Lung Cancer Screening Beyond Low-Dose Computed Tomography: The Role of Novel Biomarkers

Lung cancer is the most common and lethal malignancy in the world. The landmark National lung screening trial (NLST) showed a 20 % relative reduction in mortality in high-risk individuals with screening low-dose computed tomography. However, the poor specificity and low prevalence of lung cancer in the NLST provide major limitations to its widespread use. Furthermore, a lung nodule on CT scan requires a nuanced and individualized approach towards management. In this regard, advances in high through-put technology (molecular diagnostics, multi-gene chips, proteomics, and bronchoscopic techniques) have led to discovery of lung cancer biomarkers that have shown potential to complement the current screening standards. Early detection of lung cancer can be achieved by analysis of biomarkers from tissue samples within the respiratory tract such as sputum, saliva, nasal/bronchial airway epithelial cells and exhaled breath condensate or through peripheral biofluids such as blood, serum and urine. Autofluorescence bronchoscopy has been employed in research setting to identify pre-invasive lesions not identified on CT scan. Although these modalities are not yet commercially available in clinic setting, they will be available in the near future and clinicians who care for patients with lung cancer should be aware. In this review, we present up-to-date state of biomarker development, discuss their clinical relevance and predict their future role in lung cancer management.     

99mTc-MIBI Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography: A Preliminary Study

The differentiation of active inflammatory processes from an inactive form of the disease is of great value in the management of interstitial lung disease (ILD). The aim of this investigation was to assess the efficacy of 99mTc-methoxy-isobutyl-isonitrile (99mTc-MIBI) scans in distinguishing the severity of the disease compared to radiological and clinical parameters.In total, 19 known cases of ILD were included in this study and were followed up for 1 year. Five patients without lung disease were considered as the control group. The patients underwent pulmonary function tests (PFTs) and high-resolution computed tomography scans, followed by 99mTc-MIBI scanning. The 99mTc-MIBI scans were analyzed either qualitatively (subjectively) or semiquantitatively.All 19 ILD patients demonstrated a strong increase in 99mTc-MIBI uptake in the lungs compared to the control group. The 99mTc-MIBI scan scores were higher in the patient group in both the early phase (0.24[0.19–0.31] vs 0.11[0.10–0.15], P < 0.05) and the delayed phase (0.15[0.09–0.27] vs 0.04[0.01–0.09], P < 0.05) compared with the control group. A positive correlation was detected between the 99mTc-MIBI scan and the high-resolution computed tomography (HRCT) scores (Spearman''s correlation coefficient = 0.65, P < 0.02) in the early phase but not in the delayed phase in patients (P > 0.14). The 99mTc-MIBI scan scores were not significantly correlated with the PFT findings (P > 0.05). In total, 5 patients died and 14 patients were still alive over the 1-year follow-up period. There was also a significant difference between the uptake intensity of 99mTc-MIBI and the outcome in the early phase (dead: 0.32[0.29–0.43] vs alive: 0.21[0.18–0.24], P < 0.05) and delayed phase (dead: 0.27[0.22–0.28] vs alive: 0.10[0.07–0.19], P < 0.05).The washout rate was ∼40 min starting from 20 min up to 60 min and this rate was significantly different in our 2 study groups (ILD: 46.61[15.61–50.39] vs NL: 70.91[27.09–116.36], P = 0.04).The present study demonstrated that 99mTc-MIBI lung scans might distinguish the severity of pulmonary involvement in early views, which were well correlated with HRCT findings. These results also revealed that 99mTc-MIBI lung scans might be used as a complement to other diagnostic and clinical examinations in terms of functional information in ILD; however, further investigations are strongly required.     

Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study

BackgroundThe survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings.Material and methodsWe performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables.ResultsOf the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean ± SD global score on the modified Bhalla score was 13.7 ± 3.8 in women and 15.2 ± 3.8 in men (p = 0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV₁, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations.ConclusionsThis is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage.     

Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD

Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-α and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-α and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.     

