Publications by authors named "Irene Sansano"

27 Publications

  • Page 1 of 1

Reliability of histopathologic diagnosis of fibrotic interstitial lung disease: an international collaborative standardization project.

BMC Pulm Med 2021 Jun 1;21(1):184. Epub 2021 Jun 1.

Department of Pathology, Yale University School of Medicine, New Haven, CT, 06510, USA.

Background: Current interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation.

Methods: Using an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases.

Results: The initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice.

Conclusions: Any additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.
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http://dx.doi.org/10.1186/s12890-021-01522-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170950PMC
June 2021

Peripheral and lung resident memory T cell responses against SARS-CoV-2.

Nat Commun 2021 05 21;12(1):3010. Epub 2021 May 21.

Infectious Diseases Department, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Resident memory T cells (T) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, T are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7 T cells secreting IL-10. In convalescent patients, lung-T are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting T cells as important for future protection against SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41467-021-23333-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140108PMC
May 2021

Acute Eosinophilic Pneumonia Associated With SARS-CoV-2 Infection.

Arch Bronconeumol 2021 Apr 2;57 Suppl 2:50-52. Epub 2021 Jan 2.

Department of Infectious Diseases, Vall d'Hebron University Hospital, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.arbres.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831762PMC
April 2021

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Mol Oncol 2021 Apr 6;15(4):887-900. Epub 2021 Jan 6.

Thoracic Cancers Translational Genomics Unit, Hebron Institute of Oncology (VHIO), Vall d, Barcelona, Spain.

Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs.
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http://dx.doi.org/10.1002/1878-0261.12891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024716PMC
April 2021

Axillary staging based on molecular analysis: Results of the B-CLOSER-II study.

Pathol Res Pract 2020 Nov 3;216(11):153197. Epub 2020 Sep 3.

Pathology Department, Hospital Universitari Vall d'Hebron, Passeig de la Vall d'Hebron 119-129 08035 Barcelona, Spain; Departament de Ciències morfològiques, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron 119-129 08035 Barcelona, Spain; Spanish Medical Research Network Centre in Oncology (CIBERONC), Spain. Electronic address:

Introduction: Axillary staging (pN) is a strong predictor of outcome in early stage breast cancer yet following the publication of the Z0011 trial there has been an increasing tendency to spare lymph node dissection. Automated molecular detection of cytokeratin 19mRNA by one-step nucleic acid amplification (OSNA) has been demonstrated to be an accurate method to assess sentinel lymph node (SLN) metastasis. In this study we compare histological and molecular methods following complete axillary lymph node dissection (cALND), determine whether molecular axillary staging affects survival, and evaluate the predictive and prognostic value of total tumor load in ALND (AD-TTL) and in all positive nodes (G-TTL).

Material And Methods: Axillary lymph nodes were collected from 102 patients with primary breast cancer with histological confirmation of axillary involvement (cN+) or positive SLN. The central 1-mm portion of each non-SLN was processed for hematoxylin-eosin staining and the remaining tissue was analyzed by OSNA.

Results: Non-SLNs were diagnosed as positive in 72 out of 102 patients (70.6 %) on OSNA compared with only 53 (52 %) on histology (p < 0.01). Thirteen patients would have changed staging if the diagnoses provided had been by molecular methods (p < 0.01), but without a change in prognosis. AD-TTL and G-TTL were predictive of recurrence and mortality.

Conclusions: Compared to molecular detection, histological examination significantly underestimates the frequency of axillary node metastases. However, the increase in pN did not show a clinical effect on survival in those patients.
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http://dx.doi.org/10.1016/j.prp.2020.153197DOI Listing
November 2020

Five simple reasons to discard DIP, or why we should stop calling dolphins big fish.

J Clin Pathol 2020 Nov 25;73(11):762-768. Epub 2020 Aug 25.

Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Catalunya, Spain.

