Unresectable stage III non-small cell lung cancer: Insights from a Portuguese expert panel.

INTRODUCTION: The management of unresectable stage III non-small cell lung cancer (NSCLC) is clinically challenging and there is no current consensus on optimal strategies. Herein, a panel of Portuguese experts aims to present practical recommendations for the global management of unresectable stage III NSCLC patients. METHODS: A group of Portuguese lung cancer experts debated aspects related to the diagnosis, staging and treatment of unresectable stage III NSCLC in light of current evidence. Recent breakthroughs in immunotherapy as part of a standard therapeutic approach were also discussed. This review exposes the major conclusions obtained. RESULTS: Practical recommendations for the management of unresectable stage III NSCLC were proposed, aiming to improve the pathways of diagnosis and treatment in the Portuguese healthcare system. Clinical heterogeneity of patients with stage III NSCLC hinders the development of single standardised algorithm where all fit. CONCLUSIONS: A timely diagnosis and a proper staging contribute to the best management of each patient, optimizing treatment tolerance and effectiveness. The expert panel considered chemoradiotherapy as the preferable approach when surgery is not possible. Management of adverse events and immunotherapy as a consolidation therapy are also essential steps for a successful strategy.

Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation.

BACKGROUND: Well-differentiated papillary mesothelioma (WDPM) is a rare variant of epithelioid mesothelioma and is considered to be associated with good prognosis due to its clinically indolent behavior and long survival. Most reported cases involve the peritoneum of women at reproductive age with no history of exposure to asbestos, with pleural involvement being less common. The optimal management, including the role of chemotherapy in the treatment of WDPM, remains unsettled. PATIENTS AND METHODS: The authors describe two cases of WDPM in women of the same family (siblings); the elder with WDPM of the pleura and peritoneum with a 12-year survival period and the younger with a WDPM of the peritoneum diagnosed in 2011 and uveal melanoma diagnosed in 2012. Neither patient had any known exposure to asbestos fibers or any other mineral carcinogens. RESULTS: After the concurrent diagnosis of WDPM and uveal melanoma, genetic diagnosis was carried out taking into consideration that these two malignancies were recently associated with hereditary BAP1 gene mutations and it was positive for both the patients. CONCLUSIONS: To our knowledge, this is the first description of WDPM in two siblings who also presented with a germline BAP1 mutation. This article provides evidence of the wide clinical spectrum of cancer susceptibility associated with a BAP1 germline mutation.

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).

OBJECTIVE: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting. METHODS: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics). RESULTS: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data. CONCLUSIONS: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.

Characterization of a Staphylococcus aureus strain showing high levels of biofilm formation isolated from a vascular graft: case report.

A methicillin-susceptible Staphylococcus aureus strain, SA-DZ1, was isolated from an infected bypass crossover graft. Its general microbiological features were reminiscent of those previously described for the wound Wiley strain. Removal of the prosthetic device was necessary to resolve the infection. SA-DZ1 grown under different conditions showed a very strong and distinctive biofilm-producing phenotype, which was also visualized by confocal laser scanning microscopy. The biofilm extracellular matrix was essentially polysaccharidic, as determined by differential growth and physicochemical tests. By Multi Locus Sequence Typing (MLST), SA-DZ1 was classified as st94, a single locus variant of st8. Several other genetic traits assayed by PCR, such as agr-type and the presence of gene encoding proteins involved in adhesion and virulence (e.g. ica operon), confirmed the identifying features of this clinical isolate.

Pemetrexed in second line treatment of non-small cell lung cancer - The portuguese experience. / Pemetrexed na segunda linha de tratamento do carcinoma do pulmão de não pequenas células - A experiência portuguesa.

