We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based pat... more We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cas...
We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases... more We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases tumorogenesis, induces epithelial-to-mesenchymal transition (EMT) and chemoresistance in SCLC. We sought to evaluate circulating HGF levels in SCLC patients and assess correlation with outcome and EMT features in the tumor. Serum samples from patients with SCLC were prospectively obtained at diagnosis, response evaluation and progression. HGF serum (sHGF) was quantified by ELISA. EMT markers and p-Met/Met were assayed by immunohistochemistry in tumor samples. Clinical data were prospectively recorder. One-hundred twelve patients were included. High baseline levels of sHGF were associated with shorter overall survival (p=0.006) and remained independently associated with survival in the multivariate analysis (p=0.016). For stage IV patients, an increase of sHGF levels at response evaluation (p=0.042) and at progression (p=0.003) were associated with poor outcome. sHGF levels were associat...
Disease stage is the most important prognostic factor in lung cancer, and optimal staging is impo... more Disease stage is the most important prognostic factor in lung cancer, and optimal staging is important to determine the best therapeutic option. FDG-PET/CT has demonstrated its value in early stage non-small cell lung cancer (NSCLC) but there is still insufficient data to define its role in other stages. Information provided by FDG-PET/CT has an impact on the therapeutic management of patients with NSCLC. A retrospective review was made of patients who underwent FDG-PET/CT between January 2008 and December 2010 for the diagnosis of NSCLC. Clinical stage before and after FDG-PET/CT and information about any change in therapeutic decision due to information provided by FDG-PET/CT were collected. Using pathologic evaluation as the gold standard, sensitivity, specificity, and positive and negative predictive values for CT and FDG-PET/CT were calculated. Of the 522 patients diagnosed of NSCLC, FDG-PET/CT was performed in 246 (47.1%). In 85 cases (34.6%) FDG-PET/CT led to stage migration. Treatment was modified in 60 patients (24.4% of all FDG-PET/CT performed), avoiding a futile thoracotomy in 13 cases (5.2%), and allowing treatment with curative intent in 26 (10.5%). Out of 90 patients (36.5%) evaluated as stage iii by CT staging, FDG-PET/CT modified the therapeutic approach in 36 (40%). For the 133 cases (54%) with pathological assessment of the mediastinal lymph nodes, sensitivity, specificity, positive predictive value and negative predictive value were 0.57, 0.64, 0.48 and 0.72 for CT, and 0.68, 0.86, 0.75 and 0.81 for FDG-PET/CT. Our data support previous reports that FDG-PET/CT is essential in the staging process not only for patients with potentially operable NSCLC but also for stage iii patients, as demonstrated by our data.
... b Servei d'Anatomia Patològica, Hospital del Mar-Parc de Salut Mar, Universitat Autò... more ... b Servei d'Anatomia Patològica, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Barcelona, España. c Servei de Pneumologia, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, España. ...
The most common genetic aberration in follicular lymphoma (FL) is the t(14;18)(q32;q21) transloca... more The most common genetic aberration in follicular lymphoma (FL) is the t(14;18)(q32;q21) translocation that juxtaposes the antiapoptotic BCL2 gene with the promoter of the immunoglobulin heavy chain (IgH) gene. Our aim was to test the usefulness of two different techniques, fluorescence in situ hybridization (FISH) and PCR to detect t(14;18) in FL at diagnosis in paraffin-embedded tissue sections. A total of 51 patients diagnosed of FL were analyzed. FISH was performed with dual color dual fusion commercial probes (VYSIS) and in PCR experiments, the BIOMED-2 primers covering MBR, mcr and 3'MBR regions were applied. FISH showed positivity for the IgH/BCL2 translocation in 96% of patients and PCR in 59% of patients. FISH was able to detect variant translocations involving light chain Ig, or showing variant patterns such as deletions of the IgH portion involved in translocation. In 4% of cases, the IgH/BCL2 translocation was not detected by any of the two techniques tested. Our results show that FISH represents the best technique to detect t(14;18) at diagnosis.
Inflammatory lesions of the uterine cervix are very common, and although lymphomas in this locati... more Inflammatory lesions of the uterine cervix are very common, and although lymphomas in this location are rare, the differential diagnosis between both diseases must be considered in some cases and may be difficult to achieve. A 37-year-old woman in good health with a cervical polyp, showing a lymphoma-like reaction with blastic appearance, which was initially interpreted as a diffuse large-cell lymphoma. The immunohistochemical and molecular studies showed the reactive origin of the lesion. Immunohistochemical and molecular biology studies may be useful to dilucidate the reactive or neoplastic origin of these lesions.
