David M Hwang

Sir Charles Gairdner Hospital, Perth City, Western Australia, Australia

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Publications (87)360.8 Total impact

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    ABSTRACT: The contribution of bone marrow cells (BMC) in lung repair is controversial. We previously reported a subpopulation of BMC that express Clara cell secretory protein (CCSP). To determine the contribution of endogenous CCSP(+) BMC to airway regeneration we performed bone marrow transplantation studies using the CCtk mouse, which expresses a thymidine kinase suicide gene under regulation of the CCSP promoter. Mice were transplanted with wild type or CCtk BMC and treated with ganciclovir to eliminate CCSP(+) cells. After airway injury using naphthalene, mice depleted of CCSP(+) BMC had more inflammatory cells in lung and decreased levels of oxygen in arterial blood. They also had reduced expression of airway epithelial genes and less Clara cells compared to control mice that had intact CCSP(+) BMC and bone marrow derived CCSP(+) cells in the airways. After naphthalene injury, administration of CCSP reproduced the beneficial effect of CCSP(+) BMC by improving recovery of airway epithelium, reducing lung inflammation and increasing oxygen in arterial blood from mice depleted of CCSP(+) BMC. Our data demonstrates that ablation of CCSP(+) BMC delays airway recovery and suggests the beneficial effect of CCSP(+) BMC in lung recovery is in part due to production of CCSP itself.Molecular Therapy (2014); doi:10.1038/mt.2014.223.
    Molecular Therapy 11/2014; DOI:10.1038/mt.2014.223 · 6.43 Impact Factor
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    ABSTRACT: Fluorescence in situ hybridization (FISH) is currently the standard for diagnosing anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancers for ALK inhibitor therapies. ALK immunohistochemistry (IHC) may serve as a screening and alternative diagnostic method. The Canadian ALK (CALK) study was initiated to implement a multicenter optimization and standardization of laboratory developed ALK IHC and FISH tests across 14 hospitals. Methods: Twenty-eight lung adenocarcinomas with known ALK status were used as blinded study samples. Thirteen laboratories performed IHC using locally developed staining protocols for 5A4, ALK1, or D5F3 antibodies; results were assessed by H-score. Twelve centers conducted FISH using protocols based on Vysis’ ALK break-apart FISH kit. Initial IHC results were used to optimize local IHC protocols, followed by a repeat IHC study to assess the results of standardization. Three laboratories conducted a prospective parallel IHC and FISH analysis on 411 consecutive clinical samples using post-validation optimized assays. Results: Among study samples, FISH demonstrated 22 consensus ALK+ and six ALK wild type tumors. Preoptimization IHC scores from 12 centers with 5A4 and the percent abnormal cells by FISH from 12 centers showed intraclass correlation coefficients of 0.83 and 0.68, respectively. IHC optimization improved the intraclass correlation coefficients to 0.94. Factors affecting FISH scoring and outliers were identified. Post-optimization concurrent IHC/FISH testing in 373 informative cases revealed 100% sensitivity and specificity for IHC versus FISH. Conclusions: Multicenter standardization study may accelerate the implementation of ALK testing protocols across a country/region. Our data support the use of an appropriately validated IHC assay to screen for ALK+ lung cancers.