Until 2004, docetaxel in monotherapy was the standard for second-line treatment of non-small cell lung cancer (NSCLC). Pemetrexed (P) has shown similar activity in this setting with a better adverse event profile. In Portugal, it was introduced in October of 2004. We have carried out a retrospective analysis of patients (pts) who received P for second-line NSCLC in Portugal from October 2004 to December 2006. Data were collected from the records of pts with locally advanced or metastatic NSCLC and failed first-line chemotherapy enrolled in centers participating in the Portuguese Lung Cancer Study Group (GECP). Objective response (OR; complete [CR] or partial [PR] response) was evaluated using RECIST and safety was assessed using serious or non-serious adverse events (SAEs/AEs). By December 2006, 19 GECP centers had enrolled 244 pts who had received P for ≥1cycle, and were considered evaluable for both objective response and safety. Demography: male/female, 175/69; median age, 57.0years (range 20-81); smoking status, y/ex/n, 116/57/71; adenocarcinoma / squamous-cell carcinoma/other histology, 141/72/31; mean time to progression (TTP) 8.07months. Disease control in 209 evaluable pts was observed in 116 (55.5%): 2 CR, 45 PR and 69 SD; mean TTP 4.70months. The majority of AEs were grade 3 anemia (15 pts) and neutropenia (18 pts). The mean overall survival was 17.27months. Our retrospective analysis has observed a similar disease control rate with P in 2nd line (55.5%), and TTP (4.7months) in our current unselected population to that published in the literature. P is an option for second-line NSCLC with a good tolerability. Rev Port Pneumol 2008; XIV (Sup.2): S9-S20.

Positron emission tomography: indications in lung cancer - prospective experience of a department.

Positron emission tomography (PET) is a new technique in nuclear medicine. It uses biological radiotracers such as (18)F-fluoro-2-deoxyglucose (FDG) which permit the detection of suspected lesions with metabolic alterations that take up the glucose isotope too avidly, as is the case with neoplastic cells. PET has become an innovatory and important imaging tool for evaluating patients with lung cancer. The present recommended uses of PET include lung cancer diagnosis and the intrathoracic and extrathoracic staging in N-SCLC.

Retroperitoneoscopic lumbar sympathectomy for nonreconstructable arterial occlusive disease.

AIM: The aim of this study was to present our experience with video-assisted lumbar sympathectomy for non-reconstructive arterial occlusive disease in a series of 23 consecutive patients whose predominant symptoms were unilateral rest pain, limited skin ulcerations or gangrene of the toes. METHODS: All the procedures were performed with retroperitoneal approach, dorsal position of the patient and simple digital dissection of the retroperitoneal space. RESULTS: The operations were successfully performed in all patients except for 2, who immediately underwent open conversion. A urinoma caused by ureteral lesion was the only severe complication in this series. The mean operative time of the procedure was 55 min and the hospital stay was 2 or 3 days. No parenteral analgesics were administered postoperatively. At 1 month from operation, 20 patients out of 23 had significant relief of rest pain and improvement of ischemic lesions. After a median follow-up of 36 months, 2 patients had died, 4 underwent some type of distal amputation, 1 had recurrent rest pain and the other 16 reported persistent improvement of pain or dystrophic changes. CONCLUSIONS: Retro-peritoneoscopic technique appears the modern and less invasive version of the lumbar surgical sympathectomy.

Diffuse vascular hamartoma with malignant behavior.

Pulmonary hamartomas are benign lesions, usually asymptomatic and incidentally discovered on a routine chest radiograph; occasionally, however, this benign lesion may cause life threatening symptoms due to it's location and diffuse vascular involvement. We report the case of a 27 year-old male, non-smoker, who presented with dyspnea, cough, hemoptysis and weight loss. He was found to have a mass in the right hilar region which also involved the right main bronchus, pulmonary artery and esophagus. Surgical biopsy of the lesion led to the diagnosis of diffuse vascular hamartoma. Although it was a benign lesion, due to the size and location, surgical removal was not possible and patient died 10 years after being diagnosed with the condition.

A prospective study of gemcitabine and carboplatin as first-line therapy in advanced non-small cell lung cancer: toxicity of a three- versus a four-week schedule.

