[Show abstract][Hide abstract] ABSTRACT: Introduction and objectives:
European experience regarding lung cancer screening using low-dose chest CT (LDCT) is available. However, there is limited data on the Spanish experience in this matter. Our aim is to present the results from the longest ongoing screening program in Spain.
The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) is actively screening participants for lung cancer using LDCT since year 2000 following the IELCAP protocol, including spirometric assessments. Men and women, ≥40 years of age, current or former smokers with a tobacco history of ≥10 pack-years are included. Results are compared to those from other European trials.
A total of 2989 participants were screened until March 2014 (73% male). A median of 2 (IQR 1-3) annual screening rounds were performed. Sixty lung cancers were detected in 53 participants (73% in StageI). Adenocarcinoma was the most frequent. The lung cancer prevalence and incidence proportion was 1.0% and 1.4%, respectively, with an annual detection rate of 0.41. The estimated 10-year survival rate among individuals with lung cancer was 70%. Chronic obstructive pulmonary disease and emphysema are important lung cancer predictors.
The experience in Spain's longest lung cancer screening program is comparable to what has been described in the rest of Europe, and confirms the feasibility and efficacy of lung cancer screening using LDCT.
Archivos de Bronconeumología 03/2015; 51(4). DOI:10.1016/j.arbr.2015.02.015 · 1.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: European experience regarding lung cancer screening using low-dose chest CT (LDCT) is available. However, there is limited data on the Spanish experience in this matter. Our aim is to present the results from the longest ongoing screening program in Spain.
Archivos de Bronconeumología 01/2015; 51(4). DOI:10.1016/j.arbres.2014.09.019 · 1.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To design a novel ex-vivo acquisition technique to establish a common framework to validate different segmentation techniques for oncological PET images. To evaluate several automatic segmentation algorithms on this set of images.
Material and methods
In 15 patients with cancer, ex-vivo PET studies of surgical specimens removed during surgery were performed after injection of 18F-FDG. Images were acquired in two scanners: a clinical PET/CT and a high-resolution PET scanner. Real tumor volume was determined in each patient, and a reference image was generated for segmentation of each tumor. Images were segmented with 12 automatic algorithms and with a standard method for PET (relative threshold at 42%) and results were evaluated by quantitative parameters.
It has been possible to demonstrate by segmentation of PET images of surgical specimens that on high resolution PET images, 8 out of 12 evaluated segmentation techniques outperformed the standard method, whose value is 42%. However, none of the algorithms outperformed the standard method when applied on images from the clinical PET/CT. Due to the great interest of this set of PET images, all studies have been published on the Internet in order to provide a common framework for validation and comparison of different segmentation techniques.
We have proposed a novel technique to validate segmentation techniques for oncological PET images, acquiring ex-vivo PET studies of surgical specimens. We have demonstrated the usefulness of this set of PET images by evaluating several automatic segmentation algorithms.
Revista Española de Medicina Nuclear e Imagen Molecular 03/2014; 33(2):79–86. DOI:10.1016/j.remn.2013.06.010 · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.
A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.
Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).
The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.
[Show abstract][Hide abstract] ABSTRACT: There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments.
We assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test.
Lung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61±0.87 vs 0.16±0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13±2.02 vs 1.86±0.95 µg/mL, P < 0.001; 3.18±3.20 vs 1.13±0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93).
Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.
Journal of the National Cancer Institute 08/2013; 105(18). DOI:10.1093/jnci/djt205 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Curettage mastectomy is indicated as a palliative treatment in locally advanced breast cancer. We present our experience with the use of a DIEP flap reconstruction following extensive mastectomy.
We report the case of a patient with very advanced local breast cancer that was subsidiary to aggressive palliative surgery after chemotherapy.
It was considered that the closure that could be performed with the latissimus dorsi muscle was unsuitable, therefore a DIEP flap was performed. The patient was discharged uneventfully.
The DIEP reconstruction offers great cutaneous extension. It can be a resource in highly selected cases of locally advanced breast cancer in which surgery becomes the main treatment.
Anales del sistema sanitario de Navarra 05/2013; 36(1):141-144. · 0.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Curettage mastectomy is indicated as a palliative treatment in locally advanced breast cancer. We present our experience with the use of a DIEP flap reconstruction following extensive mastectomy. Methods. We report the case of a patient with very advanced local breast cancer that was subsidiary to aggressive palliative surgery after chemotherapy. Results. It was considered that the closure that could be performed with the latissimus dorsi muscle was unsuitable, therefore a DIEP flap was performed. The patient was discharged uneventfully. Conclusion. The DIEP reconstruction offers great cutaneous extension. It can be a resource in highly selected cases of locally advanced breast cancer in which surgery becomes the main treatment.