    Journal of Thoracic Oncology 09/2014; 9(9):1255-1263. DOI:10.1097/JTO.0000000000000239 · 5.80 Impact Factor
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    ABSTRACT: Background:It is estimated that millions of North Americans would qualify for lung cancer screening and that billions of dollars of national health expenditures would be required to support population-based computed tomography lung cancer screening programs. The decision to implement such programs should be informed by data on resource utilization and costs.Methods:Resource utilization data were collected prospectively from 2059 participants in the Pan-Canadian Early Detection of Lung Cancer Study using low-dose computed tomography (LDCT). Participants who had 2% or greater lung cancer risk over 3 years using a risk prediction tool were recruited from seven major cities across Canada. A cost analysis was conducted from the Canadian public payer’s perspective for resources that were used for the screening and treatment of lung cancer in the initial years of the study.Results:The average per-person cost for screening individuals with LDCT was $453 (95% confidence interval [CI], $400–$505) for the initial 18-months of screening following a baseline scan. The screening costs were highly dependent on the detected lung nodule size, presence of cancer, screening intervention, and the screening center. The mean per-person cost of treating lung cancer with curative surgery was $33,344 (95% CI, $31,553–$34,935) over 2 years. This was lower than the cost of treating advanced-stage lung cancer with chemotherapy, radiotherapy, or supportive care alone, ($47,792; 95% CI, $43,254–$52,200; p = 0.061).Conclusion:In the Pan-Canadian study, the average cost to screen individuals with a high risk for developing lung cancer using LDCT and the average initial cost of curative intent treatment were lower than the average per-person cost of treating advanced stage lung cancer which infrequently results in a cure.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2014; 9(10). DOI:10.1097/JTO.0000000000000283 · 5.80 Impact Factor
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    ABSTRACT: Introduction: To determine long-term outcome and risk factors for recurrence after thymectomy. Methods: Patients who underwent thymectomy (n = 262) for a thymic tumor (1986-2010) were identified from a prospective database. Patients were classified according to World Helath Organization (WHO) histologic classification, Masaoka staging system, and completeness of resection. Risk factors for recurrence: WHO histology, tumor size, Masaoka stage and completeness of resection were analyzed. Results: Of 262 patients, 51% were female, median age was 55 years, and 39% had myasthenia gravis. Median follow-up was 7.5 years, median tumor size was 5.4 cm, and Masaoka stage distribution was: I (25%), II (47%), III (17%), IV (4%), and (7%) not classified. Of 200 patients classified under the WHO system, there were (7%) type A, (22%) type AB, and (71%) type B; 83% had complete resection. One-hundred and sixty-nine patients received adjuvant radiotherapy, eight adjuvant chemoradiotherapy and 14 neoadjuvant chemoradiotherapy. Overall survival was 95% at 5 years, 91% at 10 years and 91% at 15 years. Recurrence occurred in 12 patients and disease-related death in four patients. Five patients underwent re-resection for recurrence with survival of 2-15 years. Only Masaoka stage and tumor size were associated with statistically significant risk of recurrence on multivariate analysis. Conclusion: Resectable thymoma is associated with excellent prognosis. Aggressive resection of recurrent disease yielded excellent long-term results. Higher Masaoka stage is associated with a greater chance of incomplete resection. Higher Masaoka stage and increasing tumor size are independent factors associated with recurrence.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2014; 9(7):1018-22. DOI:10.1097/JTO.0000000000000215 · 5.80 Impact Factor
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    ABSTRACT: Introduction: Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of patients with advanced non-small-cell lung cancer. This study involves a large cohort and epidemiologically unselected series of EGFR mutation testing for patients with nonsquamous non-small-cell lung cancer in a North American population to determine sample-related factors that influence success in clinical EGFR testing. Methods: Data from consecutive cases of Canadian province-wide testing at a centralized diagnostic laboratory for a 24-month period were reviewed. Samples were tested for exon-19 deletion and exon-21 L858R mutations using a validated polymerase chain reaction method with 1% to 5% detection sensitivity. Results: From 2651 samples submitted, 2404 samples were tested with 2293 samples eligible for analysis (1780 histology and 513 cytology specimens). The overall test-failure rate was 5.4% with overall mutation rate of 20.6%. No significant differences in the failure rate, mutation rate, or mutation type were found between histology and cytology samples. Although tumor cellularity was significantly associated with test-success or mutation rates in histology and cytology specimens, respectively, mutations could be detected in all specimen types. Significant rates of EGFR mutation were detected in cases with thyroid transcription factor (TTF)-1-negative immunohistochemistry (6.7%) and mucinous component (9.0%). Conclusions:EGFR mutation testing should be attempted in any specimen, whether histologic or cytologic. Samples should not be excluded from testing based on TTF-1 status or histologic features. Pathologists should report the amount of available tumor for testing. However, suboptimal samples with a negative EGFR mutation result should be considered for repeat testing with an alternate sample.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2014; 9(7). DOI:10.1097/JTO.0000000000000196 · 5.80 Impact Factor
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    ABSTRACT: Supplementary information available for this article at http://www.nature.com/ncomms/2014/140513/ncomms4796/suppinfo/ncomms4796_S1.html
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    ABSTRACT: The increasing use of nanomaterials raises concerns about the long-term effects of chronic nanoparticle exposure on human health. However, nanoparticle exposure is difficult to evaluate non-invasively using current measurement techniques. Here we show that the skin is an important site of nanoparticle accumulation following systemic administration. Mice injected with high doses of gold nanoparticles have visibly blue skin while quantum dottreated animals fluoresce under ultraviolet excitation. More importantly, elemental analysis of excised skin correlates with the injected dose and nanoparticle accumulation in the liver and spleen. We propose that skin analysis may be a simple strategy to quantify systemic nanoparticle exposure and predict nanoparticle fate in vivo. Our results suggest that in the future, dermal accumulation may also be exploited to trigger the release of ultraviolet and visible light-sensitive therapeutics that are currently impractical in vivo due to limits in optical penetration of tissues at these wavelengths.