We evaluated the toxicity and activity of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and carboplatin on a 3-week (trial A) versus a 4-week (trial B) schedule in patients with advanced/metastatic non-small cell lung cancer. Chemotherapy-naive patients in trial A received gemcitabine 1,000 mg/m(2) on days 1 and 8 plus carboplatin area under the curve of 5 on day 1, every 3 weeks. In trial B, patients received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 and carboplatin area under the curve of 6 on day 1, every 4 weeks. Thirty patients were enrolled in trial A and 28 in trial B. Patients received a total of 142 cycles in trial A and 134 in trial B. Despite more frequent treatment delays (82 cycles in trial B and 20 cycles in trial A), and dose reductions/omissions (mainly on day 15), gemcitabine mean dose intensities of both schedules were similar. The principal dose-limiting toxicity was grade 3/4 thrombocytopenia. Objective response rates were 40% in trial A and 68% in trial B (no complete response). Gemcitabine and carboplatin administered on days 1 and 8 every 3 weeks is associated with lower myelotoxicity than that of a 4-week schedule, although both schedules were active against non-small cell lung cancer. Semin Oncol 28 (suppl 10):10-14.

ACE gene polymorphism and survival in atherosclerotic renovascular disease.

Renovascular disease (RVD) is an important cause of end-stage renal disease and is associated with a high mortality rate, mostly because of coexisting cardiovascular and cerebrovascular disease. The deletion (DD) polymorphism of the angiotensin-converting enzyme (ACE) gene has been described in association with severe vascular disease affecting major organs. To investigate whether DD genotype is a risk factor for mortality in RVD, we performed a follow-up study of 61 patients with this disease. Patients (age, 68.0 +/- 6.5 years) affected by atherosclerotic vascular disease were enrolled after angiographic demonstration of a renal artery stenosis. The average follow-up was 48.1 +/- 14.9 months. Genotype was insertion/deletion (I/D) in 30 patients, DD in 27 patients, and II in 4 patients. At enrollment, a complete assessment of heart, blood vessels, and renal function was performed. During the follow-up period, 13 patients died (9 DD, 4 ID) and 7 patients evolved into end-stage renal failure. The cumulative survival rate at 5 years was 45.4% +/- 13.4%. Factors associated with mortality were analyzed with Cox proportional hazard regression. The multivariate analysis showed that DD genotype, severe carotid disease, and smoking were independent predictors of mortality. The multivariate analysis of predictors of renal failure showed that the only significant association was found with baseline serum creatinine level of 265 micromol/L or greater. We conclude that the DD genotype of the ACE gene is a marker for mortality in RVD.

Primary lymphoepithelioma-like carcinoma of the lung.

Lymphoepithelioma is an undifferentiated carcinoma with prominent lymphoid stroma in the nasopharynx. Tumors with similar histology have been reported with other localizations, including the lungs, and are designated as lymphoepithelioma-like carcinomas (LELC). Primary LELC of the lung is very rare, and scant information is available in the scientific literature. This paper details the case of a 25-year-old Caucasian male patient with the diagnosis (determined by thoracotomy) of primary LELC of the lung. Immunohistochemical analysis was negative for Epstein-Barr virus, as was the in situ hybridization of the tumor cells. Observation of the nasopharynx and a magnetic resonance image of the cavum were normal. Because the tumor (T4N2M0) could not be resected, the patient was treated with chemotherapy, carboplatin/5-fluorouracil, completing two cycles. The patient's condition worsened when he developed contralateral pneumonia, which was then followed by pericardial effusion. The patient died 36 h later from cardiac tamponade. Presented here is a revision of this rare pathology, not often reported in the literature.

Comparison of target organ damage in renovascular and essential hypertension.

