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Several studies on pregnancy-associated cancers have suggested an association with congenital anomalies in offspring. Previous studies have included maternal cancers diagnosed up to 2 years after pregnancy; however, long latency periods of some cancers mean that cancers diagnosed many years postpartum might have been present during pregnancy in a preclinical state. This paper considers the association between maternal cancers diagnosed from 2 years prior to pregnancy until the mother reaches 50 years of age, and congenital anomalies, as diagnosed at birth or within the first year of life. The current population-based study looks at associations of cancers in mothers with congenital anomalies in their children. Children were followed up from birth to diagnosis of a congenital anomaly, death, emigration or end of follow-up (whichever occurred first). A total of 56,016 children (2.6%) were considered exposed to a maternal cancer of any type; and they had a hazard ratio (HR) of 1.04 (95% confidence interval [CI]: 1.00, 1.09) compared with unexposed children. The greatest HR was seen among children whose mothers had been diagnosed with cancers before or during pregnancy (HR: 1.37, 95% CI: 1.07, 1.75). Similar results were seen when paternal cancers were used as a ‘negative control’. Statistically significant associations were seen for some specific congenital anomalies of organ systems (congenital anomalies of the musculoskeletal system [HR: 1.13, 95% CI: 1.02, 1.25]) and for some specific types of maternal cancer (leukaemia [HR: 1.31, 95% CI: 1.01, 1.61], The results of the main analyses suggest a small increase in risk of congenital anomalies in offspring of mothers diagnosed with cancer from 2 years before pregnancy, until the mother reaches 50 years of age; with the greatest increase seen for exposure in the pre-pregnancy and pregnancy period. These results may reflect shared causes for some cancers and some congenital anomalies. The similar results seen for paternal cancers indicate that the cause may be genetic or related to the families’ social and environmental conditions. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific antigen (PSA) testing for prostate cancer is controversial. There are unresolved tensions and disagreements amongst experts, and clinical guidelines conflict. This both reflects and generates significant uncertainty about the appropriateness of screening. Little is known about general practitioners’ (GPs’) perspectives and experiences in relation to PSA testing of asymptomatic men. In this paper we asked the following questions: (1) What are the primary sources of uncertainty as described by GPs in the context of PSA testing? (2) How do GPs experience and respond to different sources of uncertainty? Methods: This was a qualitative study that explored general practitioners’ current approaches to, and reasoning about, PSA testing of asymptomatic men. We draw on accounts generated from interviews with 69 general practitioners located in Australia (n = 40) and the United Kingdom (n = 29). The interviews were conducted in 2013–2014. Data were analysed using grounded theory methods. Uncertainty in PSA testing was identified as a core issue. Findings: Australian GPs reported experiencing substantially more uncertainty than UK GPs. This seemed partly explainable by notable differences in conditions of practice between the two countries. Using Han et al’s taxonomy of uncertainty as an initial framework, we first outline the different sources of uncertainty GPs (mostly Australian) described encountering in relation to prostate cancer screening and what the uncertainty was about. We then suggest an extension to Han et al’s taxonomy based on our analysis of data relating to the varied ways that GPs manage uncertainties in the context of PSA testing. We outline three broad strategies: (1) taking charge of uncertainty; (2) engaging others in managing uncertainty; and (3) transferring the responsibility for reducing or managing some uncertainties to other parties. Conclusion: Our analysis suggests some GPs experienced uncertainties associated with ambiguous guidance and the complexities of their situation as professionals with responsibilities to patients as considerably burdensome. This raises important questions about responsibility for uncertainty. In Australia in particular they feel insufficiently supported by the health care system to practice in ways that are recognisably consistent with ‘evidence based’ professional standards and appropriate for patients. More work is needed to clarify under what circumstances and how uncertainty should be communicated. Closer attention to different types and aspects of the uncertainty construct could be useful. [ABSTRACT FROM AUTHOR]

