Liquid biopsy in the management of advanced lung cancer: Implementation and practical aspects.

Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. In recent years, the discovery of actionable molecular alterations has changed the treatment paradigm of the disease. Tissue biopsies have been the gold standard for the identification of targetable alterations but present several limitations, calling for alternatives to detect driver and acquired resistance alterations. Liquid biopsies reveal great potential in this setting and also in the evaluation and monitoring of treatment response. However, several challenges currently hamper its widespread adoption in clinical practice. This perspective article evaluates the potential and challenges associated with liquid biopsy testing, considering a Portuguese expert panel dedicated to thoracic oncology point of view, and providing practical insights for its implementation based on the experience and applicability in the Portuguese context.

Sarcoidosis-like reaction secondary to adalimumab treatment in a patient with axial spondyloarthritis.

Anti-TNF agents, namely adalimumab, are safe drugs that represent an important arsenal in the treatment of immune-mediated inflammatory diseases. "Paradoxical effects" have been described with their use. A sarcoidosis "like" reaction induced by these agents is rare and is characterized by a systemic granulomatous reaction indistinguishable from sarcoidosis. We present a 55-year-old male patient, with axial spondyloarthritis, treated with with adalimumab. About 17 months under this therapy, he complained of dry cough and wheezing. Chest CT showed a peri-lymphatic and pericisural micronodular pattern and hilo-mediastinal lymph nodes, suggestive of sarcoidosis. Angiotensin converting enzyme was increased. Assuming the hypothesis of a sarcoidosis-like reaction secondary to adalimumab this therapy was discontinued with progressive improvement in the patient's complaints and in the radiological changes.

Interstitial nephritis secondary to treatment with pembrolizumab, a rare complication in two patients with lung adenocarcinoma.

Immune checkpoint inhibitors (ICPi) have become nowadays one of the most widely prescribed anticancer treatments. Pembrolizumab is a highly selective monoclonal immunoglobulin approved as a first-line monotherapy treatment in adult patients with untreated advanced non-small cell lung cancer (NSCLC) with programmed cell death 1 (PD-L1) expression greater than 50% and lack of mutations. ICPi can precipitate immune-related adverse events. Data on the incidence and characteristics of nephrotoxicity from ICPi are limited and caused largely from small case series and oncologic studies. Two patients with a diagnosis of pulmonary adenocarcinoma, undergoing treatment with pembrolizumab who manifested interstitial nephritis secondary to this treatment, are presented below. The growing use of immunotherapy in the treatment of cancer imposes the physician's attention to possible adverse effects.

Thoracic Splenosis, a Challenging Diagnosis / Esplenosis torácica, un diagnóstico complejo

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The Portuguese Severe Asthma Registry: Development, Features, and Data Sharing Policies.

The Portuguese Severe Asthma Registry (Registo de Asma Grave Portugal, RAG) was developed by an open collaborative network of asthma specialists. RAG collects data from adults and pediatric severe asthma patients that despite treatment optimization and adequate management of comorbidities require step 4/5 treatment according to GINA recommendations. In this paper, we describe the development and implementation of RAG, its features, and data sharing policies. The contents and structure of RAG were defined in a multistep consensus process. A pilot version was pretested and iteratively improved. The selection of data elements for RAG considered other severe asthma registries, aiming at characterizing the patient's clinical status whilst avoiding overloading the standard workflow of the clinical appointment. Features of RAG include automatic assessment of eligibility, easy data input, and exportable data in natural language that can be pasted directly in patients' electronic health record and security features to enable data sharing (among researchers and with other international databases) without compromising patients' confidentiality. RAG is a national web-based disease registry of severe asthma patients, available at asmagrave.pt. It allows prospective clinical data collection, promotes standardized care and collaborative clinical research, and may contribute to inform evidence-based healthcare policies for severe asthma.

The smoker's paradox in acute coronary syndrome: Is it real?

