Alexander S Krupnick

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (116)433.4 Total impact

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    ABSTRACT: The role of surgery in addition to chemotherapy and radiation for stage IIIA non-small-cell lung cancer (NSCLC) remains controversial. Because there are limited data on the benefit from surgery in this setting, we evaluated the use of combined modality therapy nationally and explored the outcomes with and without the addition of surgery. Patient variables and treatment-related outcomes were abstracted for patients with clinical stage IIIA NSCLC from the National Cancer Database. Patients receiving chemotherapy and radiation were compared with those undergoing chemotherapy, radiation, and surgery (CRS) in any sequence. Between 1998 and 2010, 61,339 patients underwent combined modality treatment for clinical stage IIIA NSCLC. Of these, 51,979 (84.7%) received chemotherapy and radiation while 9360 (15.3%) underwent CRS. Patients in the CRS group were younger, more likely female patients and Caucasians, and had smaller tumors and lower Charlson comorbidity scores. The 30-day surgical mortality was 200 of 8993 (2.2%). The median overall survival favored the CRS group in both unmatched (32.4 months versus 15.7 months, p < 0.001) and matched analysis based on patient characteristics (34.3 versus 18.4 months, p < 0.001). There is significant heterogeneity in the treatment of stage IIIA NSCLC in the United States. Patients selected for surgery in addition to chemoradiation therapy seem to have better long-term survival.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2014; 9(5):612-21. · 4.55 Impact Factor
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    ABSTRACT: Unanticipated intraoperative conversions to an open approach during VATS lobectomy are infrequent and lead to perioperative outcomes similar to lobectomy via planned open thoracotomy.
    94th Annual Meeting of the American Association for Thoracic Surgery, Toronto, Ontario, Canada.; 04/2014
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    ABSTRACT: 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. 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 χ(2) testing for categorical variables. There were 361 esophagectomies performed during the study period; 68 were excluded from analysis (for prior esophagogastric surgery or benign disease or both). Among 293 esophagectomies included, emptying procedures were performed as follows: 44 (15%), no drainage procedure; 197 (67%), pyloromyotomy/pyloroplasty; 8 (3%), dilation alone; 44 (15%), dilation plus onabotulinumtoxinA. Aspiration occurred more frequently when no pyloric intervention was performed (5 of 44 [11.4%] versus 6 of 249 [2.4%], p = 0.030). The incidences of anastomotic leak (18 [6.1%]) and gastric outlet obstruction (5 [1.7%]) were statistically similar among groups. Subgroup analysis demonstrated persistence of these findings when limiting the comparison to transthoracic esophagectomies. Major complications directly related to pyloroplasty/pyloromyotomy occurred in 2 patients (0.6%), including 1 death (0.3%). These data suggest that omission of pyloric intervention at the index operation results in more frequent aspiration events. The combination of dilation plus onabotulinumtoxinA provided for a similar complication profile compared with surgical drainage. Future prospective comparisons are needed to evaluate these short-term effects of pyloric intervention as well as long-term sequelae such as dumping syndrome and bile reflux.
    The Annals of thoracic surgery 04/2014; · 3.45 Impact Factor
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    ABSTRACT: Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade-mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8+ T cells (CD44hiCD62LhiCCR7+). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8+ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8+ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung.
    The Journal of clinical investigation 02/2014; · 15.39 Impact Factor
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    ABSTRACT: The American College of Surgery Oncology Group (ACOSOG) trials z4032 and z4033 prospectively characterized lung cancer patients as "high-risk" for surgical intervention, and these results have appeared frequently in the literature. We hypothesized that many patients who meet the objective enrollment criteria for these trials ("high-risk") have similar perioperative outcomes as "normal-risk" patients. 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. From 2000 to 2010, 1,066 patients underwent resection for clinical stage I lung cancer. Of these, 194 (18%) met ACOSOG major criteria for risk (preoperative forced expiratory volume in 1 second or diffusion capacity of the lung for carbon monoxide ≤ 50% predicted). "High-risk" patients were older (66.4 vs 64.6 years, p = 0.02) but similar to controls in sex, prevalence of hypertension, diabetes, and coronary artery disease. "High-risk" patients were less likely than "normal-risk" patients to undergo a lobectomy (117 of 194 [60%] vs 665 of 872 [76%], p < 0.001). "High-risk" and control patients experienced similar morbidity (any complication: 55 of 194 [28%] vs 230 of 872 [26%], p = 0.59) and 30-day mortality (2 of 194 [1%] vs 14 of 872 [ 2%], p = 0.75). A regression analysis showed age (hazard risk, 1.04; 95% confidence interval, 1.02 to 1.06) and coronary artery disease (hazard risk, 1.58; 95% confidence interval, 1.05 to 2.40) were associated with an elevated risk of complications in those undergoing lobectomy, whereas female sex (hazard ratio, 0.63; 95% confidence interval, 0.44 to 0.91) was protective. ACOSOG "high-risk" status was not associated with perioperative morbidity. There are no important differences in early postsurgical 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.
