Publications by authors named "Mark Krasnik"

34 Publications

Predictive Value of Endobronchial Ultrasound Strain Elastography in Mediastinal Lymph Node Staging: The E-Predict Multicenter Study Results.

Respiration 2020;99(6):484-492. Epub 2020 Jun 3.

Department of Pulmonology, Radboudumc, Nijmegen, The Netherlands,

Background: Systematic assessment of lymph node status by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is indicated in (suspected) lung cancer. Sampling is herein guided by nodal size and FDG-PET characteristics. Ultrasound strain elastography (SE) might further improve risk stratification. By imaging tissue deformation over time, SE computes relative tissue strain. In several tissues, a lower strain (deformation) has been associated with a higher likelihood of malignancy.

Objectives: To assess if EBUS-SE can independently help predict malignancy, and when combined with size and FDG uptake information.

Methods: This multicenter (n = 5 centers) prospective trial included patients with suspected or proven lung cancer using a standardized measurement protocol. Cytopathology combined with surgery or follow-up imaging (>6 months) were used as reference standard.

Results: Between June 2016 and July 2018, 327 patients and 525 lymph nodes were included (mean size 12.3 mm, malignancy prevalence 0.48). EBUS-SE had an overall AUC of 0.77. A mean strain <115 (range 0-255) showed 90% sensitivity, 43% specificity, 60% positive predictive value, and 82% negative predictive value. Combining EBUS-SE (<115) with size (<8 mm) and FDG-PET information into a risk stratification algorithm increased the accuracy. Combining size and SE showed that the 48% a priori chance of malignancy changed to 11 and 70% in double negative or positive nodes, respectively. In the subset where FDG-PET was available (n = 370), triple negative and positive nodes went from a 42% a priori chance of malignancy to 9 and 73%, respectively.

Conclusions: EBUS-SE can help predict lymph node malignancy and may be useful for risk stratification when combined with size and PET information.
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http://dx.doi.org/10.1159/000507592DOI Listing
June 2020

The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

J Thorac Oncol 2017 07 28;12(7):1109-1121. Epub 2017 Apr 28.

Thoracic Surgery Service, Hospital Universitari Mutua Terrassa, University of Barcelona; Centros de Investigación Biomédica en Red de Enfermedades Respiratorias CIBERES Lung Cancer Group, Terrassa, Barcelona, Spain.

Introduction: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons.

Methods: Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases.

Results: The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage.

Conclusions: The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.
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http://dx.doi.org/10.1016/j.jtho.2017.04.011DOI Listing
July 2017

The IASLC Lung Cancer Staging Project: Methodology and Validation Used in the Development of Proposals for Revision of the Stage Classification of NSCLC in the Forthcoming (Eighth) Edition of the TNM Classification of Lung Cancer.

J Thorac Oncol 2016 09 21;11(9):1433-46. Epub 2016 Jul 21.

Thoracic Surgery Service, Hospital Universitari Mutua Terrassa and Centros de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES) Lung Cancer Group, Terrassa, Barcelona, Spain.

Introduction: Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017.

Methods: An international database of 94,708 patients with lung cancer diagnosed in 1999-2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification.

Results: Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals.

Conclusions: An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.
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http://dx.doi.org/10.1016/j.jtho.2016.06.028DOI Listing
September 2016

The effect of different comorbidities on survival of non-small cells lung cancer patients.

Lung 2015 Apr 17;193(2):291-7. Epub 2014 Dec 17.

Center for Clinical Epidemiology, Odense University Hospital, Sdr. Boulevard 29, Entrance 101, 4rd Floor, 5000, Odense C, Denmark,

Purpose: Primary lung cancer is one of the most common types of cancers. Comorbidity has been shown to be a negative prognostic factor in the overall lung cancer population. The significance of the individual comorbidities is less well known. The purpose of this paper is to investigate the effect of each comorbid disease groups on survival.

Methods: The analysis is based on all patients with NSCLC who were registered in 2009-2011, in total 10,378 patients. To estimate the effect of each comorbidity group on the survival, we fitted a Cox regression model for each comorbidity group adjusting for age, sex, resection, and stage.

Results: Patients with cardiovascular comorbidity have a 30% higher death rate [HR 1.30 with 95% CI (1.13; 1.49)] than patients without comorbidity. Patients with diabetes and patients with cerebrovascular disorders and COPD have a 20% excess mortality than patients without comorbidity: [HR 1.19 with CI (1.02; 1.39) for diabetes, HR 1.18 with CI (1.05; 1.33) for cerebrovascular disorders, and HR 1.20 with CI (1.10; 1.39 for COPD)].

Conclusion: Our study shows the importance of cardiovascular disease in lung cancer. Diabetes, cerebrovascular disorders, and COPD also have a significant impact on survival of NSCLC patients.
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http://dx.doi.org/10.1007/s00408-014-9675-5DOI Listing
April 2015

The prevalence of EGFR mutations in non-small cell lung cancer in an unselected Caucasian population.

APMIS 2015 Feb 25;123(2):108-15. Epub 2014 Nov 25.

Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

EGFR mutation frequencies in unselected Caucasian populations are unknown. This study assesses the prevalence of EGFR mutations in an unselected population-based cohort, and the correlation between mutation and gender, age, ethnicity, smoking habits, and pathological data. NSCLC patients diagnosed in a well-defined Danish population were included. The type of the diagnostic material, and data on smoking were registered. The mutation analyses were investigated by Therascreen EGFR RGQ-PCR Kit or Sanger sequencing. A total of 658 men and 598 women were included. 6.2% were never smokers, 38.9% were ex-smokers, and 54.9% were current smokers. One thousand one hundred and sixty-one (92.4%) patients had sufficient material for mutation analysis. Cytological material was used for 38% of the mutation analyses. 5.4% had mutation in the EGFR gene (4.3% men/6.7% women). 87% were activating mutations. 8.0% of adenocarcinomas, and 1.9% of squamous cell carcinomas were mutated. 29.4%, 4.4% and 2.9% of never, ex- and current smokers were mutated (p < 0.001). No difference in mutation rate was observed between patients with cytology only, histology only or both cytology and histology available. 5.4% of the patients had EGFR mutation. Adenocarcinomas were mutated more often (8.0%) than squamous cell carcinomas (1.9%). Mutations were found in never smokers as well as in former and current smokers. No difference in gender and age regarding mutation status was observed. EGFR mutations analysis was possible in almost all patients with no difference between cytology and histology specimens.
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http://dx.doi.org/10.1111/apm.12328DOI Listing
February 2015

Guideline for the acquisition and preparation of conventional and endobronchial ultrasound-guided transbronchial needle aspiration specimens for the diagnosis and molecular testing of patients with known or suspected lung cancer.

Respiration 2014 5;88(6):500-17. Epub 2014 Nov 5.

Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Rationale: Conventional transbronchial needle aspiration (TBNA) and endobronchial ultrasound (EBUS)-TBNA are widely accepted tools for the diagnosis and staging of lung cancer and the initial procedure of choice for staging. Obtaining adequate specimens is key to provide a specific histologic and molecular diagnosis of lung cancer.

Objectives: To develop practice guidelines on the acquisition and preparation of conventional TBNA and EBUS-TBNA specimens for the diagnosis and molecular testing of (suspected) lung cancer. We hope to improve the global unification of procedure standards, maximize the yield and identify areas for research.

Methods: Systematic electronic database searches were conducted to identify relevant studies for inclusion in the guideline [PubMed and the Cochrane Library (including the Cochrane Database of Systematic Reviews)].

Main Results: The number of needle aspirations with both conventional TBNA and EBUS-TBNA was found to impact the diagnostic yield, with at least 3 passes needed for optimal performance. Neither needle gauge nor the use of miniforceps, the use of suction or the type of sedation/anesthesia has been found to improve the diagnostic yield for lung cancer. The use of rapid on-site cytology examination does not increase the diagnostic yield. Molecular analysis (i.e. EGFR, KRAS and ALK) can be routinely performed on the majority of cytological samples obtained by EBUS-TBNA and conventional TBNA. There does not appear to be a superior method for specimen preparation (i.e. slide staining, cell blocks or core tissue). It is likely that optimal specimen preparation may vary between institutions depending on the expertise of pathology colleagues.
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http://dx.doi.org/10.1159/000368857DOI Listing
November 2015

Role of comorbidity on survival after radiotherapy and chemotherapy for nonsurgically treated lung cancer.

J Thorac Oncol 2015 Feb;10(2):272-9

*Herlev University Hospital, Copenhagen, Denmark; †Cancer Epidemiology and Population Health, King's Health Partners Cancer Centre, London, United Kingdom; ‡Odense University Hospital, Odense, Denmark; and §Gentofte University Hospital, Gentofte, Denmark.

Background: Comorbidity, such as diseases of the cardiovascular, pulmonary, and other systems, may influence prognosis in lung cancer and complicate its treatment. The performance status of patients, which is a known prognostic marker, may also be influenced by comorbidity. Due to the close link between tobacco smoking and lung cancer, and because lung cancer is often diagnosed in advanced ages (median age at diagnosis in Denmark is 70 years), comorbidity is present in a large proportion of lung cancer patients.

Methods: Patients with any stage lung cancer who did not have surgical treatment were identified in the Danish Lung Cancer Registry. Danish Lung Cancer Registry collects data from clinical departments, the Danish Cancer Registry, Danish National Patient Registry, and the Central Population Register. A total of 20,552 patients diagnosed with lung cancer in 2005 to 2011 were identified. Comorbidity data were extracted from the Danish National Patient Registry, which is a register of all in- and outpatient visits to hospitals in Denmark. By record linkage, lung cancer patients who had previously been diagnosed with comorbid conditions were assigned a Charlson comorbidity index. Initial cancer treatment was categorized as chemotherapy, chemoradiation, radiotherapy, or no therapy. Data on Charlson comorbidity index, performance status, age, sex, stage, pulmonary function (forced expiratory volume in 1 second), histology, and type of initial treatment (if any) were included in univariable and multivariable Cox proportional hazard analyses.

Results: Treatment rates for chemotherapy and chemoradiation declined with increasing comorbidity and in particular increasing age. Women received treatment more often than men. In a univariable analysis of all patients combined, stage, performance status, age, sex, lung function, and comorbidity were all associated with survival. Apart from excess mortality among patients with unspecified histological subtypes (hazard ratio), there was no clear difference between the specified subtypes. When adjusting for the other factors, particularly age, sex, performance status, and stage proved to be robust while risk estimates for comorbidity were attenuated somewhat. When grouped by the three types of cancer treatment or no treatment, there was no influence of comorbidity on radiation therapy and modest influence on survival after chemotherapy and chemoradiation. In contrast, age remained a strong negative prognosticator after multivariate adjustment as did stage and performance status.