INTRODUCTION: Smoking is associated with atherosclerotic disease, but there is controversy about its protective nature after acute coronary syndrome (ACS). OBJECTIVE: To determine the impact of smoking on the presentation, treatment and outcome of ACS. METHODS: We analyzed all consecutive patients with ACS in a single center between 2005 and 2014. Current smokers and never-smokers were compared. Independent predictors of in-hospital mortality and of a composite of all-cause mortality, rehospitalization for cardiovascular causes, angiography, percutaneous coronary intervention and coronary artery bypass grafting were assessed by multivariate logistic regression. RESULTS: A total of 2727 patients were included, 41.7% current smokers and 58.3% never-smokers. Current smokers were younger, more often male, had fewer comorbidities, a typical clinical presentation, lower heart rate, systolic blood pressure, Killip class, BNP/NT-pro-BNP and creatinine, better left ventricular systolic function and less severe coronary anatomy. ST-segment elevation myocardial infarction was more common in current smokers. Current smokers received more evidence-based treatments and had less in-hospital complications, in-hospital mortality and adverse outcomes at one year. More frequent percutaneous coronary intervention at one year was noted in current smokers. Smoking was not an independent predictor of outcome when the multivariate model was fully adjusted for baseline characteristics. CONCLUSION: The smoker's paradox was not observed in this population, since all differences in outcome were explained by smokers' more benign baseline characteristics.

Complete atrioventricular block in acute coronary syndrome: prevalence, characterisation and implication on outcome.

PURPOSE: The aim was to characterise acute coronary syndrome patients with complete atrioventricular block and to assess the effect on outcome. METHODS: Patients admitted with acute coronary syndrome were divided according to the presence of complete atrioventricular block: group 1, with complete atrioventricular block; group 2, without complete atrioventricular block. Clinical, electrocardiographic and echocardiographic characteristics and prognosis during one year follow-up were compared between the groups. RESULTS: Among 4799 acute coronary syndrome patients admitted during the study period, 91 (1.9%) presented with complete atrioventricular block. At presentation, group 1 patients presented with lower systolic blood pressure, higher Killip class and incidence of syncope. In group 1, 86.8% presented with ST-segment elevation myocardial infarction (STEMI), and inferior STEMI was verified in 79.1% of patients in group 1 compared with 21.9% in group 2 ( P<0.001). Right ventricular myocardial infarction was more frequent in group 1 (3.3% vs. 0.2%; P<0.001). Among patients who underwent fibrinolysis complete atrioventricular block was observed in 7.3% in contrast to 2.5% in patients submitted to primary percutaneous coronary intervention ( P<0.001). During hospitalisation group 1 had worse outcomes, with a higher incidence of cardiogenic shock (33.0% vs. 4.5%; P<0.001), ventricular arrhythmias (17.6% vs. 3.6%; P<0.001) and the need for invasive mechanical ventilation (25.3% vs. 5.1%; P<0.001). After a propensity score analysis, in a multivariate regression model, complete atrioventricular block was an independent predictor of hospital mortality (odds ratio 3.671; P=0.045). There was no significant difference in mortality at one-year follow-up between the study groups. CONCLUSION: Complete atrioventricular block conferred a worse outcome during hospitalisation, including a higher incidence of cardiogenic shock, ventricular arrhythmias and death.

HIV and coronary disease - When secondary prevention is insufficient. / VIH e doença coronária ­ quando a prevenção secundária é insuficiente.

Highly active antiretroviral therapy (HAART) has created a new paradigm for human immunodeficiency virus (HIV)-infected patients, but their increased risk for coronary disease is well documented. We present the case of a 57-year-old man, co-infected with HIV-2 and hepatitis B virus, adequately controlled and with insulin-treated type 2 diabetes and dyslipidemia, who was admitted with non-ST elevation acute myocardial infarction. Coronary angiography performed on day four of hospital stay documented two-vessel disease (mid segment of the right coronary artery [RCA, 90% stenosis] and the first marginal). Two drug-eluting stents were successfully implanted. The patient was discharged under dual antiplatelet therapy (aspirin 100 mg/day and clopidogrel 75 mg/day) and standard coronary artery disease medication. He was admitted to the emergency room four hours after discharge with chest pain radiating to the left arm and inferior ST-segment elevation myocardial infarction was diagnosed. Coronary angiography was performed within one hour and documented thrombosis of both stents. Optical coherence tomography revealed good apposition of the stent in the RCA, with intrastent thrombus. Angioplasty was performed, with a good outcome. The acute stent thrombosis might be explained by the thrombotic potential of HIV infection and diabetes. There are no specific guidelines regarding HAART in secondary prevention of acute coronary syndromes. A multidisciplinary approach is essential for optimal management of these patients.

Wellens' Syndrome: A Bad Omen.