    The Annals of thoracic surgery 02/2014; · 3.45 Impact Factor
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    ABSTRACT: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming the preferred method of mediastinal staging for lung cancer. We investigated the learning curve for EBUS-TBNA using risk-adjusted cumulative sum (Cusum). A retrospective study of EBUS-TBNA was performed at a single academic institution for patients with mediastinal or hilar lymphadenopathy in the setting of proven or suspected lung cancer. A sampling pass was defined as a full retraction and repositioning of the aspiration needle. Rapid on-site evaluation was not available. To track proficiency, risk-adjusted Cusum analysis was performed using acceptable and unacceptable failure rates of 10% and 20%, respectively. Failure was defined as false negative or nondiagnostic results. During the study period, 231 patients underwent EBUS-TBNA. Prevalence of mediastinal or hilar malignancy was 66.7% (154 out of 231). Sensitivity was 92.2% (142 out of 154), and negative predictive value was 87.9% (58 out of 66). Node size was identified as a significant predictor of EBUS-TBNA success by multiple regression. Risk-adjusted Cusum analysis demonstrated that the first and only unacceptable decision interval was crossed at 22 cases. Individual practitioner learning curves were highly variable, and the operator with the highest volume was the most consistently proficient. In our experience, attainment of an acceptable failure rate for EBUS-TBNA required 22 cases. Node size is a predictor of EBUS-TBNA success. Risk-adjusted Cusum proved a powerful evaluative tool to monitor the training process of this new procedure.
    The Journal of thoracic and cardiovascular surgery 09/2013; · 3.41 Impact Factor
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    ABSTRACT: Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [(18) F]fluorodeoxyglucose ([(18) F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [(18) F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [(18) F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8(+) T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen-presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients.
    American Journal of Transplantation 08/2013; · 6.19 Impact Factor
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    ABSTRACT: Microsurgical cuff techniques for orthotopic vascularized murine lung transplantation have allowed for the design of studies that examine mechanisms contributing to the high failure rate of pulmonary grafts. Here, we provide a detailed technical description of orthotopic lung retransplantation in mice, which we have thus far performed in 144 animals. The total time of the retransplantation procedure is approximately 55 minutes, 20 minutes for donor harvest and 35 minutes for the implantation, with a success rate exceeding 95%. The mouse lung retransplantation model represents a novel and powerful tool to examine how cells that reside in or infiltrate pulmonary grafts shape immune responses.
    Journal of thoracic disease. 06/2013; 5(3):321-5.
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    ABSTRACT: BACKGROUND: Past series have identified completion pneumonectomy (CP) as a high-risk operation. We evaluated factors affecting outcomes of CP with a selective approach to offering this operation. METHODS: We analyzed a prospective institutional database and abstracted information on patients undergoing pneumonectomy. Patients undergoing CP were compared with those undergoing primary pneumonectomy (PP). RESULTS: Between January 2000 and February 2011, 211 patients underwent pneumonectomy, of which 35 (17%) were CPs. Ten of 35 (29%) CPs were for benign disease and 25 of 35 (71%) for cancer. Major perioperative morbidity was seen in 21 of 35 (60%) with 4 (11%) perioperative deaths. In univariate analysis, postoperative bronchopleural fistula (p = 0.05) and benign diagnosis (p = 0.07) tended to be associated with perioperative mortality. All 10 patients undergoing CP for benign disease developed a major complication compared with 11 of 25 (44%) with malignancy, p = 0.002. A bronchopleural fistula (4 of 35, 11%) was more likely to occur in patients undergoing CP shortly after the primary operation (interval between lobectomy and CP; 0.28 vs 4.5 years; p = 0.018) with a trend toward a benign indication for operation (p = 0.07). Median survival after CP for benign and malignant indications was 24.3 months and 36.5 months, respectively. Comparing CP patients to those undergoing PP (n = 176), CP patients were more likely to undergo an operation for benign disease (10 of 35, 29% vs 14 of 176, 8%, p = 0.001). Perioperative mortality for PP was 10 of 176 (5.7%), and was statistically similar to CP (11%). CONCLUSIONS: Despite a selective approach, CP remains a morbid operation, particularly for benign indications. Rigorous preoperative optimization, ruling out contraindications to operation and attention to technical detail, are recommended.