Conclusion: Comorbidity has a limited effect on survival and only for patients treated with chemotherapy. It is rather the performance of the patient at diagnosis than the medical history that prognosticates survival in this patient group.
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http://dx.doi.org/10.1097/JTO.0000000000000416DOI Listing
February 2015

Endobronchial ultrasound-guided biopsy performed under optimal conditions in patients with known or suspected lung cancer may render mediastinoscopy unnecessary.

J Bronchology Interv Pulmonol 2014 Jan;21(1):21-5

*Department of Pulmonary Medicine, Gentofte Hospital Departments of †Pathology §Thoracic Surgery, Rigshospitalet, University of Copenhagen, Denmark ‡Department of Surgery, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Mediastinoscopy is the gold standard for preoperative mediastinal staging of patients with suspected or proven lung cancer. Since the development of endoscopic ultrasound-guided biopsy via the trachea (EBUS-TBNA), this status has been challenged. The purpose of the study was to examine whether mediastinoscopy is necessary, when EBUS-TBNA is performed in a center with (1) a high level of expertise, (2) "bed side" microscopy by a pathologist, (3) general anesthesia, and (4) achievement of representative tissue from station 4R, 7 and 4L, that is, the same mediastinal stations that mediastinoscopy gives access to.

Methods: A total of 95 consecutive patients with known or suspected lung cancer were referred for staging by EBUS-TBNA, which was performed as described.

Results: Benign and malignant disease was found in the mediastinum of 6 and 13 patients, respectively. The remaining 76 patients were operated, resulting in 9 benign and 67 malignant diagnoses; spread was found to station 4R, 5, and 5 and 6 in 4 patients. The negative predictive value (NPV) was 63/67=0.94. However, if you exclude station 5 and 6, as they cannot be reached by neither EBUS nor mediastinoscopy, NPV was 66/67=0.99. The sensitivity was 0.76, and the specificity was 1.0.

Conclusions: When EBUS-TBNA is performed under optimal conditions including general anesthesia and "bed side" microscopy performed by a pathologist resulting in representative biopsies from station 4R, 7, and 4L, the NPV is so high that mediastinoscopy seems unnecessary.
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http://dx.doi.org/10.1097/LBR.0000000000000028DOI Listing
January 2014

High procedure volume is strongly associated with improved survival after lung cancer surgery.

J Clin Oncol 2013 Sep 29;31(25):3141-6. Epub 2013 Jul 29.

King's College London School of Medicine, London.

Purpose: Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect.

Methods: We analyzed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008, of whom 12,862 (9.6%) underwent surgical resection. Hospital volume was defined according to number of patients with resected lung cancer in each hospital in each year of diagnosis. We calculated hazard ratios (HRs) for death in three predefined periods according to hospital volume, sex, age, socioeconomic deprivation, comorbidity, and propensity to resect.

Results: There was increased survival in hospitals performing > 150 surgical resections compared with those carrying out < 70 (HR, 0.78; 95% CI, 0.67 to 0.90; Ptrend < .01). The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of association was greatest in the early postoperative period.

Conclusion: High-volume hospitals have higher resection rates and perform surgery among patients who are older, have lower socioeconomic status, and have more comorbidities; despite this, they achieve better survival, most notably in the early postoperative period.
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http://dx.doi.org/10.1200/JCO.2013.49.0219DOI Listing
September 2013

The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients.

Eur J Cancer 2012 Dec 13;48(18):3386-95. Epub 2012 Jul 13.

King's College London, School of Medicine, Thames Cancer Registry, 42 Weston Street, London, United Kingdom.

Aim: To quantify the effect of comorbidity on stage-specific survival in resected non-small cell lung cancer (NSCLC) patients.

Methods: From the Danish Lung Cancer Registry, 20,461 patients diagnosed with lung cancer between 1st January 2005 and 31st December 2010 were identified. Among 3152 NSCLC patients who underwent surgical resection, mortality hazard ratios were calculated during three consecutive time periods following surgery (0-1 month, 1 month-1 year and >1 year) according to Charlson comorbidity score (CCS 0, 1, 2, 3+), Eastern Cooperative Oncology Group (ECOG) performance status, lung function, age, sex, pathological T (pT) and N (pN) stage using Cox proportional hazard modelling. The Kaplan Meier method was used to describe stage-specific survival according to the CCS.

Results: Severe comorbidity (CCS 3+) was independently associated with significantly higher death rates throughout the three periods of follow-up [Hazard ratio (HR) 2.06 (1.13-3.75) for CCS 3+ in 0-1 month, 1.57 (1.17-2.12) 3+ during1 month-1 year and 1.84 (1.42-2.37) after 1 year]. Stage-specific 5-year survival in patients with severe comorbidity was significantly lower than in patients without comorbid disease [e.g. 38% (95% confidence interval (CI) 23-53%) for pT1 and CCS 3+ versus 69% (62-75%) for pT1 and CCS 0].