The aim of this review is to explain why the term 'desquamative interstitial pneumonia' (DIP) should be discarded and replaced with modern terminology. Reason 1: DIP is a misnomer. Within a few years after the term was coined, it was shown that the airspace cells in DIP are macrophages not desquamated pneumocytes. Reason 2: As a result of overly simplistic and poorly defined histologic criteria, DIP is currently a mixed bag of smoking-related diseases and unrelated processes in never-smokers. Reason 3: DIP obfuscates the modern concept that smoking causes some forms of parenchymal lung disease. Despite the fact that >80% of cases of DIP are caused by smoking, it is currently classified as a 'smoking-related idiopathic interstitial pneumonia', an oxymoron. Reason 4: The premise that the presence of numerous macrophages within airspaces defines an entity creates problematic histologic overlap with other lung diseases that may feature prominent airspace macrophages. Reason 5: DIP is outdated. It was coined in 1965, when many entities in interstitial lung disease had not been described, smoking-related interstitial lung disease was an unknown concept, computed tomograms of the chest had not been introduced and immunohistochemistry was unavailable. We suggest a way forward, which includes eliminating the term DIP and separating smoking-related lung abnormalities (including accumulation of pigmented airspace macrophages) from cases characterised by numerous non-pigmented macrophages in never-smokers. The laudable goal of smoking cessation is not served well by muddying the relationship between smoking and lung disease with inaccurate, outdated terminology.
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http://dx.doi.org/10.1136/jclinpath-2020-206669DOI Listing
November 2020

New opacities in lung allograft after transbronchial cryobiopsy.

Respir Med 2020 Aug - Sep;170:106043. Epub 2020 May 25.

Department of Respiratory Medicine, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Spain; CIBER Enfermedades Respiratorias, Barcelona, Spain; Department of Respiratory Medicine, Vall d'Hebron Research Institute, Barcelona, Spain. Electronic address:

Background: The occurrence of radiological opacities post-transbronchial cryobiopsy may pose serious difficulties in differential diagnosis and management of lung allografts. This prospective study evaluated the frequency, characteristics, and evolution of new lung opacities after performing transbronchial cryobiopsy.

Methods: From February 2018 to June 2018, 22 of 51 consecutive patients with an indication for transbronchial cryobiopsy underwent computed tomography (CT) of the thorax before and at 1, 4, and 8 weeks post-cryobiopsy. New CT images, required by the transplant team, were also evaluated during the next 6 months. Histological findings of transbronchial cryobiopsy and microbiological studies on bronchoalveolar lavage were evaluated as risk factors for opacities.

Results: After obtaining 112 cryobiopsy samples, 46 opacities >10 mm, including ground-glass, solid, cavitated, or a combination of these lesions were observed in 20 (91%) patients on post-cryobiopsy CT. All ground-glasses opacities on CT disappeared at 4 weeks. A single cavitated opacity persisted at 6 months. The remaining opacities disappeared or were decreased to <10 mm by 8 weeks. No correlations of the number, type, or evolution of opacities with the number or volume of cryobiopsy samples obtained, or with the histological diagnosis, type of transplant, or microbiologic culture results were observed.

Conclusion: New pulmonary opacities >10 mm occur frequently after transbronchial cryobiopsy; a few may persist beyond 6 months. CT studies are recommended before implementing transbronchial cryobiopsy, whenever possible.
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http://dx.doi.org/10.1016/j.rmed.2020.106043DOI Listing
June 2021

Validation of Cell-Free DNA Collection Tubes for Determination of EGFR Mutation Status in Liquid Biopsy from NSCLC Patients.

Oncol Ther 2019 Dec 19;7(2):131-139. Epub 2019 Aug 19.

Translational Molecular Pathology, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Introduction: Precision medicine has revolutionized the understanding and treatment of cancer by identifying subsets of patients who are amenable to specific treatments according to their molecular characteristics, as exemplified by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Although tissue biopsy is the gold standard for determining molecular alterations in tumors, its limitations have prompted the development of new techniques for studying tumor biomarkers in liquid biopsies, such as mutation analysis in cell-free DNA (cfDNA). cfDNA analysis can accurately determine tumor progression and prognosis and more effectively identify appropriate targeted therapies. However, cfDNA is vulnerable, particularly during plasma sample shipping.

Objective: We compared the cell- and DNA-stabilizing properties of cell-free DNA blood collection tubes (BCTs) with those of the traditional shipping method (frozen plasma) for EGFR mutation testing using the cobas EGFR Mutation Test v2 in a prospective cohort of 49 patients from three different Spanish hospitals.

Methods: In total, 98 NSCLC samples, two from each patient, were studied; five of the 49 cases were considered invalid by cobas with one of the two shipping methods analyzed. After excluding these samples, we analyzed 88 samples from 44 patients. Considering the current methodology (frozen plasma) for sending samples as the gold standard, we evaluated the sensitivity and specificity of cfDNA BCT shipment.