Wellens' syndrome is characterized by an electrocardiographic pattern of T-wave changes associated with a critical stenosis of the left anterior descending artery (LAD), which progresses to an extensive anterior myocardial infarction in the majority of cases. For this reason, its recognition and early treatment are extremely important. We report 2 cases of Wellens' syndrome: an 83-year-old male presenting with ill-characterized chest pain, biphasic T waves in V1-V3 during an asymptomatic period, negative cardiac biomarkers, and a 64% stenosis in LAD with a fractional flow reserve of 0.96 who fared well on medical therapy, and an 67-year-old male with typical angina pain, biphasic T waves in V2-V4 during asymptomatic periods, anterior ST-segment elevation at 2 min of effort during an exercise stress test, positive high-sensitivity cardiac troponin, and an 80% stenosis in the proximal LAD who was submitted to percutaneous coronary intervention which rendered him asymptomatic. The spectrum of Wellens' syndrome is very wide, and knowledge and high clinical suspicion for its diagnosis, especially in its rarest presentation of biphasic T waves, is key to avoiding catastrophic consequences.

New-Onset Hemolytic Anemia after Percutaneous Paravalvular Leak Closure.

BACKGROUND AND AIM OF THE STUDY: Despite being usually clinically silent, paravalvular leak can present with congestive heart failure (CHF) or haemolytic anemia. Here, the case is reported of a paravalvular leak presenting with CHF, complicated by new-onset severe hemolytic anemia after percutaneous closure with a large ventricular septal duct (VSD) occlude device. METHODS: A 57-year-old patient presented with infectious endocarditis of a native mitral valve with major mitral regurgitation and was submitted for mitral valvuloplasty. However, one month later failure of the valvuloplasty forced the need for mechanical prosthetic valve implantation. Early endocarditis of the mechanical valve with CHF was noted two months later and led to mechanical valve substitution. One year later the patient presented with a major paravalvular leak and CHF recurrence. Hence, percutaneous paravalvular leak closure was proposed. RESULTS: A 16-mm VSD occluder was used, and clinical and echocardiography success was noticed. However, new-onset hemolytic anemia with acute kidney injury forced surgical re-intervention, with the successful implantation of a third mechanical valve. CONCLUSIONS: Usually, percutaneous paravalvular leak closure is a safe and successful method to treat high-risk surgical patients. However, hemolytic anemia may develop after a technically successful procedure, forcing surgical intervention. Dedicated devices are needed to overcome this important safety issue. Video 1: Periprocedural acquisition of 3-D transesophageal echocardiography showing two AVP II in the left atrium after unsuccessful deployment. Video 2: Periprocedural imaging of a muscular ventricular septal duct (mVSD) occluder (16 mm), with successful closure of the paravalvular leak.

Tomografía por emisión de positrones/tomografía computarizada positiva y nódulos pulmonares múltiples: un diagnóstico poco habitual / Positive Positron Emission Tomography/computed Tomography Scan and Multiple Pulmonary Nodules: An Unusual Diagnosis

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[High-degree atrioventricular block induced by Prinzmetal angina]. / Bloqueio aurículo-ventricular de alto grau induzido por angina de Prinzmetal.

We present the case of a 46-year-old woman with episodes of chest pain with ST-T segment elevation and paroxysmal high-degree atrioventricular block and syncopal episodes. Coronary angiography revealed no significant atheromatous lesions. The patient was treated with nitrates and calcium channel blockers but syncopal episodes with atrioventricular block persisted. A DDD-R pacemaker was implanted and four-month follow-up was uneventful.

Prognostic value of a new cardiopulmonary exercise testing parameter in chronic heart failure: oxygen uptake efficiency at peak exercise - comparison with oxygen uptake efficiency slope.