Conclusion: Severe comorbidity affects survival of NSCLC patients who undergo surgical resection by as much as a single stage increment and this effect persists throughout follow-up. Further research may be necessary to help identify which patients are most likely to benefit from surgery.
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http://dx.doi.org/10.1016/j.ejca.2012.06.012DOI Listing
December 2012

Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial.

Thorax 2011 Apr 17;66(4):294-300. Epub 2010 Dec 17.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Correct mediastinal staging is a cornerstone in the treatment of patients with non-small cell lung cancer. A large range of methods is available for this purpose, making the process of adequate staging complex. The objective of this study was to describe faults and benefits of positron emission tomography (PET)-CT in multimodality mediastinal staging.

Methods: A randomised clinical trial was conducted including patients with a verified diagnosis of non-small cell lung cancer, who were considered operable. Patients were assigned to staging with PET-CT (PET-CT group) followed by invasive staging (mediastinoscopy and/or endoscopic ultrasound with fine needle aspiration (EUS-FNA)) or invasive staging without prior PET-CT (conventional work up (CWU) group). Mediastinal involvement (dichotomising N stage into N0-1 versus N2-3) was described according to CT, PET-CT, mediastinoscopy, EUS-FNA and consensus (based on all available information), and compared with the final N stage as verified by thoracotomy or a conclusive invasive diagnostic procedure.

Results: A total of 189 patients were recruited, 98 in the PET-CT group and 91 in the CWU group. In an intention-to-treat analysis the overall accuracy of the consensus N stage was not significantly higher in the PET-CT group than in the CWU group (90% (95% confidence interval 82% to 95%) vs 85% (95% CI 77% to 91%)). Excluding the patients in whom PET-CT was not performed (n=14) the difference was significant (95% (95% CI 88% to 98%) vs 85% (95% CI 77% to 91%), p=0.034). This was mainly based on a higher sensitivity of the staging approach including PET-CT.

Conclusion: An approach to lung cancer staging with PET-CT improves discrimination between N0-1 and N2-3. In those without enlarged lymph nodes and a PET-negative mediastinum the patient may proceed directly to surgery. However, enlarged lymph nodes on CT needs confirmation independent of PET findings and a positive finding on PET-CT needs confirmation before a decision on surgery is made.

Clinical Trial Number: NCT00867412.
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http://dx.doi.org/10.1136/thx.2010.154476DOI Listing
April 2011

Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer.

Chest 2010 Oct 12;138(4):790-4. Epub 2010 Feb 12.

Department of Pulmonary and Critical Care Medicine, Thoraxklinik, Heidelberg, Germany.

Background: For mediastinal lymph nodes, biopsies must often be performed to accurately stage lung cancer. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) allows real-time guidance in sampling paratracheal, subcarinal, and hilar lymph nodes, and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can sample mediastinal lymph nodes located adjacent to the esophagus. Nodes can be sampled and staged more completely by combining these procedures, but to date use of two different endoscopes has been required. We examined whether both procedures could be performed with a single endobronchial ultrasound bronchoscope.

Methods: Consecutive patients with a presumptive diagnosis of non-small cell lung cancer (NSCLC) underwent endoscopic staging by EBUS-TBNA and EUS-FNA through a single linear ultrasound bronchoscope. Surgical confirmation and clinical follow-up was used as the reference standard.

Results: Among 150 evaluated patients, 139 (91%; 83 men, 56 women; mean age 57.6 years) were diagnosed with NSCLC. In these 139 patients, 619 nodes were endoscopically biopsied: 229 by EUS-FNA and 390 by EBUS-TBNA. Sensitivity was 89% for EUS-FNA and 92% for EBUS-TBNA. The combined approach had a sensitivity of 96% and a negative predictive value of 95%, values higher than either approach alone. No complications occurred.

Conclusions: The two procedures can easily be performed with a dedicated linear endobronchial ultrasound bronchoscope in one setting and by one operator. They are complementary and provide better diagnostic accuracy than either one alone. The combination may be able to replace more invasive methods as a primary staging method for patients with lung cancer.
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http://dx.doi.org/10.1378/chest.09-2149DOI Listing
October 2010

Endoscopic and endobronchial ultrasonography according to the proposed lymph node map definition in the seventh edition of the tumor, node, metastasis classification for lung cancer.

J Thorac Oncol 2009 Dec;4(12):1576-84

Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

Accurate assessment of lymph node involvement is a critical step in patients with non-small cell lung cancer in the absence of distant metastases. The International Association for the Study of Lung Cancer has proposed a new lymph node map, which provides precise anatomic definitions for all intrathoracic lymph nodes. Transoesophageal endoscopic ultrasound with fine-needle aspiration and endobronchial ultrasound with transbronchial needle aspiration are two minimally invasive techniques that are increasingly implemented in the staging of non-small cell lung cancer. Therefore, recognition of the proposed anatomic borders by these techniques is very relevant for an accurate clinical staging. We here discuss the reach and limits of endoscopic ultrasound in the precise delineation and approach of the intrathoracic lymph nodes according to the new lymph node map for the seventh edition of the tumor, node, metastasis classification for lung cancer.
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http://dx.doi.org/10.1097/JTO.0b013e3181c1274fDOI Listing
December 2009

Efficacy of endobronchial ultrasound-guided transbronchial needle aspiration of hilar lymph nodes for diagnosing and staging cancer.