Results: The global agreement between the two methods was 95.4%, with 100% sensitivity and 94.6% specificity for the cfDNA BCTs. cfDNA BCTs had a positive predictive value of 81.8% and negative predictive value of 100%.

Conclusion: cfDNA BCTs have the same sensitivity for EGFR mutation analysis in liquid biopsy as the current methodology and very high specificity. They also have some additional advantages in terms of collection and further shipment. Therefore, cfDNA BCTs can be perfectly incorporated into the routine practice for EGFR mutation determination.

Funding: Roche Farma S.A., Spain.
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http://dx.doi.org/10.1007/s40487-019-00099-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360002PMC
December 2019

Lung cancer biomarker testing: perspective from Europe.

Transl Lung Cancer Res 2020 Jun;9(3):887-897

The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital, Hradec Kralove, Czech Republic.

A questionnaire on biomarker testing previously used in central European countries was extended and distributed in Western and Central European countries to the pathologists participating at the Pulmonary Pathology Society meeting 26-28 June 2019 in Dubrovnik, Croatia. Each country was represented by one responder. For recent biomarkers the availability and reimbursement of diagnoses of molecular alterations in non-small cell lung carcinoma varies widely between different, also western European, countries. Reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. The support for testing from alternative sources, such as the pharmaceutical industry, is no doubt partly compensating for the lack of public health system support, but it is not a viable or long-term solution. Ideally, a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. As biomarker enabled therapies deliver a 50% better probability of outcome success, improved and unbiased reimbursement remains a major challenge for the future.
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http://dx.doi.org/10.21037/tlcr.2020.04.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354119PMC
June 2020

Hypersensitivity Pneumonitis and (Idiopathic) Pulmonary Fibrosis Due to Feather Duvets and Pillows.

Arch Bronconeumol (Engl Ed) 2021 Feb 12;57(2):87-93. Epub 2020 Feb 12.

Division of Pulmonary & Critical Care Medicine, University of Washington, Center for Interstitial Lung Disease, University of Washington, Seattle, USA.

Introduction: Exposure to feather bedding may be an unnoticed cause of hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF). Thus, an in-depth clinical study of the diagnosis of patients with suspected HP and IPF is required in order to determine their etiologies. The objective of the present study is to raise awareness of HP and pulmonary fibrosis due to exposure to feather bedding, and to study the prevalence and describe long-term outcomes.

Methods: We describe a series of 33 patients diagnosed with HP and pulmonary fibrosis due to feather bedding exposure and followed over a 10-year period. The patients were from a subgroup of 127 individuals with HP undergoing in-depth evaluation using a diagnostic protocol at a regional referral center.

Results: Eleven (33%) patients were clinically diagnosed with acute HP and 22 (67%) with chronic HP. Ten (45%) chronic HP patients showed a high resolution computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP) with suspected IPF. The prevalence of HP was 6.2/100 000 feather bedding users (compared with 54.6 per 100 000 bird-breeders). The survival rates of patients over the 10-year period was 100% for acute HP and 64% for chronic HP.

Conclusions: In a series of HP patients, the diagnosis was attributed to feather bedding exposure in 26%. UIP pattern on HRCT was present in nearly half of the chronic cases. The survival of patients with chronic HP at ten years was 64%, despite avoiding further exposure.
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http://dx.doi.org/10.1016/j.arbres.2019.12.003DOI Listing
February 2021

#EBUSTwitter: Novel Use of Social Media for Conception, Coordination, and Completion of an International, Multicenter Pathology Study.

Arch Pathol Lab Med 2020 07;144(7):878-882

From the Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia (Dr Lepe); the Department of Pathology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey (Dr Oltulu); the Department of Pathology, Rhode Island Hospital, Providence (Dr Canepa); the Department of Clinical Pathology & Laboratory Medicine, University of Pennsylvania Health System, Philadelphia (Dr Wu); the Department of Pathology, Summa Health Systems, Akron, Ohio (Drs Deeken and Jelinek); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Drs Alex and Sauter); Patologia, Vall d'Hebron Hospital, Barcelona, Spain (Drs Dinares and Sansano); the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Drs Doxtader and Mukhopadhyay); the Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark (Dr Fitzhugh); Centre de Biologie, University of Lille, Lille, France (Dr Gibier); the Department of Pathology, All India Institute of Medical Sciences, New Delhi, India (Dr Jain); the Department of Pathology, Case Western Reserve University, Cleveland, Ohio (Drs Janaki and Michael); Patologia, Complejo Hospitalario de Navarra, Navarra, Spain (Drs Labiano and Panizo); the Department of Pathology, University of Milano Biocca, Monza, Italy (Dr L'Imperio and Pagni); Patologia, Hospital del Mar, Barcelona, Spain (Drs Pijuan and Sanchez-Font); the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Dr Quintana); the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Dr Roy-Chowdhuri); the Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston (Drs Skipper and Spruill); the Department of Pathology, Massachusetts General Hospital, Boston (Dr Torous); the Department of Pathology, Dermatopathology, Bone & Soft Tissue, University of Arkansas for Medical Sciences, Little Rock (Dr Gardner); and the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Jiang).