Background: To evaluate screening and treatment strategies, large-scale real-world data on liver disease-related outcomes are needed. We sought to validate health administrative data for identification of cirrhosis, decompensated cirrhosis and hepatocellular carcinoma among patients with known liver disease. Methods: Primary patient data were abstracted from patients of the Toronto Center for Liver Disease with viral hepatitis (2006–2014), and all patients with liver disease from the Kingston Health Sciences Centre Hepatology Clinic (2013). We linked clinical information to health administrative data and tested a range of coding algorithms against the clinical reference standard. Results: A total of 6,714 patients had primary chart data abstracted. A single physician visit code for cirrhosis was sensitive (98–99%), and a single hospital diagnostic code for cirrhosis was specific (91–96%). The most sensitive algorithm for decompensated cirrhosis was one cirrhosis code with any of: a hospital diagnostic code, death code, or procedure code for decompensation (range 88–99% across groups). The most specific was one cirrhosis code and one hospital diagnostic code (range 89–98% across groups). Two physician visit codes or a single hospital diagnostic code, death code, or procedure code combined with a code for cirrhosis were sensitive and specific for hepatocellular carcinoma (sensitivity 94–96%, specificity 93–98%). Conclusion: These sensitive and specific algorithms can be used to define patient cohorts or detect clinical outcomes using health administrative data. Our results will facilitate research into the adequacy of screening and treatment for patients with chronic viral hepatitis or other liver diseases. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the value of spectral CT in the differential diagnosis of benign from malignant pleural effusion. Method and materials: 14 patients with benign pleural effusion and 15 patients with malignant pleural effusion underwent non-contrast spectral CT imaging. These patients were later verified by the combination of disease history, clinical signs and other information with the consensus of surgeons and radiologists. Various Spectral CT image parameters measured for the effusion were as follows: CT numbers of the polychromatic 140kVp images, monochromatic images at 40keV and 100keV, the material density contents from the water, fat and blood-based material decomposition images, the effective atomic number and the spectral curve slope. These values were statistically compared with t test and logistic regression analysis between benign and malignant pleural effusion. Results: The CT value of benign and malignant pleural effusion in the polychromatic 140kVp images showed no differences (12.61±3.39HU vs. 14.71±5.03HU) (P>0.05), however, they were statistically different on the monochromatic images at 40keV (43.15±3.79 vs. 39.42±2.60, p = 0.005) and 100keV (9.11±1.38 vs. 6.52±2.04, p<0.001). There was difference in the effective atomic number value between the benign (7.87±0.08) and malignant pleural effusion (7.90±0.02) (P = 0.02). Using 6.32HU as the threshold for CT value measurement at 100keV, one could obtain sensitivity of 100% and specificity of 66.7% with area-under-curve of 0.843 for differentiating benign from malignant effusion. In addition, age and disease history were potential confounding factors for differentiating malignant pleural effusion from benign, since the older age (61.13±12.51 year-old vs48.57±12.33 year-old) as well as longer disease history (70.00±49.28 day vs.28.36±21.64 day) were more easily to be found in the malignant pleural effusion group than those in the benign pleural effusion group. By combining above five factors, one could obtain sensitivity of 100% and specificity of 71.4% with area-under-curve of 0.933 for differentiating benign from malignant effusion. Conclusion: The CT value measurement at both high and low energy levels and the effective atomic number obtained in a single spectral CT scan can assist the differential diagnosis of benign from malignant pleural effusion.Combining them with patient age and disease history can further improve diagnostic performance. Clinical relevance/Application: Clinical findings and Spectral CT imaging can provide significant evidences about the nature of pleural effusion. [ABSTRACT FROM AUTHOR]

Glioma is the most common malignant intracranial tumour. Recently, several publications have suggested that miRNAs can be used as potential diagnostic biomarkers of glioma. Here we performed a meta-analysis to identify the diagnostic accuracy of differentially expressed circulating miRNAs in gliomas. Using PubMed, Medline and Cochrane databases, we searched for studies which evaluated a single or panel of miRNAs from circulating blood as potential biomarkers of glioma. Sixteen publications involving 23 studies of miRNAs from serum or plasma met our criteria and were included in this meta-analysis. The pooled diagnostic parameters were calculated by random effect models and overall diagnostic performance of altered miRNAs was illustrated by the summary receiver operator characteristic (SROC) curves. The pooled sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) from each study were calculated. The pooled PLR, NLR and Diagnostic Odds Ratio were 6.39 (95% CI, 4.61–8.87), 0.15 (95% CI, 0.11–0.21) and 41.91 (95% CI, 23.15–75.88), respectively. The pooled sensitivity, specificity and area under the curve (AUC) were 0.87 (95% CI, 0.82–0.91), 0.86 (95% CI, 0.82–0.90) and 0.93 (95% CI, 0.91–0.95), respectively. This meta-analysis demonstrated that circulating miRNAs are capable of distinguishing glioma from healthy controls. Circulating miRNAs are promising diagnostic biomarkers for glioma and can potentially be used as a non-invasive early detection. [ABSTRACT FROM AUTHOR]

Background: Advances in bronchoscopy and CT-guided lung biopsy have improved the evaluation of small pulmonary lesions (PLs), leading to an increase in preoperative histological diagnosis. We aimed to evaluate the efficacy and safety of transbronchial lung biopsy using radial endobronchial ultrasound and virtual bronchoscopic navigation (TBLB-rEBUS&VBN) and CT-guided transthoracic needle biopsy (CT-TNB) for tissue diagnosis of small PLs. Methods: A systematic search was performed in five electronic databases, including MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, Web of Science, and Scopus, for relevant studies in May 2016; the selected articles were assessed using meta-analysis. The articles were limited to those published after 2000 that studied small PLs ≤ 3 cm in diameter. Results: From 7345 records, 9 articles on the bronchoscopic (BR) approach and 15 articles on the percutaneous (PC) approach were selected. The pooled diagnostic yield was 75% (95% confidence interval [CI], 69–80) using the BR approach and 93% (95% CI, 90–96) using the PC approach. For PLs ≤ 2 cm, the PC approach (pooled diagnostic yield: 92%, 95% CI: 88–95) was superior to the BR approach (66%, 95% CI: 55–76). However, for PLs > 2 cm but ≤ 3 cm, the diagnostic yield using the BR approach was improved to 81% (95% CI, 75–85). Complications of pneumothorax and hemorrhage were rare with the BR approach but common with the PC approach. Conclusions: CT-TNB was superior to TBLB-rEBUS&VBN for the evaluation of small PLs. However, for lesions greater than 2 cm, the BR approach may be considered considering its diagnostic yield of over 80% and the low risk of procedure-related complications. [ABSTRACT FROM AUTHOR]

