Attitudes toward Death among Health Care Professionals in the Balkan Region.

Background and Objectives: Death is an unavoidable experience in any person's life and affects not only the dying person but also their caregivers. The dying process has been displaced from homes to health care facilities in the majority of cases. Facing death and dying has become an everyday life of health care professionals (HCP), especially in palliative care (PC) settings. This study aimed to investigate the death attitudes among HCPs in Serbia. Materials and Methods: The Serbian version of the Death Attitude Profile-Revised (DAP-RSp) was used as a measurement instrument. Results: The average age of the 180 included participants was 42.2 ± 9.9 years; the majority were females (70.0%), with more than 10 years of working experience (73.0%), physicians (70.0%) and those working in a non-oncological (non-ONC) field (57.78%). The mean total score of DAP-RSp was 124.80 ± 22.44. The highest mean score was observed in the neutral acceptance dimension (NA) (5.82 ± 0.90) and lowest in the Escape acceptance (EA) (2.57 ± 1.21). Higher negative death attitudes were reported among nurses compared to physicians (p = 0.002). Statistically significant differences were observed in the fear of death (FD) and death avoidance (DA) domains, favoring PC specialists and oncologists (p = 0.004; p = 0.015). Physicians working in Oncology (ONC) showed lower FD values (p = 0.001) compared to non-ONC departments. Conclusions: Attitudes toward death among HCPs are of great importance for the well-being of both HCPs and patients. Negative attitudes can lead to deficient care. The fear of death is highly represented among Serbian HCPs working in non-ONC fields, including both nurses and physicians. This study emphasizes the need for further research to comprehensively explore and understand HCPs' attitudes toward death. This research highlights the need for the development of an educational curriculum across all levels of medical education, aimed at overcoming the fear of death and enhancing coping strategies, which will improve the care for patients diagnosed with terminal illnesses.

Personalized Approach to Tissue and Liquid Biopsy after Failure of First-Line EGFR-TKIs: Is There an Issue When Tissue Is Not the Issue? A Case Series.

Traditionally, tissue availability from rebiopsy is a prerequisite for adequate sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in therapy for advanced-stage lung cancer. Tissue biopsy truly is the gold standard for genetic analyses, but in some cases, such as with inadequate localization of the lesion or a patient's inadequate performance status, comorbidities, or unwillingness to undergo an invasive procedure, liquid biopsy-based ctDNA analysis can be a noninvasive alternative approach. However, in some cases the gold standard might not shine that much. It is known that tumor heterogeneity or an inadequate amount of tissue might significantly interfere with the results of testing. In this paper, we present cases of patients with a negative tissue biopsy but a positive liquid biopsy which identified coexisting T790M mutation. These results enabled adequate sequencing and treatment with third-line EGFR-TKIs. Such possibilities stress the need to individualize testing for driver mutations in cases where it is clinically highly indicated.

Intratumoral Treatment with Chemotherapy and Immunotherapy for NSCLC with EBUS-TBNA 19G.

Introduction: Immunotherapy is being used for the past five years either as first line or second line treatment with great results. Chemotherapy and radiotherapy have been also used as combination to immunotherapy to further enhance this type of treatment. Intratumoral treatment has been previously proposed as a treatment option for certain non-small cell lung cancer patients. Patients and Methods: We recruited in total seventy four patients with non-small cell lung cancer in their second line treatment who received only chemotherapy in their first line treatment with programmed death-ligand-1 ≤ 50. Only adenocarcinoma or squamous cell carcinoma, and all negative for epidermal growth factor receptor, anaplastic lymphoma kinase, proto-oncogene tyrosine-protein kinase-1 and proto-oncogene B-Raf. Data were first examined with descriptive statistics choosing frequencies for categorical variables and histograms for the continuous ones. Twenty five received only intravenous immunotherapy and forty-nine intravenous cisplatin with immunotherapy. Data were first examined with descriptive statistics choosing frequencies for categorical variables and histograms for the continuous ones. Results: The relationships between changes of performance status and disease progression were examined via a single correspondence analysis. The two-dimensional scores (coordinates) derived from the correspondence analysis were then regressed against the predictors to form distinct splits and nodes obtaining quantitative results. The best fit is usually achieved by lowering exhaustively the AICc criterion and looking in parallel the change of R2 expecting improvements more than 5%. both types of therapy are capable of producing best ameliorative effects, when either the programmed death-ligand-1 expression or parenchymal site in joint with low pack years are present in the sampling data. Conclusions: Intratumoral treatment combination with cisplatin plus immunotherapy indifferent of nivolumab or pembrolizumab combination is an effective choice. In specific for those with endobronchial lesions. Moreover; patients with programmed death-ligand-1 ≥ 50 had their performance status and disease progression improved over the eight month observation.

