G. Hardavella - Academia.edu (original) (raw)

Papers by G. Hardavella

Soft Computing, 2019

Malignant pleural effusion is diagnostically challenging in presence of negative cytology. The as... more Malignant pleural effusion is diagnostically challenging in presence of negative cytology. The assessment of tumor markers in serum has become a standard tool in cancer diagnosis, while pleural fluid sampling has not met universal consensus. The evaluation of a panel of markers both in serum and pleural fluid may be crucial to improve the diagnostic accuracy. Using a machine learning-based approach, we provide a mathematical formula capable to express the complex relation existing among the expressed markers in serum and pleural effusion and the presence of lung cancer. The formula indicates CEA and CYFRA21-1 in pleural fluid as the best diagnostic markers, with 97% accuracy, 98% sensitivity, 95% specificity, 96% area under curve, 98% positive predictive value, and 92% MCC (Matthews correlation coefficient). Keywords Machine learning • Genetic programming • Genetic algorithm • Evolutionary algorithm • Pleural effusion • Biochemical tumor marker • Thoracentesis • Thoracoscopy • Video-assisted thoracic surgery Communicated by V. Loia.

Anticancer research

Lymphangiogenesis, an essential process in the metastasis of malignant tumors, has not been thoro... more Lymphangiogenesis, an essential process in the metastasis of malignant tumors, has not been thoroughly studied. The possibility of using it to define subsets of patients with different prognosis in cancer could be of vital clinical importance. Fifty patients (5 women, 45 men; mean age, 64.47 years) with SCLC were retrospectively studied. Tumor specimens were stained for CD105, and intratumoral lymphatic microvessel density (ILMVD) and lymphatic invasion were determined. Twenty-five patients were diagnosed with limited and 25 with extensive SCLC. All patients received chemotherapy and 32.7% radiation therapy. A direct association between ILMVD (CD105 expression) and lymphatic invasion was observed (p<0.046). CD105 expression was significantly associated with the stage of the disease (p=0.004) and the presence of metastasis (p=0.05). CD105 expression and lymphatic invasion correlated significantly with the clinical parameters and patient outcome, therefore, constituting an importan...

Interactive CardioVascular and Thoracic Surgery, 2009

The identification of a primary endobronchial non-Hodgkin lymphoma (NHL) is rare. We hereby prese... more The identification of a primary endobronchial non-Hodgkin lymphoma (NHL) is rare. We hereby present the case of a primary solitary endobronchial NHL lesion in an 80-year-old patient with prostate cancer who did not present any systemic involvement at the time of diagnosis.

Cardiac Defibrillation - Mechanisms, Challenges and Implications, 2011

Journal of Surgical Case Reports, 2012

Hepatic hydrothorax is a complication of liver cirrhosis. Several invasive therapeutic approaches... more Hepatic hydrothorax is a complication of liver cirrhosis. Several invasive therapeutic approaches have been performed such as thoracentesis, video-assisted thoracic surgery and repair of the diaphragmatic defects with debatable results. Medical thoracoscopy is a minimally invasive and effective technique with challenging applications that has not been thoroughly used in the treatment of hepatic hydrothorax. We hereby present the case of a hepatic hydrothorax complicated by thoracic empyema in a 38-year-old patient with alcoholic cirrhosis that was treated with medical thoracoscopy and talc pleurodesis.

Breathe, 2014

Chairing sessions is not about smartly stealing thunder; it is about making the speakers, the att... more Chairing sessions is not about smartly stealing thunder; it is about making the speakers, the attendees and the co-chairs look smart. Effective chairing includes the practicalities of introducing your co-chairs, the speakers/presenters and yourself, keeping time, and facilitating discussion. The actual challenge is to: engage the audience's interest; create a sense of coherence throughout the diversity of presentations and speakers; ease the speakers' job of establishing their credibility with the audience; create a constructive, respectful and professional atmosphere for discussion; and wrap up in a way that leaves everyone feeling good about the session. Successful chairing leaves the presenters and audience feeling that the session was worth the time they invested in it. With all these aims in mind, herein, we address the challenge of chairing a session (thematic poster session, oral presentation and poster discussion) [1], and provide practical tips to overcome difficult situations and even turn them into advantages. Chairing thematic poster sessions Decide how much time you want to assign to poster viewing and when to start a poster walk Statement of Interest None declared.