Markers of Systemic and Lung Inflammation in Childhood Asthma

Aim. To compare different biomarkers of inflammation in children with controlled and uncontrolled asthma and to investigate their relationship with other clinical indices of asthma control (symptoms, lung function, serum IgE, and prn beta-agonist use). Materials and Methods. A total of 62 consecutive asthmatic children (age 11 ± 3.3 years, 32 girls) with controlled ([C], n = 19) and uncontrolled asthma ([NC], n = 43) were studied. Measured lung function and inflammatory biomarkers included: spirometry, exhaled NO (F_ENO), high-sensitivity C-reactive protein (hs-CRP), peripheral blood white blood cells (WBC) counts, and differentials. Results. Hs-CRP was significantly higher in uncontrolled than in controlled asthma (hs-CRP, median [IQR], mg/L; 0.56 [0.60] vs 0.25 [0.34], p = 0.008). Discriminant analysis (backward stepwise) depicted hs-CRP and lymphocytes (as Z-score for absolute count) as significant discriminative factors for asthma control (F = 8.319, p = 0.0007) with 82.3% diagnostic accuracy. Divided into quartiles hs-CRP showed the significant inverse association with F_ENO (F = 7.359, p = 0.003, ANOVA) with no significant difference for asthma control (F = 1.032, p = 0.386). Post-hoc analysis revealed that F_ENO values were significantly lower in the third and the fourth quartile of hs-CRP in comparison to the first and the second one (p < 0.05 for all). Conclusion. In asthmatic children with uncontrolled asthma serum hs-CRP was increased compared to children with controlled asthma. Although F_ENO values were also increased (insignificantly) and inversely correlated with hs-CRP they were probably reflecting different etiology underlying the loss of control. The role of peripheral blood biomarkers in asthmatics is still poorly investigated so new studies are required.     

Interstitial Lung Disease in Myositis: Clinical Subsets,Biomarkers, and Treatment

Interstitial lung disease (ILD) is the most frequent organ involvement (found in nearly half) of myositis patients, but it reveals various clinical courses and therapeutic responsiveness according to clinical and serological subsets. Autoantibodies, as well as imaging and histopathological studies, are useful for the classification of ILD in myositis and provide useful information for predicting prognosis and determining treatment. Antisynthetase antibodies are correlated with chronic and recurrent ILD, whereas anti-CADM-140 (MDA5/IFIH1) antibodies are a marker of acute progressive ILD in clinically amyopathic dermatomyositis. Serum KL-6, SP-D, and ferritin are useful biomarkers for monitoring the activity and severity of ILD. Regarding treatment, glucocorticoids are the first-line drug, but additional immunomodulating drugs are also used in refractory patients. Cyclophosphamide and calcineurin inhibitors (cyclosporine and tacrolimus) appear to be the key drugs in the treatment of refractory myositis–ILD. Rituximab may become another candidate if these drugs are not effective.     

Predictive Factors for Pneumomediastinum During Management of Connective Tissue Disease-related Interstitial Lung Disease: A Retrospective Study

Objective To identify factors associated with pneumomediastinum during management of connective tissue disease (CTD)-related interstitial lung disease (ILD). Methods Patients diagnosed with pneumomediastinum after the initiation of corticosteroid therapy for their CTD-ILD were enrolled. The baseline characteristics of patients who developed pneumomediastinum after the initiation of corticosteroid therapy (n=13, all occurring within 120 days) were compared to those of patients who did not develop pneumomediastinum (n=49). A multivariate logistic regression analysis was performed to identify factors associated with pneumomediastinum. A receiver operating characteristic (ROC) curve analysis was also performed to assess the predictive performance. Results The body mass index (BMI) [odds ratio (OR) (95% confidence interval (CI)) 0.482 (0.272-0.853)] and serum lactate dehydrogenase (LDH) [OR (95% CI) 1.013 (1-1.025)] levels at baseline were identified as independent factors associated with pneumomediastinum after corticosteroid initiation. The optimal cut-off points of the BMI and LDH levels for predicting pneumomediastinum development, as estimated by the Youden index, were 20.2 kg/m² and 378 U/L, respectively. LDH showed a sensitivity of 61.5% and the highest specificity of 87.8%. Importantly, combining these markers resulted in the highest sensitivity of 100% and a specificity of 71.4%. Conclusion A low BMI and high serum LDH levels at baseline are useful predictive factors for pneumomediastinum development in CTD-ILD patients.     

