Daniel Kreisel - Academia.edu (original) (raw)

Papers by Daniel Kreisel

Research paper thumbnail of PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction

American Journal of Transplantation

Research paper thumbnail of Transplantation of Lungs Procured From a Donor with an Atrioesophageal Fistula

The Annals of Thoracic Surgery

Lung transplantation continues to be limited by a shortage of donor organs. We report the case of... more Lung transplantation continues to be limited by a shortage of donor organs. We report the case of procurement and transplantation of lungs from a young donor who died from an atrioesophageal fistula, complicating catheter ablation for atrial fibrillation. Our case illustrates that structural damage to the left atrium is not an absolute contraindication to lung donation. As atrioesophageal fistulas are being increasingly recognized as a rare but often lethal complication of catheter ablation, such donors can contribute to the expansion of the donor pool.

Research paper thumbnail of The human heart contains distinct macrophage subsets with divergent origins and functions

Nature medicine, Jan 11, 2018

Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a criti... more Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2- and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2- and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2- macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2- and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2- and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic ...

Research paper thumbnail of Office-Based Spirometry: A New Model of Care in Preoperative Assessment for Low-Risk Lung Resections

The Annals of thoracic surgery, 2018

Formal pulmonary function testing with laboratory spirometry (LS) is the standard of care for ris... more Formal pulmonary function testing with laboratory spirometry (LS) is the standard of care for risk stratification before lung resection. LS and handheld office spirometry (OS) are clinically comparable for forced expiratory volume in 1 second and forced vital capacity. We investigated the safety of preoperative risk stratification based solely on OS. Patients at low-risk for cardiopulmonary complications were enrolled in a single-center prospective study and underwent preoperative OS. Formal LS was not performed when forced expiratory volume in 1 second was more than 60% by OS. Propensity score matching was used to compare patients in the OS group to low-risk institutional database patients (2008 to 2015) who underwent LS and lung resection. Standardized mean differences determined model covariate balance. The McNemar test and log-rank test were performed, respectively, for categorical and continuous paired outcome data. There were 66 prospectively enrolled patients who received OS ...

Research paper thumbnail of Deficiency of the Adaptor Protein SLy1 Results in a Natural Killer Cell Ribosomopathy Affecting Tumor Clearance

OncoImmunology, 2016

Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To e... more Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the Xchromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.

Research paper thumbnail of Quality Measures in Clinical Stage I Non-Small Cell Lung Cancer: Improved Performance Is Associated With Improved Survival

The Annals of Thoracic Surgery, 2016

Background. National organizations have recommended quality measures for operations in early-stag... more Background. National organizations have recommended quality measures for operations in early-stage non-small cell lung cancer (NSCLC). The outcomes of adherence to these guidelines are unknown. Methods. Information about patients who underwent an operation for clinical stage I NSCLC was abstracted from the National Cancer Database. After reviewing current guidelines, the following quality measures were selected: anatomic resection, operation within 8 weeks of diagnosis, achievement of negative surgical margins, and sampling of 10 or more lymph nodes. Multivariate models identified variables independently associated with receiving quality measures and a Cox model created to evaluate overall survival.

Research paper thumbnail of Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity

Journal of immunology (Baltimore, Md. : 1950), Jul 1, 2016

More than one third of patients with chronic lung disease undergoing lung transplantation have pr... more More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance. Therefore, we hypothesized that lung-tissue injury can lead to lung-restricted immunity if it occurs in a setting when Tregs are impaired. We found that human lung recipients who suffer respiratory viral infections experienced a decrease in peripheral Tregs. Pre-existing lung allograft injury from donor-directed Abs or gastroesophageal reflux led to new Col...

Research paper thumbnail of progression of valvular stenosis species-induced prosthetic valve endocarditis associated with rapid Bartonella

Research paper thumbnail of Clinical T2N0 Esophageal Cancer: Identifying Pretreatment Characteristics Associated With Pathologic Upstaging and the Potential Role for Induction Therapy