Thorax, 2013

We have used in this study a combination of genome expression profiling and cytokine arrays to sc... more We have used in this study a combination of genome expression profiling and cytokine arrays to screen for candidates mediating MSC homing to two different cancer cell lines: A549 and MDAMB231. We found a variety of interleukines and cytokines already described as players in the process, such as IL6, IL8, CCL2. Additionally, from in vitro migration and invasion assays, we show that CXCR4 is a major player in this mechanism being the essential MSC receptor for the process to occur. Furthermore, we have identified MIF as the major trigger for MSC homing, being secreted from tumour cells at high levels. For the first time, we have identified in this study a novel axis: MIF-CXCR4, showing a physical interaction between them and validating their essential role in vitro and in vivo. Importantly, knocking down the expression of CXCR4 in MSCs or MIF in tumour cells, drastically decreased MSC recruitment to tumours in a in vivo model of lung metastasis. A better understanding of MSC homing players towards tumours will help the development of novel strategies in their use as vehicles in cancer cell therapy.

Chest, 2010

Lymphangiogenesis has been reported to be driven by mediators (e.g hyaluronic acid) and inflammat... more Lymphangiogenesis has been reported to be driven by mediators (e.g hyaluronic acid) and inflammatory cells (e.g activated CD11b+ macrophages), both commonly met in COPD. We hypothesized that lymphangiogenesis is part of COPD pathogenesis. This study aims to investigate the lymphangiogenetic expression in COPD measuring the lymphatic microvessel density (LMVD) and the correlation with the presence of lymphatic invasion(L.I), clinical and laboratory parameters. METHODS: Lung surgical specimens from 20 smokers [10 COPD-smokers (30% stage 2 GOLD) and 10 non-COPD smokers] with mean age of 62.6 years (range 38-82) were immunohistochemically stained for D2-40 and LYVE-1. Calculation of LMVD and assessment of L.I were performed and correlation with clinical and spirometric data followed. RESULTS: D2-40 and LYVE-1 were expressed in all specimens presenting higher expression (LMVD) in COPD-smokers (p=0.00). L.I was presented in all COPD specimens. D2-40 and LYVE-1 LMVD were associated with the presence of COPD (x2=20, p<0.001), smoking status (t=-1.8, p=0.09), and disease severity (GOLD)(p=0.00). CONCLUSION: D2-40 and LYVE-1 being selective lymphatic endothelial markers were highly expressed in COPD specimens in comparison with non-COPD smokers and associated with clinical and spirometric data. CLINICAL IMPLICATIONS: Our results reported for the first time the presence of newly formed lymphatic vessels in COPD, thus providing a novel insight in the pathogenesis of COPD including lymphangiogenesis.

