Alexander S Krupnick

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

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Publications (129)602.43 Total impact

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    ABSTRACT: Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell membrane-associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia/reperfusion injury (IRI), we took advantage of a clinically relevant mouse model of transplant-mediated lung IRI. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient, deficiency in DAP12 protected against pulmonary IRI. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking. Copyright © 2015 by The American Association of Immunologists, Inc.
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    ABSTRACT: To investigate the impact of modern postoperative radiotherapy (PORT) on overall survival (OS) for patients with N2 non-small-cell lung cancer (NSCLC) treated nationally with surgery and adjuvant chemotherapy. Patients with pathologic N2 NSCLC who underwent complete resection and adjuvant chemotherapy from 2006 to 2010 were identified from the National Cancer Data Base and stratified by use of PORT (≥ 45 Gy). A total of 4,483 patients were identified (PORT, n = 1,850; no PORT, n = 2,633). The impact of patient and treatment variables on OS was explored using Cox regression. Median follow-up time was 22 months. On univariable analysis, improved OS correlated with younger age, treatment at an academic facility, female sex, urban population, higher income, lower Charlson comorbidity score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT. On multivariable analysis, improved OS remained independently predicted by younger age, female sex, urban population, lower Charlson score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT (hazard ratio, 0.886; 95% CI, 0.798 to 0.988). Use of PORT was associated with an increase in median and 5-year OS compared with no PORT (median OS, 45.2 v 40.7 months, respectively; 5-year OS, 39.3% [95% CI, 35.4% to 43.5%] v 34.8% [95% CI, 31.6% to 38.3%], respectively; P = .014). For patients with N2 NSCLC after complete resection and adjuvant chemotherapy, modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 02/2015; DOI:10.1200/JCO.2014.58.5380 · 17.88 Impact Factor
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    ABSTRACT: The study objective was to evaluate the influence of surgeon experience on outcomes in early-stage non-small cell lung cancer. 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. 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 video-assisted 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 ± 1.6, moderate experience: 3.5 ± 1.7, high experience: 2.3 ± 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 = .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 = .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. 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. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Introduction There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of this data is from inbred rodent models indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung allograft dysfunction (PGD). Methods Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, N=7) or saline vehicle (N=7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels. Results APT102-treated dogs had progressively better lung function and less pulmonary edema over the 3-hour reperfusion period when compared to vehicle-treated controls. Protection from IRI was observed with lower BALF eATP levels, fewer airway leukocytes and blunted inflammatory mediator expression. Additionally, human lung recipients with moderate to severe PGD had significantly higher eATP levels when compared to recipients without this injury. Conclusions Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI.
    The Journal of Heart and Lung Transplantation 10/2014; 34(2). DOI:10.1016/j.healun.2014.09.034 · 5.61 Impact Factor
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    ABSTRACT: The prevalence of mediastinal lymph node metastases is unknown for patients with clinical N0 lung cancer who are thought to be at high risk for occult nodal metastases. Further, the utility of mediastinoscopy in these patients is unknown. We performed a prospective trial to evaluate the utility of routine cervical mediastinoscopy for patients who may be at high risk of occult nodal metastases. From January 1, 2008, July 31, 2013, 90 patients with lung cancer with clinical stage T2N0 or T1N0 with standardized uptake value greater than 10 by positron emission tomography/computed tomography underwent routine cervical mediastinoscopy before lung resection. Biopsy of a minimum of 3 nodal stations at mediastinoscopy and a minimum of 4 nodal stations with lung resection was advised. The prevalence of nodal