Determination and pharmacokinetic study of riociguat by UPLC-MS/MS in human plasma.

Pulmonary hypertension (PH) is frequent in the general population and is linked to an increased risk of death. Riociguat is a kind of endothelin receptor antagonist that is often used to treat PH. For pharmacokinetic studies and the determination of riociguat in PH patients, a new, quick, easy, and sensitive UPLC-MS/MS approach was designed and validated. Riociguat and irbesartan (IS) were detected using ESI in positive ion and multiple reaction monitoring mode, respectively, by monitoring the mass transitions m/z 423.0 â†’ 391.0 and 429.1 â†’ 206.9. A reverse-phase C18 column (5 µm, 4.6 × 150 mm) was used with an isocratic mobile phase of water containing 0.1 % formic acid-acetonitrile (25:75, v/v) at a flow rate of 1 ml/min for chromatographic separation. In the range of 5-400 ng/ml, the calibration curve was linear and had a good correlation coefficient (0.9972). This is the first UPLC-MS/MS technique that has been developed and validated for determining riociguat from human plasma. The developed analytical method was extensively validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery, according to FDA criteria. The devised approach was successfully used for a pharmacokinetic research and riociguat determination in PH patients.

A 19-Year-Old-Woman With Backache, Hemoptysis, and Hypereosinophilia.

CASE PRESENTATION: A 19-year-old woman presented to our ED with complaints of backache and massive hemoptysis. Her medical history included acute dyspnea that developed within hours caused by angioneurotic edema 6 months earlier. Two days later, she was given thrombolytic treatment because of massive pulmonary thromboembolism. She had been given methylprednisolone 4 mg and tinzaparin sodium 0.7 mL subcutaneously and was still under treatment on the current admission. She had no history of smoking, alcohol, or oral contraceptive use, surgery, trauma, recent travel, clotting disorders, or familial diseases.

Association of plasma netrin-1 level with inflammatory balance and comorbidities in patients with acute exacerbation of COPD.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by airflow restriction and systemic inflammation. Netrin-1 is a protein mainly produced in the central nervous system and has proven anti-inflammatory activity. The aim of this study was to determine netrin-1 level and its relationship with comorbidities in patients with acute exacerbation of COPD. MATERIALS AND METHODS: The study included 232 patients aged over 40 years who were divided into 3 groups: Group 1: ex-smokers (≥ 20 pack-years) with COPD hospitalized for COPD exacerbation (n= 142), Group 2: current-smokers (≥ 20 pack-years) without COPD (n= 30), Group 3: a control group comprising healthy non-smokers (n= 60). Plasma netrin-1 levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kit. RESULT: There were significant differences in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, C-reactive protein (CRP), and plasma netrin-1 levels between patients with acute exacerbation of COPD and current smokers without COPD, healthy controls (p= 0.001 for all). Netrin-1 levels at discharge were lower in COPD patients with diabetes mellitus (DM) compared to nondiabetic COPD patients (p= 0.01). Weak correlation was observed between netrin-1 level at admission and FEV1, FVC, partial pressure of oxygen, and CRP levels (r= 0.394, p= 0.01; r= -0.366, p= 0.01; r= -0.19, p= 0.05; r= 0.306, p= 0.01). Netrin-1 level at admission was also moderately correlated with smoking history (pack-years) (r= 0.579, p= 0.01). CONCLUSIONS: Netrin-1 was elevated in acute exacerbation of COPD and may be an important element in inflammatory balance. Patients with both COPD and DM were found to have lower netrin-1 levels at discharge after resolution of the acute exacerbation.

Are Trace Element Concentrations in Lung Cancer Tissue Associated with Metastasis?

OBJECTIVE: Lung cancer is among the leading causes of cancer-related deaths. Many exogenous and endogenous factors are associated with the development and progression of this cancer. Among these factors are trace elements, which have many biological functions despite their low concentrations in the body and may disrupt cellular functions and contribute to tumorigenesis when present in excessive or insufficient quantities. In this study, we performed elemental analysis of lung cancer tissues to evaluate the role of trace element concentrations in the formation of metastasis in lung cancer. MATERIALS AND METHODS: Lung cancer tissue specimens were collected from 65 patients with different cancer stages and histological subtypes for elemental analysis. After the tissues were embedded in paraffin blocks and prepared, the concentrations of 19 elements were analyzed by using inductively coupled plasma-optical emission spectroscopy (ICP-OES). All of the patients included in the study underwent diagnosis, treatment, and follow-up in our center between 2015 and 2020. RESULTS: Comparison of trace element concentrations in three different lung cancer subtypes according to cancer stage showed that lead (Pb) and aluminum (Al) concentrations increased significantly as cancer stage advanced (P < .0001 for both). Trace element concentrations did not differ significantly based on patient sex or age. CONCLUSION: Lead and aluminum concentrations in the tissues of lung cancer patients may contribute to the formation of metastases, which have a major impact on the prognosis of lung cancer.