Thorax, 2013

Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive, incurable, chemoresista... more Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive, incurable, chemoresistant tumour. Recent studies have shown that Mesenchymal stem cells (MSC) can home to and incorporate into the tumour stroma. Their tumour tropism can be used to deliver Tumour necrosis factor related apoptosis inducing ligand (TRAIL), a transmembrane protein that selectively induces apoptosis in transformed cells. However, not all tumours are sensitive to TRAIL. TRAIL works through triggering the extrinsic apoptotic pathway while conventional chemotherapeutic agents act by triggering the intrinsic apoptotic pathway. We hypothesised the crosstalk between these two pathways could be exploited by combining chemotherapy and MSC-TRAIL in MPM tumour cell lines. Methods MSC were engineered to express TRAIL using a lentiviral plasmid vector. A Tetracycline (Tet)-inducible system was used as a backbone to control the expression of TRAIL. Apoptosis induced by recombinant TRAIL, MSC-TRAIL in MPM cell lines on combination with Vorinostat, a chemotherapeutic agent, was measured by Annexin-V/DAPI based flow cytometry. Results The combination of recombinant TRAIL and Vorinostat act synergistically to induce apoptosis in MPM cell lines. Recombinant TRAIL and Vorinostat, as monotherapies induce 7.17% and 51.35% apoptosis in an MPM cell line JU77 respectively. In CRL2081 and ONE58 cell lines, recombinant TRAIL induces 56.75% and 13.41% apoptosis while Vorinostat leads to 78.95% and 43.97% apoptosis respectively. The combination of recombinant TRAIL and Vorinostat shows an increased amount of apoptosis in JU77, CRL2081 and ONE58 cell lines at 80.77%, 96.6% and 77.27% respectively (Table 1). Similar synergistic affect was observed when TRAIL expressing MSCs were co-cultured with Vorinostat treated MPM cell lines. MSC-TRAIL induced apoptosis in JU77 (48.73%), CRL2081 (57.63%) and ONE58(53.8%). Combined treatment of Vorinostat and MSC-TRAIL significantly increased apoptosis to 77.7% in JU77, 90.93% in CRL2081 and 77.8% in ONE58 cells (Table 1). Conclusion The combination of Vorinostat and recombinant TRAIL acts synergistically to induce apoptosis in malignant plural mesothelioma cells. Similar affect is observed with the combination of MSC-TRAIL and Vorinostat. This study indicates that Mesenchymal stem cells can be used as vectors for delivery of TRAIL and upon combination with Vorinostat, could be a potential therapy for malignant pleural mesothelioma.

European Respiratory Journal

Radiological evaluation of incidentally detected lung nodules on computed tomography (CT) influen... more Radiological evaluation of incidentally detected lung nodules on computed tomography (CT) influences management. We assessed international radiological variation in 1) pulmonary nodule characterisation; 2) hypothetical guideline-derived management; and 3) radiologists' management recommendations.107 radiologists from 25 countries evaluated 69 CT-detected nodules, recording: 1) first-choice composition (solid, part-solid or ground-glass, with percentage confidence); 2) morphological features; 3) dimensions; 4) recommended management; and 5) decision-influencing factors. We modelled hypothetical management decisions on the 2005 and updated 2017 Fleischner Society, and both liberal and parsimonious interpretations of the British Thoracic Society 2015 guidelines.Overall agreement for first-choice nodule composition was good (Fleiss' κ=0.65), but poorest for part-solid nodules (weighted κ 0.62, interquartile range 0.50–0.71). Morphological variables, including spiculation (κ=0.35...

European Respiratory Journal, 2015

European Respiratory Journal, 2015

Introduction: There is no standardized practice for the use of sedation in EBUS-TBNA and hence th... more Introduction: There is no standardized practice for the use of sedation in EBUS-TBNA and hence there is a continuous debate about bronchoscopist -administered versus anaesthetist-administered sedation. Their impact in patient and operator satisfaction has not been thoroughly studied. Aim: To evaluate patients9 and operators9 satisfaction, complications and efficiency of EBUS-TBNA with propofol versus midazolam and fentanyl. Materials and methods: Adult patients, anaesthetists and bronchoscopists were offered a survey questionnaire after completion of each EBUS-TBNA. The questionnaire assessed demographics, type of sedation, complications, duration of procedure, operator9s and patient9s satisfaction. Results: During August 2013-January 2014, 133 patients (mean age 58.3 years) that underwent EBUS TBNA completed the questionnaire. Sixty patients received propofol+/- reminfentanyl (Group A) by an anaesthetist and 73/133 received midazolam and fentanyl (Group B) by the operator. The number of passes per lymph node and complications were not significantly associated with the type of sedation (p Conclusions: Propofol is an important drug for EBUS-TBNA sedation with immense benefits for both patients and operators. Its use should be encouraged in EBUS-TBNA and it should be offered by an anaesthetist or the operator provided that the latter has received appropriate training and the national guidelines permit this.

