Venceslau Hespanhol

Survival predictors in advanced non-small cell lung cancer

The authors studied the influence on survival of 21 clinical, anatomical, haematological and biochemical factors evaluated, at diagnosis, of 411 patients (pts) with advanced Non Small Cell Lung Cancer (NSCLC) followed in our department between 1984 and 1990. Most of the patients were male (347--84.4%) and only 64 (15.6%) were females. Median age was 62 years, but was slightly higher in females. Only 34 patients were aged under 45 years. Squamous cell carcinoma (215 pts--52%) and adenocarcinoma (152 pts--37%) were the most frequent histologic types. Performance status was poor--only 103 (25%) continued active; 120 (29%) spent at least half of the time in bed; 188 (46%) were severely limited. After staging, 179 (44%) presented locally advanced disease (stage IIIB) and 232 (56%) metastatic dissemination (stage IV). Therapy was defined by the oncologic group according to individual characteristics and based on clinical grounds. Anti-neoplastic therapy was performed in 225 (55%), chemotherapy alone in 121 (30%), radiation therapy alone in 67 (16%), and sequential combined treatment (chemotherapy and thoracic radiation) in 37 (9%). Until 1987, the main chemotherapy regimen was MACC (Metrotrexate + Adriamycine + Cyclophosphamide + Lomustin), afterwards VP(M) (Cisplatin + Vimblastin + Mitomycine). Radiation therapy was performed using Co60, 2 Gy/day, 5 days a week, for 4 weeks (approximately 45 Gy total). The response rate was poor--four complete responses (2%), 42 (19%) partial responses. The overall median survival was 4.3 months and only 5% of patients were alive after 18 months of follow up. Prognostic importance of each characteristic studied was initially done by unifactorial analysis, followed by multifactorial analysis according to two methods: Cox proportional hazards model and recursive partitioning amalgamation--RECPAM. Regardless of the method used, the main determinants of survival were found to be performance status (Zubrod), weight loss and serum albumin. Other factors such as the staging (presence or absence of metastasis), lymphocytes, lactic dehydrogenase, and hoarseness were also significant. It is noteworthy that age and histological type were irrelevant; sex and hoarseness only proved important when integrated within a multifactorial model. The overall prognostic evaluation and therapeutic decision of advanced NSCLC patients could be improved by combining the prognostic value of TNM with that of performance status, weight loss and serum albumin. These prognostic guidelines must be taken into account when designing new clinical trials.

Insights into Angiogenesis in Non-Small Cell Lung Cancer: Molecular Mechanisms, Polymorphic Genes, and Targeted Therapies

Lung cancer is a highly prevalent disease worldwide. Currently, there are more than 150 million patients with lung cancer in the world, with more than 1 million new cases diagnosed per year. Tumoral angiogenesis is an important hallmark of this disease, but despite being extensively studied, the complete angiogenic mechanisms are not fully elucidated. Recent studies have reported a correlation between pharmacological inhibition of these angiogenic mechanisms and improvement of overall survival in lung cancer patients, mainly for those in advanced stages. The family of vascular endothelial growth factor (VEGF) proteins has critical roles in tumoral angiogenesis. An interaction between VEGF-A and VEGF receptor 2 (VEGFR-2) is the main pathway of activation and maintenance of angiogenesis. In tumors, this process is intimately correlative with progression and metastasis. Some studies suggested that serum levels of VEGF are higher in patients with lung cancer, especially in some types of non-small cell lung cancer (NSCLC). Other studies revealed that genetic polymorphisms of VEGF correlate with susceptibility, prognosis, and therapeutic response of some patients with NSCLC. This paper aims to review the impact of angiogenesis, especially on VEGF pathways, in NSCLC, and highlights the relevance of known and new patents disclosed of anti-angiogenic therapies in these patients.