Severe Acute Pancreatitis Requiring Drainage Therapy: Findings on Computed Tomography as Predictor of Patient Outcome

Background/Aims: To evaluate whether morphologic features on computed tomography (CT) correlate with outcome of patients with severe acute pancreatitis (SAP). Methods: 80 patients with SAP requiring percutaneous drainage therapy were retrospectively analyzed. Twelve CT features beyond the CT severity index (CTSI) were studied. Endpoints for patient outcome were patient death, length of hospital and ICU stay. The twelve features and the CTSI score were correlated with mortality using Kaplan-Meier estimator and correlated with length of hospital and ICU stay using the χ² test. A p value ≤0.05 was considered statistically significant. Results: Two CT features exhibited a significant correlation with mortality: (1) the number of parts of pancreas (head, corpus, tail) that exhibited areas of necrosis and (2) the presence of distant fluid collections (posterior para renal space and/or paracolic gutter). Mortality was 42% (21 of 50 patients) and 20% (6 of 30 patients) if two/all three parts or none/one part of the pancreas exhibited necrosis, respectively. Mortality was 46% (18 of 39 patients) and 22% (9 of 41 patients) if distant fluid collections were present or absent, respectively. All other imaging features including the CTSI showed no significant correlation with patient outcome. Conclusion: We identified two morphologic features on CT that might be helpful to predict prognosis of patients suffering from SAP.     

Computed Tomography Findings of Hepatic Lesions in Human Fascioliasis: Report of Two Cases

Two patients with hepatic fascioliasis are presented. Computed tomography demonstrated multiple low density areas located in the center and periphery of the liver. In one patient a spontaneous decrease in the size of the low-density areas occurred but the abdominal symptoms were persistent before bithionol treatment. After the treatment both patients became asymptomatic. The computed tomography scan can be a useful tool for the diagnosis and follow-up of the patients with hepatic fascioliasis.     

Metastases to the Pancreas: Computed Tomography Imaging Spectrum and Clinical Features: A Retrospective Study of 18 Patients With 36 Metastases

The aim of this study is to identify the key computed tomography (CT) imaging findings and clinical characteristics of pancreatic metastases for its differential diagnosis. CT images and clinical features of 18 patients with 36 histopathologically proven pancreatic metastases were retrospectively reviewed. The primary malignancy included non-small cell lung cancer (NSCLC) (n = 7), gastrointestinal carcinoma (n = 5), renal cell carcinoma (RCC) (n = 3), osteosarcoma (n = 1), cardiac sarcomas (n = 1), and neuroendocrine ethmoid sinus carcinoma (n = 1). Pancreatic metastases were metachronous in 12 patients (ranging from 4 to 72 months). Tumor markers were elevated for 8 patients, of which 7 patients had NSCLC and gastrointestinal carcinoma, and 1 patient had osteosarcoma. Metastases from NSCLC and gastrointestinal carcinoma frequently presented as small well-circumscribed lesions, with homogeneous or rim enhancement, and or local pancreatic infiltration instead of focal mass, mimicking local pancreatitis. Neuroendocrine ethmoid sinus carcinoma affecting the pancreas also exhibited local pancreatic infiltration. Metastases from RCC and cardiac sarcomas had typical characteristics of hypervascular lesions. Osteosarcoma metastasizing to pancreas had special manifestation, that is, cystic lesion with thick wall and calcification.Although pancreatic metastases have a broad spectrum of CT appearances, lesions from some types of primary tumors exhibited characteristic imaging features, which, in combination with oncological history, will contribute to correct diagnosis.     

Pathogenesis of Pulmonary Fibrosis in Systemic Sclerosis: Lessons from Interstitial Lung Disease

Interstitial lung disease is a frequent complication of systemic sclerosis and currently is the leading cause of death. Our ability to predict which individuals are at greatest risk of developing clinically significant, progressive interstitial lung disease remains inadequate. Identification of circulating autoantibodies and other biomarkers, as well as genetic polymorphisms and aberrant gene expression, all hold promise as diagnostic and prognostic tools, as well as therapeutic targets. Many practice patterns for the diagnosis and monitoring of connective tissue disease-associated interstitial lung disease are based upon published experience with idiopathic interstitial lung diseases. Although there are likely commonalities in the pathophysiologic mechanisms and clinical progression among all fibrosing lung diseases, a better understanding of features unique to systemic sclerosis-associated interstitial lung disease is essential to the development of more effective monitoring and treatment strategies.     

Morphological and Biochemical Properties of Alveolar Fibroblasts in Interstitial Lung Diseases