    The Annals of thoracic surgery 05/2013; · 3.45 Impact Factor
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    ABSTRACT: Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting.
    Oncoimmunology. 03/2013; 2(3):e23563.
  • Pamela Rose Hesker, Alexander Sasha Krupnick
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    ABSTRACT: Natural killer (NK) cells were originally identified as lymphocytes capable of killing cancer cells without prior sensitization (1). Further characterization of these cells in both humans and rodent models has expanded their role towards a broad-based immunosurveillance of diseased and healthy peripheral tissues. Among peripheral organs, the lung contains the largest percentage of NK cells. Accordingly, NK cells are implicated in many immunological responses within the lung, including innate effector functions as well as initiation of the adaptive immune response. In this article, we review the characteristics of NK cells, current models of NK maturation and cell activation, migration of NKs to the lung, and effector functions of NKs in cancer and infection in the airways. Specific emphasis is placed on the functional significance of NKs in cancer immunosurveillance. Therapeutic modulation of NK cells appears to be a challenging but promising approach to limit cancer, inflammation, and infection in the lung.
    Frontiers in bioscience (Scholar edition) 01/2013; S5:575-587.
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    ABSTRACT: The mechanisms that link bacterial infection to solid organ rejection remain unclear. In this study, we show that following the establishment of lung allograft acceptance in mice, Pseudomonas aeruginosa airway infection induces a G-CSF-dependent neutrophilia that stimulates acute rejection. Graft-infiltrating neutrophils sharply upregulate the B7 molecules CD80 and CD86, but they do not express CD40 or MHC class II in response to P. aeruginosa infection. Neutrophil B7 promotes naive CD4(+) T cell activation and intragraft IL-2(+), IFN-γ(+), and IL-17(+) T lymphocyte accumulation. Intravital two-photon microscopy reveals direct interactions between neutrophils and CD4(+) T cells within pulmonary allografts. Importantly, lung rejection in P. aeruginosa-infected recipients is triggered by CD80/86 on neutrophils and can be prevented by B7 blockade without affecting clearance of this pathogen. These data show that neutrophils enhance T cell activation through B7 trans-costimulation and suggest that inhibiting neutrophil-mediated alloimmunity can be accomplished without compromising bacterial immune surveillance.
    The Journal of Immunology 09/2012; 189(9):4221-5. · 5.52 Impact Factor
  • Stefano Schena, Alexander S Krupnick
    The Journal of thoracic and cardiovascular surgery 08/2012; · 3.41 Impact Factor
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    ABSTRACT: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide and results from a complex interaction between carcinogen exposure and inherent susceptibility. Despite its prevalence, genetic factors that predispose to the development of lung cancer remain elusive. Inbred mouse models offer a unique and clinically relevant tool to study genetic factors that contribute to lung carcinogenesis due to the development of tumors that resemble human adenocarcinoma and broad strain-specific variation in cancer incidence after carcinogen administration. Here, we set out to investigate whether strain-specific variability in tumor immunosurveillance contributes to differences in lung cancer. Using bone marrow transplantation, we determined that hematopoietic cells from lung cancer-resistant mice could significantly impede the development of cancer in a susceptible strain. Furthermore, we show that this is not due to differences in tumor-promoting inflammatory changes or variability in immunosurveillance by the adaptive immune system but results from strain-specific differences in natural killer (NK) cell cytotoxicity. Using a newly discovered congenic strain of mice, we show a previously unrecognized role for strain-specific polymorphisms in the natural killer gene complex (NKC) in immunosurveillance for carcinogen-induced lung cancer. Because polymorphisms in the NKC are highly prevalent in man, our data may explain why certain individuals without obvious risk factors develop lung cancer whereas others remain resistant to the disease despite heavy environmental carcinogen exposure.