In many reports, the prevalence of target organ damage in renovascular hypertension (RVH) appears to be higher than in essential hypertension (EH). Since in most studies the renal artery stenosis is part of a diffuse atherosclerotic disease, it is not known whether these complications are due to RVH itself or to the vascular disease. We have undertaken a case control study of 92 patients divided into two groups (46 in each), one with RVH and the other with EH and abdominal aortic aneurysm, with a comparable degree of diffuse atherosclerotic vascular disease. The vascular state of the extracranial carotid arteries and abdominal and inferior limb districts was investigated with angiography and sonography. The prevalence of left ventricular hypertrophy (LVH) and ischemic heart disease (IHD) were assessed by electrocardiography. Serum creatinine and urinary protein excretion were employed in the renal evaluation. While the analysis of the results confirmed an even diffusion of atherosclerotic vascular disease between the two groups, a significant difference was found in the prevalence of heart and renal damage. LVH was present in 32.6% of RVH patients versus 10.8% in EH (P = .02). Serum creatinine > 1.4 mg/dL was found in 50% of RVH and in 23.9% of EH, (P = .01). The prevalence of proteinuria in RVH was also higher although not reaching the statistical significance. The results suggest that, in patients with comparable degrees of atherosclerotic vascular disease, RVH is responsible for the higher prevalence of target organ damage in this condition compared to those with EH.

Angiotensin-converting enzyme gene I/D polymorphism and carotid artery disease in renovascular hypertension.

There is evidence linking the activation of the renin-angiotensin system (RAS) with target organ damage in renovascular hypertension (RVH). A genetic association of the DD genotype of the angiotensin-converting enzyme (ACE) gene with cardiovascular complications has been found in various clinical conditions. The aim of our study was to determine whether the insertion/deletion (I/D) polymorphism of the ACE gene is associated with the high prevalence of target organ damage reported in RVH. A total of 65 atherosclerotic patients (age 68.2 +/- 5.2 years) with RVH and 49 atherosclerotic patients (age 68.0 +/- 6.3 years) with essential hypertension (EH) were sequentially enrolled when attending the outpatient clinic for specialist assessment of their vascular disorder. Cardiac, renal, and vascular involvement were assessed in both groups and blood was taken for genetic analysis. Patients with RVH had a higher prevalence of left ventricular hypertrophy (LVH), carotid artery disease, and albuminuria than those with EH. In RVH, but not in EH, the DD genotype was significantly associated with severe arterial disease. In RVH, carotid disease (lumen narrowing >60%) was present in 62% of DD patients versus 25% of the other genotypes (OR = 4.90, 95% CI: 1.70-14.13). Such an association was also present in peripheral vascular disease: 72.4% in DD patients versus 41.6% in the other genotypes (OR = 3.67, 95% CI = 1.29-10.36). Logistic regression analysis showed that the DD genotype was the strongest predictor of risk of severe carotid disease. We conclude that, in atherosclerotic RVH, there is an association of the severity of vascular disease with the DD genotype of the ACE gene.

Survival of patients with renovascular disease and ACE inhibition.

AIM: Renovascular hypertension (RVH) is associated with a high prevalence of target organ damage and a high mortality. We have undertaken this follow-up study to assess the role played by comorbid conditions, and pharmacological treatment on survival, and on renal function in 64 patients with diffuse atherosclerotic vascular and renovascular disease (RVD). PATIENTS AND METHODS: The patients were followed for an average period of 37.3+/-20.4 months. RESULTS: At the end of the follow-up we found a cumulative survival at 5 years of 60%+/-10. Cerebrovascular and cardiovascular disease were responsible for 92% of deaths. A decrease in creatinine clearance >10 ml/min at 5 years was found in 65% of patients, 3 of whom ended in dialysis. Multivariate analysis of predictors of survival showed that treatment with angiotensin converting enzyme inhibitors (ACEi) was significantly associated with a favourable outcome (p = 0.019). Conversely, proteinuria had a negative effect. Renal survival was best predicted by the level of renal function at entry (p = 0.02), and was not influenced by pharmacological treatment. CONCLUSION: We conclude that ACEi exerts a beneficial effect on survival without affecting renal function in patients with RVD due to unilateral renal stenosis.