Anales del sistema sanitario de Navarra 04/2013; 36(1):141-144. DOI:10.4321/S1137-66272013000100019 · 0.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone.
From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test.
Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group.
The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.
[Show abstract][Hide abstract] ABSTRACT: We report on nine highly selected patients in whom the resection of the tumor was only possible with cardiopulmonary bypass (CPB).
Between November 1996 and November 2009, nine patients with non-cardiac tumors underwent surgery under CPB. Indications were: infiltration of the pulmonary vein in the left atrium (four cases), one case where the tumor (a paraganglioma apparently located in the subcarinal space) was actually in the atrium wall, one mediastinal liposarcoma with massive infiltration of the pericardium and the main pulmonary artery, and three tracheal tumors (2 cylindromas and 1 carcinoid).
Indication for CPB was decided preoperatively in 7 cases and intraoperatively in the other 2 patients. Cardiac infiltration was confirmed with intraoperative transesophageal cardiac echography in 2 patients, which proved to be very useful. Concerning postoperative complications, one patient died intraoperatively because it was impossible to stop the CPB after reconstruction of the bifurcation of the main pulmonary artery. Although the duration of the operation was significantly increased by the use of cardiopulmonary by-pass, it did not influence postoperative recovery in any of the other eight patients, as far as bleeding or infection was concerned. In one patient, a thoracic drain had to be replaced due to a partial pneumothorax. In another patient a partial dehiscence of the neo-carina was conservatively treated. Long-term results were influenced by the initial pathology of the patient.
CPB provides the possibility of safely resecting intrathoracic tumors invading cardiac structures that were previously inoperable. This can be achieved with an acceptable level of risk and - in very selected cases - may achieve long-term survival.
The Journal of cardiovascular surgery 03/2012; 53(3):381-6. · 1.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non-small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC).
We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC.
The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC.
Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.
[Show abstract][Hide abstract] ABSTRACT: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we examined the role of SF2/ASF in human non-small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in SF2/ASF-related carcinogenesis.
SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry. SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to identify the association between the expression of the proteins and time to progression.
Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex 1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore, combined expression of these proteins was associated with prognosis.
This study provides novel data on the mTORC1- and survivin-dependent mechanisms of SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in NSCLC progression.
Clinical Cancer Research 08/2010; 16(16):4113-25. DOI:10.1158/1078-0432.CCR-10-0076 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary metastases from bone sarcomas occur in approximately 40% of the cases. The combination of both chemotherapy and surgical resection is currently the standard treatment options for these patients. We aim to study the influence of different prognostic factors on long-term survival.
We reviewed the prognostic factors and survival rate in 52 consecutive patients with pulmonary metastases from bone sarcomas. All of them were previously treated with chemotherapy and submitted to metastasectomy at our institution from 1996 to 2006. Clinical and demographic variables, related to the primary tumour as well as to the pulmonary metastases, and treatment procedures were registered. Univariate (log-rank) and multivariate (Cox regression) analysis were carried out to identify significant prognostic factors related to overall survival. Five-year survival rates were estimated using Kaplan-Meier methods.
Median follow-up was 28 months. Follow-up duration ranged 7-148 months; the median survival was 27 months. As many as 31% of the patients were alive without disease, 3% were alive with disease, 64% died of disease while 2% died from other causes. Complete resection was achieved in 49 cases (94%). The overall 3- and 5-year survival rates were 43% and 31%, respectively. Univariate analysis showed (1) disease-free interval between treatment of the primary bone tumour and first lung metastasectomy (DFI) and (2) disease-free interval between first and second lung surgery (DFI2) as prognostic factors. Gender, primary site, histology of primary tumour, surgical approach, number of lung nodules, type of lung resection and re-do lung surgery did not have a significant impact on survival.
The long-term survival after bone sarcoma lung metastasectomy is encouraging. In our series, DFI and DFI2 were identified as the only prognostic factors.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 12/2009; 37(5):1205-8. DOI:10.1016/j.ejcts.2009.11.026 · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Optimal management of SST is still controversial several years after the proposal of a multidisciplinary approach including neoadjuvant chemotherapy and external radiation. Our objective is to report our experience of this multidisciplinary approach from the surgical point of view.