    Cancer Research 06/2012; 72(17):4311-7. · 9.28 Impact Factor
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    ABSTRACT: Two-photon intravital microscopy has substantially broadened our understanding of tissue- and organ-specific differences in the regulation of inflammatory responses. However, little is known about the dynamic regulation of leukocyte recruitment into inflamed heart tissue, largely due to technical difficulties inherent in imaging moving tissue. Here, we report a method for imaging beating murine hearts using intravital 2-photon microscopy. Using this method, we visualized neutrophil trafficking at baseline and during inflammation. Ischemia reperfusion injury induced by transplantation or transient coronary artery ligation led to recruitment of neutrophils to the heart, their extravasation from coronary veins, and infiltration of the myocardium where they formed large clusters. Grafting hearts containing mutant ICAM-1, a ligand important for neutrophil recruitment, reduced the crawling velocities of neutrophils within vessels, and markedly inhibited their extravasation. Similar impairment was seen with the inhibition of Mac-1, a receptor for ICAM-1. Blockade of LFA-1, another ICAM-1 receptor, prevented neutrophil adherence to endothelium and extravasation in heart grafts. As inflammatory responses in the heart are of great relevance to public health, this imaging approach holds promise for studying cardiac-specific mechanisms of leukocyte recruitment and identifying novel therapeutic targets for treating heart disease.
    The Journal of clinical investigation 06/2012; 122(7):2499-508. · 15.39 Impact Factor
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    ABSTRACT: It has been 5 years since our team reported the first successful model of orthotopic single lung transplantation in the mouse. There has been great demand for this technique due to the obvious experimental advantages the mouse offers over other large and small animal models of lung transplantation. These include the availability of mouse-specific reagents as well as knockout and transgenic technology. Our laboratory has utilized this mouse model to study both immunological and non-immunological mechanisms of lung transplant physiology while others have focused on models of chronic rejection. It is surprising that despite our initial publication in 2007 only few other laboratories have published data using this model. This is likely due to the technical complexity of the surgical technique and perioperative complications, which can limit recipient survival. As two of the authors (XL and WL) have a combined experience of over 2500 left and right single lung transplants, this review will summarize their experience and delineate tips and tricks necessary for successful transplantation. We will also describe technical advances made since the original description of the model.
    Journal of thoracic disease. 06/2012; 4(3):247-58.
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    ABSTRACT: Patients with malignant pleural effusion (MPE) have varied expected survival and treatment options. We studied the relative cost-effectiveness of various interventions. Decision analysis was used to compare repeated thoracentesis (RT), tunneled pleural catheter (TPC), bedside pleurodesis (BP), and thoracoscopic pleurodesis (TP). Outcomes and utility data were obtained from institutional data and review of literature. Medicare allowable charges were used to ensure uniformity. Base case analysis was performed for two scenarios: expected survival of 3 months and expected survival of 12 months. The incremental cost-effectiveness ratio (ICER) was estimated as the cost per quality-adjusted life-year gained over the patient's remaining lifetime. Under base case analysis for 3-month survival, RT was the least expensive treatment ($4,946) and provided the fewest utilities (0.112 quality-adjusted life-years). The cost of therapy for the other options was TPC $6,450, BP $11,224, and TP $18,604. Tunneled pleural catheter dominated both pleurodesis arms, namely, TPC was both less expensive and more effective. The ICER for TPC over RT was $49,978. The ICER was sensitive to complications and ability to achieve pleural sclerosis with TPC. Under base case analysis for 12-month survival, BP was the least expensive treatment ($13,057) and provided 0.59 quality-adjusted life-years. The cost of treatment for the other options was TPC $13,224, TP $19,074, and RT $21,377. Bedside pleurodesis dominated TPC and thoracentesis. Thoracoscopic pleurodesis was more effective than BP but the ICER for TP over BP was greater than $250,000. Using decision analysis, TPC is the preferred treatment for patients with malignant pleural effusion and limited survival; BP is the most cost-effective treatment for patients with more prolonged expected survival.