Background: Exhaled volatile organic compounds (VOC) are being considered as biomarkers for various lungs diseases, including cancer. However, the accurate measurement of extremely low concentrations of VOC in expired air is technically challenging. We evaluated the clinical contribution of exhaled VOC measured with a new, double cold-trap method in the diagnosis of lung cancer. Methods: Breath samples were collected from 116 patients with histologically confirmed lung cancer and 37 healthy volunteers (controls) after inspiration of purified air, synthesized through a cold-trap system. The exhaled VOC, trapped in the same system, were heat extracted. We analyzed 14 VOC with gas chromatography. Results: The concentrations of exhaled cyclohexane and xylene were significantly higher in patients with lung cancer than in controls (p = 0.002 and 0.0001, respectively), increased significantly with the progression of the clinical stage of cancer (both p < 0.001), and decreased significantly after successful treatment of 6 patients with small cell lung cancer (p = 0.06 and 0.03, respectively). Conclusion: Measurements of exhaled VOCs by a double cold-trap method may help diagnose lung cancer and monitor its progression and regression. [ABSTRACT FROM AUTHOR]

Background: Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing.Methods and Findings: We validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of £339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of "real world" data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds.Conclusions: This study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers. [ABSTRACT FROM AUTHOR]

Background: The National Lung Screening Trial (NLST) results indicate that computed tomography (CT) lung cancer screening for current and former smokers with three annual screens can be cost-effective in a trial setting. However, the cost-effectiveness in a population-based setting with >3 screening rounds is uncertain. Therefore, the objective of this study was to estimate the cost-effectiveness of lung cancer screening in a population-based setting in Ontario, Canada, and evaluate the effects of screening eligibility criteria.Methods and Findings: This study used microsimulation modeling informed by various data sources, including the Ontario Health Insurance Plan (OHIP), Ontario Cancer Registry, smoking behavior surveys, and the NLST. Persons, born between 1940 and 1969, were examined from a third-party health care payer perspective across a lifetime horizon. Starting in 2015, 576 CT screening scenarios were examined, varying by age to start and end screening, smoking eligibility criteria, and screening interval. Among the examined outcome measures were lung cancer deaths averted, life-years gained, percentage ever screened, costs (in 2015 Canadian dollars), and overdiagnosis. The results of the base-case analysis indicated that annual screening was more cost-effective than biennial screening. Scenarios with eligibility criteria that required as few as 20 pack-years were dominated by scenarios that required higher numbers of accumulated pack-years. In general, scenarios that applied stringent smoking eligibility criteria (i.e., requiring higher levels of accumulated smoking exposure) were more cost-effective than scenarios with less stringent smoking eligibility criteria, with modest differences in life-years gained. Annual screening between ages 55-75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago yielded an incremental cost-effectiveness ratio of $41,136 Canadian dollars ($33,825 in May 1, 2015, United States dollars) per life-year gained (compared to annual screening between ages 60-75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago), which was considered optimal at a cost-effectiveness threshold of $50,000 Canadian dollars ($41,114 May 1, 2015, US dollars). If 50% lower or higher attributable costs were assumed, the incremental cost-effectiveness ratio of this scenario was estimated to be $38,240 ($31,444 May 1, 2015, US dollars) or $48,525 ($39,901 May 1, 2015, US dollars), respectively. If 50% lower or higher costs for CT examinations were assumed, the incremental cost-effectiveness ratio of this scenario was estimated to be $28,630 ($23,542 May 1, 2015, US dollars) or $73,507 ($60,443 May 1, 2015, US dollars), respectively. This scenario would screen 9.56% (499,261 individuals) of the total population (ever- and never-smokers) at least once, which would require 4,788,523 CT examinations, and reduce lung cancer mortality in the total population by 9.05% (preventing 13,108 lung cancer deaths), while 12.53% of screen-detected cancers would be overdiagnosed (4,282 overdiagnosed cases). Sensitivity analyses indicated that the overall results were most sensitive to variations in CT examination costs. Quality of life was not incorporated in the analyses, and assumptions for follow-up procedures were based on data from the NLST, which may not be generalizable to a population-based setting.Conclusions: Lung cancer screening with stringent smoking eligibility criteria can be cost-effective in a population-based setting. [ABSTRACT FROM AUTHOR]

Purpose: The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma. Experimental design: Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort. Results: The median age was 61 years (range 16–92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers. Conclusions: This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although bevacizumab (BV) has been approved as second-line therapy for recurrent glioblastoma (GB), the efficacy and safety of BV for patients with newly diagnosed GB remain unclear. Methodology/Principal Findings: We systematically searched electronic databases (PubMed, EMBASE, OVID, etc.) to identify related studies published from January 1966 and August 2016. Eight randomized controlled trials including a total of 2,185 patients with GB were included. We found that the median progression-free survival (PFS) was higher in the BV group than in the standard therapy (ST) group (pooled hazard ratio, 0.73; 95%CI, 0.62–0.86; P = 0.0001). Compared with ST, BV improved the PFS rate at 6 months (OR 3.33, 95% CI 2.73–4.06, p<0.00001) and 12 months (OR 2.10, 95% CI 1.74–2.54, p<0.00001). There were no significant differences in median overall survival between the BV and ST groups (OR, 1.01; 95%CI, 0.83–1.23; P = 0.95). The BV group had higher survival rates at 6 months (OR, 1.41; 95% CI, 1.09–1.84; P = 0.01) and 12 months (OR, 1.23; 95% CI, 1.02–1.48; P = 0.03), but a low survival rate at the 36-month follow-up (OR, 0.57; 95% CI, 0.32–0.98; P = 0.04). For the incidence of adverse events, three adverse outcomes were found to be significantly different between BV and ST groups, including hypertension (8.37% vs. 1.62%, p<0.000001), proteinuria (7.65% vs. 0%, p<0.001), and fatigue (14.54% vs. 9.01%, p = 0.05). Conclusions/Significance: Our study indicates that combination of BV with ST for newly diagnosed GB did not improve the median overall survival but result in longer median PFS, maintaining the quality of life and functional status. However, the long-term use of BV is associated with a higher incidence of adverse events and mortality. Study Registration: This research was registered at PROSPERO. (Registration Number: CRD42016038247). [ABSTRACT FROM AUTHOR]