Context.—: Social media sites are increasingly used for education, networking, and rapid dissemination of medical information, but their utility for facilitating research has remained largely untapped.

Objective.—: To describe in detail our experience using a social media platform (Twitter) for the successful initiation, coordination, and completion of an international, multi-institution pathology research study.

Design.—: Following a tweet describing a hitherto-unreported biopsy-related histologic finding in a mediastinal lymph node following endobronchial ultrasound-guided transbronchial needle aspiration, a tweet was posted to invite pathologists to participate in a validation study. Twitter's direct messaging feature was used to create a group to facilitate communication among participating pathologists. Contributing pathologists reviewed consecutive cases of mediastinal lymph node resection following endobronchial ultrasound-guided transbronchial needle aspiration and examined them specifically for biopsy site changes. Data spreadsheets containing deidentified data and digital photomicrographs of suspected biopsy site changes were submitted via an online file hosting service for central review by 5 pathologists from different institutions.

Results.—: A total of 24 pathologists from 14 institutions in 5 countries participated in the study within 143 days of study conception, and a total of 297 cases were collected and analyzed. The time interval between study conception and acceptance of the manuscript for publication was 346 days.

Conclusions.—: To our knowledge, this is the first time that a social media platform has been used to generate a research idea based on a tweet, recruit coinvestigators publicly, communicate with collaborating pathologists, and successfully complete a pathology study.
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http://dx.doi.org/10.5858/arpa.2019-0297-OADOI Listing
July 2020

A Multidisciplinary Proposal for a Diagnostic Algorithm in Idiopathic Pulmonary Fibrosis: The Role of Transbronchial Cryobiopsy.

Arch Bronconeumol (Engl Ed) 2020 Feb 13;56(2):99-105. Epub 2019 Aug 13.

Servicio de Neumología, Hospital de la Santa Creu i Sant Pau, Barcelona, España.

The diagnosis of idiopathic pulmonary fibrosis (IPF) is a complex process that requires the multidisciplinary integration of clinical, radiological, and histological variables. Due to its diagnostic yield, surgical lung biopsy has been the recommended procedure for obtaining samples of lung parenchyma, when required. However, given the morbidity and mortality of this technique, alternative techniques which carry a lower risk have been explored. The most important of these is transbronchial cryobiopsy -transbronchial biopsy with a cryoprobe- which is useful for obtaining lung tissue with less comorbidity. Yield may be lower than surgical biopsy, but it is higher than with transbronchial biopsy with standard forceps. This option has been discussed in the recent clinical guidelines for the diagnosis of IPF, but the authors do not go so far as recommend it. The aim of this article, the result of a multidisciplinary discussion forum, is to review current evidence and make proposals for the use of transbronchial cryobiopsy in the diagnosis of IPF.
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http://dx.doi.org/10.1016/j.arbres.2019.07.001DOI Listing
February 2020

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

J Thorac Oncol 2019 12 23;14(12):2120-2132. Epub 2019 Jul 23.

Alvaro Cunqueiro Hospital, Vigo, Spain.

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data.

Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific).

Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively).

Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.
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http://dx.doi.org/10.1016/j.jtho.2019.07.005DOI Listing
December 2019

Impact of delayed and prolonged fixation on the evaluation of immunohistochemical staining on lung carcinoma resection specimen.

Virchows Arch 2019 Aug 1;475(2):191-199. Epub 2019 Jul 1.

Department of Pathology, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands.