The Annals of Thoracic Surgery, 2016

Background-While studies have suggested standard therapy for clinical T2N0 esophageal cancer shou... more Background-While studies have suggested standard therapy for clinical T2N0 esophageal cancer should be primary surgery, we hypothesize there is a subgroup for whom induction therapy may result in improved overall survival (OS). Methods-cT2N0 esophageal cancer patients receiving induction therapy or upfront esophagectomy (UE) were identified in the National Cancer Data Base (NCDB). UE patients were dichotomized as 1) pathologically upstaged or 2) same-or down-staged. Logistic regression models identified variables associated with upstaging and Kaplan-Meier analysis compared median OS. Results-From 2006-2012, 932 (52.2%) cT2N0 patients received UE, while 853 (47.8%) received induction therapy first. 326/713 (45.7%) UE patients were upstaged. 87/326 (26.7%) patients had T upstaging, 98/326 (30.1%) had N upstaging, and 141/326 (43.3%) had both. Patients upstaged after UE had a higher tumor grade (35.1% versus 57.1% Grade 3), and a higher rate of lymphovascular invasion (LVI, 57.1% versus 17.7%), both p<0.001. Variables associated with upstaging included LVI (OR 6.0, 95% CI 2.9-12.5, p<0.001) and tumor grade 3 (OR 9.4, 1.8-48.4, p=0.007). Of upstaged UE patients, only 144 (44.2%) received adjuvant therapy. The median OS for cT2N0 patients upstaged after UE was 27.5 ± 2.5 months versus 43.9 ± 2.9 months for induction therapy patients (any resultant pathologic stage, p<0.001).

Research paper thumbnail of Cell delivery patch for myocardial tissue engineering

Research paper thumbnail of The Role of Lymphoid Neogenesis in Allografts

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 28, 2015

De novo induction of organized lymphoid aggregates at non-lymphoid sites has been observed in man... more De novo induction of organized lymphoid aggregates at non-lymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, auto- or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3(+) cells are present in long term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of "tolerogenic" TLOs may pr...

Research paper thumbnail of Deletion of Myeloid Cell I-κB Kinase β Prevents Induction of Mouse Lung Allograft Tolerance

B91. THE YIN AND YANG OF LUNG INJURY: NEW INSIGHTS INTO MECHANISMS OF PROGESSION AND RESOLUTION, 2009

Research paper thumbnail of Unexpected Readmission after Lung Cancer Surgery: A Benign Event?

The Journal of Thoracic and Cardiovascular Surgery, 2015

Objective-To study incidence, predictors, and implications of unanticipated early postoperative r... more Objective-To study incidence, predictors, and implications of unanticipated early postoperative readmission after lung resection for non-small cell lung cancer (NSCLC). Methods-Patients undergoing surgery for clinical stage I-III NSCLC were abstracted from the National Cancer Database (NCDB). Regression models were fitted to identify predictors of 30-day readmission, and to study the association of unplanned readmission with 30-day and long-term survival. Results-Between 1998 and 2010, 129893 patients underwent resection for stage I-III NSCLC. Of these, 5624 (4.3%) were unexpectedly readmitted within 30 days. In a multivariate regression model, increasing age, male gender, preoperative radiation, and pneumonectomy (OR 1.77, 1.56-2.00) were associated with unexpected readmissions. Longer index hospitalization and higher Charlson comorbidity score were also predictive of readmission. The 30-day mortality for readmitted patients was higher (3.9% vs. 2.8%), as was the 90-day mortality (7.0% vs. 3.3%, both p<0.001). In a multivariate cox proportional hazards model of long-term survival, increasing age, higher Charlson comorbidity score, and higher pathologic stage (HR for stage III 1.81, 1.42-2.29) were associated with greater risk of mortality. Unplanned readmission was independently associated with higher risk of long-term mortality (HR 1.40, 1.34-1.47). The median survival for readmitted patients was significantly shorter (38.7 months vs. 58.5 months, p<0.001). Conclusions-Unplanned readmissions are not rare after resection for NSCLC. Such events are associated with a greater risk of short-and long-term mortality. With the renewed national focus on readmissions and potential financial disincentives, greater resource allocation is needed to identify patients at risk and develop measures to avoid the associated adverse outcomes.

Research paper thumbnail of MicroRNA-144 dysregulates the transforming growth factor-β signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, Jan 27, 2015

Bronchiolitis obliterans syndrome (BOS), chronic lung allograft rejection, remains an impediment ... more Bronchiolitis obliterans syndrome (BOS), chronic lung allograft rejection, remains an impediment for the function of the transplanted organ. In this study, we defined the role of the microRNA (miRNA) miR-144 in fibroproliferation leading to BOS. Biopsy specimens were obtained from 20 lung transplant recipients with BOS((+)) and 19 without BOS((-)). Expression of miR-144 and its target, transforming growth factor-β (TGF-β)-induced factor homeobox 1(TGIF1), were analyzed by real-time polymerase chain reaction and Western blot. Overexpression of miR-144 and luciferase reporter genes were performed to elucidate miRNA-target interactions. The function of miR-144 was evaluated by transfecting fibroblasts and determining the response to TGF-β by analyzing Sma- and Mad-related family (Smads), fibroblast growth factor, TGF-β, and vascular endothelial growth factor. Smooth muscle actin-α-positive stress fibers and F-actin filaments in lung fibroblasts were analyzed by immunofluorescence. Anal...