Soft Computing, 2019

Malignant pleural effusion is diagnostically challenging in presence of negative cytology. The as... more Malignant pleural effusion is diagnostically challenging in presence of negative cytology. The assessment of tumor markers in serum has become a standard tool in cancer diagnosis, while pleural fluid sampling has not met universal consensus. The evaluation of a panel of markers both in serum and pleural fluid may be crucial to improve the diagnostic accuracy. Using a machine learning-based approach, we provide a mathematical formula capable to express the complex relation existing among the expressed markers in serum and pleural effusion and the presence of lung cancer. The formula indicates CEA and CYFRA21-1 in pleural fluid as the best diagnostic markers, with 97% accuracy, 98% sensitivity, 95% specificity, 96% area under curve, 98% positive predictive value, and 92% MCC (Matthews correlation coefficient). Keywords Machine learning • Genetic programming • Genetic algorithm • Evolutionary algorithm • Pleural effusion • Biochemical tumor marker • Thoracentesis • Thoracoscopy • Video-assisted thoracic surgery Communicated by V. Loia.

Anticancer research

Lymphangiogenesis, an essential process in the metastasis of malignant tumors, has not been thoro... more Lymphangiogenesis, an essential process in the metastasis of malignant tumors, has not been thoroughly studied. The possibility of using it to define subsets of patients with different prognosis in cancer could be of vital clinical importance. Fifty patients (5 women, 45 men; mean age, 64.47 years) with SCLC were retrospectively studied. Tumor specimens were stained for CD105, and intratumoral lymphatic microvessel density (ILMVD) and lymphatic invasion were determined. Twenty-five patients were diagnosed with limited and 25 with extensive SCLC. All patients received chemotherapy and 32.7% radiation therapy. A direct association between ILMVD (CD105 expression) and lymphatic invasion was observed (p<0.046). CD105 expression was significantly associated with the stage of the disease (p=0.004) and the presence of metastasis (p=0.05). CD105 expression and lymphatic invasion correlated significantly with the clinical parameters and patient outcome, therefore, constituting an importan...

Interactive CardioVascular and Thoracic Surgery, 2009

The identification of a primary endobronchial non-Hodgkin lymphoma (NHL) is rare. We hereby prese... more The identification of a primary endobronchial non-Hodgkin lymphoma (NHL) is rare. We hereby present the case of a primary solitary endobronchial NHL lesion in an 80-year-old patient with prostate cancer who did not present any systemic involvement at the time of diagnosis.

Cardiac Defibrillation - Mechanisms, Challenges and Implications, 2011

Journal of Surgical Case Reports, 2012

Hepatic hydrothorax is a complication of liver cirrhosis. Several invasive therapeutic approaches... more Hepatic hydrothorax is a complication of liver cirrhosis. Several invasive therapeutic approaches have been performed such as thoracentesis, video-assisted thoracic surgery and repair of the diaphragmatic defects with debatable results. Medical thoracoscopy is a minimally invasive and effective technique with challenging applications that has not been thoroughly used in the treatment of hepatic hydrothorax. We hereby present the case of a hepatic hydrothorax complicated by thoracic empyema in a 38-year-old patient with alcoholic cirrhosis that was treated with medical thoracoscopy and talc pleurodesis.

Breathe, 2014

Chairing sessions is not about smartly stealing thunder; it is about making the speakers, the att... more Chairing sessions is not about smartly stealing thunder; it is about making the speakers, the attendees and the co-chairs look smart. Effective chairing includes the practicalities of introducing your co-chairs, the speakers/presenters and yourself, keeping time, and facilitating discussion. The actual challenge is to: engage the audience's interest; create a sense of coherence throughout the diversity of presentations and speakers; ease the speakers' job of establishing their credibility with the audience; create a constructive, respectful and professional atmosphere for discussion; and wrap up in a way that leaves everyone feeling good about the session. Successful chairing leaves the presenters and audience feeling that the session was worth the time they invested in it. With all these aims in mind, herein, we address the challenge of chairing a session (thematic poster session, oral presentation and poster discussion) [1], and provide practical tips to overcome difficult situations and even turn them into advantages. Chairing thematic poster sessions Decide how much time you want to assign to poster viewing and when to start a poster walk Statement of Interest None declared.