Pre-analytical factors, such as fixation time, influence morphology of diagnostic and predictive immunohistochemical staining, which are increasingly used in the evaluation of lung cancer. Our aim was to investigate if variations in fixation time influence the outcome of immunohistochemical staining in lung cancer. From lung resections, specimen with tumor size bigger than 4 cm, 10 samples were obtained: 2 were put through the standard fixation protocol, 5 through the delayed, and 3 through the prolonged fixation protocol. After paraffin embedding, tissue microarrays (TMAs) were made. They were stained with 20 antibodies and scored for quality and intensity of staining. Samples with delay in fixation showed loss of TMA cores on glass slides and deterioration of tissue quality leading to reduction in the expression of CK 7, Keratin MNF116, CAM 5.2, CK 5/6, TTF-1, C-MET, Napsin A, D2-40, and PD-L1. Prolonged fixation had no influence on the performance of immunohistochemical stains. Delay of fixation negatively affects the expression of different immunohistochemical markers, influencing diagnostic (cytokeratins) and predictive (PD-L1) testing. These results emphasize the need for adequate fixation of resection specimen.
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http://dx.doi.org/10.1007/s00428-019-02595-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647403PMC
August 2019

Optimization of Transbronchial Cryobiopsy in Lung Transplant Recipients.

Ann Thorac Surg 2019 10 21;108(4):1052-1058. Epub 2019 Jun 21.

Department of Respiratory Medicine, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER Enfermedades Respiratorias (Ciberes), Barcelona, Spain. Electronic address:

Background: Previous studies suggest that transbronchial lung biopsy using a cryoprobe is superior to transbronchial lung biopsy using forceps for evaluating lung grafts, although the technique can be associated an increase in complications. Because cryoprobe experience is limited, assessment of a greater number of cases is warranted. This prospective study evaluates the diagnostic yield, complications, and risk factors associated with the cryoprobe technique.

Methods: From April 2013 to April 2016, 321 consecutive cryoprobe transbronchial biopsies were indicated in single or bilateral lung transplant patients with acute or chronic clinical lung injury or in asymptomatic patients before hospital discharge after lung transplantation.

Results: With a mean of 4.32 lung parenchyma specimens per procedure, adequate alveolar lung parenchyma was obtained in 96.6% (84.27 ± 44.14 mm) of cases. Obtaining at least 4 samples increased the histological diagnostic certainty (P < .001). Moderate to severe bleeding was observed in 7.48% of patients and was significantly more frequent in patients with unilateral transplantation (odds ratio, 0.10; 95% confidence interval, 0.02-0.30; P < .001) and in those with high blood pressure during scanning (odds ratio, 0.31; 95% confidence interval, 0.12-0.86; P = .019). Pneumothorax was observed in 7.7% of the patients, but only 3.7% of these patients required pleural drainage.

Conclusions: Obtaining 4 or more cryobiopsy samples is valuable and safe for lung allograft monitoring. Being a recipient of a unilateral lung transplant or having arterial hypertension during bronchoscopy seem to be risk factors associated with increased bleeding.
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http://dx.doi.org/10.1016/j.athoracsur.2019.04.096DOI Listing
October 2019

Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis.

Cancers (Basel) 2019 03 6;11(3). Epub 2019 Mar 6.

Translational Molecular Pathology, Vall d'Hebron Research Institute (VHIR), Barcelona 08035, Spain.

Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival ( = 0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype ( = 0.002) but not in the squamous carcinoma subtype ( = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.
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http://dx.doi.org/10.3390/cancers11030320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468764PMC
March 2019

Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry - Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort.

J Thorac Oncol 2018 12 18;13(12):1851-1863. Epub 2018 Sep 18.

Lunaphore Technologies SA, EPFL Innovation Park, Lausanne, Switzerland.

Introduction: Phosphatase and tensin homolog (PTEN) loss is frequently observed in NSCLC and associated with both phosphoinositide 3-kinase activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable readout, but lacks standardized staining protocol and cutoff value.

Methods: After an external quality assessment using SP218, 138G6 and 6H2.1 anti-PTEN antibodies, scored on webbook and tissue microarray, the European Thoracic Oncology Platform cohort samples (n = 2245 NSCLC patients, 8980 tissue microarray cores) were stained with SP218. All cores were H-scored by pathologists and by computerized pixel-based intensity measurements calibrated by pathologists.

