Effective Differences between 2D and 3D Planned Brachytherapy in Lung Cancer: An Institutional Retrospective Study.

Background and Objectives: Advanced lung cancer is usually manifested by endoluminal tumor propagation, resulting in central airway obstruction. The objective of this study is to compare the high dose rate brachytherapy treatment outcomes in non-small-cell lung cancer (NSCLC) depending on the treatment planning pattern-two-dimension (2D) or three-dimension (3D) treatment planning. Materials and Methods: The study was retrospective and two groups of patients were compared in it (a group of 101 patients who underwent 2D planned high-dose-rate endobronchial brachytherapy (HDR-EBBT) in 2017/18 and a group of 83 patients who underwent 3D planned HDR-EBBT between January 2021 and June 2023). Results: In the group of 3D planned brachytherapy patients, there was a significant improvement in terms of loss of symptoms of bronchial obstruction (p = 0.038), but no improvement in terms of ECOG PS (European Cooperative Oncology Group Performance Status) of the patient (p = 0.847) and loss of lung atelectasis (if there was any at the beginning of the disease) (p = 0.781). Two-year overall survival and time-to-progression periods were similar for both groups of patients (p = 0.110 and 0.154). Fewer treatment complications were observed, and 91.4% were in 3D planned brachytherapy (BT) patients. Conclusions: Three-dimensionally planned HDR-EBBT is a suggestive, effective palliative method for the disobstruction of large airways caused by endobronchial lung tumor growth. Independent or more often combined with other types of specific oncological treatment, it certainly leads to the loss of symptoms caused by bronchial obstruction and the improvement of the quality of life of patients with advanced NSCLC. Complications of the procedure with 3D planning are less compared to 2D planned HDR-EBBT.

Invasive Diagnostic Procedures from Bronchoscopy to Surgical Biopsy-Optimization of Non-Small Cell Lung Cancer Samples for Molecular Testing.

Background and Objectives: Treatment of advanced lung cancer (LC) has become increasingly personalized over the past decade due to an improved understanding of tumor molecular biology and antitumor immunity. The main task of a pulmonologist oncologist is to establish a tumor diagnosis and, ideally, to confirm the stage of the disease with the least invasive technique possible. Materials and Methods: The paper will summarize published reviews and original papers, as well as published clinical studies and case reports, which studied the role and compared the methods of invasive pulmonology diagnostics to obtain adequate tumor tissue samples for molecular analysis, thereby determining the most effective molecular treatments. Results: Bronchoscopy is often recommended as the initial diagnostic procedure for LC. If the tumor is endoscopically visible, the biopsy sample is susceptible to molecular testing, the same as tumor tissue samples obtained from surgical resection and mediastinoscopy. The use of new sampling methods, such as cryobiopsy for peripheral tumor lesions or cytoblock obtained by ultrasound-guided transbronchial needle aspiration (TBNA), enables obtaining adequate small biopsies and cytological samples for molecular testing, which have until recently been considered unsuitable for this type of analysis. During LC patients' treatment, resistance occurs due to changes in the mutational tumor status or pathohistological tumor type. Therefore, the repeated taking of liquid biopsies for molecular analysis or rebiopsy of tumor tissue for new pathohistological and molecular profiling has recently been mandated. Conclusions: In thoracic oncology, preference should be given to the least invasive diagnostic procedure providing a sample for histology rather than for cytology. However, there is increasing evidence that, when properly processed, cytology samples can be sufficient for both the cancer diagnosis and molecular analyses. A good knowledge of diagnostic procedures is essential for LC diagnosing and treatment in the personalized therapy era.

The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity.