Research paper thumbnail of Effects of Delayed Surgical Resection on Short-Term and Long-Term Outcomes in Clinical Stage I Non-Small Cell Lung Cancer

The Annals of Thoracic Surgery, 2015

Conflicting evidence currently exists regarding the causes and effects of delay of care in non-sm... more Conflicting evidence currently exists regarding the causes and effects of delay of care in non-small cell lung cancer (NSCLC). We hypothesized that delayed surgery in early-stage NSCLC is associated with worse short-term and long-term outcomes. Treatment data of clinical stage I NSCLC patients undergoing surgical resection were obtained from the National Cancer Data Base (NCDB). Treatment delay was defined as resection 8 weeks or more after diagnosis. Propensity score matching for patient and tumor characteristics was performed to create comparable groups of patients receiving early (less than 8 weeks from diagnosis) and delayed surgery. Multivariable regression models were fitted to evaluate variables influencing delay of surgery. From 1998 to 2010, 39,995 patients with clinical stage I NSCLC received early surgery, while 15,658 patients received delayed surgery. Of these, 27,022 propensity-matched patients were identified. Those with a delay in care were more likely to be pathologically upstaged (18.3% stage 2 or higher versus 16.6%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), have an increased 30-day mortality (2.9% vs 2.4%, p = 0.01), and have decreased median survival (57.7 ± 1.0 months versus 69.2 ± 1.3 months, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Delay in surgery was associated with increasing age, non-white race, treatment at an academic center, urban location, income less than $35,000, and increasing Charlson comorbidity score (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001 for all). Delayed patients were more likely to receive a sublobar resection (17.2% vs 13.1%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Patients receiving delayed resection for clinical stage I NSCLC have higher comorbidity scores that may affect ability to perform lobectomy and result in higher perioperative mortality. However, delay in resection is independently associated with increased rates of upstaging and decreased median survival. Strategies to minimize delay while medically optimizing higher risk patients are needed.

Research paper thumbnail of 18-FLUORODEOXYGLUCOSE Positron Emission Tomography as a Novel Imaging Tool for the Diagnosis of Aortoenteric Fistula and Aortic Graft Infection--A Case Report

Vascular and endovascular surgery

The diagnosis of aortic graft infection and aortoenteric fistula can be difficult to establish us... more The diagnosis of aortic graft infection and aortoenteric fistula can be difficult to establish using conventional radiographic imaging modalities. Positron emission tomography (PET) imaging with 18-fluorodeoxyglucose (FDG) can rapidly provide anatomically clear images and define areas of inflammation with increased glucose metabolism. In this report the authors present a case of aortoenteric fistula diagnosed by FDG-PET. Early diagnosis led to rapid surgical intervention with graft removal and extraanatomic bypass. These encouraging results warrant larger controlled studies to evaluate the utility of FDG-PET in the diagnosis of prosthetic aortic graft infection.

Research paper thumbnail of National Cooperative Group Trials of “High-Risk” Patients With Lung Cancer: Are They Truly “High-Risk”?

The Annals of Thoracic Surgery, 2014

Background-The American College of Surgery Oncology Group (ACOSOG) trials z4032 and z4033 prospec... more Background-The American College of Surgery Oncology Group (ACOSOG) trials z4032 and z4033 prospectively characterized lung cancer patients as "high-risk" for surgery and these results have appeared frequently in literature. We hypothesized that many patients meeting objective enrollment criteria for these trials ("high-risk") have similar perioperative outcomes as "normalrisk" patients. Methods-We reviewed a prospective institutional database, and classified patients undergoing resection for clinical stage I lung cancer as "high-risk" and "normal-risk" by ACOSOG major criteria. Results-From 2000-2010, 1066 patients underwent surgery for clinical stage I lung cancer. Of these, 194 (18%) met ACOSOG major criteria for risk (preoperative FEV1 or DLCO ≤50% predicted). "High-risk" patients were older (66.4 vs. 64.6 years, p=0.02) but similar to controls in gender, prevalence of hypertension, diabetes, and coronary artery disease (CAD). "High-risk" patients were less likely than normal patients to undergo a lobectomy (117/194, 60% vs. 665/872, 76%, p<0.001). "High-risk" and control patients experienced similar morbidity (any complication: 55/194, 28% vs. 230/872, 26%, p=0.59), and 30-day mortality (2/194, 1% vs. 14/872, 2%, p=0.75). In a regression analysis, age (HR 1.04, 95% CI 1.02-1.06), and CAD (HR 1.58, 95% CI 1.05-2.40) were associated with an elevated risk of complications in those undergoing lobectomy, while female gender (HR 0.63, 95% CI 0.44-0.91) was protective. ACOSOG "high-risk" status was not associated with perioperative morbidity. Conclusions-There are no important differences in early outcomes between lung cancer patients characterized as "high-risk" and "normal-risk" by ACOSOG trial enrollment criteria, despite a significant proportion of "high-risk" patients undergoing lobectomy.