Often, for medical decisions based on test scores, a single decision threshold is determined and the test results are dichotomized into positive and negative diagnoses. It is therefore important to identify the decision threshold with the least number of misclassifications. The proposed method uses trichotomization: it defines an Uncertain Interval around the point of intersection between the two distributions of individuals with and without the targeted disease. In this Uncertain Interval the diagnoses are intermixed and the numbers of correct and incorrect diagnoses are (almost) equal. This Uncertain Interval is considered to be a range of test scores that is inconclusive and does not warrant a decision. It is expected that defining such an interval with some precision, prevents a relatively large number of false decisions, and therefore results in an increased accuracy or correct classifications rate (CCR) for the test scores outside this Uncertain Interval. Clinical data and simulation results confirm this. The results show that the CCR is systematically higher outside the Uncertain Interval when compared to the CCR of the decision threshold based on the maximized Youden index. For strong tests with a very small overlap between the two distributions, it can be difficult to determine an Uncertain Interval. In simulations, the comparison with an existing method for test-score trichotomization, the Two-graph Receiver Operating Characteristic (TG-ROC), showed smaller differences between the two distributions for the Uncertain Interval than for TG-ROC’s Intermediate Range and consequently a more improved CCR outside the Uncertain Interval. The main conclusion is that the Uncertain Interval method offers two advantages: 1. Identification of patients for whom the test results are inconclusive; 2. A higher estimated rate of correct decisions for the remaining patients. [ABSTRACT FROM AUTHOR]

Purpose: Minimal axial diameter (MIAD) in magnetic resonance imaging (MRI) was recognized as the most useful parameter in diagnosing lateral retropharyngeal lymph (LRPL) nodes in nasopharyngeal carcinoma (NPC). This study aims to explore the additional nodal parameters in MRI and positron emission tomography–computed tomography for increasing the prediction accuracy. Materials and Methods: A total of 663 LRPL nodes were retrospectively collected from 335 patients with NPC. The LRPL nodes ascertained on follow-up MRI were considered positive for metastases. First, the optimal cutoff value of each parameter was derived for each parameter. In addition, neural network (NN) nodal evaluation was tested for all combinations of three parameters, namely MIAD, maximal axial diameter (MAAD), and maximal coronal diameter (MACD). The optimal approach was determined through brute force attack, and the results of two methods were compared using a bootstrap sampling method. Second, the mean standard uptake value (NSUVmean) was added as the fourth parameter and tested in the same manner for 410 nodes in 219 patients. Results: In first and second analysis, the accuracy rate (percentage) for the MIAD was 89.0% (590/663) and 89.0% (365/410), with the optimal cutoff values being 6.1 mm and 6.0 mm, respectively. With the combination of all three and four parameters, the accuracy rate of the NN was 89% (288/332) and 88.8% (182/205), respectively. In prediction, the optimal combinations of the three and four parameters resulted in correct identification of three (accuracy: 593/663, 89.4%) and six additional nodes (371/410, 90.5%), representing 4% (3/73) and 13.3% (6/45) decreases in incorrect prediction, respectively. Conclusion: NPC LRPL nodes with an MIAD ≥ 6.1 mm are positive. Among nodes with an MIAD < 6.1 mm, if the NSUVmean ≥ 2.6 or MACD ≥ 25 mm and MAAD ≥ 8 mm, the nodes are positive; otherwise, they are negative. [ABSTRACT FROM AUTHOR]

Background: Glioma remains a diagnostic challenge because of its variable clinical presentation and a lack of reliable screening tools. Long noncoding RNAs (lncRNAs) regulate gene function in a wide range of pathophysiological processes and are therefore emerging biomarkers for prostate cancer, hepatic cancer, and other tumor diseases. However, the effective use of lncRNAs as biomarkers for the diagnosis of glioma remains unproven. Methods: This study included 42 glioma patients and 10 healthy controls. lncRNA and mRNA microarray chips were used to identify dysregulated lncRNAs in tumor tissue and tumor-adjacent normal tissue, and SYBR Green–based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate upregulated lncRNAs. A receiver operating characteristic curve analysis was conducted to evaluate the diagnostic accuracy of the lncRNA identified as the candidate biomarker. Results: miR210HG levels were significantly higher in tumor tissue than in tumor-adjacent normal tissue in participating glioma patients. Serum miR210HG levels were also significantly higher in glioma patients than in healthy controls. The receiver operating characteristic curve showed that serum miR210HG was a specific diagnostic predictor of acute pulmonary embolism with an area under the curve of 0.8323 (95% confidence interval, 0.7347 to 0.9299, p < 0.001). Conclusion: Our findings indicate that miR210HG could be an important biomarker for the diagnosis of glioma, and, as such, large-scale investigations are urgently needed to pave the way from basic research to clinical use. [ABSTRACT FROM AUTHOR]