Results: All three antibodies differentiated six PTEN+ versus six PTEN- cases on external quality assessment. For 138G6 and SP218, high sensitivity and specificity was found for all H-score threshold values including prospectively defined 0, calculated 8 (pathologists), and calculated 5 (computer). High concordance among pathologists in setting computer-based intensities and between pathologists and computer in H-scoring was observed. Because of over-integration of the human eye, pixel-based computer H-scores were overall 54% lower. For all cutoff values, PTEN- was associated with smoking history, squamous cell histology, and higher tumor stage (p < 0.001). In adenocarcinomas, PTEN- was associated with poor survival.

Conclusion: Calibration of immunoreactivity intensities by pathologists following computerized H-score measurements has the potential to improve reproducibility and homogeneity of biomarker detection regarding epitope validation in multicenter studies.
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http://dx.doi.org/10.1016/j.jtho.2018.08.2034DOI Listing
December 2018

High Resolution Computed Tomography and Fiberoptic Bronchoscopy in the Study of Severe Asthma.

Arch Bronconeumol (Engl Ed) 2018 Dec 24;54(12):627. Epub 2018 Jul 24.

Servicio de Neumología, Departamento de Medicina, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España; Servicio de Anatomía Patológica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España; CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, España. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2018.05.018DOI Listing
December 2018

Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation.

J Natl Cancer Inst 2018 08;110(8):914-917

Cancer Genomic Group, Barcelona, Spain.

Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation. The striking efficacy of HSP90i plus chemotherapy vs chemotherapy alone was reproduced in a patient-derived xenograft (PDX) model from a breast cancer patient with a BRCA1 mutation (mean tumor volume [SD], No. of tumors: vehicle 8.38 [7.07] mm3, n = 3; HSP90i 4.18 [1.93] mm3, n = 5; cisplatin plus gemcitabine 3.31 [1.95] mm3, n = 5; cisplatin plus gemcitabine plus HSP90i 0.065 [0.076] mm3, n = 6). This case and the PDX demonstrate the efficacy for therapeutic inhibition of HSP90 in a BRCA-mutated patient, opening a new potential avenue for better identifying patients who might benefit most from HSP90i.
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http://dx.doi.org/10.1093/jnci/djy012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093313PMC
August 2018

miR-99a reveals two novel oncogenic proteins E2F2 and EMR2 and represses stemness in lung cancer.

Cell Death Dis 2017 10 26;8(10):e3141. Epub 2017 Oct 26.

Biomedical Research in Cancer Stem Cells Group, Pathology Department, Institut de Recerca Hospital Vall d'Hebron (VHIR), Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA expression is found in human tumours because it is involved in tumour growth, progression and metastasis. In this study, we analysed microRNA expression in 47 lung cancer biopsies. Among the most downregulated microRNAs we focussed on the miR-99a characterisation. In vitro experiments showed that miR-99a expression decreases the proliferation of H1650, H1975 and H1299 lung cancer cells causing cell cycle arrest and apoptosis. We identified two novel proteins, E2F2 (E2F transcription factor 2) and EMR2 (EGF-like module-containing, mucin-like, hormone receptor-like 2), downregulated by miR-99a by its direct binding to their 3'-UTR. Moreover, miR-99a expression prevented cancer cell epithelial-to-mesenchymal transition (EMT) and repressed the tumourigenic potential of the cancer stem cell (CSC) population in both these cell lines and mice tumours originated from H1975 cells. The expression of E2F2 and EMR2 at protein level was studied in 119 lung cancer biopsies. E2F2 and EMR2 are preferentially expressed in adenocarcinomas subtypes versus other tumour types (squamous and others). Interestingly, the expression of E2F2 correlates with the presence of vimentin and both E2F2 and EMR2 correlate with the presence of β-catenin. Moreover, miR-99a expression correlates inversely with E2F2 and directly with β-catenin expression in lung cancer biopsies. In conclusion, miR-99a reveals two novel targets E2F2 and EMR2 that play a key role in lung tumourigenesis. By inhibiting E2F2 and EMR2, miR-99a represses in vivo the transition of epithelial cells through an EMT process concomitantly with the inhibition of stemness features and consequently decreasing the CSC population.
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http://dx.doi.org/10.1038/cddis.2017.544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680913PMC
October 2017

Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project.

Lung Cancer 2017 09 22;111:143-149. Epub 2017 Jul 22.

University Hospital Zürich, Zurich, Switzerland.

Introduction: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome.

Methods: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio≥2 (with average MET GCN≥4), high MET GCN as CGN≥5 and MET IHC+ as ≥2+ intensity in ≥50% of tumor cells. A total of 182 MET IHC+ and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation.