metastases at mediastinoscopy and lung resection was recorded. Some 64% of patients with lung cancer were male with a mean age of 67.3 years. A total of 81 patients had clinical T2N0 and 9 patients had T1N0 with standardized uptake value greater than 10. Mean tumor size was 4.3 ± 1.7 cm, and mean standardized uptake value was 13.5 ± 6.8. One patient (1.1%) had occult metastases detected at mediastinoscopy. A total of 86 patients underwent surgical resection; 4 patients (4.6%) were upstaged to pN2, and 18 patients (21%) were upstaged to pN1. Of 90 patients with clinically staged N0 lung cancer by positron emission tomography/computed tomography, 5.6% (5) were upstaged to pN2 and 20% (18) were upstaged to pN1 (total nodal upstaging = 25.6%). Mediastinoscopy seems to have limited utility in these patients with T1 and T2 clinically staged N0 by positron emission tomography/computed tomography. Selective use of mediastinoscopy is recommended, along with thorough mediastinal lymph node evaluation in all patients at the time of lung cancer resection. Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
    Journal of Thoracic and Cardiovascular Surgery 09/2014; 149(1). DOI:10.1016/j.jtcvs.2014.08.075 · 3.99 Impact Factor
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    ABSTRACT: To study causes and implications of intraoperative conversion to thoracotomy during video-assisted thoracoscopic surgery (VATS) lobectomy. We performed an institutional review of patients undergoing lobectomy for known or suspected lung cancer with root cause analysis of every conversion from VATS to open thoracotomy. Between 2004 and 2012, 1227 patients underwent lobectomy. Of these, 517 procedures (42%) were completed via VATS, 87 procedures (7%) were converted to open procedures, and 623 procedures (51%) were performed via planned thoracotomy. Patients undergoing thoracotomy were younger and had a higher incidence of prior lung cancers. Planned thoracotomy and conversion group patients had higher clinical T stage than patients in the VATS group, whereas the planned thoracotomy group had higher pathologic stage than patients in the other groups. Postoperative complications were more frequent in patients in the conversion group (46%) than in the VATS group (23%; P < .001), but similar to the open group (42%; P = .56). Validating a previous classification of causes for conversion, 22 out of 87 conversions (25%) were due to vascular causes, 56 conversions (64%) were for anatomy (eg, adhesions or tumor size), and 8 conversions (9%) were the result of lymph nodes. No specific imaging variables predicted conversion. Within the conversion groups, emergent (20 out of 87; 23%) and planned (67 out of 87; 77%) conversion groups were similar in patient and tumor characteristics and incidence of perioperative morbidity. The conversion rate for VATS lobectomy dropped from 21 out of 74 (28%), to 29 out of 194 (15%), to 37 out of 336 (11%) (P < .001) over 3-year intervals. Over the same periods, the proportion of operations started via VATS increased significantly. With increasing experience, a higher proportion of lobectomy operations can be completed thoracoscopically. VATS should be strongly considered as the initial approach for the majority of patients undergoing lobectomy. Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
    Journal of Thoracic and Cardiovascular Surgery 09/2014; 149(1). DOI:10.1016/j.jtcvs.2014.08.074 · 3.99 Impact Factor
  • Chad A Witt, Varun Puri, Andrew E Gelman, Alexander Sasha Krupnick, Daniel Kreisel
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    ABSTRACT: Outcomes after lung transplantation remain worse compared to other solid organ transplants, which is in large part due to high rates of graft rejection. Despite emerging data that immune responses to lungs differ from other organs, immunosuppression for lung transplant recipients is still based on strategies established for recipients of other grafts. There exists an urgent need to develop immunosuppressive strategies for lung transplant recipients that take the unique immunological features of this organ into account.
    Expert Review of Clinical Immunology 09/2014; 10(11):1-3. DOI:10.1586/1744666X.2014.959499 · 3.34 Impact Factor
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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. DOI:10.1097/JTO.0000000000000152 · 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; 97(6). DOI:10.1016/j.athoracsur.2014.02.046 · 3.45 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S97-S98. DOI:10.1016/j.healun.2014.01.295 · 5.61 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; 124(3). DOI:10.1172/JCI71359 · 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; DOI:10.1016/j.athoracsur.2013.12.028 · 3.45 Impact Factor