Current screening methods towards prostate cancer (PCa) are not without limitations. Research work has been on-going to assess if there are other better tests suitable for primary or secondary screening of PCa to supplement the serum prostate specific antigen (PSA) test, which fails to work accurately in a grey zone of 4-10ng/ml. In this pilot study, the potential roles of urinary polyamines as prostate cancer biomarkers were evaluated. PCa, benign prostatic hyperplasia (BPH) patients and healthy controls (HC) showing PSA>4.0ng/ml were enrolled in the study. Their urine samples were obtained, and the urinary levels of putrescine (Put), spermidine (Spd) and spermine (Spm) were determined by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS). Receiver operating characteristics (ROC) curve and Student’s t-test were used to evaluate their diagnostic accuracies. Among the three biogenic polyamines, Spm had demonstrated a good diagnostic performance when comparing their levels in PCa patients with BPH patients (1.47 in PCa vs 5.87 in BPH; p<0.0001). Results are in accordance with transrectal ultrasound prostatic biopsy (TRUSPB) results, with an area under curve (AUC) value of 0.83±0.03. Therefore urinary Spm shows potential to serve as a novel PCa diagnostic biomarker, which in turn can help to address the limited sensitivity and specificity problem of serum PSA test. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the role of high-resolution magic angle spinning (HR-MAS) 1H nuclear magnetic resonance (NMR) spectroscopy in patients with ductal carcinoma in situ (DCIS) diagnosed on preoperative biopsy. We investigated whether the metabolic profiling of tissue samples using HR-MAS 1H NMR spectroscopy could be used to distinguish between DCIS lesions with or without an invasive component. Our institutional review board approved this combined retrospective and prospective study. Tissue samples were collected from 30 patients with pure DCIS and from 30 with DCIS accompanying invasive carcinoma. All patients were diagnosed with DCIS by preoperative core-needle biopsy and underwent surgical resection. The metabolic profiling of tissue samples was performed by HR-MAS 1H NMR spectroscopy. All observable metabolite signals were identified and quantified in all tissue samples. Metabolite intensity normalized by total spectral intensities was compared according to the tumor type using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA). By univariate analysis, the metabolite concentrations of choline-containing compounds obtained with HR-MAS 1H NMR spectroscopy did not differ significantly between the pure DCIS and DCIS accompanying invasive carcinoma groups. However, the GPC/PC ratio was higher in the pure DCIS group than in the DCIS accompanying invasive carcinoma group (p = 0.004, Bonferroni-corrected p = 0.064), as well as the concentration of myo-inositol and succinate. By multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles could clearly discriminate between pure DCIS and DCIS accompanying invasive carcinoma. Our preliminary results suggest that HR-MAS MR metabolomics on breast tissue may be able to distinguish between DCIS lesions with or without an invasive component. [ABSTRACT FROM AUTHOR]

Objective: The aim of our study was to evaluate the role of 18F-FDG PET/CT integrated imaging in differentiating malignant from benign pleural effusion. Methods: A total of 176 patients with pleural effusion who underwent 18F-FDG PET/CT examination to differentiate malignancy from benignancy were retrospectively researched. The images of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging were visually analyzed. The suspected malignant effusion was characterized by the presence of nodular or irregular pleural thickening on CT imaging. Whereas on PET imaging, pleural 18F-FDG uptake higher than mediastinal activity was interpreted as malignant effusion. Images of 18F-FDG PET/CT integrated imaging were interpreted by combining the morphologic feature of pleura on CT imaging with the degree and form of pleural 18F-FDG uptake on PET imaging. Results: One hundred and eight patients had malignant effusion, including 86 with pleural metastasis and 22 with pleural mesothelioma, whereas 68 patients had benign effusion. The sensitivities of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging in detecting malignant effusion were 75.0%, 91.7% and 93.5%, respectively, which were 69.8%, 91.9% and 93.0% in distinguishing metastatic effusion. The sensitivity of 18F-FDG PET/CT integrated imaging in detecting malignant effusion was higher than that of CT imaging (p = 0.000). For metastatic effusion, 18F-FDG PET imaging had higher sensitivity (p = 0.000) and better diagnostic consistency with 18F-FDG PET/CT integrated imaging compared with CT imaging (Kappa = 0.917 and Kappa = 0.295, respectively). The specificities of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging were 94.1%, 63.2% and 92.6% in detecting benign effusion. The specificities of CT imaging and 18F-FDG PET/CT integrated imaging were higher than that of 18F-FDG PET imaging (p = 0.000 and p = 0.000, respectively), and CT imaging had better diagnostic consistency with 18F-FDG PET/CT integrated imaging compared with 18F-FDG PET imaging (Kappa = 0.881 and Kappa = 0.240, respectively). Conclusion: 18F-FDG PET/CT integrated imaging is a more reliable modality in distinguishing malignant from benign pleural effusion than 18F-FDG PET imaging and CT imaging alone. For image interpretation of 18F-FDG PET/CT integrated imaging, the PET and CT portions play a major diagnostic role in identifying metastatic effusion and benign effusion, respectively. [ABSTRACT FROM AUTHOR]