J Thorac Oncol 2009 Aug;4(8):947-50

Department of Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is used mostly in patients with non-small cell lung cancer (NSCLC) to sample mediastinal lymph nodes that are visible on computed tomography (CT). We sought to determine the efficacy of EBUS-TBNA in sampling enlarged hilar lymph nodes in this patient population.

Methods: From January 2004 to May 2007, patients with suspected NSCLC and CT or positron emission tomography (PET) imaging demonstrating enlarged (>1 cm) or PET-positive hilar lymph nodes underwent EBUS-TBNA. Patients with enlarged central mediastinal nodes were excluded. Identifiable lymph nodes at locations 10R, 10L, 11R, and 11L were aspirated. All patients underwent subsequent surgical staging or clinical follow-up as indicated. Diagnoses based on aspirates were compared with those based on surgical or clinical results.

Results: Of 213 patients evaluated (mean age, 56 years; 138 men), 188 (mean age, 56.3 years; 120 men) were diagnosed with NSCLC and were analyzed. In these patients, 229 lymph nodes, ranging 8 to 20 mm, were detected, and all were sampled. Of the 188 patients, 25 had a single enlarged node in a contralateral hilar position (N3), 40 had multiple enlarged ipsilateral nodes in the N1 position, and 123 had an ipsilateral single enlarged node in the N1 position. Overall, diagnostic sensitivity of EBUS-TBNA was 91%, specificity was 100%, and the positive predictive value was 92.4%. In the 25 patients with contralateral hilar nodes, sensitivity was 66%, specificity was 100%, and the positive predictive value was 96%.

Conclusions: No complications occurred. In experienced hands, EBUS-TBNA of enlarged hilar lymph visible on CT or hilar nodes that are PET scan-positive can provide diagnostic results similar to those for central mediastinal nodes.
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http://dx.doi.org/10.1097/JTO.0b013e3181add88dDOI Listing
August 2009

[EBUS-TBNA and EUS-FNA in diagnostics and staging of lung cancer].

Authors:
Mark Krasnik

Ugeskr Laeger 2009 Mar;171(13):1095

Thoraxkirurgisk Afdeling R, Gentofte Hospital, DK-2900 Hellerup.

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March 2009

[Screening for asbestos-related conditions].

Ugeskr Laeger 2009 Feb;171(6):433-6

Arbejdsmedicinsk Klinik, Glostrup Hospital, DK-2600 Glostrup.

Screening programs for early detection of asbestos-related cancer have been considered. Conventional X-ray, computed tomography of the thorax, and the biomarkers osteopontin and mesothelin have been critically reviewed in the literature, together with survival data from screening programs in asbestos-exposed populations. Data do not currently support implementation of screening programs for asbestos-exposed persons in Denmark. Since mesothelioma is most often an occupational disease, these patients should be admitted to an occupational clinic for aetiological evaluation.
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February 2009

Reclassification of neuroendocrine tumors improves the separation of carcinoids and the prediction of survival.

J Thorac Oncol 2008 Dec;3(12):1410-5

Department of Pathology, Herlev University Hospital, division Gentofte, Copenhagen, Denmark.

Introduction: The classification of neuroendocrine lung tumors has changed over the last decades. Reliable diagnoses are crucial for the quality of clinical databases. The purpose of this study is to determine to which extent the use of different diagnostic criteria of neuroendocrine lung tumors has influenced the classification of these tumors. The prognostic information of tumor, node, metastasis descriptors was also evaluated.

Methods: We retrieved 110 tumors from the period 1989 to 2007. All tumors were reclassified according to the World Health Organization classification of 2004. Tumor, node, metastasis descriptors were evaluated.

Results: By reclassification, the diagnoses on 48 tumors (44%) were changed. More diagnoses were changed in the older part of the material. A significantly different survival was shown for all patients in relation to tumor size (p < 0.0001). An endobronchial component was seen in 54%, 31%, and 11% of typical carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma, respectively with no impact on survival (p = 0.90). For all included patients the survival was significantly worse for patients having metastasis to N1 nodes as compared with N0 (p = 0.03). However, the number of removed lymph nodes were insufficient for definitive determination of the prognostic impact of node metastases. Regarding the revised diagnoses, a significant difference in survival between typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma was noted (p < 0.005).

Conclusion: Tumors must be rediagnosed before entering a central database. Tumor and node seem to be useful predictors of survival.
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http://dx.doi.org/10.1097/JTO.0b013e31818e0dd4DOI Listing
December 2008

Please lead, but don't mislead.

Chest 2008 Sep;134(3):672-673

Gentofte University Hospital, Copenhagen, Denmark.

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http://dx.doi.org/10.1378/chest.08-1404DOI Listing
September 2008

Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy.

J Thorac Oncol 2008 Jun;3(6):577-82

Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Background: Real-time endobronchial ultrasound has increased the accuracy of conventional transbronchial needle aspiration biopsy in sampling mediastinal lymph nodes. Nevertheless, direct comparisons with mediastinoscopy are not available to determine the role of endobronchial ultrasound in pathologic staging.

Objectives: To compare the diagnostic yield of endobronchial ultrasound against cervical mediastinoscopy in the diagnosis and staging of radiologically enlarged mediastinal lymph nodes stations accessible by both modalities in patients with suspected nonsmall cell lung cancer.