Thyroid cancer diagnosis with transdermal probe 22G U/S versus EBUS-convex probe TBNA-B 22G and 19G: pros and cons.

INTRODUCTION: Thyroid cancer is usually diagnosed both with imaging techniques and transdermal biopsy. Laboratory tests are also included in the initial work-up. PATIENTS AND METHODS: One hundred and thirty patients were included in our study with pathological imaging findings in the thyroid region. Biopsies were performed with 22 G with transdermal convex probe, EBUS 22 G Mediglobe® needle and 19 G Olympus® needle. We investigated the efficiency and safety of both techniques and identified the best candidates for each method. DISCUSSION: 19 G needle identified cancer types such as; Lymphoma, Medullary thyroid cancer, and Hurthle cell cancer, which we know from previous pathology studies that a larger sample is necessary for diagnosis. No safety issues were observed for both techniques and the EBUS technique produced more cell block material when 22 G needle was compared to transdermal biopsy in peritracheal lesions. CONCLUSION: The method of biopsy should be made based on the size and accessibility of the lesion.

Long Term Respiratory Follow-Up for COVID-19 Patients a Multicenter Study.

BACKGROUND: The first wave of the COVID-19 pandemic initiated officially in October 2020. Since then several observations have been made regarding the disease and its symptoms. PATIENTS AND METHODS: We included eighty seven in our observational study. Our main aim was to investigate their long term respiratory follow-up in correlation with their initial radiological and laboratory findings and values. The nose swab PCR test for COVID-19 was used for diagnosis. Patients were monitored at 3 and 6 months after their hospital reception whereas basic parameters of health condition (smoking, PO2, SPO2, WBC, CXR, CRP, intercurrent findings, days of nursing, colchicine administration) in joint with gender and age were recorded. RESULTS: Males seem more susceptible to the viral disease than females in a ratio 1,8:1. The parameters FEV1 and FVC (as % relative changes) were not affected, apart from the DLCO to which CRP (in loge+1 transformation) and SPO2 showed a statistically significant effect. CONCLUSION: None of these patients were intubated, or admitted to the intensive care unit. The respiratory function is affected by the virus and the effect is reversed within the first three months. Males are more affected and the radiological and laboratory findings are associated with the respiratory functions.

Connection between PD-L1 expression and standardized uptake value in NSCLC: an early prognostic treatment combination.

Objectives: Lung cancer is still diagnosed at advanced stage and early treatment initiation is needed. Therefore, we need biomarkers or clusters of information that can provide early treatment prognosis.Methods: Biopsies were acquired from 471 patients-lung masses with CT-guided biopsy, convex probe transthorasic biopsy, and EBUS-TBNA convex probe with 18 G needles and 19 G needles.Results: Standardized uptake value (SUV) measurement is associated with female, smoking status, hepatic metastasis, adenocarcinoma and programmed death-ligand 1 (PD-L1). In specific we expect that SUV ≥ 7 is associated with PD-L1 ≥ 50.Conclusions: Lung masses indifferent of size that have SUV ≥ 7 will also have PD-L1 expression ≥ 50. Also, it is likely that these patients will be female with intense smoking habit and hepar or multiple metastasis.

Lung cancer biopsies: Comparison between simple 22G, 22G upgraded and 21G needle for EBUS-TBNA.

Introduction: Novel technologies are currently used for lung cancer diagnosis. EBUS-TBNA 22G is considered one of the most important tools. However; there are still issues with the sample size.Patients and Methods: 223 patients underwent EBUS-TBNA with a 21G Olympus needle, 22GUS Mediglobe and 22GUB Mediglobe. In order to evaluate the efficiency of 22GUB novel needle design. In order to evaluate the sample size of each needle, we constructed cell blocks and measured the different number of slices from each biopsy site. Results: The 22GUB novel needle had similar and larger number of slices from each biopsy site compared to 21G needle. Discussion: Firstly as a novel methodology we used the number of slices from the constructed cell blocks in order to evaluate the sample size. Secondly, we should seek novel needle designs and not only concentrate on the volume of the sample size.