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    ABSTRACT: Objective Controversy persists regarding appropriate radiographic surveillance strategies following lung cancer resection. We compared the impact of surveillance CT scan (CT) vs. chest radiograph (CXR) in patients who underwent resection for stage I lung cancer. Methods A retrospective analysis was performed of all patients undergoing resection for pathologic stage I lung cancer from January 2000-April 2013. After resection, follow-up included routine history and physical exam in conjunction with CXR or CT at the discretion of the treating physician. Identification of successive lung malignancy (i.e. recurrence at any new site or new primary) and survival were recorded. Results There were 554 evaluable patients with 232 undergoing routine postoperative CT and 322 receiving routine CXR. Postoperative five-year survival was 67.8% in the CT group vs. 74.8% in the CXR group (p = 0.603). Successive lung malignancy was found in 27% (63/232) of patients undergoing CT vs. 22% (72/322) receiving CXR (p = 0.19). The mean time from surgery to diagnosis of successive malignancy was 1.93 years for CT vs. 2.56 years for CXR (p = 0.046). For the CT group, 41% (26/63) of successive malignancies were treated with curative intent vs. 40% (29/72) in the CXR group (p = 0.639). Cox-proportional hazard analysis indicated imaging modality (CT vs. CXR) was not associated with survival (p = 0.958). Conclusion Surveillance CT may result in earlier diagnosis of successive malignancy vs. CXR in stage I lung cancer, although no difference in survival was demonstrated. A randomized trial would help determine the impact of postoperative surveillance strategies on survival.
    Journal of Thoracic and Cardiovascular Surgery 01/2014; 149(1). DOI:10.1016/j.jtcvs.2014.07.095 · 3.99 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; 146(6). DOI:10.1016/j.jtcvs.2013.07.077 · 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; 13(10). DOI:10.1111/ajt.12389 · 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.
    06/2013; 5(3):321-5. DOI:10.3978/j.issn.2072-1439.2013.04.15
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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; DOI:10.1016/j.athoracsur.2013.04.014 · 3.45 Impact Factor
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    ABSTRACT: Purpose Mitochondrial danger associated molecular patterns (DAMPS) such as circulating mitochondrial DNA (mtDNA) is known to be released by injured cells following bone crush trauma and may induce acute lung injury in patients with systemic inflammatory response syndrome. However, it remains unclear if injured lungs also release mtDNA possibly contributing to primary graft dysfunction (PGD). Here we assess circulating mt DNA levels in lung recipients with or without PGD. Methods and Materials PGD (N=33) was graded immediately after arrival in the ICU in accordance with ISHLT criteria and plasma was isolated and purified for DNA using a Qiagen blood DNA isolation kit. Primers specific for cytochrome c oxidase, a single copy gene found only in the mitochondrial genome, were used to determine plasma mtDNA concentrations by comparison to a standard curve generated by purified mtDNA. Results Patients without PGD and healthy controls have comparable mtDNA levels and when compared to patients with PGD have significantly less mtDNA. [figure 1] Notably, mtDNA plasma concentration also increases with PGD severity as PGD 2 patients have significantly higher mtDNA as compared to PGD 1 patients (p<0.01). Conclusions Mitochondrial DAMPs are released in high amounts in patients with PGD suggesting a role in promoting inflammation. Quantitation of circulating mtDNA may be a sensitive non-invasive method to independently evaluate pulmonary tissue injury following lung transplantation.
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S33. DOI:10.1016/j.healun.2013.01.885 · 5.61 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. DOI:10.4161/onci.23563 · 6.28 Impact Factor

Publication Stats

2k Citations
602.43 Total Impact Points

Institutions

  • 2005–2015
    • Washington University in St. Louis
      • • Department of Surgery
      • • Alvin J. Siteman Cancer Center
      San Luis, Missouri, United States
  • 2007
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States
  • 2000–2004
    • Hospital of the University of Pennsylvania
      • • Department of Surgery
      • • Division of Vascular Surgery
      Philadelphia, PA, United States
  • 2003
    • Thomas Jefferson University
      • Department of Medicine
      Filadelfia, Pennsylvania, United States
  • 2001–2003
    • University of Pennsylvania
      • Department of Surgery
      Filadelfia, Pennsylvania, United States
  • 2002
    • The Children's Hospital of Philadelphia
      • Children's Institute for Surgical Science
      Philadelphia, Pennsylvania, United States