Are Serum Interleukin 6 and Surfactant Protein D Levels Associated with the Clinical Course of COVID-19?

PURPOSE: SARS-CoV-2 (COVID-19) has infected more than 7 million people worldwide in the short time since it emerged in Wuhan, China in December 2019. The aim of this study was to investigate the relationship between serum interleukin 6 (IL-6) and surfactant protein D (SP-D) levels and the clinical course and prognosis of COVID-19. MATERIALS AND METHODS: The study included a total of 108 individuals: 88 patients who were diagnosed with COVID-19 by real-time PCR of nasopharyngeal swab samples and admitted to the Atatürk University Pulmonary Diseases and the Erzurum City Hospital Infectious Diseases department between March 24 and April 15, and 20 asymptomatic healthcare workers who had negative real-time PCR results during routine COVID-19 screening in our hospital. RESULTS: Patients who developed macrophage activation syndrome had significantly higher IL-6 and SP-D levels at the time of admission and on day 5 of treatment compared to the other patients (IL-6: p = 0.001 for both; SP-D: p = 0.02, p = 0.04). Patients who developed acute respiratory distress syndrome had significantly higher IL-6 and SP-D levels at both time points compared to those who did not (p = 0.001 for all). Both parameters at the time of admission were also significantly higher among nonsurvivors compared to survivors (IL-6: p = 0.001, SP-D: p = 0.03). CONCLUSION: In addition to IL-6, which has an important role in predicting course and planning treatment in COVID-19, SP-D may be a novel pneumoprotein that can be used in the clinical course, follow-up, and possibly in future treatments.

Can tissue elemental analysis be used to differentiate sarcoidosis and tuberculous lymphadenitis?

INTRODUCTION: Sarcoidosis and tuberculous lymphadenitis are granulomatous inflammatory diseases. Differentiating lymph node involvement in these two diseases can be challenging. This study evaluated whether elemental analysis of tissue samples could facilitate the differentiation of these histopathologically and clinically similar diseases. MATERIALS AND METHODS: A total of 152 tissue samples were included: 57 caseating granulomatous inflammation, 58 non-caseating granulomatous inflammation, and 37 reactive lymph node specimens. The tissue samples were analyzed for calcium, magnesium, iron, copper, zinc, chrome, molybdenum, nickel and selenium with inductively coupled plasma-optical emission spectroscopy (ICP-OES). RESULT: Comparison of element levels in the three groups revealed that caseating granulomatous inflammation had higher calcium content (662.6 ± 4.6 ppm, p< 0.001) and lower iron content (48.7 ± 83 ppm, p< 0.001) compared to non-caseating granulomatous inflammation. Compared to reactive lymph tissue, caseating granulomatous inflammation had higher calcium and lower iron and magnesium content while non-caseating granulomatous inflammation had higher levels of iron and lower magnesium; however, these differences were not statistically significant. In caseating granulomatous inflammation, a calcium cut-off value of 207 ppm yielded 85% specificity and 63% sensitivity. For iron, a cut-off value of 51 ppm had 74% specificity and 58% sensitivity. CONCLUSIONS: High calcium and low iron levels in lymph tissue may be suggestive of caseating granulomatous inflammation and tuberculosis. In cases where differentiating between sarcoidosis and tuberculous lymphadenitis is difficult, performing tissue elemental analysis may provide additional supportive evidence for differential diagnosis.

Comparison of Functional Capacity and Symptoms of COPD Patients with and without Pulmonary Hypertension.

OBJECTIVE: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) associated with a decrease in the survival rate of patients with COPD. Our aim was to investigate whether PH impairs the functional capacity and symptoms in patients with COPD. In addition, we aimed to evaluate the correlation between the functional capacity and symptoms score in patients with COPD. MATERIALS AND METHODS: This prospective cross-sectional study enrolled 64 patients with moderate to severe COPD, prospectively. All patients underwent the pulmonary function test, echocardiography, 6-minute walk test (6MWT), and cardiopulmonary exercise testing (CPET). We applied the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) to all patients. The mean pulmonary arterial pressure (mPAP) >30 mmHg with echocardiography was considered as PH. The patients were grouped according to the presence of PH as COPD-PH (n=30) and COPD-nonPH (n=34). RESULTS: Hospitalization rate was higher in the COPD-PH group than in the COPD-nonPH group (p=0.006). The 6MWT results were lower in the COPD-PH group compared to the COPD-nonPH group (325±61 m vs. 354±46 m, respectively, p=0.025). In the COPD-PH group, the maximum oxygen consumption (VO2max) was lower, but the difference did not reach statistical significance (p=0.118). Although the maximum load and minute ventilation were lower in the COPD-PH group, the end-tidal pressure of CO2 (PETCO2) was higher (p=0.033, p=0.036, and p=0.009, respectively). However, the CAT score and mMRC were similar between the groups (p=0.405 and p=0.238, respectively). CONCLUSION: An elevated PAP in patients with COPD limits the exercise capacity. Using CPET in the functional evaluation of patients with COPD may be beneficial in the early detection of PH.