Methods: Prospective, crossover trial with surgical lymph node dissection used as the accepted standard. Biopsy results of paratracheal and subcarinal lymph nodes were compared.

Results: Sixty-six patients with a mean age 60 +/- 10 years were studied. The prevalence of malignancy was 89% (59/66 cases). Endobronchial ultrasound had a higher overall diagnostic yield (91%) compared with mediastinoscopy (78%; p = 0.007) in the per lymph node analysis. There was disagreement in the yield between the two procedures in the subcarinal lymph nodes (24%; p = 0.011). There were no significant differences in the yield at other lymph node stations. The sensitivity, specificity, and negative predictive value of endobronchial ultrasound were 87, 100, and 78%, respectively. The sensitivity, specificity, and negative predictive value of mediastinoscopy were 68, 100, and 59%, respectively. No significant differences were found between endobronchial ultrasound (93%) and mediastinoscopy (82%; p = 0.083) in determining true pathologic N stage (per patient analysis).

Conclusions: In suspected nonsmall cell lung cancer, endobronchial ultrasound may be preferred in the histologic sampling of paratracheal and subcarinal mediastinal adenopathy because the diagnostic yield can surpass mediastinoscopy.
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http://dx.doi.org/10.1097/JTO.0b013e3181753b5eDOI Listing
June 2008

Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer.

J Clin Oncol 2008 Jul 2;26(20):3346-50. Epub 2008 Jun 2.

Department of Internal Medicine, Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Amalienstr 5, D-69126, Heidelberg, Germany.

Purpose: To investigate the sensitivity and accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for restaging the mediastinum after induction chemotherapy in patients with non-small-cell lung cancer (NSCLC).

Patients And Methods: One hundred twenty-four consecutive patients with tissue-proven stage IIIA-N2 disease who were treated with induction chemotherapy and who had undergone mediastinal restaging by EBUS-TBNA were reviewed. On the basis of computed tomography, 58 patients were classified as having stable disease and 66 were judged to have had a partial response. All patients subsequently underwent thoracotomy with attempted curative resection and a lymph node dissection regardless of EBUS-TBNA findings.

Results: Persistent nodal metastases were detected by using EBUS-TBNA in 89 patients (72%). Of the 35 patients in whom no metastases were assessed by EBUS-TBNA, 28 were found to have residual stage IIIA-N2 disease at thoracotomy. The majority (91%) of these false negative results were due to nodal sampling error rather than detection error. Overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of EBUS-TBNA for mediastinal restaging after induction chemotherapy were 76%, 100%, 100%, 20%, and 77%, respectively.

Conclusion: EBUS-TBNA is a sensitive, specific, accurate, and minimally invasive test for mediastinal restaging of patients with NSCLC. However, because of the low negative predictive value, tumor-negative findings should be confirmed by surgical staging before thoracotomy.
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http://dx.doi.org/10.1200/JCO.2007.14.9229DOI Listing
July 2008

Resistance index in mediastinal lymph nodes: a feasibility study.

J Thorac Oncol 2008 Apr;3(4):348-50

Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Germany.

Objective: The purpose of this study was to determine the range of Doppler ultrasonographic measurements of the resistance index in presumed normal mediastinal lymph node arteries.

Methods: Consecutive patients referred for bronchoscopy for various indications and normal CT findings in the mediastinum were included. The resistance index (RI) in mediastinal lymph node arteries was examined with Color Doppler ultrasonography. The peak systolic velocity (PSV) and the end-diastolic velocity were measured, which allowed for calculation of the resistance indices in different lymph node stations and in each lymph node artery.

Results: Eighty-nine patients (32 female; 57 male; mean age, 42.2 years) were examined, and of these, 50 patients (24 female; 36 male; mean age, 44.7 years) had measurable RIs. PSV and ESV were measured in all visible nodes (n = 196) and an interpretable value was obtained in 127 nodes (2.5 nodes per patient.). The median PSV was 15.6 cm/s (range, 8.9-23.2 cm/s, SD +/- 2.6, 25-75% percentile 13.8-17.5), and the median end-diastolic velocity was 5.8 cm/s (range, 3.6-11.4 cm/s, SD 1.15 cm/s, 25-75% percentile 5.1-6.3). The median RI values for arteries were 0.63 (range, 0.52-0.75, SD 0.04, 25-75% percentile 0.6-0.64) respectively. The Doppler measurements lasted on average 4.3 minutes and no complications were seen.

Conclusion: Color Doppler ultrasonography allows for quantification of velocities like PSV and ESV in mediastinal lymph node arteries, which in turn allow calculation of a resistance index. Knowledge of the resistance index's normal range (which describes the resistance of the blood flow within the lumen of the lymph node artery) may be a useful adjunct to the ultrasonic assessment of the mediastinum.
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http://dx.doi.org/10.1097/JTO.0b013e318168f084DOI Listing
April 2008

Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer.

Chest 2008 Apr 8;133(4):887-91. Epub 2008 Feb 8.