    Nature Communications 05/2014; 5(3796). DOI:10.1038/ncomms4796 · 10.74 Impact Factor
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    ABSTRACT: The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunt-tip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5 × 10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies.
    The Annals of thoracic surgery 05/2014; 97(5):1771-5. DOI:10.1016/j.athoracsur.2014.01.048 · 3.65 Impact Factor
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    ABSTRACT: The long-term success of lung transplantation is limited by chronic lung allograft dysfunction (CLAD). The purpose of this study was to investigate the alveolar alarmin profiles in CLAD subtypes, restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). Bronchoalveolar lavage (BAL) samples were collected from 53 recipients who underwent double lung or heart-lung transplantation, including patients with RAS (n = 10), BOS (n = 18) and No CLAD (n = 25). Protein levels of alarmins such as S100A8, S100A9, S100A8/A9, S100A12, S100P, high-mobility group box 1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in BAL fluid were measured. RAS and BOS showed higher expressions of S100A8, S100A8/A9 and S100A12 compared with No CLAD (p < 0.0001, p < 0.0001, p < 0.0001 in RAS vs. No CLAD, p = 0.0006, p = 0.0044, p = 0.0086 in BOS vs. No CLAD, respectively). Moreover, RAS showed greater up-regulation of S100A9, S100A8/A9, S100A12, S100P and HMGB1 compared with BOS (p = 0.0094, p = 0.038, p = 0.041, p = 0.035 and p = 0.010, respectively). sRAGE did not show significant difference among the three groups (p = 0.174). Our results demonstrate distinct expression patterns of alveolar alarmins in RAS and BOS, suggesting that RAS and BOS may represent biologically different subtypes. Further refinements in biologic profiling will lead to a better understanding of CLAD.
    American Journal of Transplantation 04/2014; DOI:10.1111/ajt.12718 · 6.19 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S98. DOI:10.1016/j.healun.2014.01.296 · 5.61 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S112-S113. DOI:10.1016/j.healun.2014.01.019 · 5.61 Impact Factor
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    ABSTRACT: PDT is a safe procedure with most post procedural complications reported as minor. We report a case of severe acute stridor and trachea-bronchial airway obstruction with mucosal sloughing and fibrous plugs resulting in respiratory failure within three hours following PDT. To our knowledge this is the first reported case where stridor and acute respiratory failure resulted within hours following PDT treatment.
