Tomi Kovacevic

Interleukin-6 and procalcitonin as biomarkers in mortality prediction of hospitalized patients with community acquired pneumonia.

INTRODUCTION: Community acquired pneumonia (CAP) may present as life-threatening infection with uncertain progression and outcome of treatment. Primary aim of the trial was determination of the cut-off value of serum interleukin-6 (IL-6) and procalcitonin (PCT) above which, 30-day mortality in hospitalized patients with CAP, could be predicted with high sensitivity and specificity. We investigated correlation between serum levels of IL-6 and PCT at admission and available scoring systems of CAP (pneumonia severity index-PSI, modified early warning score-MEWS and (Confusion, Urea nitrogen, respiratory rate, Blood pressure, ≥65 years of age-CURB65). METHODS: This was prospective, non-randomized trial which included 101 patients with diagnosed CAP. PSI, MEWS and CURB65 were assessed on first day of hospitalization. IL-6 and PCT were also sampled on the first day of hospitalization. RESULTS: Based on ROC curve analysis (AUC ± SE = 0.934 ± 0.035; 95%CI(0.864-1.0); P = 0.000) hospitalized CAP patients with elevated IL-6 level have 93.4% higher risk level for lethal outcome. Cut-off value of 20.2 pg/ml IL-6 shows sensitivity of 84% and specificity of 87% in mortality prediction. ROC curve analysis confirmed significant role of procalcitonin as a mortality predictor in CAP patients (AUC ± SE = 0.667 ± 0.062; 95%CI(0.546-0.789); P = 0.012). Patients with elevated PCT level have 66.7% higher risk level for lethal outcome. As a predictor of mortality at the cut-off value of 2.56 ng/ml PCT shows sensitivity of 76% and specificity of 61.8%. CONCLUSIONS: Both IL-6 and PCI are significant for prediction of 30-day mortality in hospitalized patients with CAP. Serum levels of IL6 correlate with major CAP scoring systems.

Clinical Characteristics, Tumor, Node, Metastasis Status, and Mutation Rate in Domain of Epidermal Growth Factor Receptor Gene in Serbian Patients with Lung Adenocarcinoma

Objective: Mutation rate in domain of EGFR gene varies between populations of lung cancer patients. Primary aim of this study was to analyze clinical and pathological characteristics, and tumor, node, metastasis status and stage of diseases, in relation to mutation status. Methods: After histological confirmation of lung adenocarcinoma tissue obtained during bronchoscopy was consecutively sent for EGFR testing. Genomic DNA extraction was performed with the QIAamp DNA FFPE Tissue kit. Clinical data for multivariate analysis were extracted from hospital based-lung cancer registry. Results: Among 360 tested patients, there was 67.8% males and 32.2% females, aged 61 ± 9.8 years. Majority of patients were smokers (57.0%) with Eastern Cooperative Oncology Group 1 performance status (92.2%). Mutation in EGFR gene was detected in 42 (11.7%) patients. Deletion in exon 19 was detected in 24 (6.7%) patients, mutation in exon 21 in 17 (4.7%), and mutation in exon 18 in one patient (0.3%). Patients were mostly diagnosed in stage IV adenocarcinoma (74.4%). Statistically significant differences were determined in relation to smoking (p < 0.001), T descriptor (size; p = 0.019) and gender (p = 0.002). Conclusions: Mutation rate in domain of EGFR gene in investigated lung cancer population is in range with reported data in Caucasian race. Smoking, T descriptor and gender were found to be related to the EGFR status.

Radial Endobronchial Ultrasound (EBUS) Guided Suction Catheter-Biopsy in Histological Diagnosis of Peripheral Pulmonary Lesions

Background: EBUS guided trans-bronchial biopsy became routine in diagnosis of peripheral pulmonary lesions (PPL). Suction catheter-biopsy is a technique for obtaining a tissue sample from peripheral lung parenchyma. Aim of this study was to evaluate diagnostic efficiency, feasibility and safety of EBUS guided suction catheter-biopsy (SCB) in comparison to trans-bronchial biopsy (TBB) in diagnosis of PPL. The main intention was to demonstrate non-inferiority of the technique over trans-bronchial biopsy, especially when used under navigation of the EBUS. Methods: Radial EBUS probe (UM-3R, Olympus Co, Japan.) without guiding sheath was used to navigate suction catheter and TBB forceps to the PPL. The catheter was connected to the collection canister via vacuum pump. The SCB specimens were fixed with 10% buffered formalin. Results: There were 168 patients enrolled in this study; 69.9% males and 30.1% females. Main lesion diameter was 4.1±1.9 cm. Majority of patients, 131(77.9%) were diagnosed with lung cancer. Per-biopsy calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for EBUS-SCB were 92.4%, 100%, 100% and 67.7%, respectively. Corresponding values for EBUS-TBB were 92.3%, 100%, 100% and 69.7%. Only the size of the lesion significantly influenced (p=0.005) diagnostic performance. Complications occurred in 2 patients; one pneumothorax and one excessive bleeding. Conclusion: EBUS guided SCB is efficient, feasible and safe in diagnosis of peripheral lung cancer. The technique is complementary to trans-bronchial biopsy.