Department of Pneumology and Critical Care Medicine, Thoraxklinik am Universitätsklinikum Heidelberg, Germany.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) can reliably sample enlarged mediastinal lymph nodes in patients with non-small cell lung cancer (NSCLC), and in practice is mostly used to sample nodes visible on CT or positron emission tomography (PET). Few data are available on the use of endoscopic procedures to stage the mediastinum in clinical stage 1 lung cancer. The aim of the present study was to determine the results of EBUS-TBNA in sampling mediastinal lymph nodes in patients with lung cancer and a radiographically normal mediastinum and no PET activity. From January 2004 to May 2007, patients highly suspicious for NSCLC with CT scans showing no enlarged lymph nodes (no node > 1 cm) and a negative PET finding of the mediastinum underwent EBUS-TBNA. Identifiable lymph nodes at locations 2r, 2L, 4r, 4L, 7, 10r, 10L, 11r, and 11L were aspirated. All patients underwent subsequent surgical staging. Diagnoses based on aspiration results were compared with those based on surgical results. One hundred patients (mean age, 52.4 years; 59 men) were included. After surgery, 97 patients (mean age, 52.9 years; 57 men) had NSCLC confirmed and were included in the analysis. In this group, 156 lymph nodes ranging 5 to 10 mm in size were detected and sampled. Malignancy was detected in nine patients but missed in one patient. Mean diameter of the punctured lymph nodes was 7.9 mm. The sensitivity of EBUS-TBNA for detecting malignancy was 89%, specificity was 100%, and the negative predictive value was 98.9%. No complications occurred. In conclusion, EBUS-TBNA can be used to accurately sample and stage patients with clinical stage 1 lung cancer and no evidence of mediastinal involvement on CT and PET. Potentially operable patients with no signs of mediastinal involvement may benefit from presurgical staging with EBUS-TBNA.
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http://dx.doi.org/10.1378/chest.07-2535DOI Listing
April 2008

The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.

J Thorac Oncol 2007 Aug;2(8):694-705

Queen's Cancer Research Institute, Kingston, Ontario, Canada.

Introduction: In 1996, the International Association for the Study of Lung Cancer (IASLC) launched a worldwide TNM staging project to inform the next edition (seventh) of the TNM lung cancer staging system. In this article, we describe the methods and validation approaches used and discuss the internal and external validity of the recommended changes.

Methods: The International Staging Committee agreed on a number of general principles that guided the decision-making process. Internal validity was addressed by visually assessing the consistency of Kaplan-Meier curves across database types, geographic regions and addressing external validity, by assessing the similarity of curves generated using the population-based Surveillance Epidemiology and End Results cancer registry data to those generated using the project database. Cox proportional hazards regression was used to calculate hazard ratios between the proposed stage groupings with adjustment for cell type, sex, age, and region.

Results: Calls for data by the International Staging Committee resulted in the creation of an international database containing information on more than 100,000 cases. The present work is based on analyses of the 67,725 cases of non-small cell lung cancer. Validation checks were robust, demonstrating that the suggested staging changes are stable within the data sources used and externally. For example, suggested changes based on tumor size were well supported, with statistically significant hazard ratios ranging from 1.14 to 1.51 between adjacent pairs in the Surveillance Epidemiology and End Results data.

Conclusions: Lung cancer stage definitions have never been subjected to such an intense validation process. We do accept, however, that this work is limited in ways that can only be addressed by a prospective database, which we intend to develop. In the meantime, we think that this new system will greatly improve the usefulness of TNM lung staging across all of its purposes.
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http://dx.doi.org/10.1097/JTO.0b013e31812d05d5DOI Listing
August 2007

Cytopathologic diagnoses of fine-needle aspirations from endoscopic ultrasound of the mediastinum: reproducibility of the diagnoses and representativeness of aspirates from lymph nodes.

Cancer 2007 Aug;111(4):234-41

Department of Pathology, Herlev University Hospital, Division Gentofte, Hellerup, Denmark.

Background: Endoscopic ultrasound-guided fine-needle aspiration biopsy through the esophagus (EUS-FNA) or the bronchial tree (endobronchial ultrasound guided transbronchial needle aspiration [EBUS-TBNA]) may be used to obtain specimens from mediastinal structures. The accuracy of this procedure has been well documented. However, no studies have studied the reproducibility of the pathologic assessment of the aspirated material.

Methods: A total of 102 slides from EUS-FNA or EBUS-TBNA were assessed 2 times by 4 pathologists who classified each slide to 1 of 5 diagnostic categories and judged if the aspirate came from a lymph node. Between the 2 rounds the criteria to be used in the assessment of the slides were reviewed in a limited education session. The 4 observers had at least 15 years of pathology experience, but their experience in EUS-FNA and/or EBUS-TBNA varied from almost none to more than 10 years. The kappa statistic was applied for the analysis of reproducibility.

Results: The reproducibility of the diagnoses in the first round was good to excellent (kappa, 0.52-0.89). The teaching session led to a significant improvement of the reproducibility between the least and the most experienced observers (kappa ranges of 0.52-0.55 in the first round improved to 0.65-0.71 in the second round).

Conclusions: The reproducibility of the diagnosis on EBUS-TBNA and EUS-FNA is excellent among pathologists experienced with these types of samples. Pathologists who are generally experienced but have little experience with EBUS-TBNA and EUS-FNA show a steep learning curve. From a pathologic point of view, EBUS-TBNA and EUS-FNA are feasible, but only experienced pathologists should do the assessments.
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http://dx.doi.org/10.1002/cncr.22866DOI Listing
August 2007

Endoscopic ultrasound guided biopsy performed routinely in lung cancer staging spares futile thoracotomies: preliminary results from a randomised clinical trial.