Research paper thumbnail of Does surgeon experience affect outcomes in pathologic stage I lung cancer?

The Journal of Thoracic and Cardiovascular Surgery, 2014

Objective: The study objective was to evaluate the influence of surgeon experience on outcomes in... more Objective: The study objective was to evaluate the influence of surgeon experience on outcomes in early-stage non-small cell lung cancer. Methods: In an institutional database, patients undergoing operations for pathologic stage I non-small cell lung cancer were categorized by surgeon experience: within 5 years of completion of training, the low experience group; with 5 to 15 years of experience, the moderate experience group; and with more than 15 years, the high experience group. Results: From 2000 to 2012, 800 operations (638 lobectomies, 162 sublobar resection) were performed with the following distribution: low experience 178 (22.2%), moderate experience 224 (28.0%), and high experience 398 (49.8%). Patients in the groups were similar in age and comorbidities. The use of videoassisted thoracoscopic surgery was higher in the moderate experience group (low experience: 62/178 [34.8%], moderate experience: 151/224 [67.4%], and high experience: 133/398 [33.4%], P <.001), as was the mean number of mediastinal (N2) lymph node stations sampled (low experience: 2.8 AE 1.6, moderate experience: 3.5 AE 1.7, high experience: 2.3 AE 1.4, P<.001). The risk of perioperative morbidity was similar across all groups (low experience: 54/178 [30.3%], moderate experience: 51/224 [22.8%], and high experience: 115/398 [28.9%], P ¼ .163). Five-year overall survival in the moderate experience group was 76.9% compared with 67.5% in the low experience group (P < .001) and 71.4% in the high experience group (P ¼ .006). In a Cox proportional hazard model, increasing age, male gender, prior cancer, and R1 resection were associated with an elevated risk of mortality, whereas being operated on by surgeons with moderate experience and having a greater number of mediastinal (N2) lymph node stations sampled were protective. Conclusions: The experience of the surgeon does not affect perioperative outcomes after resection for pathologic stage I non-small cell lung cancer. At least moderate experience after fellowship is associated with improved long-term survival.

Research paper thumbnail of Comparison of Pyloric Intervention Strategies at the Time of Esophagectomy: Is More Better?

The Annals of Thoracic Surgery, 2014

Background. Controversy remains regarding the role of pyloric drainage procedures after esophagec... more Background. Controversy remains regarding the role of pyloric drainage procedures after esophagectomy with gastric conduit reconstruction. We aimed to compare the effect of pyloric drainage strategies upon subsequent risk of complications suggestive of conduit distention, including aspiration and anastomotic leak. Methods. A retrospective study was conducted reviewing patients undergoing esophagectomy between January 2007 and April 2012. Prospectively collected data included baseline comorbidities, operative details, hospital course, and complications. Statistical comparisons were performed using analysis of variance for continuous variables and c 2 testing for categorical variables.

Research paper thumbnail of Outcomes and late complications after pulmonary resections in the pediatric population

Seminars in Thoracic and Cardiovascular Surgery, 2004

Neonates and children undergo lung resections for a variety of indications. These procedures can ... more Neonates and children undergo lung resections for a variety of indications. These procedures can be performed with low mortality and low morbidity rates in the early postoperative period. There exist important anatomic and physiologic differences between the pediatric and the adult population, which thoracic surgeons need to be aware of. On the one hand, the capacity of the lung to grow during the first few years of life is associated with relative preservation of postoperative pulmonary function in children. On the other hand, the relative flexibility of their tissue structures places pediatric patients at increased risk for developing postpneumonectomy syndrome. Moreover, surgeons need to take the child's growth and development into consideration when planning their operative approach for thoracic procedures.