BACKGROUND: Inflammation, oxidative stress and an imbalance between proteases and protease inhibitors are recognized pathophysiological features of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with COPD and to assess their relationship with lung function, symptom severity scores and recent acute exacerbations. METHODS: In this observational cohort study, serum levels of MMP-9 and TIMP-1 and the MMP-9/TIMP-1 ratio in the peripheral blood of COPD patients with stable disease and healthy controls were determined, and their association with lung function (postbronchodilator spirometry, body plethysmography, single breath diffusion capacity for carbon monoxide), symptom severity scores (mMRC and CAT) and exacerbation history were assessed. RESULTS: COPD patients (n = 98) had significantly higher levels of serum MMP-9 and TIMP-1 and a higher MMP-9/TIMP-1 ratio than healthy controls (n = 47) (p ≤ 0.001). The areas under the receiver operating characteristic curve for MMP-9, TIMP-1 and the MMP-9/TIMP-1 ratio for COPD diagnosis were 0.974, 0.961 and 0.910, respectively (all p < 0.05). MMP-9 and the MMP-9/TIMP-1 ratio were both negatively correlated with FVC, FEV1, FEV1/FVC, VC, and IC (all p < 0.05). For MMP-9, a positive correlation was found with RV/TLC% (p = 0.005), and a positive correlation was found for the MMP-9/TIMP-1 ratio with RV% and RV/TLC% (p = 0.013 and 0.002, respectively). Patients with COPD GOLD 3 and 4 presented greater MMP-9 levels and a greater MMP-9/TIMP-1 ratio compared to GOLD 1 and 2 patients (p ≤ 0.001). No correlation between diffusion capacity for carbon monoxide and number of acute exacerbations in the previous year was found. CONCLUSIONS: COPD patients have elevated serum levels of MMP-9 and TIMP-1 and MMP-9/TIMP-1 ratio. COPD patients have an imbalance between MMP-9 and TIMP-1 in favor of a pro-proteolytic environment, which overall indicates the importance of the MMP-9/TIMP-1 ratio as a potential biomarker for COPD diagnosis and severity.

Autoimmune and immunoserological markers of COVID-19 pneumonia: Can they help in the assessment of disease severity.

Background: Immune dysregulation and associated inefficient anti-viral immunity during Coronavirus Disease 2019 (COVID-19) can cause tissue and organ damage which shares many similarities with pathogenetic processes in systemic autoimmune diseases. In this study, we investigate wide range autoimmune and immunoserological markers in hospitalized patients with COVID-19. Methods: Study included 51 patients with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 infection and hospitalized due to COVID-19 pneumonia. Wide spectrum autoantibodies associated with different autoimmune inflammatory rheumatic diseases were analyzed and correlated with clinical and laboratory features and pneumonia severity. Results: Antinuclear antibodies (ANA) positivity was found in 19.6%, anti-cardiolipin IgG antibodies (aCL IgG) in 15.7%, and anti-cardiolipin IgM antibodies (aCL IgM) in 7.8% of patients. Positive atypical x anti-neutrophil cytoplasmic antibodies (xANCA) were detected in 10.0% (all negative for Proteinase 3 and Myeloperoxidase) and rheumatoid factor was found in 8.2% of patients. None of tested autoantibodies were associated with disease or pneumonia severity, except for aCL IgG being significantly associated with higher pneumonia severity index (p = 0.036). Patients with reduced total serum IgG were more likely to require non-invasive mechanical ventilation (NIMV) (p < 0.0001). Serum concentrations of IgG (p = 0.003) and IgA (p = 0.032) were significantly lower in this group of patients. Higher total serum IgA (p = 0.009) was associated with mortality, with no difference in serum IgG (p = 0.115) or IgM (p = 0.175). Lethal outcome was associated with lower complement C4 (p = 0.013), while there was no difference in complement C3 concentration (p = 0.135). Conclusion: Increased autoimmune responses are present in moderate and severe COVID-19. Severe pneumonia is associated with the presence of aCL IgG, suggesting their role in disease pathogenesis. Evaluation of serum immunoglobulins and complement concentration could help assess the risk of non-invasive mechanical ventilation NIMV and poor outcome.

UNUSUAL CLINICAL COURSE OF NEUROSARCOIDOSIS MANIFESTED WITH ACUTE HYDROCEPHALUS.