Sialylation regulates galectin-3/ligand interplay during mammary tumour progression - a case of targeted uncloaking

Galectin-3 is involved both in facilitating detachment of cells from primary tumour sites and favouring cancer cell adhesion and survival to anoikis in the blood stream. The mechanisms behind these apparently contradictory roles of the lectin have not yet been resolved. In order to investigate possible interplays between galectin-3 and its ligands underlying their role in the metastatic process, we examined mucin-1 (MUC1) and epidermal growth factor receptor (EGFR), well-known galectin-3 ligands, as well as galectin-3-binding site expression in a series of spontaneous canine malignant mammary tumours (CMMT) and a metastatic CMMT cell line. Despite the fact that CMMT cells expressed MUC1 and EGFR homogeneously over their plasma membrane, intravascular tumour cells, positive for galectin-3, expressed MUC1 and EGFR in a more focal membrane localization. Moreover, MUC1 overexpression in primary CMMT was present in parallel with down-regulation of galectin-3. Furthermore, in the CMT-U27 cell line, galectin-3 knock-down led to increased MUC1 expression, while MUC1 knock-down led to down-regulation of the lectin. Finally, removal of sialic acid from both CMMT and CMT-U27 xenograft samples exposed galectin-3-ligands throughout the tumour tissue, whereas these ligands were only present in galectin-3-positive invading cells in untreated samples. Interestingly indeed, we show that in vessel-invading cells, there is interaction between galectin-3 and the T antigen in vivo. We therefore hypothesized that loss of galectin-3 and sialylation-related masking of its ligands, in conjunction with their overexpression in specific tumour cell subpopulations, are crucial in regulating adhesive/de-adhesive events in the progression and invasive capacity of metastatic cells.

Pulmonary rehabilitation in patients with bronchiectasis: pulmonary function, arterial blood gases, and the 6-minute walk test.

BACKGROUND: Information regarding the effects of pulmonary rehabilitation (PR) on pulmonary function (PF), arterial blood gases (ABG), and 6-minute walk distance (6MWD) in patients with bronchiectasis is scant in the literature. METHODS: To evaluate the effects of PR on these indices in this population, a retrospective evaluation of those who attended PR from 2007 to 2010, was made. Pulmonary rehabilitation lasted a mean of 12 weeks and included cycle ergometer exercise for 30 minutes, 3 times per week, with additional upper limbs and quadriceps training. PF, ABG, and 6MWD were evaluated before and after PR to determine the potential influence of gender, exacerbations, underlying cause of bronchiectasis, severity of obstruction, and colonization with bacteria. RESULTS: Forty-one patients (48.8% males; median age, 54 years) were included; 25 had severe obstruction and 19 were colonized with bacteria. Following PR, no significant changes were detected in PF or ABG. Median 6MWD before PR was 425 m and post-PR was 450 m (P = .431). Outcomes did not show any interaction with gender, colonization, or exacerbations. However, patients with idiopathic bronchiectasis did show a significant improvement in forced vital capacity in percent of predicted and residual volume after PR (P = .016 and .048, respectively). Patients with severe obstruction showed a statistically significant decrease in percent of predicted residual volume (P = .025). CONCLUSION: There appears to be a beneficial impact of PR on PF in certain groups of patients with bronchiectasis. In addition, PR indications and protocols for patients with bronchiectasis may need to be adapted to accommodate specific patients, so that expressive exercise capacity improvement can be achieved.

Coordinated expression of galectin-3 and galectin-3-binding sites in malignant mammary tumors: implications for tumor metastasis