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

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.

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.

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.

Advanced bronchoscopic techniques in diagnosis and staging of lung cancer.

The role of advanced brochoscopic diagnostic techniques in detection and staging of lung cancer has steeply increased in recent years. Bronchoscopic imaging techniques became widely available and easy to use. Technical improvement led to merging in technologies making autofluorescence or narrow band imaging incorporated into one bronchoscope. New tools, such as autofluorescence imagining (AFI), narrow band imaging (NBI) or fuji intelligent chromo endoscopy (FICE), found their place in respiratory endoscopy suites. Development of endobronchial ultrasound (EBUS) improved minimally invasive mediastinal staging and diagnosis of peripheral lung lesions. Linear EBUS proven to be complementary to mediastinoscopy. This technique is now available in almost all high volume centers performing bronchoscopy. Radial EBUS with mini-probes and guiding sheaths provides accurate diagnosis of peripheral pulmonary lesions. Combining EBUS guided procedures with rapid on site cytology (ROSE) increases diagnostic yield even more. Electromagnetic navigation technology (EMN) is also widely used for diagnosis of peripheral lesions. Future development will certainly lead to new improvements in technology and creation of new sophisticated tools for research in respiratory endoscopy. Broncho-microscopy, alveoloscopy, optical coherence tomography are some of the new research techniques emerging for rapid technological development.

Adjuvant chemotherapy and radiotherapy in the treatment of non-small cell lung cancer (NSCLC).

Lung cancer is one of the most common human malignancies and remains the leading cause of cancer related deaths worldwide. Many recent technological advances led to improved diagnostics and staging of lung cancer. With development of new treatment options such as targeted therapies there might be improvement in progression free survival of patients with advanced stage non-small cell lung cancer (NSCLC). Improvement in overall survival is still reserved for selected patients and selected treatments. One of the mostly investigated therapeutic options is adjuvant treatment. There are many open issues in selection of patients and administration of appropriate adjuvant treatment.

Linear and radial endobronchial ultrasound in diagnosis and staging of lung cancer.

Endobronchial ultrasound (EBUS) in recent years has become a routine diagnostic procedure in bronchology. Linear EBUS shows high diagnostic yield in evaluation of mediastinal lymph nodes. It is mainly used for nodal evaluation in lung cancer, but has also proven to be efficient in diagnostic evaluation of mediastinal masses. This technique has been shown to be complementary to mediastinoscopy. In combination with PET and rapid on site cytology (ROSE), the diagnostic yield of EBUS is significantly higher. Radial EBUS is used for diagnosis of peripheral lung lesions. This technique facilitates evaluation of bronchial wall in central lung cancer lesions, enabling differentiation between early and invasive lung cancer. The diagnostic yield of radial EBUS in the diagnostics of peripheral lung lesions is high, reducing the number of diagnostic thoracotomies. The application of miniature radial EBUS probes, together with guiding sheaths and other guiding accessories, allow the access to smaller and more peripheral lung lesions. In addition, EBUS bronchoscopy can be utilized for the placement of brachytherapy catheters, or evaluation of the distal bronchi in order to chose between different therapeutic bronchoscopic techniques for desobstruction. An experienced bronchoscopist, availability of ROSE and additional guiding devices might be necessary to accomplish the best possible results of EBUS bronchoscopy.

Detection of premalignant bronchial lesions can be significantly improved by combination of advanced bronchoscopic imaging techniques.