Approximately 5% to 15% of patients with systemic sarcoidosis develop neurological complications. However, the actual prevalence of subclinical disease may be higher. Symptoms are not specific, and may resemble those of other neurological diseases. Hydrocephalus occurs in 6% of patients with neurosarcoidosis. Acute hydrocephalus is extremely rare and when it occurs, it is usually difficult to diagnose, thus leading to possible complications. We present a patient who developed acute hydrocephalus due to neurosarcoidosis, for which he had to be operated on; soon after the operation, cranial infection developed that required definitive drainage system and ventriculoperitoneal shunt had to be implanted. In further complicated clinical course, after four years on corticosteroid therapy (corticosteroid dependent sarcoidosis), he had to be urgently operated on because of significant ventricular catheter adhesions, but several days after the operation he died in coma because of progressive brain edema not responding to treatment. As hydrocephalus due to neurosarcoidosis has high morbidity and mortality, early diagnosis and proper treatment are of utmost importance.

Assessing coronavirus disease 2019 (COVID-19) transmission to healthcare personnel: The global ACT-HCP case-control study.

OBJECTIVE: To characterize associations between exposures within and outside the medical workplace with healthcare personnel (HCP) SARS-CoV-2 infection, including the effect of various forms of respiratory protection. DESIGN: Case-control study. SETTING: We collected data from international participants via an online survey. PARTICIPANTS: In total, 1,130 HCP (244 cases with laboratory-confirmed COVID-19, and 886 controls healthy throughout the pandemic) from 67 countries not meeting prespecified exclusion (ie, healthy but not working, missing workplace exposure data, COVID symptoms without lab confirmation) were included in this study. METHODS: Respondents were queried regarding workplace exposures, respiratory protection, and extra-occupational activities. Odds ratios for HCP infection were calculated using multivariable logistic regression and sensitivity analyses controlling for confounders and known biases. RESULTS: HCP infection was associated with non-aerosol-generating contact with COVID-19 patients (adjusted OR, 1.4; 95% CI, 1.04-1.9; P = .03) and extra-occupational exposures including gatherings of ≥10 people, patronizing restaurants or bars, and public transportation (adjusted OR range, 3.1-16.2). Respirator use during aerosol-generating procedures (AGPs) was associated with lower odds of HCP infection (adjusted OR, 0.4; 95% CI, 0.2-0.8, P = .005), as was exposure to intensive care and dedicated COVID units, negative pressure rooms, and personal protective equipment (PPE) observers (adjusted OR range, 0.4-0.7). CONCLUSIONS: COVID-19 transmission to HCP was associated with medical exposures currently considered lower-risk and multiple extra-occupational exposures, and exposures associated with proper use of appropriate PPE were protective. Closer scrutiny of infection control measures surrounding healthcare activities and medical settings considered lower risk, and continued awareness of the risks of public congregation, may reduce the incidence of HCP infection.

Soluble sPD-L1 and Serum Amyloid A1 as Potential Biomarkers for Lung Cancer.

BACKGROUND: The objective of this prospective study was to evaluate whether soluble programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) and serum amyloid A1 (SAA1) are potential diagnostic, predictive or prognostic biomarkers in lung cancer. METHODS: Lung cancer patients (n=115) with advanced metastatic disease, 101 with non-small cell lung cancer, NSCLC (77 EGFR wild-type NSCLC patients on chemotherapy, 15 EGFR mutation positive adenocarcinoma patients, 9 patients with mPD-L1 Expression ≥50% NSCLC - responders to immunotherapy), and 14 patients with small cell lung cancer (SCLC) were examined. ELISA method was used to determine sPD-L1 and SAA1 concentrations in patients' plasma. RESULTS: Significantly higher blood concentrations of sPD-L1 and SAA1 were noted in lung cancer patients compared with a healthy control group. In PD-L1+ NSCLC patients, a significantly higher sPD-L1 level was noticed compared to any other lung cancer subgroup, as well as the highest average SAA1 value compared to other subgroups. CONCLUSIONS: It seems that sPD-1/PD-L1 might be a potential biomarker, prognostic and/ or predictive, particularly in patients treated with immunotherapy. Serum amyloid A1 has potential to act as a good predictor of patients' survival, as well as a biomarker of a more advanced disease, with possibly good capability to predict the course of disease measured at different time points.