Thorax, 2013

We have used in this study a combination of genome expression profiling and cytokine arrays to sc... more We have used in this study a combination of genome expression profiling and cytokine arrays to screen for candidates mediating MSC homing to two different cancer cell lines: A549 and MDAMB231. We found a variety of interleukines and cytokines already described as players in the process, such as IL6, IL8, CCL2. Additionally, from in vitro migration and invasion assays, we show that CXCR4 is a major player in this mechanism being the essential MSC receptor for the process to occur. Furthermore, we have identified MIF as the major trigger for MSC homing, being secreted from tumour cells at high levels. For the first time, we have identified in this study a novel axis: MIF-CXCR4, showing a physical interaction between them and validating their essential role in vitro and in vivo. Importantly, knocking down the expression of CXCR4 in MSCs or MIF in tumour cells, drastically decreased MSC recruitment to tumours in a in vivo model of lung metastasis. A better understanding of MSC homing players towards tumours will help the development of novel strategies in their use as vehicles in cancer cell therapy.

Chest, 2010

Lymphangiogenesis has been reported to be driven by mediators (e.g hyaluronic acid) and inflammat... more Lymphangiogenesis has been reported to be driven by mediators (e.g hyaluronic acid) and inflammatory cells (e.g activated CD11b+ macrophages), both commonly met in COPD. We hypothesized that lymphangiogenesis is part of COPD pathogenesis. This study aims to investigate the lymphangiogenetic expression in COPD measuring the lymphatic microvessel density (LMVD) and the correlation with the presence of lymphatic invasion(L.I), clinical and laboratory parameters. METHODS: Lung surgical specimens from 20 smokers [10 COPD-smokers (30% stage 2 GOLD) and 10 non-COPD smokers] with mean age of 62.6 years (range 38-82) were immunohistochemically stained for D2-40 and LYVE-1. Calculation of LMVD and assessment of L.I were performed and correlation with clinical and spirometric data followed. RESULTS: D2-40 and LYVE-1 were expressed in all specimens presenting higher expression (LMVD) in COPD-smokers (p=0.00). L.I was presented in all COPD specimens. D2-40 and LYVE-1 LMVD were associated with the presence of COPD (x2=20, p<0.001), smoking status (t=-1.8, p=0.09), and disease severity (GOLD)(p=0.00). CONCLUSION: D2-40 and LYVE-1 being selective lymphatic endothelial markers were highly expressed in COPD specimens in comparison with non-COPD smokers and associated with clinical and spirometric data. CLINICAL IMPLICATIONS: Our results reported for the first time the presence of newly formed lymphatic vessels in COPD, thus providing a novel insight in the pathogenesis of COPD including lymphangiogenesis.