Relevance of Pulmonary Alveolar Echinococcosis.

BACKGROUND: Pulmonary alveolar echinococcosis (PAE) is a chronic disease caused by Echinococcus multilocularis with very low incidence in developed countries. METHODS: This single-center, retrospective study included 34 patients who were diagnosed with PAE between January 2001 and February 2019 (15 males, 19 females, mean age: 52.4±15.8 years, age range: 28-78 years) in Ataturk University Medical School, Erzurum, Turkey. RESULTS: The liver was the primary involved organ in all cases. Pulmonary involvement was detected in 13.0% (34/261) of all cases with hepatic alveolar echinococcosis (AE), and three patients (8.8%) had both pulmonary metastasis and brain metastasis. The route of spread to the lungs based on radiological data was hematogeneous in 25 patients (73.5%), transdiaphragmatic in three patients (8.8%) and both hematogeneous and transdiaphragmatic in six patients (17.7%). AE showed bilateral involvement in 19 patients (55.9%), whereas only the right lung was involved in 12 patients (35.3%) and the left lung in three patients (8.8%). Of the patients, five underwent surgery due to PAE and 29 patients received medical therapy with albendazole. A total of three patients died during the follow-up period (2, 5 and 10 years after the diagnosis of PAE), while 31 patients continued with follow-up and treatment for a mean duration of 5.4±3.8 years (1-14 years). CONCLUSIONS: Patients with hepatic AE must, as a matter of course, be screened for possible lung involvement. Albendazole therapy may slow down disease progression in patients with widespread pulmonary involvement who are not eligible for surgery.

The diagnostic value of fiberoptic bronchoscopy in ruptured lung hydatid cysts.

BACKGROUND: This study aims to evaluate the diagnostic yield of fiberoptic bronchoscopy in ruptured pulmonary hydatid cysts indistinguishable from pulmonary masses on imaging techniques. METHODS: Between January 2000 and January 2018, a total of 45 consecutive patients (27 males, 18 females; mean age 46.4±13.5 years; range, 23 to 78 years) who underwent fiberoptic bronchoscopy to establish the definitive diagnosis following radio-diagnostic procedures were retrospectively analyzed. Data including demographic and clinical characteristics of the patients, preoperative diagnostic studies, bronchoscopic findings, and postoperative diagnosis were recorded. RESULTS: Endobronchial hyperemia (n=42) and purulent secretion (n=34) are the most common findings of bronchoscopy. The most specific finding was the presence of pieces of cystic membranes in 23 patients. Scolices were seen in five patients in bronchial aspirate. In one patient, both pieces of cystic membranes and scolices in bronchial aspirate were detected. The preliminary diagnosis of a hydatid cyst was made based on these findings in 28 patients (62.2%) preoperatively. The definitive diagnosis of a hydatid cyst was confirmed through thoracotomy in all patients. CONCLUSION: Bronchoscopy is a particularly valuable method in the definitive diagnosis of ruptured lung hydatid cysts. The definite diagnosis is based on the visualization of the endobronchial membrane during bronchoscopy or scolices in the bronchial aspirate. It can be also used to prevent complications such as bronchial dissemination and asphyxia due to intra-bronchial membrane pieces.

The effect of surgical specimen-derived phosphorus and lead concentrations in non small cell lung cancer patients on disease course.

INTRODUCTION: Lung cancer is one of the leading causes of cancer-related mortality. There are many exogenic and endogenic factors associated with the development of lung cancer. One of these factors is trace elements. Under- or overabundance of trace elements can disrupt cellular functions and lead to the formation of cancer. In this study we conducted elemental analysis of lung cancer tissue and normal lung tissue to investigate the role of tissue trace element concentrations in lung cancer. MATERIALS AND METHODS: Elemental analysis was performed on 30 lung cancer tissue samples and a control group of 15 normal lung tissue samples, all taken from patients diagnosed, treated and followed at our hospital between 2005 and 2010. The solubilized tissue samples were analyzed for the presence of 19 elements using inductively coupled plasma-optical emission spectroscopy (ICP-OES). Total element amounts in the tissue were calculated. RESULT: Concentrations of magnesium, potassium, zinc, manganese, lead, boron, chromium and phosphorus were significantly higher in the patient group compared to the control group. Deceased patients had significantly lower phosphorus concentrations and significantly higher lead concentrations than the other patients. CONCLUSIONS: Elevated levels of magnesium, potassium, zinc, manganese, lead, boron, chromium and phosphorus in lung cancer tissue indicate that these elements may play a role in the development of lung cancer. The results of our evaluation of the association between trace elements and lung cancer suggest that, together with other factors, low phosphorus concentration and high lead concentration in tumor tissue may influence disease course.