Review of lung sealant technologies for lung volume reduction in pulmonary disease.

Emphysema is an incurable and underdiagnosed disease with obstructive ventilatory impairment of lung function. Despite decades of research, medical treatments available so far did not significantly improve the survival benefits. Different bronchoscopic methods for lung volume reduction (LVR) in emphysema were used in the past 2 decades aiming to close the airways serving the hyperinflated lung regions and to allow the gas in the more distal bullas to be absorbed. Sealants and adhesives can be natural/biological, synthetic and semisynthetic. In lung surgery, lung sealants are used to treat prolonged air leak, which is the most common complication. Sealants can also be applied in bronchoscopic lung volume reduction (BLVR) as they administer into the peripheral airways where they polymerize and act as tissue glue on the surface of the lung to seal the target area to cause durable permanent absorption atelectasis. Initial studies analyzed the efficacy of bronchoscopic instillation of a fibrinogen-thrombin complex solution in advanced emphysema. Future studies will analyze the effects of adding chondroitin sulfate and poly-L-lysine to thrombin-fibrinogen complex thus promoting fibroblast attachment, proliferation and scarring, causing bronchial fibrostenosis and preventing ventilation of the affected part of the lung. Modifications of these methods were later developed, and the efficacy of BLVR with other sealants was analyzed in clinical studies. Results from current studies using this treatment method are promising showing that it is effective in improving exercise tolerance and quality of life in patients with advanced emphysema. It seems that subjective benefits in dyspnea scores and quality of life are more marked than improvements in lung function tests. The safety profile of sealant techniques in BLVR was mostly acceptable in clinical studies. The definite conclusions about the effectiveness of sealant in BLVR could be difficult because only a small population was involved in the current studies. More randomized large controlled studies are needed in establishing the definite role of biological BLVR in the bronchoscopic treatment of emphysema.

Utility of angiotensin-converting enzyme activity in aqueous humor in the diagnosis of ocular sarcoidosis.

PURPOSE: Many studies include elevated activity of angiotensin-converting enzyme (ACE) in serum in sarcoidosis and in ocular sarcoidosis as well, but there are only a few analyzing ACE activities in aqueous humor. The aim of this study is to illuminate the diagnostic value of ACE in aqueous humor in patients with ocular sarcoidosis. METHODS: We analyzed twenty patients with ocular sarcoidosis and 18 patients with nonocular involvement. All patients have biopsy-positive sarcoidosis of the lungs and/or mediastinal lymph nodes. Blood samples for ACE serum levels were obtained from all patients. Aqueous humor samples were taken by paracentesis with a 25-gauge needle in local anesthesia. With appropriate statistical tests, we compared ACE activity in serum and aqueous humor in patients with and without ocular sarcoidosis. RESULTS: The majority of our patients with ocular sarcoidosis were female (12/20), also in the group with systemic sarcoidosis and without ocular involvement (12/6). Mean age of the whole analyzed group of sarcoidosis patients was 45 ± 6 years. There is no statistically significant difference in ACE activity in serum between two groups of patients (with and without ocular sarcoidosis). There is statistically significant difference in ACE activity in aqueous humor among patients with ocular and nonocular sarcoidosis. ACE activity in aqueous humor is significantly higher in patients with ocular sarcoidosis. CONCLUSION: Increased ACE activity in aqueous humor can point to a diagnosis of ocular sarcoidosis, without the need for ocular biopsy.

Comparison of mediastinal lymph node status and relapse pattern in clinical stage IIIA non-small cell lung cancer patients treated with neoadjuvant chemotherapy versus upfront surgery: A single center experience.

