with these findings, KO mice showed increased IL-10 levels and decreased proinflammatory cytokine secretion, ameliorated bacterial translocation on treatment with dextran sulfate sodium, and regulation of with no lysine (WNK) kinase activity. Together, these features may reduce epithelial permeability. In conclusion, SPAK deficiency increases intestinal innate immune homeostasis, which is important for control or attenuation of pathological responses in inflammatory bowel diseases.