Research paper thumbnail of PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction

American Journal of Transplantation

Research paper thumbnail of Transplantation of Lungs Procured From a Donor with an Atrioesophageal Fistula

The Annals of Thoracic Surgery

Lung transplantation continues to be limited by a shortage of donor organs. We report the case of... more Lung transplantation continues to be limited by a shortage of donor organs. We report the case of procurement and transplantation of lungs from a young donor who died from an atrioesophageal fistula, complicating catheter ablation for atrial fibrillation. Our case illustrates that structural damage to the left atrium is not an absolute contraindication to lung donation. As atrioesophageal fistulas are being increasingly recognized as a rare but often lethal complication of catheter ablation, such donors can contribute to the expansion of the donor pool.

Research paper thumbnail of The human heart contains distinct macrophage subsets with divergent origins and functions

Nature medicine, Jan 11, 2018

Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a criti... more Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2- and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2- and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2- macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2- and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2- and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic ...

Research paper thumbnail of Office-Based Spirometry: A New Model of Care in Preoperative Assessment for Low-Risk Lung Resections

The Annals of thoracic surgery, 2018

Formal pulmonary function testing with laboratory spirometry (LS) is the standard of care for ris... more Formal pulmonary function testing with laboratory spirometry (LS) is the standard of care for risk stratification before lung resection. LS and handheld office spirometry (OS) are clinically comparable for forced expiratory volume in 1 second and forced vital capacity. We investigated the safety of preoperative risk stratification based solely on OS. Patients at low-risk for cardiopulmonary complications were enrolled in a single-center prospective study and underwent preoperative OS. Formal LS was not performed when forced expiratory volume in 1 second was more than 60% by OS. Propensity score matching was used to compare patients in the OS group to low-risk institutional database patients (2008 to 2015) who underwent LS and lung resection. Standardized mean differences determined model covariate balance. The McNemar test and log-rank test were performed, respectively, for categorical and continuous paired outcome data. There were 66 prospectively enrolled patients who received OS ...

Research paper thumbnail of Deficiency of the Adaptor Protein SLy1 Results in a Natural Killer Cell Ribosomopathy Affecting Tumor Clearance

OncoImmunology, 2016

Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To e... more Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the Xchromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.

Research paper thumbnail of Quality Measures in Clinical Stage I Non-Small Cell Lung Cancer: Improved Performance Is Associated With Improved Survival

The Annals of Thoracic Surgery, 2016

Background. National organizations have recommended quality measures for operations in early-stag... more Background. National organizations have recommended quality measures for operations in early-stage non-small cell lung cancer (NSCLC). The outcomes of adherence to these guidelines are unknown. Methods. Information about patients who underwent an operation for clinical stage I NSCLC was abstracted from the National Cancer Database. After reviewing current guidelines, the following quality measures were selected: anatomic resection, operation within 8 weeks of diagnosis, achievement of negative surgical margins, and sampling of 10 or more lymph nodes. Multivariate models identified variables independently associated with receiving quality measures and a Cox model created to evaluate overall survival.

Research paper thumbnail of Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity

Journal of immunology (Baltimore, Md. : 1950), Jul 1, 2016

More than one third of patients with chronic lung disease undergoing lung transplantation have pr... more More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance. Therefore, we hypothesized that lung-tissue injury can lead to lung-restricted immunity if it occurs in a setting when Tregs are impaired. We found that human lung recipients who suffer respiratory viral infections experienced a decrease in peripheral Tregs. Pre-existing lung allograft injury from donor-directed Abs or gastroesophageal reflux led to new Col...

Research paper thumbnail of progression of valvular stenosis species-induced prosthetic valve endocarditis associated with rapid Bartonella

Research paper thumbnail of Clinical T2N0 Esophageal Cancer: Identifying Pretreatment Characteristics Associated With Pathologic Upstaging and the Potential Role for Induction Therapy