Comparison of long-term outcomes of 50 and 100 mg rt-PA in the management of acute pulmonary thromboembolism.

BACKGROUND: Pulmonary thromboembolism (PTE) is a life-threatening disease. In this study, we aimed to evaluate long-term outcomes of the use of 50 mg recombinant tissue-type plasminogen activator (rt-PA) in the management of PTE in terms of relapse, pulmonary hypertension (PH), mortality and hemorrhage and to compare with the use of 100 mg rt-PA. METHODS: The study was designed as a retrospective cohort. Patients who were diagnosed as acute PTE and received either 50 or 100 mg rt-PA in a tertiary care hospital between 2010 and 2015 were included in the study. Rates of relapse, PH, mortality (in-hospital and long-term) and hemorrhage (major and minor) were calculated for each treatment group. RESULTS: A total 117 patients, 73 females and 44 males, were evaluated. Eighty-three patients were administered 100 mg rt-PA, and 34 were administered 50 mg rt-PA. The mean age was lower in the 100 mg group compared to the 50 mg group (61 ± 15 vs 69 ± 14 years). There was a significant decrease in PH in each group at 3 months follow-up (P < .001). Although statistically nonsignificant, the relapse rate was lower in the 50 mg rt-PA group, but the 5-year mortality rate was higher in 50 mg rt-PA group (35.2% vs 27.7%, P = .50). Mortality was associated with older age and presence of malignancy. CONCLUSIONS: Our results suggest that both doses of rt-PA have similar efficacy. The high mortality rate in the 50 mg group may have resulted from patient selection.

Acute respiratory distress syndrome; A rare complication caused by usage of ruxolitinib.

Ruxolitinib-associated acute respiratory distress has rarely been reported, mostly due to discontinuation of treatment. Herein we report a 58-year-old male patient with primary myelofibrosis who presented with malaise and dyspnea 15 days after initiation of the treatment. The patient was diagnosed as mild acute respiratory distress syndrome (ARDS). After excluding other potential causes such as infection and cardiac pathologies, it was considered secondary to ruxolitinib use. The medication was discontinued and 1 mg/kg methylprednisolone was given to prevent cytokine rebound syndrome and continuous positive airway pressure therapy was prescribed for ARDS. Symptomatic improvement and complete radiological resolution was observed. This case suggests that ARDS may develop secondary to ruxolitinib use and ARDS should be keep in mind in the cases with respiratory symptoms who were on treatment.

Added value of DCE-MRI in the management of cystic-cavitary lung lesions.

BACKGROUND AND OBJECTIVE: We evaluated the added value of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to CT in the evaluation of cystic-cavitary lung lesions. We aimed to compare morphological parameters, including wall thickness and inner wall irregularity, and to determine whether DCE-MRI with morphological and dynamic parameters was useful in indeterminate lesions. We also aimed to investigate the added value of DCE-MRI in terms of whether to biopsy, and if so the site of biopsy. METHODS: This prospective study included 39 consecutive patients with cystic and/or cavitary lung lesions detected by CT who then underwent additional DCE-MRI. After initial evaluation, the lesions were classified as benign, indeterminate or malignant and the findings of CT and DCE-MRI compared with each other by considering the final diagnosis that was determined by histopathological findings and clinical evaluation and follow up. RESULTS: The mean values for wall thickness obtained by DCE-MRI were lower and the range of wall thickness for indeterminate lesions was narrower than those obtained by CT (5.50-11.50 mm and 5.75-13.50 mm for DCE-MRI and CT), and inner wall irregularity on DCE-MRI was more sensitive in malignant lesions. Also, DCE-MRI obviated biopsy in three benign patients and changed the biopsy site in two patients. CONCLUSION: Our study suggests that DCE-MRI is helpful in indeterminate cystic-cavitary lung lesions, with morphological and dynamic features. It narrowed the range of wall thickness used for indeterminate lesions, was more sensitive than CT in determining malignant inner wall irregularity, and was also useful in determining the need for and appropriate site of biopsy. See article, page 576.