From January 1997 to January 2008, 24 patients were treated surgically (18 with induction chemotherapy and 15 with radiotherapy). The surgical approach was thoracic (14 cases, 1 with a spinal approach) or cervical (10 patients, 2 thoracotomies). Pulmonary surgery performed consisted of 11 wedge resections, 10 lobectomies, 1 pneumonectomy and 2 cases without lung resection (1 exploratory thoracotomy and 1 local progression after a previously resected tumor). Intraoperative radiotherapy (IORT) was given in 7 cases. Partial vertebral body resection was performed in 5 cases. A pathologically complete response (pT0) was found in 7 cases (29 %).
Surgery-related morbidity was mainly due to respiratory distress (5 patients). Two patients died in the first month after surgery (mortality: 8 %). The surgical approach (cervical vs. thoracic) did not influence postoperative morbidity ( p = NS). Overall 5-year survival was 56.6 % according to the Kaplan-Meier method. No influence on survival was observed with regard to the approach (cervical vs. thoracic), the use of IORT, or the performance of spinal surgery. Patients with a complete pathological response had a better 5-year survival, but this did not reach statistical significance.
Surgery has a role in the multidisciplinary approach, especially when we consider long-term survival. A multidisciplinary approach using neoadjuvant chemo and radiotherapy has a high rate of complete pathological response. It is also associated with a high incidence of postoperative distress syndrome. The 5-year survival is acceptable.
The Thoracic and Cardiovascular Surgeon 10/2009; 57(6):353-7. DOI:10.1055/s-0029-1185786 · 0.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carcinosarcomas are malignant tumors with a mixture of carcinomatous and differentiated sarcomatous elements. We investigate the morphology, immunohistochemistry, and comparative genomic hybridization analysis of 3 mixed squamous carcinoma and osteosarcoma of the lung. All patients were male and their ages were 72, 43, and 58 years. The sizes of the neoplasms were 7, 5, and 5 cm in maximum diameter, respectively. Two patients died of the disease 9 and 14 months after surgery; and one is alive 6 months later. By light microscopy, all cases had both squamous and osteosarcomatous structures. Immunohistochemistry was positive for AE3AE1, p63, 34 E12, CAM 5.2 (2/3 cases), CK-7 (2/3 cases), epithelial membrane antigen, E-cadherin, p53, and carcinogenic embryonic antigen in carcinomatous areas, and for vimentin and CD-68 in sarcomatous component. Areas of transition positive for both cytokeratins and vimentin were seen in all cases. A total of 55 copy number changes were detected with a median of 18 abnormalities per case: 48 gains, 6 losses, and 1 high-level amplification. Chromosome alterations in osteosarcomatous areas were similar to those found in lung metastatic osteosarcoma, comparable to those found in carcinomatous areas and to lung squamous carcinomas. Coincidences between carcinomatous areas and osteosarcomatous zones were found as gains in chromosomes 1q, 3q, 5p, 8q, and 12p. These findings provide arguments that favor a common origin for both types of cells, supported by the mixture of cells, the existence of undifferentiated cells positive to both cytokeratin and vimentin markers, and the CGH overlaps of chromosomal gains between carcinomatous and sarcomatous areas.
Diagnostic molecular pathology: the American journal of surgical pathology, part B 04/2008; 17(3):151-8. DOI:10.1097/PDM.0b013e31815d05b3 · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low-dose spiral computerized axial tomography (spiral CT) is effective for the detection of small early lung cancers. Although published data seem promising, there has been a significant degree of discussion concerning the potential of overdiagnosis in the context of spiral CT-based screening. The objective of the current study was to analyze the phenotypic and genetic alterations in the small pulmonary malignancies resected after detection in the University of Navarra/International Early Lung Cancer Action Project spiral CT screening trial and to determine whether their malignant molecular features are similar to those of resected lung tumors diagnosed conventionally.
We analyzed 17 biomarkers of lung epithelial malignancy in a series of 11 tumors resected at our institution during the last 4 years (1,004 high-risk individuals screened), using immunohistochemistry and fluorescence in situ hybridization (FISH). A parallel series of 11 gender-, stage-, and histology-matched lung cancers diagnosed by other means except screening was used as control.
The molecular alterations and the frequency of phenotypic or genetic aberrations were very similar when screen-detected and nonscreen-detected lung cancers were compared. Furthermore, most of the alterations found in the screen-detected cancers from this study were concordant with what has been described previously for stage I-II lung cancer.
Small early-stage lung cancers resected after detection in a spiral CT-based screening trial reveal malignant molecular features similar to those found in conventionally diagnosed lung cancers, suggesting that the screen-detected cancers are not overdiagnosed.