EGFR-TKIs in adjuvant treatment of lung cancer: to give or not to give?

Epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs) brought a significant revolution in the treatment of non-small-cell lung cancer (NSCLC). In a short period of time, EGFR-TKIs became the standard of treatment for mutation-positive, advanced stage non-squamous NSCLC. In recent years, second- and third-generation EGFR-TKIs are emerging, further widening the clinical use. However, the question of EGFR-TKIs efficiency in the treatment of early stage NSCLC still remains open. Early clinical trials failed to approve the use of EGFR-TKIs in adjuvant setting. The majority of these early trials were performed in unselected NSCLC populations and without standardized biomarker identification. One should certainly not rely solely on these results and dismiss the use of EGFR-TKIs as adjuvant therapy. Many important questions are still unanswered. Most important issues such as stage heterogeneity (IA–IIIA), timing (after or concomitantly with chemotherapy), and type of administration (monotherapy or combination) need to be answered in near future. Adjuvant TKIs in the treatment of lung cancer might offer significant number of advancements. Having in mind the significant duration of response observed in advance disease setting, there could be place for prolongation of response in adjuvant setting potentially, leading to improvement in survival. TKIs could offer less-toxic adjuvant treatment with better efficiency than chemotherapy. However, there is a chronic lack of randomized controlled trials in this field, leading to inability to draw any scientifically sound conclusion with regard to the adjuvant treatment. For now, the use of EGFR-TKIs outside clinical trial setting is not recommended. The purpose of this review is to evaluate current and available data.

Neodymium yttrium-aluminium-garnet laser resection significantly improves quality of life in patients with malignant central airway obstruction due to lung cancer.

Neodymium yttrium-aluminium-garnet (Nd : YAG) laser resection is one of the mostly used interventional pulmonology techniques for urgent desobstruction of malignant central airway obstruction (CAO). The major aim of this trial was to evaluate potential influence of Nd : YAG laser resection on overall quality of life (QoL) in patients with central lung cancer. Patients with malignant CAO scheduled for Nd : YAG laser resection were prospectively recruited in the trial. All patients were given European Organization for Research and Treatment, Quality of Life questionnaire (EORTC QLQ-30 v.3) before the procedure and approximately 2 weeks after the treatment. There were 37 male and 10 female patients, average age 54 ± 10 years. Most common tumour type was adenocarcinoma diagnosed in 51% of patients. Majority of patients were diagnosed in stage IIIB (53.2%) and stage IV (25.5%). Most common Eastern Cooperative Oncology Group performance status was 1 (72.3%). Nd : YAG laser resection significantly improved (P<0.0001) QoL and overall health according to EORTC QLQ-30. However, in some of the questions dealing with nausea, vomiting, diarrhoea, constipation, family life, social activities and financial situation, we did not observe statistically significant improvement. Nd : YAG laser resection of malignant CAO significantly improves QoL and overall health in patients with lung cancer.

PD-1 and PD-L1 Protein Expression Predict Survival in Completely Resected Lung Adenocarcinoma

&NA; The prognostic value of programmed cell death 1 (PD‐1) and/or programmed cell death ligand 1 (PD‐L1) expression in completely resected lung adenocarcinoma is still unclear. The expression of PD‐1 and PD‐L1 was determined using immunohistochemistry in 161 patients with lung adenocarcinoma. PD‐1 and PD‐L1 expression was associated with favorable overall survival. This knowledge could be important in the design of future clinical trials evaluating immune checkpoint inhibitors. Background: We assessed the prognostic value of programmed cell death 1 (PD‐1) and programmed cell death ligand 1 (PD‐L1) in patients with completely resected lung adenocarcinoma. Patients and Methods: PD‐1 and PD‐L1 expression was determined using immunohistochemistry in formalin‐fixed paraffin‐embedded surgical specimens and correlated with the clinicopathologic features and survival of 161 patients with lung adenocarcinoma. Results: PD‐1 expression on immune cells was observed in 71 of 159 evaluable tumor samples (45%) and was not significantly associated with the clinicopathologic features. Multivariate analyses identified PD‐1 expression as an independent prognostic factor for recurrence (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36‐0.95; P = .03) and death (adjusted HR, 0.48; 95% CI, 0.27‐0.86; P = 0.01). PD‐L1 expression on tumor cells was seen in 59 of 161 cases (37%) and correlated with KRAS mutation status (P = .02) and type of surgery (P = .01). PD‐L1 expression was not associated with recurrence‐free survival in the patients (adjusted HR, 0.90; 95% CI, 0.55‐1.48; P = .68) but correlated with longer overall survival (adjusted HR, 0.54; 95% CI, 0.30‐0.97; P = .04). Conclusion: PD‐1 and PD‐L1 expression was associated with favorable overall survival in patients with completely resected adenocarcinoma of the lung.

Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

Introduction: The incidence of echinoderm microtubule-associated protein-like4-anaplastic lymphoma kinase (EML4-ALK) mutation among surgically treated patients with adenocarcinoma of the lung of the Eastern European ethnicity is underreported. The aim of this trial was the determination of EML4-ALK mutation frequency in investigated population, and the evaluation of correlations between lung adenocarcinoma subtype and clinical characteristics with mutation status. Patients and methods: This was a prospective trial which included 195 patients with adenocarcinoma of the lung who underwent surgical treatment. ALK mutation screening was performed by immunohistochemistry (IHC). IHC scores of 2+ and 3+ were regarded as positive. Confirmatory FISH was performed in all IHC positive and in 2:1 ratio in negative patients. Results: Overall ALK mutation rate established by IHC was 6.2%, while FISH confirmed rate of 5.1%. The FISH confirmed ALK positivity in 7.6% Hungarians, 5.5% Serbians, and 6.6% Slovakians. Acinar subtype of adenocarcinoma of the lung was significantly (p=0.02) related to EML4-ALK positive mutation status. Most of the patients were males (56.9%), smokers (50.8%), or former smokers (28.7%) with acinar (55.4%) or solid (35.9%) adenocarcinoma of the lung. Sensitivity and specificity of IHC were 100% and 98.9% respectively. Conclusions: ALK mutation rate in surgically treated patients with adenocarcinoma of the lung was found to be 6.2% by IHC and 5.1% by FISH. Acinar subtype of the adenocarcinoma of the lung was significantly related to ALK positive mutation.

New technologies in diagnostic bronchoscopy – an age of meta-analyses

Last several years were more than dynamic in the field of interventional pulmonology. A variety of new diagnostic tools emerged on the scene, some remained, some were redefined, and some are still waiting in line to be used. The most experienced bronchoscopists would comment: ‘Now we have the technology, what shall we do with it?’ Technological advances influence daily practice in interventional pulmonology in many ways. New techniques make easier identification of pathological sites on the bronchial mucosa. That is more than evident in case of autofluorescence bronchoscopy (AFB) or narrow band imaging (NBI). AFB allows identification of pathological sites even in the absence of radiological signs of disease, such as in cases of positive sputum cytology in radio-occult lung cancers, and it can attribute better definition of submucosal tumor spread. Even with low specificity and high sensitivity, one can never deny high negative predictive value of AFB. On the other hand, NBI could be even more useful, having in mind proposed relationship between NBI vascular pattern and histology of lung cancer. In an era of increased demand for tumor tissue, due to extensive molecular and genetic testing necessary for adequate molecular profiling of lung cancer, this technique might be the additional tool we have been searching for. Proposed five biopsies of tumorous lesion might not be sufficient for all the tests we need. If bronchoscopist finds dotted vascular NBI pattern, having in mind it might be adenocarcinoma of the lung requiring initially immunohistochemistry evaluation followed by further genetic testing (epidermal growth factor [EGFR] mutations, anaplastic lymphoma kinase [ALK] mutations, ROS proto-oncogene 1 [ROS1] mutations, programmed death receptor and ligands [PD/PDL-1/PDL-2], etc.), it is clear why we need more than five biopsies (of viable tissue). If particular NBI pattern appears, some additional risk of taking more biopsies can initially be justified [1,2]. Endobronchial ultrasound revolutionized bronchoscopy in many ways. Linear EBUS with ultrasound probe and camera on tip of the device is useful for evaluation of mediastinal lymph nodes and masses. Even if we know that experienced bronchoscopists, and less experienced but well-trained ones, do know natural positions of mediastinal lymph nodes – some nodes might not be naturally positioned. Linear EBUS provides real-time image of the mediastinal structures, real-time punctures of nodes 5–10 mm in diameter, and insight into relationship with major blood vessels providing extraordinary safety. Radial EBUS, which utilizes ultrasound (US) probe easily protruded through the working channel of standard bronchoscope and connected to the driving unit, provides detection of peripheral lesions. When combined, radial EBUS miniprobes and guiding sheaths demonstrate high diagnostic accuracy for solitary pulmonary nodules and other peripheral lung lesions. Electromagnetic navigation bronchoscopy (EMN), as a new but widely used technique, shows more and more benefit, not only in diagnostic area (for peripheral lesions) but also in therapeutic manner for the placement of fiducial markers for radiotherapy. Major benefit in diagnostics of peripheral lesions EMN shows in combination with other techniques [3,4].