The Annals of Thoracic Surgery, 2016

Background-While studies have suggested standard therapy for clinical T2N0 esophageal cancer shou... more Background-While studies have suggested standard therapy for clinical T2N0 esophageal cancer should be primary surgery, we hypothesize there is a subgroup for whom induction therapy may result in improved overall survival (OS). Methods-cT2N0 esophageal cancer patients receiving induction therapy or upfront esophagectomy (UE) were identified in the National Cancer Data Base (NCDB). UE patients were dichotomized as 1) pathologically upstaged or 2) same-or down-staged. Logistic regression models identified variables associated with upstaging and Kaplan-Meier analysis compared median OS. Results-From 2006-2012, 932 (52.2%) cT2N0 patients received UE, while 853 (47.8%) received induction therapy first. 326/713 (45.7%) UE patients were upstaged. 87/326 (26.7%) patients had T upstaging, 98/326 (30.1%) had N upstaging, and 141/326 (43.3%) had both. Patients upstaged after UE had a higher tumor grade (35.1% versus 57.1% Grade 3), and a higher rate of lymphovascular invasion (LVI, 57.1% versus 17.7%), both p<0.001. Variables associated with upstaging included LVI (OR 6.0, 95% CI 2.9-12.5, p<0.001) and tumor grade 3 (OR 9.4, 1.8-48.4, p=0.007). Of upstaged UE patients, only 144 (44.2%) received adjuvant therapy. The median OS for cT2N0 patients upstaged after UE was 27.5 ± 2.5 months versus 43.9 ± 2.9 months for induction therapy patients (any resultant pathologic stage, p<0.001).

Research paper thumbnail of Cell delivery patch for myocardial tissue engineering

Research paper thumbnail of The Role of Lymphoid Neogenesis in Allografts

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 28, 2015

De novo induction of organized lymphoid aggregates at non-lymphoid sites has been observed in man... more De novo induction of organized lymphoid aggregates at non-lymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, auto- or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3(+) cells are present in long term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of "tolerogenic" TLOs may pr...

Research paper thumbnail of Deletion of Myeloid Cell I-κB Kinase β Prevents Induction of Mouse Lung Allograft Tolerance

B91. THE YIN AND YANG OF LUNG INJURY: NEW INSIGHTS INTO MECHANISMS OF PROGESSION AND RESOLUTION, 2009

Research paper thumbnail of Unexpected Readmission after Lung Cancer Surgery: A Benign Event?

The Journal of Thoracic and Cardiovascular Surgery, 2015

Objective-To study incidence, predictors, and implications of unanticipated early postoperative r... more Objective-To study incidence, predictors, and implications of unanticipated early postoperative readmission after lung resection for non-small cell lung cancer (NSCLC). Methods-Patients undergoing surgery for clinical stage I-III NSCLC were abstracted from the National Cancer Database (NCDB). Regression models were fitted to identify predictors of 30-day readmission, and to study the association of unplanned readmission with 30-day and long-term survival. Results-Between 1998 and 2010, 129893 patients underwent resection for stage I-III NSCLC. Of these, 5624 (4.3%) were unexpectedly readmitted within 30 days. In a multivariate regression model, increasing age, male gender, preoperative radiation, and pneumonectomy (OR 1.77, 1.56-2.00) were associated with unexpected readmissions. Longer index hospitalization and higher Charlson comorbidity score were also predictive of readmission. The 30-day mortality for readmitted patients was higher (3.9% vs. 2.8%), as was the 90-day mortality (7.0% vs. 3.3%, both p<0.001). In a multivariate cox proportional hazards model of long-term survival, increasing age, higher Charlson comorbidity score, and higher pathologic stage (HR for stage III 1.81, 1.42-2.29) were associated with greater risk of mortality. Unplanned readmission was independently associated with higher risk of long-term mortality (HR 1.40, 1.34-1.47). The median survival for readmitted patients was significantly shorter (38.7 months vs. 58.5 months, p<0.001). Conclusions-Unplanned readmissions are not rare after resection for NSCLC. Such events are associated with a greater risk of short-and long-term mortality. With the renewed national focus on readmissions and potential financial disincentives, greater resource allocation is needed to identify patients at risk and develop measures to avoid the associated adverse outcomes.

Research paper thumbnail of MicroRNA-144 dysregulates the transforming growth factor-β signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, Jan 27, 2015

Bronchiolitis obliterans syndrome (BOS), chronic lung allograft rejection, remains an impediment ... more Bronchiolitis obliterans syndrome (BOS), chronic lung allograft rejection, remains an impediment for the function of the transplanted organ. In this study, we defined the role of the microRNA (miRNA) miR-144 in fibroproliferation leading to BOS. Biopsy specimens were obtained from 20 lung transplant recipients with BOS((+)) and 19 without BOS((-)). Expression of miR-144 and its target, transforming growth factor-β (TGF-β)-induced factor homeobox 1(TGIF1), were analyzed by real-time polymerase chain reaction and Western blot. Overexpression of miR-144 and luciferase reporter genes were performed to elucidate miRNA-target interactions. The function of miR-144 was evaluated by transfecting fibroblasts and determining the response to TGF-β by analyzing Sma- and Mad-related family (Smads), fibroblast growth factor, TGF-β, and vascular endothelial growth factor. Smooth muscle actin-α-positive stress fibers and F-actin filaments in lung fibroblasts were analyzed by immunofluorescence. Anal...