Thorax, 2013

Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive, incurable, chemoresista... more Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive, incurable, chemoresistant tumour. Recent studies have shown that Mesenchymal stem cells (MSC) can home to and incorporate into the tumour stroma. Their tumour tropism can be used to deliver Tumour necrosis factor related apoptosis inducing ligand (TRAIL), a transmembrane protein that selectively induces apoptosis in transformed cells. However, not all tumours are sensitive to TRAIL. TRAIL works through triggering the extrinsic apoptotic pathway while conventional chemotherapeutic agents act by triggering the intrinsic apoptotic pathway. We hypothesised the crosstalk between these two pathways could be exploited by combining chemotherapy and MSC-TRAIL in MPM tumour cell lines. Methods MSC were engineered to express TRAIL using a lentiviral plasmid vector. A Tetracycline (Tet)-inducible system was used as a backbone to control the expression of TRAIL. Apoptosis induced by recombinant TRAIL, MSC-TRAIL in MPM cell lines on combination with Vorinostat, a chemotherapeutic agent, was measured by Annexin-V/DAPI based flow cytometry. Results The combination of recombinant TRAIL and Vorinostat act synergistically to induce apoptosis in MPM cell lines. Recombinant TRAIL and Vorinostat, as monotherapies induce 7.17% and 51.35% apoptosis in an MPM cell line JU77 respectively. In CRL2081 and ONE58 cell lines, recombinant TRAIL induces 56.75% and 13.41% apoptosis while Vorinostat leads to 78.95% and 43.97% apoptosis respectively. The combination of recombinant TRAIL and Vorinostat shows an increased amount of apoptosis in JU77, CRL2081 and ONE58 cell lines at 80.77%, 96.6% and 77.27% respectively (Table 1). Similar synergistic affect was observed when TRAIL expressing MSCs were co-cultured with Vorinostat treated MPM cell lines. MSC-TRAIL induced apoptosis in JU77 (48.73%), CRL2081 (57.63%) and ONE58(53.8%). Combined treatment of Vorinostat and MSC-TRAIL significantly increased apoptosis to 77.7% in JU77, 90.93% in CRL2081 and 77.8% in ONE58 cells (Table 1). Conclusion The combination of Vorinostat and recombinant TRAIL acts synergistically to induce apoptosis in malignant plural mesothelioma cells. Similar affect is observed with the combination of MSC-TRAIL and Vorinostat. This study indicates that Mesenchymal stem cells can be used as vectors for delivery of TRAIL and upon combination with Vorinostat, could be a potential therapy for malignant pleural mesothelioma.

European Respiratory Journal

Radiological evaluation of incidentally detected lung nodules on computed tomography (CT) influen... more Radiological evaluation of incidentally detected lung nodules on computed tomography (CT) influences management. We assessed international radiological variation in 1) pulmonary nodule characterisation; 2) hypothetical guideline-derived management; and 3) radiologists' management recommendations.107 radiologists from 25 countries evaluated 69 CT-detected nodules, recording: 1) first-choice composition (solid, part-solid or ground-glass, with percentage confidence); 2) morphological features; 3) dimensions; 4) recommended management; and 5) decision-influencing factors. We modelled hypothetical management decisions on the 2005 and updated 2017 Fleischner Society, and both liberal and parsimonious interpretations of the British Thoracic Society 2015 guidelines.Overall agreement for first-choice nodule composition was good (Fleiss' κ=0.65), but poorest for part-solid nodules (weighted κ 0.62, interquartile range 0.50–0.71). Morphological variables, including spiculation (κ=0.35...

European Respiratory Journal, 2015

European Respiratory Journal, 2015

Introduction: There is no standardized practice for the use of sedation in EBUS-TBNA and hence th... more Introduction: There is no standardized practice for the use of sedation in EBUS-TBNA and hence there is a continuous debate about bronchoscopist -administered versus anaesthetist-administered sedation. Their impact in patient and operator satisfaction has not been thoroughly studied. Aim: To evaluate patients9 and operators9 satisfaction, complications and efficiency of EBUS-TBNA with propofol versus midazolam and fentanyl. Materials and methods: Adult patients, anaesthetists and bronchoscopists were offered a survey questionnaire after completion of each EBUS-TBNA. The questionnaire assessed demographics, type of sedation, complications, duration of procedure, operator9s and patient9s satisfaction. Results: During August 2013-January 2014, 133 patients (mean age 58.3 years) that underwent EBUS TBNA completed the questionnaire. Sixty patients received propofol+/- reminfentanyl (Group A) by an anaesthetist and 73/133 received midazolam and fentanyl (Group B) by the operator. The number of passes per lymph node and complications were not significantly associated with the type of sedation (p Conclusions: Propofol is an important drug for EBUS-TBNA sedation with immense benefits for both patients and operators. Its use should be encouraged in EBUS-TBNA and it should be offered by an anaesthetist or the operator provided that the latter has received appropriate training and the national guidelines permit this.