Lung Cancer 2005 Sep;49(3):377-85

Department of Surgical Gasteroenterology, Gentofte University Hospital, Copenhagen, Denmark.

Background: Up to 45% of operations with curative intent for non-small-cell lung cancer (NSCLC) can be regarded as futile, apparently because the stage of the disease is more advanced than expected preoperatively. During the past decade several studies have evaluated the usefulness of endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) in lung cancer staging with promising results. However, no randomised trials have been performed, in which a staging strategy with EUS-FNA performed in all patients is compared with a conventional workup.

Methods: Before surgery (i.e. mediastinoscopy and subsequent thoracotomy) 104 patients from one hospital were randomly assigned to either a conventional workup (CWU), including EUS-FNA only for selected patients, or a strategy where all patients were offered EUS-FNA (routine EUS-FNA) in addition to CWU. Patients were followed up for a median period of 1.3 years (range 0.2-2.4 years). Thoracotomy was regarded as futile if the patient had an explorative thoracotomy without tumour resection or if a resected patient had recurrent disease or died from lung cancer during follow-up. Analysis was by intention to treat.

Results: Fifty-three patients were randomly assigned to routine EUS-FNA and 51 patients to CWU. EUS-FNA was performed in 50 patients (94%) in the routine EUS-FNA group and in 14 patients (27%) in the CWU group. In the routine EUS-FNA group five patients (9%) had a futile thoracotomy, compared with 13 (25%) in the CWU group, p = 0.03.

Conclusion: Addition of routine-EUS-FNA to standard workup in routine clinical practice improved selection of surgically curable patients with NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2005.04.005DOI Listing
September 2005

Endoscopic ultrasound guided biopsy versus mediastinoscopy for analysis of paratracheal and subcarinal lymph nodes in lung cancer staging.

Lung Cancer 2005 Apr 13;48(1):85-92. Epub 2004 Dec 13.

Department of Cardio-Thoracic Surgery, Gentofte University Hospital, Copenhagen, Denmark.

Background: Exact mediastinal evaluation of patients with non-small-cell lung cancer (NSCLC) is mandatory to improve selection of resectable and curable patients for surgery. Mediastinoscopy (MS) and endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) are considered complementary, MS covering the anterior- and EUS-FNA the posterior mediastinum. Both methods can reach the paratracheal- and subcarinal-regions, but little is known about which method is most accurate, when compared in patients having both procedures performed. The aim of this study was to assess and compare the diagnostic value of MS and EUS-FNA with regard to mediastinal malignancy in the paratracheal- and subcarinal-regions.

Methods: Sixty patients considered to be potential candidates for resection of verified or suspected NSCLC underwent MS and EUS-FNA. The EUS-FNA diagnoses were confirmed either by open thoracotomy, MS or clinical follow-up.

Results: MS and EUS-FNA were conclusive for paratracheal or subcarinal mediastinal disease in 6 and 24 patients, respectively. Two patients with N2 disease diagnosed by EUS-FNA were upstaged to N3 by MS. The sensitivity for lymph node metastases in the right paratracheal region (2/4R) was 67% for EUS-FNA versus 33% for MS (p=0.69). In the left paratracheal region (2/4L) the sensitivity of EUS-FNA was 80% versus 33% for MS (p=0.06). In the subcarinal region (7) the sensitivity of EUS-FNA was 100% versus 7% for MS (p<0.01). The sensitivity for lymph node metastases in region 2/4L and/or 2/4R and/or 7 was 96% for EUS-FNA versus 24% for MS (p<0.01).

Conclusion: In our hands EUS-FNA was superior to MS in the examination of paratracheal- and subcarinal-regions of patients considered for resection of lung cancer.
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http://dx.doi.org/10.1016/j.lungcan.2004.10.002DOI Listing
April 2005

Psychosocial aspects of lung cancer.

Lung Cancer 2005 Mar;47(3):293-300

Department of Psychosocial Cancer Research, Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.

Background: Lung cancer is one of the commonest cancers in the industrialised world, and persons with this grave disease must deal not only with the physical effects but also with the psychosocial aspects.

Methods: This review is based on an examination of intervention, prospective and case-control studies with more than 50 participants published between 1966 and 2003.

Results: The studies show that on average one out of four persons with lung cancer experience periods of depression or other psychosocial problems during their illness. Persons who are not offered treatment for their cancer and persons with small-cell lung cancer have a higher risk compared to other groups of lung cancer patients. The degree of depression can be reduced by psychosocial interventions.

Conclusions: We suggest that psychosocial screening of persons with lung cancer could prevent depression and might result in improved quality of care.
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http://dx.doi.org/10.1016/j.lungcan.2004.08.002DOI Listing
March 2005

[Endoscopic ultrasound-guided biopsy in the mediastinum].

Ugeskr Laeger 2004 Oct;166(41):3592-4

Amtssygehuset i Gentofte, Kirurgisk Gastroenterologisk Afdeling D.

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October 2004

[The professionalism is probably not enough].

Authors:
Mark Krasnik

Ugeskr Laeger 2004 Mar;166(10):928

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March 2004
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