Research paper thumbnail of Effects of Delayed Surgical Resection on Short-Term and Long-Term Outcomes in Clinical Stage I Non-Small Cell Lung Cancer

The Annals of Thoracic Surgery, 2015

Conflicting evidence currently exists regarding the causes and effects of delay of care in non-sm... more Conflicting evidence currently exists regarding the causes and effects of delay of care in non-small cell lung cancer (NSCLC). We hypothesized that delayed surgery in early-stage NSCLC is associated with worse short-term and long-term outcomes. Treatment data of clinical stage I NSCLC patients undergoing surgical resection were obtained from the National Cancer Data Base (NCDB). Treatment delay was defined as resection 8 weeks or more after diagnosis. Propensity score matching for patient and tumor characteristics was performed to create comparable groups of patients receiving early (less than 8 weeks from diagnosis) and delayed surgery. Multivariable regression models were fitted to evaluate variables influencing delay of surgery. From 1998 to 2010, 39,995 patients with clinical stage I NSCLC received early surgery, while 15,658 patients received delayed surgery. Of these, 27,022 propensity-matched patients were identified. Those with a delay in care were more likely to be pathologically upstaged (18.3% stage 2 or higher versus 16.6%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), have an increased 30-day mortality (2.9% vs 2.4%, p = 0.01), and have decreased median survival (57.7 ± 1.0 months versus 69.2 ± 1.3 months, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Delay in surgery was associated with increasing age, non-white race, treatment at an academic center, urban location, income less than $35,000, and increasing Charlson comorbidity score (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001 for all). Delayed patients were more likely to receive a sublobar resection (17.2% vs 13.1%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Patients receiving delayed resection for clinical stage I NSCLC have higher comorbidity scores that may affect ability to perform lobectomy and result in higher perioperative mortality. However, delay in resection is independently associated with increased rates of upstaging and decreased median survival. Strategies to minimize delay while medically optimizing higher risk patients are needed.

Research paper thumbnail of 18-FLUORODEOXYGLUCOSE Positron Emission Tomography as a Novel Imaging Tool for the Diagnosis of Aortoenteric Fistula and Aortic Graft Infection--A Case Report

Vascular and endovascular surgery

The diagnosis of aortic graft infection and aortoenteric fistula can be difficult to establish us... more The diagnosis of aortic graft infection and aortoenteric fistula can be difficult to establish using conventional radiographic imaging modalities. Positron emission tomography (PET) imaging with 18-fluorodeoxyglucose (FDG) can rapidly provide anatomically clear images and define areas of inflammation with increased glucose metabolism. In this report the authors present a case of aortoenteric fistula diagnosed by FDG-PET. Early diagnosis led to rapid surgical intervention with graft removal and extraanatomic bypass. These encouraging results warrant larger controlled studies to evaluate the utility of FDG-PET in the diagnosis of prosthetic aortic graft infection.

Research paper thumbnail of National Cooperative Group Trials of “High-Risk” Patients With Lung Cancer: Are They Truly “High-Risk”?

The Annals of Thoracic Surgery, 2014

Background-The American College of Surgery Oncology Group (ACOSOG) trials z4032 and z4033 prospec... more Background-The American College of Surgery Oncology Group (ACOSOG) trials z4032 and z4033 prospectively characterized lung cancer patients as "high-risk" for surgery and these results have appeared frequently in literature. We hypothesized that many patients meeting objective enrollment criteria for these trials ("high-risk") have similar perioperative outcomes as "normalrisk" patients. Methods-We reviewed a prospective institutional database, and classified patients undergoing resection for clinical stage I lung cancer as "high-risk" and "normal-risk" by ACOSOG major criteria. Results-From 2000-2010, 1066 patients underwent surgery for clinical stage I lung cancer. Of these, 194 (18%) met ACOSOG major criteria for risk (preoperative FEV1 or DLCO ≤50% predicted). "High-risk" patients were older (66.4 vs. 64.6 years, p=0.02) but similar to controls in gender, prevalence of hypertension, diabetes, and coronary artery disease (CAD). "High-risk" patients were less likely than normal patients to undergo a lobectomy (117/194, 60% vs. 665/872, 76%, p<0.001). "High-risk" and control patients experienced similar morbidity (any complication: 55/194, 28% vs. 230/872, 26%, p=0.59), and 30-day mortality (2/194, 1% vs. 14/872, 2%, p=0.75). In a regression analysis, age (HR 1.04, 95% CI 1.02-1.06), and CAD (HR 1.58, 95% CI 1.05-2.40) were associated with an elevated risk of complications in those undergoing lobectomy, while female gender (HR 0.63, 95% CI 0.44-0.91) was protective. ACOSOG "high-risk" status was not associated with perioperative morbidity. Conclusions-There are no important differences in early outcomes between lung cancer patients characterized as "high-risk" and "normal-risk" by ACOSOG trial enrollment criteria, despite a significant proportion of "high-risk" patients undergoing lobectomy.