The phenotype of alveolar-associated fibroblasts (Afb) in sarcoidosis (SA) and idiopathic pulmonary fibrosis (IPF) is unclear. In the present study, we characterized the cytoskeletal proteins and the contraction properties in alveolar-associated fibroblasts recovered by bronchoalveolar lavage (BAL) in the two diseases. Afb were studied from BAL cells in eight IPF and seven SA patients. Cytoskeletal proteins were identified by ELISA and immunofluorescent methods. Biochemical measurements were done by dry chemistry. Contraction was performed by a gel contraction assay. Afb alpha-SM actin measured by ELISA was higher in IPF than in SA (p = 0.042). Vimentin, desmin, myosin, and fibroblast markers were expressed equally. Only in IPF did the Afb reveal the myofibroblast phenotype showing alpha-SM actin immunofluorescence labeling and, by electron microscopy, filaments with associated dense bodies with rough endoplasmic reticulum. Gel contraction showed that cells in IPF contracted significantly more than in SA (p = 0.046 IPF versus SA). The addition of ET-1 increased contraction in all groups. Dry chemistry analysis showed higher levels (p = 0.0065) of creatine phosphokinase (CPK), lower levels of glucose (p = 0.0082), and similar levels of Ca(2+) and lactate in the IPF and SA Afb. Dinitrofluorobenzene (DNFB), a potent inhibitor of CPK, completely abolished spontaneous cell contraction. Afb differentiates into myofibroblasts with different biochemical and energetic properties in IPF. Moreover, Afb from IPF patients showed increased contractile properties. This may explain the difference in the behavior patterns and outcomes of the two diseases.     

Endoscopic Ultrasonography Findings in Patients with Non-Specific Changes of the Pancreas on Computed Tomography: A Single-Center Experience

Inconclusive findings on abdominal computerized tomography (CT) scans such as "enlarged or prominent pancreas" are commonly reported; however, their clinical significance is not clearly understood. The objective was to evaluate the efficacy of endoscopic ultrasound (EUS) in a cohort of patients with indeterminate findings on CT. We undertook a retrospective, single-center study at a tertiary care university hospital. About 107 consecutive patients (56 men) underwent EUS evaluation for inconclusive CT findings. The main intervention was EUS with fine needle aspiration (FNA) The main outcome measurement was to describe lesions identified by EUS in this cohort of patients. About 22 patients (21%) had pancreatic adenocarcinoma, 14 (13%) had chronic pancreatitis, 28 (26%) had benign lesions, and 35 patients (33%) had a normal EUS exam. Pancreatic cancer was more likely to be found on EUS in patients with significant weight loss (OR 10.1; 95% CI: 3.3-30.60), hyperbilirubinemia (OR 9; 95% CI: 3-26.0), or common bile duct (CBD) dilatation (OR 3.2; 95% CI: 1.25-8.5). The limitations of the study were that we were unable to control the uniformity of CT interpretation because the scans were reviewed by multiple radiologists. There were also limited follow-up data on patients who had benign lesions or normal EUS. In conclusion, EUS is an effective modality for evaluating pancreatic lesions in patients with inconclusive findings on abdominal CT. This assists in the prompt diagnosis and institution of appropriate treatment strategies for a variety of pancreatic diseases including cancer. In the setting of inconclusive CT findings, patients with hyperbilirubinemia, significant weight loss, or CBD dilatation should undergo EUS evaluation as they are at a higher risk of having underlying pancreatic cancer.     

Mycophenolate Versus Cyclophosphamide for Progressive Interstitial Lung Disease Associated with Systemic Sclerosis: A 2-Year Case Control Study

Objective

Cyclophosphamide is considered the treatment of choice for interstitial lung disease (ILD) secondary to systemic sclerosis (SSc), albeit having a minimal effect. Although controlled evidence does not exist, mycophenolate is used increasingly in clinical practice as an alternative. We aimed to compare the long-term efficacy of these drugs.

Methods

Patients from our SSc cohort who received mycophenolate for over 1 year for progressive ILD were 1:1 matched for age, gender, and baseline forced vital capacity (FVC ±3 %) with cyclophosphamide-treated patients. Changes in FVC, total lung capacity (TLC), diffusion capacity for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) scans were compared between groups. Changes in pulmonary function tests (PFTs) over at least 1 year in six unmatched control patients, who had denied mycophenolate or cyclophosphamide, also were examined.

Results

FVC, TLC, and DLCO did not change significantly in either mycophenolate (from 79.0 ± 12.5 to 80.2 ± 8.1 to 81.2 ± 11.4, from 71.5 ± 16.1 to 74.3 ± 10.8 to 71.8 ± 13.0, from 56.8 ± 12.0 to 55.2 ± 9.9 to 50.6 ± 8.5, respectively) or cyclophosphamide group (from 77.3 ± 12.5 to 79.7 ± 10.3 to 82.5 ± 12.9, from 64.7 ± 14.9 to 68.6 ± 16.0 to 66.1 ± 15.5, from 53.1 ± 14.3 to 56.4 ± 13.5 to 56.3 ± 6.7, respectively), after 1 or 2 years of treatment. PFTs also remained stable in the control group. In either the mycophenolate or cyclophosphamide groups, six patients remained stable, three improved, and one deteriorated according to the definitions of the American Thoracic Society. However, and despite the fact that patients in the cyclophosphamide group had more extended ILD at baseline, a deterioration of lung HRCT findings at 2 years was noticed after mycophenolate (from 10.0 ± 8.9 to 12.7 ± 8.2, p = 0.039) but not after cyclophosphamide.