[Lung cancer and women]. / A mulher e o cancro do pulmão.

The epidemiology of lung cancer has changed in the last years in several countries all over the world. In the 19th century, the lung cancer was rare but it incidence increase drastically during the 20th century, and the tendency is to continue in the 20th century. Actually the lung cancer's incidence and mortality are higher in the developed countries, especially in Europe and Unites States of America, with a increasing in the women incidence. These geographic differences and gender differences are related with smoking habits. Women begin to smoke earlier and have more difficulty to stop, because of problems related with obesity; they have more sensibility to the carcinogens and the risk of lung cancer is 1.5 times higher than the men with the same habits. Adenocarcinoma is the more frequent histological type in young people, in the total of the women and in non-smokers. Many factors since tobacco, home and professional pollution, nutritional, associated diseases even genetic and hormonal factors have been investigated to define its influence in development in women lung cancer. It specificity in women with lung cancer is the common problem for the medical people to treat this disease (pathology).The literature about this problem is not clear, and is necessary to advance with many studies in this area with the objective to clarify this important question.

Dermatomyositis as the first manifestation of a lung tumor.

Dermatomyositis (DM) is a rare disease characterised by proximal muscle weakness and a typical cutaneous rash. The muscle biopsy shows inflammatory lesions consistent with myositis, being related to an increased risk of cancer, often considered as a paraneoplastic syndrome. The authors present a case of a 63-year-old man, with progressive proximal muscle weakness and cutaneous rash, appearing in two months. The muscle and skin biopsies were consistent with DM. Chest tomography showed a nodular image in the lingular region and bronchy biopsy confirmed the diagnosis of small cell lung carcinoma (SCLC). This clinical case intends to enhance the importance of a thorough diagnostic study in patients with DM, as it is often a paraneoplastic syndrome.

Lung cancer in Northern Portugal: A hospital-based study.

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.

Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer.

INTRODUCTION: In 2006, the Vila Nova de Gaia/Espinho Hospital Centre Pulmonary Oncology Unit started performing EGFR (Epidermal Growth Factor Receptor) mutation sequencing in selected patients with NSCLC and systematically in all patients since 2010, regardless of histology, smoking habits, age or sex. The aim of this study was to characterize the group of patients that carried out the sequencing between 2006-2010, to determine EGFR mutation frequency, to evaluate the overall survival and the survival after the use of tyrosine kinase inhibitors (TKI), in patients who performed this therapy in second and third line, knowing the EGFR mutation status. METHODS: Descriptive statistical analysis of patients who did EGFR sequencing in 2006-2010 and of overall survival in patients treated with TKI as 2nd and 3rd line therapy. Record of the material available for analysis and average delay of exam results, according to the material submitted. RESULTS: The sequencing was performed in 374 patients, 71,1% males, 67,1% non/ex-smokers, 32,9% smokers, 57,8% adenocarcinoma and 23,5% squamous cell carcinoma (SCC). The mutation was detected in 49 patients (13,1%). In all studied patients, the mutation rate was 9% in males and 23% in females. Median overall survival after erlotinib use of was 14 months for patients with positive EGFR mutation versus 6 months in not mutated patients (p = 0.003). CONCLUSION: Our group had an overall mutation rate of 13.1% with female, non-smokers, adenocarcinoma histology predominance. In selected patients (2006/2009), the mutation rate was 16%, in not selected patients (2010) the mutation rate was 10.4%. This study has permitted a better understanding of the EGFR mutation rate in the Portuguese population as welll as an evaluation of the patients survival after the use of of tyrosine kinase inhibitors, in second and third line therapy with previous knowledge of the EGFR mutational status. Statistical significant differences in survival were found in the two patient groups (EGFR mutated and non mutated). The EGFR mutation research should be performed in all patients with NSCLC, giving the possibility to a considerable number of patients to perform a first line treatment with TKI (EGFR mutated patients) and the advantage of performing other chemotherapy schemes, when progression occurs.