    Photodiagnosis and photodynamic therapy 02/2014; 11(2). DOI:10.1016/j.pdpdt.2014.02.004 · 2.52 Impact Factor
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    ABSTRACT: We developed an innovative approach for malignant pleural mesothelioma (MPM) with a short accelerated course of high-dose hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP). This phase I/II study assessed the feasibility of Surgery for Mesothelioma After Radiation Therapy (SMART). All resectable clinical T1-3N0M0 histologically proven, previously untreated MPMs were eligible. Patients received 25 Gy in five daily fractions during 1 week to the entire ipsilateral hemithorax with concomitant 5 Gy boost to areas at risk followed by EPP within 1 week of completing neoadjuvant IMRT. Adjuvant chemotherapy was offered to ypN2 patients on final pathologic findings. The primary end point was treatment-related mortality and secondary end points were overall survival, disease-free survival, treatment-related morbidity, and patterns of failure. Targeted accrual of 25 patients was completed between November 2008 and October 2012. All patients completed SMART. IMRT was well tolerated with no grade 3+ toxicities. EPP was performed 6 ± 2 days after completing IMRT without any perioperative mortality. Thirteen patients developed grade 3+ surgical complications. One patient (4%) died from treatment-related toxicity (empyema) during follow-up. All but one patient had stage III or IV disease on final pathologic findings. Five of 13 ypN2 patients received adjuvant chemotherapy. After a median follow-up of 23 months (range, 6-51), the cumulative 3-year survival reached 84% in epithelial subtypes compared with 13% in biphasic subtypes (p = 0.0002). SMART is feasible in resectable MPM patients. This innovative protocol presents encouraging results and supports future studies looking at long-term outcome in patients with epithelial subtypes.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2014; DOI:10.1097/JTO.0000000000000078 · 5.80 Impact Factor
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    ABSTRACT: Context.-Surgical removal and pathologic handling of lung tissue has a compressive effect upon its architecture. The effect of surgical atelectasis on morphology has not been examined in depth, especially with respect to lung adenocarcinomas. Objective.-To examine the influence of surgical atelectasis on morphologic lepidic growth pattern, mimicking papillary adenocarcinoma pattern. Design.-In 2 cases serial sections of resected pulmonary adenocarcinoma were used, as was a 3-dimensional reconstruction. Elastin stains were performed on primary and metastatic adenocarcinomas. Results.-Perfusion fixation of another case showed marked morphologic differences of less compressed peripheral lung tissue, emphasizing the preexisting alveolar structure. An elastic stain may help identify true lesional architecture. Conclusions.-We demonstrate that microscopic sections of adenocarcinoma in situ in compressed/collapsed tissue may give rise to a pseudopapillary pattern mimicking invasive adenocarcinoma. Accurate appreciation of different tumor architecture in lung adenocarcinoma has important biologic and clinical implications. Pathologists should be aware of the possibility of misclassification of adenocarcinoma pattern due to tissue artifacts caused by lung tissue handling.
    Archives of pathology & laboratory medicine 12/2013; 137(12):1792-1797. DOI:10.5858/arpa.2012-0613-SA · 2.88 Impact Factor
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    ABSTRACT: In vivo lung perfusion (IVLP) is an emergent strategy to treat lung metastases because it allows localized delivery of chemotherapy with minimal systemic exposure. Previously, short-term (±30 minutes) IVLP resulted in variable efficacy and significant lung toxicity. We hypothesize that a modified IVLP strategy derived from an ex vivo lung perfusion technique could minimize lung injury. Our objective was to demonstrate the feasibility and safety of a modified prolonged (4 hours) IVLP. Six Yorkshire pigs were used for the experiments. A thoracotomy was performed, the left pulmonary artery and pulmonary veins were cannulated, and the left lung was isolated in situ. IVLP was performed at normothermia for 4 hours using Steen Solution (XVIVO Perfusion, Göteburg, Sweden) as perfusate. The flow rate was 16% of estimated cardiac output and left atrial pressure was maintained between 3 and 5 mm Hg. Perfusate was deoxygenated and supplied with CO2 to physiologic levels before entering the lungs. A protective mode of ventilation was used. After IVLP, the left lung was allowed to reperfuse for additional 4 hours. Airway dynamics, gas exchange, and pulmonary vascular resistance were used to assess left lung physiology. Histologic signs of lung injury were assessed before and after IVLP, and 4 hours after reperfusion. Lung function parameters were stable throughout the 4-hour IVLP and during reperfusion. No significant histologic evidence of acute lung injury was observed. Four hours of IVLP is feasible without adding significant lung injury. Prolonged perfusion time and a protective protocol might provide safer and more efficacious treatment of pulmonary metastases.
    The Journal of thoracic and cardiovascular surgery 11/2013; DOI:10.1016/j.jtcvs.2013.10.009 · 3.99 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 10/2013; 188(7):878-880. DOI:10.1164/rccm.201302-0368LE · 11.99 Impact Factor
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    ABSTRACT: Context.-The International Collaboration on Cancer Reporting (ICCR) is a quadripartite alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, and the Canadian Partnership Against Cancer. The ICCR was formed with a view to reducing the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish, and maintain standardized cancer-reporting data sets. The resultant standardization of cancer reporting would be expected to benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. Objectives.-To develop an evidence-based reporting data set for each cancer site. Design.-A project to develop data sets for prostate, endometrium, and lung cancers and malignant melanoma was piloted by the quadripartite group. Results.-A set of required and recommended data elements and appropriate responses for each element were agreed upon for the reporting of lung cancer. Conclusions.-This review describes the process of development of the lung cancer data set.