    The Annals of thoracic surgery 05/2012; 94(2):374-9; discussion 379-80. · 3.45 Impact Factor
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    ABSTRACT: Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance, we developed a method to retransplant mouse lungs. Retransplantation into T-cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 h of transplantation are reversible. In contrast to hearts, a 72-h period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3(+) cells accumulate and recipient T cells interact with CD11c(+) dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.
    Mucosal Immunology 05/2012; 5(5):544-54. · 7.54 Impact Factor
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    ABSTRACT: Although surgeons are constantly making efforts to improve efficiency of care, it is important to also optimize the patients' understanding and satisfaction with their surgical experience. We investigated the effect of a preoperative educational video on patient outcomes and perception of surgery. An educational video was developed outlining preoperative, operative, and postoperative expectations for patients undergoing pulmonary resection. A prospective study was conducted with 150 patients undergoing surgery with routine preoperative discussion (control group, January 2008 to June 2009) and 150 patients who were provided a supplemental video module (video or study group, September 2009 to October 2010) in addition to routine discussion. Demographics and outcomes data were recorded. Patients completed a pain survey (McGill Questionnaire) and a standardized patient satisfaction survey at discharge and within 1 month of operation. The groups were similar in sex, age, comorbidities, and forced expiratory volume, 1 second, % predicted. Length of hospital stay (5.19 ± 7.4 days vs 4.31 ± 4.3 days; p = 0.2) and hospital readmission rates (12 of 134 [9%] vs 5 of 103 [4.9%]; p = 0.3) were similar for the 2 groups. At discharge, patients in the study group reported less pain at rest (0.98 ± 0.09) vs controls (1.39 ± 0.11) (p = 0.01) with no difference in pain with lifting or coughing. Patients in the study group reported better overall satisfaction with their operation (2.14 ± 0.07 vs 1.85 ± 0.07; p = 0.02), believed they were better prepared (2.01 ± 0.07 vs 1.70 ± 0.06; p = 0.006), and reported less anxiety about the surgical experience (2.79 ± 0.10 vs 2.24 ± 0.09; p = 0.0001). Implementation of a pulmonary resection education module improves patient preparedness, relieves anxiety, and improves pain perception. Additional development and dissemination of a comprehensive education program can improve patients' experience with lung surgery and impact outcomes.
    Journal of the American College of Surgeons 03/2012; 214(5):816-21.e2. · 4.50 Impact Factor
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    Stephanie H Chang, Alexander S Krupnick
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    ABSTRACT: No official guidelines exist for perioperative antibiotic use in noncardiac thoracic surgery. Despite some conflicting data and few randomized clinical trials there exists strong evidence supporting the use of perioperative antibiotic prophylaxis in pulmonary resection. This article discusses the evidence-based indications for antibiotic prophylaxis after lung resection, esophageal surgery, and lung transplantation.
    Thoracic Surgery Clinics 02/2012; 22(1):35-45, vi.

Publication Stats

1k Citations
433.40 Total Impact Points

Institutions

  • 2005–2014
    • Washington University in St. Louis
      • • Department of Surgery
      • • Division of Cardiothoracic Surgery
      • • Department of Medicine
      San Luis, Missouri, United States
  • 2013
    • University of Virginia
      • Department of Surgery
      Charlottesville, VA, United States
  • 2005–2012
    • University of Washington Seattle
      • • Department of Surgery
      • • Division of Cardiothoracic Surgery
      Seattle, WA, United States
  • 2011
    • University of Louisville
      • Division of Thoracic and Cardiovascular Surgery
      Louisville, KY, United States
  • 2008–2011
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 2001–2004
    • Hospital of the University of Pennsylvania
      • • Department of Surgery
      • • Division of Vascular Surgery
      Philadelphia, PA, United States
  • 2002
    • The Children's Hospital of Philadelphia
      • Children's Institute for Surgical Science
      Philadelphia, Pennsylvania, United States
  • 2001–2002
    • University of Pennsylvania
      • Department of Surgery
      Philadelphia, PA, United States