BACKGROUND: In spite of the progress made in neoadjuvant therapy for operable non small-cell lung cancer (NSCLC), many issues remain unsolved, especially in locally advanced stage IIIA. METHODS: Retrospective data of 163 patients diagnosed with stage IIIA NSCLC after surgery was analyzed. The patients were divided into two groups: a preoperative chemotherapy group including 59 patients who received platinum-etoposide doublet treatment before surgery, and an upfront surgery group including 104 patients for whom surgical resection was the first treatment step. Adjuvant chemotherapy or/and radiotherapy was administered to 139 patients (85.3%), while 24 patients (14.7%) were followed-up only. RESULTS: The rate of N2 disease was significantly higher in the upfront surgery group ( P < 0.001). The one-year relapse rate was 49.5% in the preoperative chemotherapy group compared to 65.4% in the upfront surgery group. There was a significant difference in relapse rate in relation to adjuvant chemotheraphy treatment ( P = 0.007). The probability of relapse was equal whether radiotherapy was applied or not ( P = 0.142). There was no statistically significant difference in two-year mortality ( P = 0.577). The median survival duration after two years of follow-up was 19.6 months in the preoperative chemotherapy group versus 18.8 months in the upfront surgery group ( P = 0.608 > 0.05). CONCLUSION: There was significant difference in preoperative chemotherapy group regarding relapse rate and treatment outcomes related to the lymph node status comparing to the upfront surgery group. Neoadjuvant/adjuvant chemo-therapy is a part of treatment for patients with stage IIIA NSCLC, but further investigation is required to determine optimal treatment.

Verifying Sarcoidosis Activity: Chitotriosidase versus ACE in Sarcoidosis - a Case-control Study.

BACKGROUND: Until now, a proper biomarker(s) to evaluate sarcoidosis activity has not been recognized. The aims of this study were to evaluate the sensitivity and specificity of the two biomarkers of sarcoidosis activity already in use (serum angiotensin converting enzyme - ACE and serum chitotriosidase) in a population of 430 sarcoidosis patients. The activities of these markers were also analyzed in a group of 264 healthy controls. METHODS: Four hundred and thirty biopsy positive sarcoidosis patients were divided into groups with active and inactive disease, and groups with acute or chronic disease. In a subgroup of 55 sarcoidosis patients, activity was also assessed by F-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scanning. Both serum chitotriosidase and ACE levels showed non-normal distribution, so nonparametric tests were used in statistical analysis. RESULTS: Serum chitotriosidase activities were almost 6 times higher in patients with active sarcoidosis than in healthy controls and inactive disease. A serum chitotriosidase value of 100 nmol/mL/h had the sensitivity of .5% and specificity of 70.0%. A serum ACE activity cutoff value of 32.0 U/L had the sensitivity of 66.0% and the specificity of 54%. A statistically significant correlation was obtained between the focal granulomatous activity detected on 18F-FDG PET/CT and serum chitotriosidase levels, but no such correlation was found with ACE. The levels of serum chitotriosidase activity significantly correlated with the disease duration (P < 0.0001). Also, serum chitotriosidase significantly correlated with clinical outcome status (COS) categories (ρ =0.272, P =0.001). CONCLUSIONS: Serum chitotriosidase proved to be a reliable biomarker of sarcoidosis activity and disease chronicity.

Clinical features of endobronchial tuberculosis.