    Archives of pathology & laboratory medicine 08/2013; 137(8):1054-1062. DOI:10.5858/arpa.2012-0511-OA · 2.88 Impact Factor
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    ABSTRACT: We have previously reported a subpopulation of bone marrow cells (BMC) that express Clara cell secretory protein (CCSP), generally felt to be specific to lung Clara cells. Ablation of lung Clara cells has been reported using a transgenic mouse that expresses thymidine kinase under control of the CCSP promoter. Treatment with ganciclovir results in permanent elimination of CCSP(+) cells, failure of airway regeneration, and death. To determine if transtracheal delivery of wild-type bone marrow CCSP(+) cells is beneficial after ablation of lung CCSP(+) cells, transgenic mice were treated with ganciclovir followed by transtracheal administration of CCSP(+) or CCSP(-) BMC. Compared with mice administered CCSP(-) cells, mice treated with CCSP(+) cells had more donor cells lining the airway epithelium, where they expressed epithelial markers including CCSP. Although donor CCSP(+) cells did not substantially repopulate the airway, their administration resulted in increased host ciliated cells, better preservation of airway epithelium, reduction of inflammatory cells, and an increase in animal survival time. Administration of CCSP(+) BMC is beneficial after permanent ablation of lung Clara cells by increasing bronchial epithelial repair. Therefore, CCSP(+) BMC could be important for treatment of lung diseases where airways re-epithelialization is compromised.Molecular Therapy (2013); doi:10.1038/mt.2013.53.
    Molecular Therapy 04/2013; 21(6). DOI:10.1038/mt.2013.53 · 6.43 Impact Factor
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    ABSTRACT: The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.
    American Journal of Transplantation 04/2013; 13(6). DOI:10.1111/ajt.12230 · 6.19 Impact Factor
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    ABSTRACT: BACKGROUND: The timing of disease onset may affect the prognosis in chronic lung allograft dysfunction (CLAD). The relationship between the timing of disease onset and the prognosis of CLAD and its sub-types, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), was examined. METHODS: Clinical records and pulmonary function data of 597 patients who underwent bilateral lung transplantation from 1996 to 2010 and survived for >3 months were examined. RESULTS: Among 155 patients with a final diagnosis of BOS, patient survival after disease onset was significantly different according to disease-onset timing (BOS onset/post-BOS median survival: overall/1,438 days; <1 year/511 days; 1-2 years/1,199 days; 2-3 years/1,403 days; >3 years/did not reach median survival; p < 0.0001). The prognosis of RAS was generally poorer than that of BOS (overall post-RAS median survival, 377 days). Treating non-CLAD, CLAD, BOS, and RAS as time-dependent covariates, recipient sex-adjusted and age-adjusted Cox regression analysis demonstrated an overall mortality risk of BOS (reference: no CLAD) of 6.7 (95% confidence interval, 4.6-9.9). However, when patients survived 3 years without CLAD, the mortality risk of subsequent BOS was only 1.9 (95% confidence interval, 0.8-4.4) compared with no CLAD. The number of RAS patients was too small to obtain sufficient power to estimate time-dependent mortality risk. CONCLUSION: Late-onset BOS showed a better prognosis than early-onset BOS. Studies that do not distinguish BOS from RAS may overestimate the mortality risk of BOS. Multicenter studies will be required to further elucidate risk factors toward the development of better management strategies for CLAD.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 02/2013; 32(5). DOI:10.1016/j.healun.2013.01.1054 · 5.61 Impact Factor

Publication Stats

664 Citations
360.80 Total Impact Points

Institutions

  • 2014
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
  • 2007–2014
    • University Health Network
      • • Thoracic Surgery Clinic
      • • Department of Pathology
      Toronto, Ontario, Canada
  • 2006–2014
    • University of Toronto
      • • Department of Surgery
      • • Department of Laboratory Medicine and Pathobiology
      • • Department of Medical Imaging
      • • Division of Respirology
      Toronto, Ontario, Canada
  • 2009–2012
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada
  • 2011
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2008
    • Saint Michael's Medical Center
      Newark, New Jersey, United States