Results: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN≥5 in 4.1% of 1572 patients. MET amplification and MET GCN≥5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p<0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC+ WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR.

Conclusion: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.
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http://dx.doi.org/10.1016/j.lungcan.2017.07.021DOI Listing
September 2017

Role of total tumour load of sentinel lymph node on survival in early breast cancer patients.

Breast 2017 Jun 28;33:8-13. Epub 2017 Feb 28.

Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain; Morphological Sciences Department, Universidad Autónoma de Barcelona, Spain.

Background: Axillary staging (pN) is considered one of the most important prognostic factors in breast cancer patients. However, the Z0011 study data drastically reduced the number of surgical axillary dissections in a selected group of patients, limiting the prognostic information relating to axillary involvement to the sentinel lymph node (SLN). It is known that there is a relationship between SLN total tumour load (TTL) and axillary involvement. The objective of this study is to analyse the relationship between the TTL and outcomes in patients with early stage breast cancer.

Patients And Methods: clinicopathological and follow-up data were collected from 950 patients with breast cancer between 2009 and 2010 on whom SLN analysis was conducted by molecular methods (One Step Nucleic Acid Amplification, Sysmex, Kobe, Japan).

Results: TTL (defined as the total number of CK19 mRNA copies in all positive SLN) correlates with disease free survival (HR, 1.08; p = 0.000004), with local recurrence disease free survival (HR = 1.07; p = 0.0014) and overall survival (HR: 1.08, p = 0.0032), clearly defining a low-risk group (TTL <2.5 × 10 CK19 mRNA copies/μL) versus a high-risk group (>2.5 × 10 CK 19 mRNA copies/μL).

Conclusions: SLN TTL permits the differentiation between two patient groups in terms of DFS and OS, independently of axillary staging (pN), age and tumour characteristics (size, grade, lymphovascular invasion). This new data confirms the clinical value of low axillary involvement and could partially replace the information that staging of the entire axilla provides in patients on whom no axillary lymph node dissection is performed.
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http://dx.doi.org/10.1016/j.breast.2017.02.011DOI Listing
June 2017

Pleuroparenchymal Fibroelastosis: A New Entity within the Spectrum of Rare Idiopathic Interstitial Pneumonias.

Case Rep Pulmonol 2015 26;2015:810515. Epub 2015 Aug 26.

Department of Pulmonary Medicine, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Badalona, 08916 Catalonia, Spain ; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Palma de Mallorca, Spain ; Department of Internal Medicine, Universitat Autónoma de Barcelona, Catalonia, Spain.

Pleuroparenchymal fibroelastosis (PPFE) is a rare entity that has been recently included in the official American Thoracic Society/European Respiratory Society (ATS/ERS) statement in 2013 as a group of rare idiopathic interstitial pneumonias (IIPs). PPFE is characterized by pleural and subpleural parenchymal thickening due to elastic fiber proliferation, mainly in the upper lobes. The etiology of the disease is unclear, although some cases have been associated as a complication after bone marrow transplantation, lung transplantation (LT), chemotherapy, and recurrent respiratory infections. The patients usually report progressive dyspnea and dry cough and are predisposed to develop spontaneous or iatrogenic pneumothoraces after surgical lung biopsy (SLB) for its diagnosis. That is why better awareness with the clinical and radiologic features can help optimal management by the multidisciplinary team. Novel invasive techniques such as cryobiopsy may become useful tools in these patients as it could spare SLB. We present the first reported cases in Spain.
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http://dx.doi.org/10.1155/2015/810515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563085PMC
September 2015

Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).

PLoS One 2015 16;10(3):e0121071. Epub 2015 Mar 16.

Medical Oncology Service/Vall d´Hebron Institute Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: The increasing incidence and poor outcome associated with MPM requires finding effective treatment for this disease. PD1/PD-L1 pathway plays a central role in tumor immune evasion and appears to be predictive and prognostic marker. PD-L1 is expressed in many different human cancers but its role in MPM has yet to be established. The aim of this study is to evaluate the expression of PD-L1 in MPM.

Methods: 119 MPM patients (p) from two institutions between November 2002 and February 2014 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained with anti-PD-L1 (clone E1L3N). Cases showing more than 1% of tumor cells expression of PD-L1 were considered positive.

Results: PD-L1 was analyzed in 77 p with tumor tissue available and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 4 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was a significant relationship between PD-L1 expression and histology (PD-L1 expression 37.5% in no-epithelioid tumor and 13.2% in epithelioid; p=0.033). The median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012).