We previously developed a method for determining MYCN gene amplification status using cell-free DNA fragments released from cancer cells into the blood of patients with neuroblastoma (NB). Here, we analyzed the relationship between MYCN amplification (MNA) status and neuroblastoma prognosis. We screened serum samples from 151 patients with NB for MNA, using real-time quantitative PCR, and compared the results with MYCN status determined using paired tumor samples. We additionally investigated whether MNA status correlates with patient survival. When a cut-off value of 5 was used, serum-based MNA analysis was found to show good sensitivity (86%) and very high specificity (95%). The sensitivities for stage 1 and 2 might be acceptable, even though it is not as good as for stage 3 and 4 (67% for stage 1 and 2, 92% for stage 3, and 87% for stage 4). MNA status correlated with overall survival in our cohort of 82 patients, with survival data available (p < 0.01). The hazard ratio of MNA status was 4.98 in patients diagnosed at less than 18 months of age (95% confidence interval, 1.00–24.78), and 1.41 (95% confidence interval, 0.63–3.14) for those diagnosed at 18 months of age or older. Serum-based MNA analysis is rapid and non-invasive compared with tumor-based MNA analysis, and has potential to predict tumor MNA status. There is still a room to improve the sensitivity of the test for tumors of stages 1 and 2, nonetheless this assay might help to determine therapeutic strategies prior to tumor biopsy, especially for patients with a life-threatening condition, as well as for patients of less than 18 months of age whose risk-grouping and treatment allocation depends on their MNA status. [ABSTRACT FROM AUTHOR]

Introduction: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score.Methods and Findings: Diagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow-up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96-2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04-5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25-7.80]) and Group 5 (HR 17.28 [95% CI 11.2-26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short.Conclusions: A novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance. [ABSTRACT FROM AUTHOR]

Background: A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models. Methods: An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient-derived neurospheres (TS543) and U251 cells, with different degrees of blood-brain barrier (BBB) disruption were also used for PET imaging experiments. Results: 89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models. Conclusion: A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In vivo validation showed high-specific-contrast imaging of MT1-MMP positive GBM tumors and provided strong evidence for utility of MT1-MMP-targeted immunoPET as an alternate to nonspecific imaging of GBM. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the diagnostic performance of an automated analysis tool for the assessment of prostate cancer based on multiparametric magnetic resonance imaging (mpMRI) of the prostate. Methods: A fully automated analysis tool was used for a retrospective analysis of mpMRI sets (T2-weighted, T1-weighted dynamic contrast-enhanced, and diffusion-weighted sequences). The software provided a malignancy prediction value for each image pixel, defined as Malignancy Attention Index (MAI) that can be depicted as a colour map overlay on the original images. The malignancy maps were compared to histopathology derived from a combination of MRI-targeted and systematic transperineal MRI/TRUS-fusion biopsies. Results: In total, mpMRI data of 45 patients were evaluated. With a sensitivity of 85.7% (with 95% CI of 65.4–95.0), a specificity of 87.5% (with 95% CI of 69.0–95.7) and a diagnostic accuracy of 86.7% (with 95% CI of 73.8–93.8) for detection of prostate cancer, the automated analysis results corresponded well with the reported diagnostic accuracies by human readers based on the PI-RADS system in the current literature. Conclusion: The study revealed comparable diagnostic accuracies for the detection of prostate cancer of a user-independent MAI-based automated analysis tool and PI-RADS-scoring-based human reader analysis of mpMRI. Thus, the analysis tool could serve as a detection support system for less experienced readers. The results of the study also suggest the potential of MAI-based analysis for advanced lesion assessments, such as cancer extent and staging prediction. [ABSTRACT FROM AUTHOR]

Background: The appropriate management of the large number of lung nodules detected during the course of routine medical care presents a challenge. We aimed to evaluate the usual clinical practice in solitary pulmonary nodule (SPN) management and associated radiation exposure. Methods: We examined 893 radiology reports of consecutive patients undergoing chest computed tomography (CT) and radiography at two public hospitals in Spain. Information on diagnostic procedures from SPN detection and lung cancer diagnosis was collected prospectively for 18 months. Results: More than 20% of patients with SPN detected on either chest radiograph (19.8%) or CT (26.1%) underwent no additional interventions and none developed lung cancer (100% negative predictive value). 346 (72.0%) patients with SPN detected on chest radiograph and 254 (61.5%) patients with SPN detected on CT had additional diagnostic tests and were not diagnosed with lung cancer. In patients undergoing follow-up imaging for SPNs detected on CT median number of additional imaging tests was 3.5 and the mean cumulative effective dose was 24.4 mSv; for those detected on chest radiograph the median number of additional imaging tests was 2.8 and the mean cumulative effective dose was 10.3 mSv. Conclusions: Patients who did not have additional interventions were not diagnosed of lung cancer. There was an excessive amount of interventions in a high percentage of patients presenting SPN, which was associated with an excess of radiation exposure. [ABSTRACT FROM AUTHOR]