INTRODUCTION: A growing body of evidence shows the prognostic value of oxygen uptake efficiency slope (OUES), a cardiopulmonary exercise test (CPET) parameter derived from the logarithmic relationship between O(2) consumption (VO(2)) and minute ventilation (VE) in patients with chronic heart failure (CHF). OBJECTIVE: To evaluate the prognostic value of a new CPET parameter - peak oxygen uptake efficiency (POUE) - and to compare it with OUES in patients with CHF. METHODS: We prospectively studied 206 consecutive patients with stable CHF due to dilated cardiomyopathy - 153 male, aged 53.3±13.0 years, 35.4% of ischemic etiology, left ventricular ejection fraction 27.7±8.0%, 81.1% in sinus rhythm, 97.1% receiving ACE-Is or ARBs, 78.2% beta-blockers and 60.2% spironolactone - who performed a first maximal symptom-limited treadmill CPET, using the modified Bruce protocol. In 33% of patients an cardioverter-defibrillator (ICD) or cardiac resynchronization therapy device (CRT-D) was implanted during follow-up. Peak VO(2), percentage of predicted peak VO(2), VE/VCO(2) slope, OUES and POUE were analyzed. OUES was calculated using the formula VO(2) (l/min) = OUES (log(10)VE) + b. POUE was calculated as pVO(2) (l/min) / log(10)peakVE (l/min). Correlation coefficients between the studied parameters were obtained. The prognosis of each variable adjusted for age was evaluated through Cox proportional hazard models and R2 percent (R2%) and V index (V6) were used as measures of the predictive accuracy of events of each of these variables. Receiver operating characteristic (ROC) curves from logistic regression models were used to determine the cut-offs for OUES and POUE. RESULTS: pVO(2): 20.5±5.9; percentage of predicted peak VO(2): 68.6±18.2; VE/VCO(2) slope: 30.6±8.3; OUES: 1.85±0.61; POUE: 0.88±0.27. During a mean follow-up of 33.1±14.8 months, 45 (21.8%) patients died, 10 (4.9%) underwent urgent heart transplantation and in three patients (1.5%) a left ventricular assist device was implanted. All variables proved to be independent predictors of this combined event; however, VE/VCO2 slope was most strongly associated with events (HR 11.14). In this population, POUE was associated with a higher risk of events than OUES (HR 9.61 vs. 7.01), and was also a better predictor of events (R2: 28.91 vs. 22.37). CONCLUSION: POUE was more strongly associated with death, urgent heart transplantation and implantation of a left ventricular assist device and proved to be a better predictor of events than OUES. These results suggest that this new parameter can increase the prognostic value of CPET in patients with CHF.

Combining ventilatory efficiency and peak oxygen consumption in the prognostic assessment of patients with chronic heart failure.

UNLABELLED: Cardiopulmonary exercise testing (CPET) is an objective method for assessment of functional capacity and for prognostic stratification of patients with chronic heart failure (CHF). In this study, we analyzed the prognostic value of a recently described CPET-derived parameter, the minute ventilation to carbon dioxide production slope normalized for peak oxygen consumption (VE/VCO2 slope/pVO2). METHODS: We prospectively studied 157 patients with stable CHF and dilated cardiomyopathy who performed maximal CPET using the modified Bruce protocol. The prognostic value of VE/VCO2 slope/pVO2 was determined and compared with traditional CPET parameters. RESULTS: During follow-up 37 patients died and 12 were transplanted. Mean follow-up in surviving patients was 29.7 months (12-36). Cox multivariate analysis revealed that VE/VCO2 slope/pVO2 had the greatest prognostic power of all the parameters studied. A VE/VCO2 slope/pVO2 of > or = 2.2 signaled cases at higher risk. CONCLUSION: Normalization of the ventilatory response to exercise for peak oxygen consumption appears to increase the prognostic value of CPET in patients with CHF.

Pseudoxanthoma elasticum papillary dermal elastolysis: a case report.

PXE-PDE is a rare clinicopathological entity with few cases reported. It affects more often elderly women and is characterized by asymptomatic bilateral and symmetrical yellowish papules localized predominantly on the neck and supraclavicular regions. It is clinically similar to Pseudoxanthoma Elasticum. The authors report a case of a 64-year-old woman presenting asymptomatic, yellowish, non-follicular papules, affecting the occipital and the posterior region of the neck for 1 year. The patient denied pruritic or inflammatory changes, marked solar exposition or trauma on the affected areas. Routine laboratory studies: thoracic x-ray and ophthalmologic examination were normal. The histopathologic examination of a biopsy of one of the cutaneous lesions showed an absence of elastic fibers in the papillary dermis.The diagnosis of Pseudoxanthoma Elasticum-like Papillary Dermal Elastolysis (PXE-PDE) was made. Of great importance is the differential diagnosis with Pseudoxanthoma elasticum (PXE), but we have also to consider other elastolytic disorders: mid-dermal elastolysis (MDE), linear focal elastosis (LFE) and white fibrous papulosis of the neck (WFPN). Until know, there is no effective treatment for this pathology.

Brown plaques on the lower back.

A 12-year-old girl presented with a 2-year history of a 10 cm area of asymptomatic brown coalescent plaques of coalescent, linearly arranged papules on the lower back. No other physical or systemic abnormality was detected. Routine laboratory investigations, including thyroid function tests, were normal. The histopathological examination revealed hyperkeratosis, papillomatosis, and elongated rete ridges in the epidermis. On special staining (Alcian blue), mucin deposition was seen in the papillary dermis. The remaining dermis was normal. A diagnosis of Mucinous Nevus was made.