Galectin-3 is a glycan-binding protein that mediates cell-cell and/or cell-extracellular matrix (ECM) interactions. Although galectin-3 is implicated in the progression of various types of cancers, the mechanisms by which galectin-3 enhances metastasis remain unclear. In order to elucidate the role of galectin-3 in the complex multistage process of cancer metastasis, we examined galectin-3 and galectin-3-binding site expression in a series of 82 spontaneous canine mammary tumors (CMT) and two CMT cell lines. Benign CMT tumors exhibited strong nuclear/cytoplasmic galectin-3 immunostaining, whereas malignant CMT tumors and metastases exhibited dramatically decreased galectin-3 expression with the majority of the immunostaining confined to the cytoplasm. Interestingly, intravascular tumor cells overexpressed galectin-3 regardless of their location. CMT-U27 xenografts displayed the same pattern of galectin-3 expression found in spontaneous malignant CMT. In parallel with the downregulation of galectin-3, malignant CMT displayed an overall loss of galectin-3-binding sites in the ECM and focal expression of galectin-3-binding sites mainly detected in intravascular tumor cells and endothelium. Furthermore, loss of galectin-3-binding sites was correlated with the downregulation of GLT25D1, a β (1-O) galactosyltransferase that modifies collagen, and upregulation of stromal galectin-1. Finally, GLT25D1 mRNA expression was strikingly downregulated in malignant CMT-U27 compared with the benign cell line, and its expression was further decreased in a galectin-3 knockdown CMT-U27 cell line. We therefore hypothesized that the loss of galectin-3-binding sites in the ECM in conjunction with the overexpression of galectin-3 in specific tumor cell subpopulations are crucial events for the development of mammary tumor metastases.

The Impact of Polymorphic Variations in the 5p15, 6p12, 6p21 and 15q25 Loci on the Risk and Prognosis of Portuguese Patients with Non-Small Cell Lung Cancer

Introduction Polymorphic variants in the 5p15, 6p12, 6p21, and 15q25 loci were demonstrated to potentially contribute to lung cancer carcinogenesis. Therefore, this study was performed to assess the role of those variants in non-small cell lung cancer (NSCLC) risk and prognosis in a Portuguese population. Materials and Methods Blood from patients with NSCLC was prospectively collected. To perform an association study, DNA from these patients and healthy controls were genotyped for a panel of 19 SNPs using a Sequenom® MassARRAY platform. Kaplan-Meier curves were used to assess the overall survival (OS) and progression-free survival (PFS). Results One hundred and forty-four patients with NSCLC were successfully consecutively genotyped for the 19 SNPs. One SNP was associated with NSCLC risk: rs9295740 G/A. Two SNPs were associated with non-squamous histology: rs3024994 (VEGF intron 2) T/C and rs401681 C/T. Three SNPs were associated with response rate: rs3025035 (VEGF intron 7) C/T, rs833061 (VEGF –460) C/T and rs9295740 G/A. One SNP demonstrated an influence on PFS: rs401681 C/T at 5p15, p = 0.021. Four SNPs demonstrated an influence on OS: rs2010963 (VEGF +405 G/C), p = 0.042; rs3025010 (VEGF intron 5 C/T), p = 0.047; rs401681 C/T at 5p15, p = 0.046; and rs31489 C/A at 5p15, p = 0.029. Conclusions Our study suggests that SNPs in the 6p12, 6p21, and 5p15 loci may serve as risk, predictive and prognostic NSCLC biomarkers. In the future, SNPs identified in the genomes of patients may improve NSCLC screening strategies and therapeutic management as well.

MUC1 expression in canine malignant mammary tumours and relationship to clinicopathological features.

Mucin-1 (MUC1) is over-expressed in human breast carcinomas and is linked to a poorer prognosis. In this study, MUC1 expression in 32 spontaneous canine malignant mammary tumours was characterised in relation to histological type, mode of growth, grade, lymph node metastases and distant metastases. All tumours exhibited immunostaining for MUC1. In the normal canine mammary gland, MUC1 was expressed mainly in the apical cellular membrane, while in carcinomas MUC1 was detected in the cytoplasm only (56.3%) or in the cytoplasm with membrane accentuation (43.7%). There was a significant association between development of distant metastases and MUC1 over-expression (P=0.03), but no association with histological type, histological grade, mode of growth or lymph node metastasis.