... F. Alameda Quitllet, L. Pijuan, S. Planas, P. Fusté, M. Vernet, S. Serrano, R. Carreras ... c... more ... F. Alameda Quitllet, L. Pijuan, S. Planas, P. Fusté, M. Vernet, S. Serrano, R. Carreras ... células germinales quedan in-corporadas a una masa de células superficiales pro-liferantes que resulta en un córtex engrosado co-rrespondiente al embrión del córtex ovárico inma-duro1. ...
Organizing pneumonia is a clinical and histological condition in which the onset is usually subac... more Organizing pneumonia is a clinical and histological condition in which the onset is usually subacute with respiratory symptoms and pulmonary infiltrates. It may be unknown origin (cryptogenic) or associated with other illnesses, infectious diseases or drugs. We present a 60 year-old female patient with a previous history of breast cancer, who was being treated with trastuzumab, an antiHER2 monoclonal antibody. She was diagnosed with casual pulmonary infiltrates that had histological changes compatible with organizing pneumonia. The pulmonary infiltrates disappeared on withdrawing trastuzumab treatment. Due to the increasing use of biological therapies in different medical areas, we believe it is of interest to report this pulmonary involvement attributed to the monoclonal antibody trastuzumab.
Fluoroscopy-guided bronchoscopy is usually performed for the diagnosis of peripheral pulmonary le... more Fluoroscopy-guided bronchoscopy is usually performed for the diagnosis of peripheral pulmonary lesions (PPL), but the diagnostic yield varies widely among studies. Endobronchial ultrasound (EBUS) can increase the diagnostic yield of bronchoscopic diagnosis of PPL. To compare the diagnostic yield of fluoroscopy-guided bronchoscopy and EBUS with fluoroscopy-guided bronchoscopy in the study of PPL. All patients who underwent bronchoscopy to study PPL from January 2009 to December 2012 were prospectively included. 145 consecutive patients were randomly distributed in two groups: EBUS and fluoroscopy (50 patients, 71.3 ± 8.2 years) or fluoroscopy alone (95 patients, 68 ± 10.5 years). The mean diameter of the lesions was 41.97 ± 19.22 mm. Cytological brushing and transbronchial biopsies were obtained. All procedures were performed under fluoroscopic guidance with intravenous conscious sedation. EBUS was performed using an endoscopic ultrasound system equipped with a 20-MHz radial miniprobe introduced via a guide-sheath. Bronchoscopist, cytologist, study protocol, techniques and tools were the same throughout the whole study. 129 (89%) patients had malignant disease. A diagnosis with bronchoscopy was established in 105 (72.4%) patients. EBUS plus fluoroscopy obtained a diagnostic yield in 78% of patients and fluoroscopy alone in 69.5% (non-significant). In contrast, for lesions smaller than 30 mm, EBUS plus fluoroscopy guidance provided significantly greater diagnostic performance than fluoroscopy alone (90 vs. 52%; P=.05). Bronchoscopy under EBUS plus fluoroscopy guidance is a technique that has become useful for the diagnostic of LPPs, especially those smaller than 30 mm in diameter.
High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung in... more High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung injury and systemic inflammation in animal models of ventilator-induced lung injury. The authors aimed to explore whether high VT mechanical ventilation per se induces early oxidative stress and inflammation in the diaphragm, limb muscles, and lungs of healthy rats exposed to ventilator-induced lung injury. Protein carbonylation and nitration, antioxidants (immunoblotting), and inflammation (immunohistochemistry) were evaluated in the diaphragm, gastrocnemius, soleus, tibialis anterior, and lungs of mechanically ventilated healthy rats and in nonventilated control animals (n = 8/group) for 1 h, using two different strategies (moderate VT [VT = 9 ml/kg] and high VT [VT = 35 ml/kg]). The main findings are summarized as follows: compared with controls, (1) the diaphragms and gastrocnemius of high-VT rats exhibited a decrease in reactive carbonyls, (2) the soleus and tibialis of high- and moderate-VT rodents showed a reduction in reactive carbonyls and malondialdehyde-protein adducts, (3) the lungs of high-VT rats exhibited a significant rise in malondialdehyde-protein adducts, (4) the soleus and tibialis of both high- and moderate-VT rats showed a reduction in protein nitration, (5) the lungs of high- and moderate-VT rats showed a reduction in antioxidant enzyme levels, but not in the muscles, and (6) the diaphragms and gastrocnemius of all groups exhibited very low inflammatory cell counts, whereas the lungs of high-VT rats exhibited a significant increase in inflammatory infiltrates. Although oxidative stress and inflammation increased in the lungs of rats exposed to high VT, the diaphragm and limb muscles exhibited a decline in oxidative stress markers and very low levels of cellular inflammation.
Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accu... more Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples. Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioview's automated scanning system. All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively. The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations.