BACKGROUND/AIM: Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis which often affect the tracheobronchial tree, and can be microbiologically and/or pathohistologically confirmed. The aim of the study was to determine the clinical features and diagnostic aspects of EBTB. METHODS: This retrospective study was conducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. All patients with EBTB confirmed by bronchoscopy with biopsy during a study period were analysed. Data included the patient's medical history, a physical exam, chest X-ray, mycobacterial analysis of sputum samples, endoscopic types and patohistological confirmation. RESULTS: In the study, 57.6% of the patients were males. The most frequent symptoms were cough (71.2%), malaise (54.20%), fever (49.2%), weight loss (40.7%), and hemoptysis (13.60%). Most of the patients were diagnosed within 30 days of symptoms onset. Sputum examination showed acid-fast bacilli in 31.4% of the patients, while sputum culture for tuberculosis bacilli were positive in 55.9% of the patients. The most common radiographic localization was in the upper lung lobes (63.5%). Cavities were present in 60.4% of the patients. The most common endoscopic subtype determined by bronchoscopy were nonspecific bronchitis (39.9%) and edematous-hyperemic subtype (36.4%). CONCLUSION: EBTB was more frequent among men, and among people in their fifties in our country. Detailed bronchoscopic examination, correlated with clinical and laboratory findings, will improve diagnostic rate and provide timely therapy.

The utility of 18F-FDG PET/CT for diagnosis and adjustment of therapy in patients with active chronic sarcoidosis.

UNLABELLED: The purpose of this study was to assess the utility of (18)F-FDG PET/CT for detection of inflammation in granulomatous sites and management of patients with chronic sarcoidosis. The 3 specific aims were to assess differences between (18)F-FDG PET/CT and multidetector CT (MDCT) findings, to compare (18)F-FDG PET/CT results with serum levels of angiotensin-converting enzyme (ACE), and to determine whether (18)F-FDG PET/CT findings are associated with the decision to change therapy. METHODS: We studied 90 sarcoidosis patients (mean age ± SD, 47 ± 12 y; 32 men and 58 women) with persistent symptoms who were referred for (18)F-FDG PET/CT evaluation to assess the extent of inflammation. They also underwent MDCT and measurement of serum ACE level. After the follow-up (12 ± 5 mo after (18)F-FDG PET/CT), the clinical status and changes in therapy were analyzed. RESULTS: (18)F-FDG PET/CT detected inflammation in 74 patients (82%) (maximum standardized uptake value, 8.1 ± 3.9). MDCT was positive for sarcoidosis in 6 additional patients (80, 89%). The difference between the 2 methods was not significant (P = 0.238, McNemar test), and their agreement was fair (κ = 0.198). Although ACE levels were significantly higher in patients with positive than negative (18)F-FDG PET/CT results (P = 0.002, Mann-Whitney test), 38 patients (51%) with positive (18)F-FDG PET/CT results had normal ACE levels. The therapy was initiated or changed in 73 out of 90 patients (81%). Both univariate and multivariate logistic regression analyses indicated that positive (18)F-FDG PET/CT results were significantly (P < 0.001) associated with changes in therapy, with no contribution from age, sex, ACE level, CT results, or previous therapy. CONCLUSION: Our results indicate that (18)F-FDG PET/CT is a useful adjunct to other diagnostic methods for detecting active inflammatory sites in chronic sarcoidosis patients with persistent symptoms, especially those with normal ACE levels. (18)F-FDG PET/CT proved advantageous for determining the spread of active disease throughout the body and influenced the decision to adjust the therapy.

[Mounier-Kuhn syndrome].

BACKGROUND: Mounier-Kuhn syndrome or tracheobronchomegaly is a rare disorder characterized by marked dilatation of the trachea and main bronchi, bronchiectasis, and recurrent respiratory tract infections. Its clinical presentation may vary and mimick a variety of disorders. CASE REPORT: A 43-year-old female patient, non smoker, complained of intermittent mild dyspnea. Lung function tests and cardiologic findings were within normal limits. The diagnosis was established by computed tomography, which was undertaken due to recurrent lower respiratory tract infections suggestive of bronchiectasis. The transversal tracheal diameter was 2.8 cm that was the criteria for making the diagnosis. In this sporadic case, no association with other disease or condition known to cause secondary tracheobronchomegaly was established. CONCLUSION: Although rare in clinical practice, Mounier-Kuhn syndrome is an impor tant differential diagnosis in cardio-pulmonary medicine due to a variety of its clinical manifestations. Nowadays, it is easy to diagnose it owing to advanced imaging techniques.