Bronchiectasis: A retrospective study of clinical and aetiological investigation in a general respiratory department

BACKGROUND Bronchiectasis can result from many diseases, which makes the aetiological investigation a complex process demanding special resources and experience. The aetiological diagnosis has been proven to be useful for the therapeutic approach. OBJECTIVE Evaluate how accurately and extensive the clinical and aetiological research was for adult bronchiectasis patients in pulmonology outpatient service which were not following a pre-existing protocol. METHODS We retrospectively reviewed the records of 202 adult patients with bronchiectasis, including the examinations performed to explain the aetiology. RESULTS The mean age of the patients was 54 ± 15 years, there was a predominance of female (63.9%) and non-smoker (70%) patients. Functional evaluation showed a mild airway obstruction. The sputum microbiological examination was available for 168 patients (43.1% had 3 or more sputum examinations during one year). Immunoglobulins and α1-antitrypsin were measured in around 50% of the patients. The sweat test and the CF genotyping test were performed in 18% and 17% of the patients, respectively. The most commonly identified cause was post-infectious (30.3%), mostly tuberculosis (27.2%). No definitive aetiological diagnosis was established in 57.4% of the patients. We achieved a lower aetiological diagnosis if we compare our series with studies in which a diagnostic algorithm was applied prospectively. CONCLUSIONS The general characteristics of our patients were similar with other series. Detailed investigation of bronchiectasis is not a standard practice in our outpatient service. These results suggest that the use of a predefined protocol, based on current guidelines, could improve the assessment of these patients and facilitate the achievement of a definitive aetiology.

How to write a scientific paper-Writing the methods section

The methods section is the most important part of a scientific paper because it provides the essential information that allows the reader to judge the validity of the results and conclusions of the study reported. Therefore, in this section the authors should provide a clear and precise description of how the study was performed and the rationale for the methodological choices and characteristics of the study design. This section should be written in a clear and concise manner, but should always present enough information so that: (1) the study could be replicated by other researchers, in order to evaluate the reproducibility of results (it should not be a step-by-step tutorial but should be a systematic and complete description of what was done), and (2) the readers are able to judge the validity of results and conclusions presented. This will typically be the first section to be written in a paper (although many times the last to be finalized after corrections and reviews of authors and reviewers), mainly because it should be already thought of and written as a part of the research protocol/proposal, prepared at the initial phase of the research work, and because it sets the stage for the results and conclusions presented in a paper. From

Cancro do pulmão no norte de Portugal: um estudo de base hospitalar

INTRODUCTION Lung cancer is the deadliest cancer worldwide. In Portugal, the disease remains the main cause of cancer death in males. AIM This study aims to evaluate the demographic and clinical characteristics of lung cancer patients diagnosed and treated in northern Portugal hospitals from 2000 to 2010. PATIENTS AND METHODS Twelve hospitals in the north of Portugal contributed to this study. The demographic and clinic characteristics of the patients registered in each hospital from 2000 to 2010 and the patterns of their occurrence were analyzed. RESULTS During an 11-year period (2000-2010), 9767 lung cancer patients were registered in the participating hospitals. Comparing the number of the patients registered in the year 2000 to those registered during 2010, there was a significant increase in lung cancer cases. Females represent only 20% of the total registered lung cancer cases; however, during the study period, the number of female patients increased by 30%. A significant number of the patients, 3117 (48.6%), had poor performance status at presentation. The adenocarcinoma histology became more preponderant over the study period. Most of the patients were diagnosed as stages IIIB or IV: 7206 of 9267 (77.8%). Chemotherapy was the treatment of choice for 3529 (40.4%) patients, whereas surgical treatment was achieved in 1301 (14.9%) cases. CONCLUSION A significant number of lung cancer patients have been diagnosed and treated in hospitals in northern Portugal, and the incidence of the disease among females has been increasing. The overwhelming majority of the tumors were diagnosed in advanced stage; nevertheless, surgical treatment was possible in 14.9% of the patients.