We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based pat... more We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cas...
We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases... more We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases tumorogenesis, induces epithelial-to-mesenchymal transition (EMT) and chemoresistance in SCLC. We sought to evaluate circulating HGF levels in SCLC patients and assess correlation with outcome and EMT features in the tumor. Serum samples from patients with SCLC were prospectively obtained at diagnosis, response evaluation and progression. HGF serum (sHGF) was quantified by ELISA. EMT markers and p-Met/Met were assayed by immunohistochemistry in tumor samples. Clinical data were prospectively recorder. One-hundred twelve patients were included. High baseline levels of sHGF were associated with shorter overall survival (p=0.006) and remained independently associated with survival in the multivariate analysis (p=0.016). For stage IV patients, an increase of sHGF levels at response evaluation (p=0.042) and at progression (p=0.003) were associated with poor outcome. sHGF levels were associat...
Disease stage is the most important prognostic factor in lung cancer, and optimal staging is impo... more Disease stage is the most important prognostic factor in lung cancer, and optimal staging is important to determine the best therapeutic option. FDG-PET/CT has demonstrated its value in early stage non-small cell lung cancer (NSCLC) but there is still insufficient data to define its role in other stages. Information provided by FDG-PET/CT has an impact on the therapeutic management of patients with NSCLC. A retrospective review was made of patients who underwent FDG-PET/CT between January 2008 and December 2010 for the diagnosis of NSCLC. Clinical stage before and after FDG-PET/CT and information about any change in therapeutic decision due to information provided by FDG-PET/CT were collected. Using pathologic evaluation as the gold standard, sensitivity, specificity, and positive and negative predictive values for CT and FDG-PET/CT were calculated. Of the 522 patients diagnosed of NSCLC, FDG-PET/CT was performed in 246 (47.1%). In 85 cases (34.6%) FDG-PET/CT led to stage migration. Treatment was modified in 60 patients (24.4% of all FDG-PET/CT performed), avoiding a futile thoracotomy in 13 cases (5.2%), and allowing treatment with curative intent in 26 (10.5%). Out of 90 patients (36.5%) evaluated as stage iii by CT staging, FDG-PET/CT modified the therapeutic approach in 36 (40%). For the 133 cases (54%) with pathological assessment of the mediastinal lymph nodes, sensitivity, specificity, positive predictive value and negative predictive value were 0.57, 0.64, 0.48 and 0.72 for CT, and 0.68, 0.86, 0.75 and 0.81 for FDG-PET/CT. Our data support previous reports that FDG-PET/CT is essential in the staging process not only for patients with potentially operable NSCLC but also for stage iii patients, as demonstrated by our data.
... b Servei d'Anatomia Patològica, Hospital del Mar-Parc de Salut Mar, Universitat Autò... more ... b Servei d'Anatomia Patològica, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Barcelona, España. c Servei de Pneumologia, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, España. ...
The most common genetic aberration in follicular lymphoma (FL) is the t(14;18)(q32;q21) transloca... more The most common genetic aberration in follicular lymphoma (FL) is the t(14;18)(q32;q21) translocation that juxtaposes the antiapoptotic BCL2 gene with the promoter of the immunoglobulin heavy chain (IgH) gene. Our aim was to test the usefulness of two different techniques, fluorescence in situ hybridization (FISH) and PCR to detect t(14;18) in FL at diagnosis in paraffin-embedded tissue sections. A total of 51 patients diagnosed of FL were analyzed. FISH was performed with dual color dual fusion commercial probes (VYSIS) and in PCR experiments, the BIOMED-2 primers covering MBR, mcr and 3'MBR regions were applied. FISH showed positivity for the IgH/BCL2 translocation in 96% of patients and PCR in 59% of patients. FISH was able to detect variant translocations involving light chain Ig, or showing variant patterns such as deletions of the IgH portion involved in translocation. In 4% of cases, the IgH/BCL2 translocation was not detected by any of the two techniques tested. Our results show that FISH represents the best technique to detect t(14;18) at diagnosis.
Inflammatory lesions of the uterine cervix are very common, and although lymphomas in this locati... more Inflammatory lesions of the uterine cervix are very common, and although lymphomas in this location are rare, the differential diagnosis between both diseases must be considered in some cases and may be difficult to achieve. A 37-year-old woman in good health with a cervical polyp, showing a lymphoma-like reaction with blastic appearance, which was initially interpreted as a diffuse large-cell lymphoma. The immunohistochemical and molecular studies showed the reactive origin of the lesion. Immunohistochemical and molecular biology studies may be useful to dilucidate the reactive or neoplastic origin of these lesions.