Research paper thumbnail of Does surgeon experience affect outcomes in pathologic stage I lung cancer?

The Journal of Thoracic and Cardiovascular Surgery, 2014

Objective: The study objective was to evaluate the influence of surgeon experience on outcomes in... more Objective: The study objective was to evaluate the influence of surgeon experience on outcomes in early-stage non-small cell lung cancer. Methods: In an institutional database, patients undergoing operations for pathologic stage I non-small cell lung cancer were categorized by surgeon experience: within 5 years of completion of training, the low experience group; with 5 to 15 years of experience, the moderate experience group; and with more than 15 years, the high experience group. Results: From 2000 to 2012, 800 operations (638 lobectomies, 162 sublobar resection) were performed with the following distribution: low experience 178 (22.2%), moderate experience 224 (28.0%), and high experience 398 (49.8%). Patients in the groups were similar in age and comorbidities. The use of videoassisted thoracoscopic surgery was higher in the moderate experience group (low experience: 62/178 [34.8%], moderate experience: 151/224 [67.4%], and high experience: 133/398 [33.4%], P <.001), as was the mean number of mediastinal (N2) lymph node stations sampled (low experience: 2.8 AE 1.6, moderate experience: 3.5 AE 1.7, high experience: 2.3 AE 1.4, P<.001). The risk of perioperative morbidity was similar across all groups (low experience: 54/178 [30.3%], moderate experience: 51/224 [22.8%], and high experience: 115/398 [28.9%], P ¼ .163). Five-year overall survival in the moderate experience group was 76.9% compared with 67.5% in the low experience group (P < .001) and 71.4% in the high experience group (P ¼ .006). In a Cox proportional hazard model, increasing age, male gender, prior cancer, and R1 resection were associated with an elevated risk of mortality, whereas being operated on by surgeons with moderate experience and having a greater number of mediastinal (N2) lymph node stations sampled were protective. Conclusions: The experience of the surgeon does not affect perioperative outcomes after resection for pathologic stage I non-small cell lung cancer. At least moderate experience after fellowship is associated with improved long-term survival.

Research paper thumbnail of Comparison of Pyloric Intervention Strategies at the Time of Esophagectomy: Is More Better?

The Annals of Thoracic Surgery, 2014

Background. Controversy remains regarding the role of pyloric drainage procedures after esophagec... more Background. Controversy remains regarding the role of pyloric drainage procedures after esophagectomy with gastric conduit reconstruction. We aimed to compare the effect of pyloric drainage strategies upon subsequent risk of complications suggestive of conduit distention, including aspiration and anastomotic leak. Methods. A retrospective study was conducted reviewing patients undergoing esophagectomy between January 2007 and April 2012. Prospectively collected data included baseline comorbidities, operative details, hospital course, and complications. Statistical comparisons were performed using analysis of variance for continuous variables and c 2 testing for categorical variables.

Research paper thumbnail of Outcomes and late complications after pulmonary resections in the pediatric population

Seminars in Thoracic and Cardiovascular Surgery, 2004

Neonates and children undergo lung resections for a variety of indications. These procedures can ... more Neonates and children undergo lung resections for a variety of indications. These procedures can be performed with low mortality and low morbidity rates in the early postoperative period. There exist important anatomic and physiologic differences between the pediatric and the adult population, which thoracic surgeons need to be aware of. On the one hand, the capacity of the lung to grow during the first few years of life is associated with relative preservation of postoperative pulmonary function in children. On the other hand, the relative flexibility of their tissue structures places pediatric patients at increased risk for developing postpneumonectomy syndrome. Moreover, surgeons need to take the child's growth and development into consideration when planning their operative approach for thoracic procedures.