Conclusions

Although these results derive from patients selected for receiving at least 1 year of treatment and therefore they do not represent an intention-to-treat cohort, an eagerness to replace cyclophosphamide by mycophenolate in SSc-associated ILD treatment is not supported.     

Effect of Glucocorticoid Treatment on Computed Tomography Angiography Detected Large-Vessel Inflammation in Giant-Cell Arteritis. A Prospective,Longitudinal Study

Computed tomography angiography (CTA) detects signs of large-vessel vasculitis (LVV) in about 67.5% of patients with giant-cell arteritis (GCA) at the time of diagnosis and early aortic dilatation in 15%. The outcome of CTA-findings of LVV upon glucocorticoid treatment has not been prospectively evaluated.The aim of our study was to prospectively assess glucocorticoid-induced changes in CTA findings of LVV in patients with GCA.Forty biopsy-proven GCA patients evaluated by CTA at diagnosis were prospectively followed and scheduled a new CTA approximately after 1 year of treatment. Vessel wall thickening, diameter, and contrast enhancement of the aorta and its tributaries were evaluated. Results were compared to those obtained at the time of diagnosis.CTA was repeated to 35 patients after a median follow-up of 13.5 months (IQ25–75% 12.4–15.8). Arterial wall thickening was still present in 17 patients (68% of the patients who initially had LVV). The number of affected segments and wall thickness at various aortic segments significantly decreased and no patients developed new lesions, new aortic dilation or increase in previous dilation. Contrast enhancement disappeared in 15 (93.75%) of 16 patients in whom this finding could be assessed.Signs of LVV improve with treatment. While contrast enhancement resolves in the majority of patients, vessel wall thickening persists in two thirds. However, the number of affected aortic segments as well as aortic wall thickness significantly decreases. Longer follow-up is necessary to determine the clinical significance of persisting wall thickening and its relationship with relapses or subsequent development of aortic dilatation or large-vessel stenoses.     

正电子发射计算机断层显像计算机断层扫描在系统性血管炎诊断及病情评估中的应用

系统性血管炎临床表现复杂,对于缺乏特征性表现者的诊断和病情严重程度评估,临床医生面临巨大的挑战。现有影像学检查手段对系统性血管炎的早期、活动性病变敏感性较低。正电子发射计算机断层显像与计算机断层扫描技术(positron emission tomographycomputed tomography,PETCT)对系统性血管炎中巨细胞动脉炎风湿性多肌痛、大动脉炎等大血管炎的诊断具有比较高的敏感新和特异性,特别是在疾病的早期和活动期,而对于中小血管受累的系统性血管炎并无太大帮助。通过PETCT可以全面了解系统性血管炎的解剖和功能定位,弥补其他影像学检查的不足。应注意在PETCT上系统性血管炎与其他血管疾病的鉴别。PETCT检查在系统性血管炎疗效评估中的作用尚有待进一步研究。     

Diagnosis of Ovarian Vein Syndrome (OVS) by Computed Tomography (CT) Imaging: A Retrospective Study of 11 Cases

This article aims to explore the characteristics of computed tomography (CT) images of ovarian vein syndrome (OVS). The approval of the research ethics committee and the written informed consent of the patients were obtained. The CT images of 11 patients who had been diagnosed with OVS were retrospectively analyzed. All patients were examined with CT urogram, both plain CT scans and enhanced CT scans (including arterial phase, venous phase, and secretory phase). The datum was pulled into a computer workstation for post-processing. Ureteral obstruction at the position and ureteral dilation above it, where the ovarian vein crosses over the ureter, were found in all 11 patients. In addition, 4 patients presented with right upper ureteric calculi, 10 with right renal calculi (including 8 patients with multiple renal calculi that also had obvious uronephrosis), and 2 with a urinary calculus or cystolith. The diameter of the ovarian vein in them ranged from 5 mm to 13 mm. Varicose veins around the uterus were found in 2 patients, and the diameter of the left ovarian vein was larger than 7 mm in 1 patient.In conclusion, analysis of CT images is a vital method in diagnosing OVS.