Recent studies suggest that extracellular vesicles may be the key to timely diagnosis and monitoring of genito-urological malignancies. In this study we investigated the composition and content of extracellular vesicles found in the urine of healthy donors and prostate cancer patients. Urine of 14 PCa patients and 20 healthy volunteers was clarified by low-speed centrifugation and total extracellular vesicles fraction was obtain by high-speed centrifugation. The exosome-enriched fraction was obtained by filtration of total extracellular vesicles through a 0.1 μm pore filter. Transmission electron microscopy showed that cell-free urine in both groups contained vesicles from 20 to 230 nm. Immunogold staining after ultrafiltration demonstrated that 95% and 90% of extracellular vesicles in healthy individuals and cancer patients, respectively, were exosomes. Protein, DNA and RNA concentrations as well as size distribution of extracellular vesicles in both fractions were analyzed. Only 75% of the total protein content of extracellular vesicles was associated with exosomes which amounted to 90–95% of all vesicles. Median DNA concentrations in total extracellular vesicles and exosome-enriched fractions were 18 pg/ml and 2.6 pg/ml urine, correspondingly. Urine extracellular vesicles carried a population of RNA molecules 25 nt to 200 nt in concentration of no more than 290 pg/ml of urine. Additionally, concentrations of miR-19b, miR-25, miR-125b, and miR-205 were quantified by qRT-PCR. MiRNAs were shown to be differently distributed between different fractions of extracellular vesicles. Detection of miR-19b versus miR-16 in total vesicles and exosome-enriched fractions achieved 100%/93% and 95%/79% specificity/sensitivity in distinguishing cancer patients from healthy individuals, respectively, demonstrating the diagnostic value of urine extracellular vesicles. [ABSTRACT FROM AUTHOR]

Despite being the basis of one of the most effective interventions in lung cancer, little is known about the patterns of epidermal growth factor receptor (EGFR) mutation testing in the general population. We assessed the frequencies and determinants of EGFR testing and erlotinib treatment among a population-based sample. A random sample (n = 1,358) of patients diagnosed in 2010 with histologically-confirmed NSCLC, as reported to the Surveillance Epidemiology and End Results (SEER) program, had their medical records abstracted and treating physicians queried. Logistic regression was used to identify factors associated with EGFR testing and erlotinib treatment. Survival was examined using Cox proportional hazards regression. The frequency of EGFR testing was 16.8% overall and 22.6% for stage IV adenocarcinoma patients. Given an EGFR mutation, 33.6% of all patients and 48.3% of stage IV patients received erlotinib. Among stage IV patients, increased age, Medicaid/no/unknown insurance status, death within 2 months of diagnosis and comorbidity were inversely associated with EGFR testing; erlotinib treatment was less likely among smokers and patients with non-adenocarcinomas. EGFR-mutation was associated with improved survival, albeit only among stage IV adenocarcinomas. Less than a quarter of NSCLC patients diagnosed in 2010 received EGFR testing and less than half of the patients with EGFR-mutant stage IV tumors received erlotinib. Significant disparities were observed in EGFR mutation testing by health insurance status, comorbidity and age. A national strategy is imperative to ensure that resources and processes are in place to efficiently implement molecular testing of cancer. [ABSTRACT FROM AUTHOR]

Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS) data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR) to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]). However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months). The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real-world observational data, is needed to compare effectiveness between cabozantinib and nivolumab. [ABSTRACT FROM AUTHOR]

Objective: Despite recent advances in imaging and core or endoscopic biopsies, a percentage of patients have a major lung resection without diagnosis. We aimed to assess the feasibility of a rapid tissue preparation/analysis to discriminate cancerous from non-cancerous lung tissue. Methods: Fresh sample preparations were analyzed with the Microflex LTTM MALDI-TOF analyzer. Each main reference spectra (MSP) was consecutively included in a database. After definitive pathological diagnosis, each MSP was labeled as either cancerous or non-cancerous (normal, inflammatory, infectious nodules). A strategy was constructed based on the number of concordant responses of a mass spectrometry scoring algorithm. A 3-step evaluation included an internal and blind validation of a preliminary database (n = 182 reference spectra from the 100 first patients), followed by validation on a whole cohort database (n = 300 reference spectra from 159 patients). Diagnostic performance indicators were calculated. Results: 127 cancerous and 173 non-cancerous samples (144 peripheral biopsies and 29 inflammatory or infectious lesions) were processed within 30 minutes after biopsy sampling. At the most discriminatory level, the samples were correctly classified with a sensitivity, specificity and global accuracy of 92.1%, 97.1% and 95%, respectively. Conclusions: The feasibility of rapid MALDI-TOF analysis, coupled with a very simple lung preparation procedure, appears promising and should be tested in several surgical settings where rapid on-site evaluation of abnormal tissue is required. In the operating room, it appears promising in case of tumors with an uncertain preoperative diagnosis and should be tested as a complementary approach to frozen-biopsy analysis. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the clinical features and prognostic factors associated with the survival of patients with a very rare occurrence of brain metastasis (BM) from differentiated thyroid cancer (DTC). Methods and Materials: A total of 37 patients with DTC who were diagnosed with BM between 1995 and 2014 were included. We reviewed the clinical characteristics, treatment modalities, and image findings of BM. Factors associated with survival were evaluated, and the patients were divided into three prognostic groups (Groups A, B, and C) for comparative analysis. Results: The median age at BM was 63 years, and the median time from initial thyroid cancer diagnosis to BM was 3.8 years. The median survival and the 1-year actuarial survival rate after BM were 8.8 months and 47%, respectively. According to univariate and multivariate analyses, four good prognostic factors (GPFs) were identified including age ≤ 60 years, PS ≤ ECOG 2, ≤ 3 BM sites, and without extracranial metastasis prior to BM. Three prognostic groups were designed based on age and number of remaining GPFs: patients ≤ 60 years of age with at least 2 GPFs (Group A) had the most favorable prognosis with a median survival of 32.8 months; patients ≤ 60 years of age with fewer than 2 GPFs and those > 60 years of age with at least 2 GPFs (Group B) had an intermediate prognosis with a median survival of 9.4 months; and patients > 60 years of age with fewer than 2 GPFs (Group C) had the least favorable prognosis with a median survival of 1.5 months. Conclusions: The survival of patients with BM form DTC differed among the prognostic groups based on the total number of good prognostic factors. [ABSTRACT FROM AUTHOR]