Conclusions: We have shown PD-L1 is expressed in 20% of patients, associated with no epithelioid histology and poor prognostic in MPM. Our results suggest PD-L1 warrants further exploration in selecting p for immunotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361537PMC
October 2015

Adaptive resistance to targeted therapies in cancer.

Transl Lung Cancer Res 2013 Jun;2(3):152-9

IOR, Dexeus University Institute, Barcelona, Spain ;

It is widely acknowledged that there is a need for molecular profiling in non-small-cell lung cancer. For example, treatment based on EGFR mutation status has attained successful results. However, in spite of excellent initial response to oral EGFR tyrosine kinase inhibitors (TKIs), progression-free survival is still limited. Current research has focused mostly on acquired resistance mechanisms, such as overexpression of AXL and loss of the Mediator MED12. In this review, in contrast, we discuss adaptive, rather than acquired, resistance. Adaptive resistance can occur almost immediately after starting targeted therapy through a rapid rewiring of cancer cell signaling. By losing ERK negative feedback on receptor tyrosine kinase (RTK) expression, cancer cells are exposed to the stimuli of several ligands, and the ensuing activation of several RTKs reprograms all the canonical signaling pathways. The overexpression of several RTKs was observed in breast cancer cell lines treated with a MEK inhibitor and in BRAF(V600E) melanoma cell lines treated with BRAF inhibitors. This rebound effect of overexpression of several RTKs, including ERBB3, also occurs in lung cancers driven by Kras or EGFR mutations when treated with MEK, PI3K or dual PI3K/mTOR inhibitors. Synthetic lethality can be effectively induced by co-targeting these overexpressed RTKs. We speculate that in patients with EGFR mutations, adaptive resistance occurs in a significant proportion of patients. Rebiopsies performed hours after starting treatment with EGFR TKIs can identify which RTKs are overexpressed after treatment. Efficient co-targeting of these RTKs can induce synthetic lethality and help overcome the limited effect of EGFR TKI monotherapy.
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http://dx.doi.org/10.3978/j.issn.2218-6751.2012.12.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367602PMC
June 2013

Intraoperative molecular analysis of total tumor load in sentinel lymph node: a new predictor of axillary status in early breast cancer patients.

Breast Cancer Res Treat 2013 May 11;139(1):87-93. Epub 2013 Apr 11.

Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.

Objective: To assess the intraoperative positive sentinel lymph node (SLN) total tumor load (TTL, defined as the amount of CK19 mRNA copies [copies/μL] in all positive SLNs) obtained by one-step nucleic acid amplification (OSNA) and to determine whether it is predictive of non-SLNs involvement. SUMMARY/BACKGROUND/DATA: The OSNA assay (Sysmex Corporation, Kobe, Japan) is a new diagnostic technique that uses molecular biological techniques to analyze SLN that has been validated as an accurate method for detection of positive SLN. Although the American College of Surgeons Oncology Group Z0011 trial has defined a select cohort of patients in whom a completion axillary lymph node dissection (cALND) may be safely omitted, there are a still a number of patients where prediction of non-SLN metastasis may be helpful for cALND decision making. Multiple studies suggest that specific pathologic characteristics of the primary tumor and the SLN metastases are associated with an increased likelihood of additional positive non-SLN.

Methods: This is a retrospective multicentric cohort study of 697 patients with cT1-3N0 breast cancer, who had had intraoperative SLN evaluation by OSNA assay with a cALND. TTL is defined as the amount of CK19 mRNA copies number in all positives SLN (copies/μL).

Results: Univariate logistic regression showed that, in addition to TTL (p < 0.001), the number of affected SLNs (p < 0.001), tumor size (p < 0.001), HER2 status (p = 0.007), and lymphovascular invasion (LVI, p < 0.001) were predictive of ALND status. The multivariate logistic regression analysis showed that TTL is an independent predictor of metastatic non-SLNs, after adjusting for the tumor size, HER2 status, LVI and, in particular, the number of affected SLNs.

Conclusions: TTL by OSNA is a newly standardized and automated tool that predicts axillary node status better and independently of the number of affected SLNs and the type of surgery. This value can then help clinicians to personalize surgical treatment. Prospective studies will be carried out to determine the clinical impact of this variable in the management of patients.
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http://dx.doi.org/10.1007/s10549-013-2524-zDOI Listing
May 2013