... F. Alameda Quitllet, L. Pijuan, S. Planas, P. Fusté, M. Vernet, S. Serrano, R. Carreras ... c... more ... F. Alameda Quitllet, L. Pijuan, S. Planas, P. Fusté, M. Vernet, S. Serrano, R. Carreras ... células germinales quedan in-corporadas a una masa de células superficiales pro-liferantes que resulta en un córtex engrosado co-rrespondiente al embrión del córtex ovárico inma-duro1. ...
Organizing pneumonia is a clinical and histological condition in which the onset is usually subac... more Organizing pneumonia is a clinical and histological condition in which the onset is usually subacute with respiratory symptoms and pulmonary infiltrates. It may be unknown origin (cryptogenic) or associated with other illnesses, infectious diseases or drugs. We present a 60 year-old female patient with a previous history of breast cancer, who was being treated with trastuzumab, an antiHER2 monoclonal antibody. She was diagnosed with casual pulmonary infiltrates that had histological changes compatible with organizing pneumonia. The pulmonary infiltrates disappeared on withdrawing trastuzumab treatment. Due to the increasing use of biological therapies in different medical areas, we believe it is of interest to report this pulmonary involvement attributed to the monoclonal antibody trastuzumab.
Fluoroscopy-guided bronchoscopy is usually performed for the diagnosis of peripheral pulmonary le... more Fluoroscopy-guided bronchoscopy is usually performed for the diagnosis of peripheral pulmonary lesions (PPL), but the diagnostic yield varies widely among studies. Endobronchial ultrasound (EBUS) can increase the diagnostic yield of bronchoscopic diagnosis of PPL. To compare the diagnostic yield of fluoroscopy-guided bronchoscopy and EBUS with fluoroscopy-guided bronchoscopy in the study of PPL. All patients who underwent bronchoscopy to study PPL from January 2009 to December 2012 were prospectively included. 145 consecutive patients were randomly distributed in two groups: EBUS and fluoroscopy (50 patients, 71.3 ± 8.2 years) or fluoroscopy alone (95 patients, 68 ± 10.5 years). The mean diameter of the lesions was 41.97 ± 19.22 mm. Cytological brushing and transbronchial biopsies were obtained. All procedures were performed under fluoroscopic guidance with intravenous conscious sedation. EBUS was performed using an endoscopic ultrasound system equipped with a 20-MHz radial miniprobe introduced via a guide-sheath. Bronchoscopist, cytologist, study protocol, techniques and tools were the same throughout the whole study. 129 (89%) patients had malignant disease. A diagnosis with bronchoscopy was established in 105 (72.4%) patients. EBUS plus fluoroscopy obtained a diagnostic yield in 78% of patients and fluoroscopy alone in 69.5% (non-significant). In contrast, for lesions smaller than 30 mm, EBUS plus fluoroscopy guidance provided significantly greater diagnostic performance than fluoroscopy alone (90 vs. 52%; P=.05). Bronchoscopy under EBUS plus fluoroscopy guidance is a technique that has become useful for the diagnostic of LPPs, especially those smaller than 30 mm in diameter.
High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung in... more High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung injury and systemic inflammation in animal models of ventilator-induced lung injury. The authors aimed to explore whether high VT mechanical ventilation per se induces early oxidative stress and inflammation in the diaphragm, limb muscles, and lungs of healthy rats exposed to ventilator-induced lung injury. Protein carbonylation and nitration, antioxidants (immunoblotting), and inflammation (immunohistochemistry) were evaluated in the diaphragm, gastrocnemius, soleus, tibialis anterior, and lungs of mechanically ventilated healthy rats and in nonventilated control animals (n = 8/group) for 1 h, using two different strategies (moderate VT [VT = 9 ml/kg] and high VT [VT = 35 ml/kg]). The main findings are summarized as follows: compared with controls, (1) the diaphragms and gastrocnemius of high-VT rats exhibited a decrease in reactive carbonyls, (2) the soleus and tibialis of high- and moderate-VT rodents showed a reduction in reactive carbonyls and malondialdehyde-protein adducts, (3) the lungs of high-VT rats exhibited a significant rise in malondialdehyde-protein adducts, (4) the soleus and tibialis of both high- and moderate-VT rats showed a reduction in protein nitration, (5) the lungs of high- and moderate-VT rats showed a reduction in antioxidant enzyme levels, but not in the muscles, and (6) the diaphragms and gastrocnemius of all groups exhibited very low inflammatory cell counts, whereas the lungs of high-VT rats exhibited a significant increase in inflammatory infiltrates. Although oxidative stress and inflammation increased in the lungs of rats exposed to high VT, the diaphragm and limb muscles exhibited a decline in oxidative stress markers and very low levels of cellular inflammation.
Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accu... more Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples. Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioview's automated scanning system. All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively. The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations.
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Papers by Lara Pijuán