BACKGROUND: The search for the most efficient bronchoscopic imaging tool in detection of early lung cancer is still active. The major aim of this study was to determine sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each bronchoscopic technique and their combination in detection of premalignant bronchial lesions. METHODS: This was a prospective trial that enrolled 96 patients with indication for bronchoscopy. Lesions were classified as visually positive if pathological fluorescence was observed under autofluorescence imaging (AFI) videobronchoscopy or dotted, tortuous, and abrupt-ending blood vessels were identified under narrow band imaging (NBI) videobronchoscopy. Squamous metaplasia, mild, moderate, or severe dysplasia, and carcinoma in situ (CIS) were regarded as histologically positive lesions. RESULTS: Sensitivity, specificity, PPV, and NPV of white light videobronchoscopy (WLB) in detection of premalignant lesions were 26.5%, 63.9%, 34.4%, and 54.9%, respectively; the corresponding values for AFI were 52%, 79.6%, 64.6%, and 69.9% respectively, for NBI were 66%, 84.6%, 75.4%, 77.7%, respectively, while the values for combination of NBI and AFI were 86.1%, 86.6%, 84.6%, and 88%, respectively. Combination of NBI and AFI significantly improves sensitivity when compared to each individual technique (P < 0.001). When specificity is of concern, combination of techniques improves specificity of WLB (P < 0.001) and specificity of AFI (P = 0.03), but it does not have significant influence on specificity of NBI (P = 0.53). CONCLUSION: Combination of NBI and AFI in detection of premalignant bronchial lesions increases both sensitivity and specificity of each technique. However, it seems that NBI is most sufficient and effective in detection of these lesions.

Relation between vascular patterns visualized by Narrow Band Imaging (NBI) videobronchoscopy and histological type of lung cancer.

Narrow Band Imaging (NBI) videobronchoscopy is a new technique for visualization of microvascular changes in bronchial mucosa. The primary aim of this study was to evaluate relation between vascular patterns visualized by NBI and histology of lung cancer. We prospectively evaluated 65 patients with suspected lung cancer scheduled for bronchoscopy. NBI followed conventional WL videobronchoscopy. After identification of endoscopically visible tumor, NBI was used to determine predominant type of pathological vascular pattern (dotted, tortuous, abrupt-ending blood vessels-Shibuya descriptors). All the lesions were biopsied and histologically confirmed. There were 81.5 % male and 18.5 % female patients evaluated in the study. Lung cancer was confirmed in all patients; 63.1 % were diagnosed with squamous cell lung cancer (SCC), 24.6 % had adenocarcinoma, 9.2 % had small-cell (SCLC) and 3.1 % large-cell lung cancer (LC). Dotted blood vessels were significantly (p < 0.000) associated with adenocarcinoma, identified in 68.4 % adenocarcinoma and 31.6 % SCC. Tortuous blood vessels were identified in 72 % SCC, 8 % adenocarcinoma, 12 % SCLC and 8 % of LC. Tortuous blood vessels were significantly (p < 0.000) associated with SCC. Abrupt-ending vessels were identified in 81 % SCC, 14.3 % SCLC and 4.8 % adenocarcinoma and were significantly associated (p < 0.000) with SCC. Dotted visual pattern of blood vessels identified during NBI videobronchoscopy is highly suggesting adenocarcinoma histology of lung cancer. Tortuous and abrupt-ending blood vessels visualized under NBI videobronchoscopy significantly suggest squamous cell histology of lung cancer. Large-scale studies should be designed in order to determine true relation between visual appearance and histology in lung cancer.

Diagnostic value of autofluorescence bronchoscopy in lung cancer.

The role of autofluorescence bronchoscopy (AFB) was primarily investigated in regard to the detection of precancerous lesions of bronchial mucosa. Most of the results confirmed higher sensitivity for the detection of precancerous bronchial lesions, when compared to white light bronchoscopy (WLB) alone. However, it is commonly known that the specificity of AFB remains low. Our findings agree in terms of the detection of premalignant bronchial lesions and early lung cancer, but regarding the detection of synchronous lesions or in the evaluation of lung cancer extension, the specificity of AFB is significantly higher. There is still an ongoing debate in the scientific community whether or not autofluorescence should be used as a screening tool for lung cancer. Results of the majority of published series did not support the general use of AFB as a screening tool for lung cancer; however, these results suggest its use in groups of patients with a high risk of lung cancer. Despite this, some authors still do not recommend its use even in high-risk cases. In recent years, the indications for AFB have been widening and this tool may find its place in routine bronchoscopy. With new indications for AFB, such as the evaluation of tumor extension or follow up after surgical resection, bronchoscopists may make use of this tool more often. A sharp learning curve and a clear distinction between healthy and pathologically altered mucosa make this technology acceptable for inexperienced bronchoscopists. We also investigate new hardware and software improvements in AFB. The addition of backscattered light analysis, ultraviolet spectra, fluorescence-reflectance or dual digital systems could improve the diagnostic yield of this technology.