The inevitable switch from standard molecular methods to next-generation sequencing for the molecular profiling of tumors is challenging for most diagnostic laboratories. However, fixed validation criteria for diagnostic accreditation are not in place because of the great variability in methods and aims. Here, we describe the validation of a custom panel of hotspots in 24 genes for the detection of somatic mutations in non-small cell lung carcinoma, colorectal carcinoma and malignant melanoma starting from FFPE sections, using 14, 36 and 5 cases, respectively. The targeted hotspots were selected for their present or future clinical relevance in solid tumor types. The target regions were enriched with the TruSeq approach starting from limited amounts of DNA. Cost effective sequencing of 12 pooled libraries was done using a micro flow cell on the MiSeq and subsequent data analysis with MiSeqReporter and VariantStudio. The entire workflow was diagnostically validated showing a robust performance with maximal sensitivity and specificity using as thresholds a variant allele frequency >5% and a minimal amplicon coverage of 300. We implemented this method through the analysis of 150 routine diagnostic samples and identified clinically relevant mutations in 16 genes including KRAS (32%), TP53 (32%), BRAF (12%), APC (11%), EGFR (8%) and NRAS (5%). Importantly, the highest success rate was obtained when using also the low quality DNA samples. In conclusion, we provide a workflow for the validation of targeted NGS by a custom-designed pan-solid tumor panel in a molecular diagnostic lab and demonstrate its robustness in a clinical setting. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, have been associated with lowered cancer incidence and mortality. We examined overall cancer mortality and mortality from specific cancer sites among the 80,144 men in the Finnish Prostate Cancer Screening Trial. Information on prescription drug use was acquired from the national drug reimbursement database. Over-the-counter use information was gathered by a questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) by prescription and over-the-counter NSAID use for overall and specific cancer deaths were calculated using Cox regression. During the median follow-up time of 15 years, 7,008 men died from cancer. Men with prescription NSAID use had elevated cancer mortality (HR 2.02 95% CI 1.91–2.15) compared to non-users. The mortality risk was increased for lung, colorectal and pancreas cancer mortality (HR 2.68, 95%CI 2.40–2.99, HR 1.91, 95% CI 1.57–2.32 and HR 1.93, 95% CI 1.58–2.37, respectively). The increased risk remained in competing risks regression (HR 1.11, 95% CI 1.05–1.18). When the usage during the last three years of follow-up was excluded, the effect was reversed (HR 0.69, 95% CI 0.65–0.73). Cancer mortality was not decreased for prescription or over-the-counter aspirin use. However, in the competing risk regression analysis combined prescription and over-the-counter aspirin use was associated with decreased overall cancer mortality (HR 0.76, 95% CI 0.70–0.82). Cancer mortality was increased for NSAID users. However, the risk disappeared when the last 3 years were excluded. [ABSTRACT FROM AUTHOR]

Blood-circulating miRNAs could be useful as a biomarker to detect lung cancer early. We investigated the serum levels of four different miRNAs in patients with non-small cell lung cancer (NSCLC) and assessed their diagnostic value for NSCLC. Serum samples from 112 NSCLC patients and 104 controls (20 current smokers without lung cancer, 23 pneumonia patients, 21 gastric cancer patients, and 40 healthy controls) were subjected to Taqman probe-based quantitative reverse transcription–polymerase chain reaction (RT-PCR). The data showed that the serum levels of miR-182, miR-183, and miR-210 were significantly upregulated and that the miR-126 level was significantly downregulated in NSCLC patients, compared with the healthy controls. Further receiver operating characteristic (ROC) curve analysis revealed that the serum miR-182, miR-183, miR-210, or miR-126 level could serve as a diagnostic biomarker for NSCLC early detection, with a high sensitivity and specificity. The combination of these four miRNAs with carcinoembryonic antigen (CEA) further increased the diagnostic value, with an area under the curve (AUC) of 0.965 (sensitivity, 81.3%; specificity, 100.0%; and accuracy, 90.8%) using logistic regression model analysis. In addition, the relative levels of serum miR-182, miR-183, miR-210, and miR-126 could distinguish NSCLC or early-stage NSCLC from current tobacco smokers without lung cancer and pneumonia or gastric cancer patients with a high sensitivity and specificity. Data from the current study validated that the four serum miRNAs could serve as a tumor biomarker for NSCLC early diagnosis. [ABSTRACT FROM AUTHOR]

An efficient serum marker for hepatocellular carcinoma (HCC) is currently lacking and requires intensive exploration. We aimed to evaluate the performance of des-gamma-carboxy prothrombin (DCP) for identifying hepatitis B virus-related HCC in a large, multicentre study in China. A total of 1034 subjects in three cohorts (A, B, and C) including HCC and various non-HCC controls were enrolled from 4 academic medical centers in China from January 2011 to February 2014. Blind parallel detections were conducted for DCP and AFP. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic efficacies. In cohort A, which comprised 521 subjects, including patients with HCC, liver metastasis, liver cirrhosis (LC), and liver hemangiomas as well as healthy controls (HCs), the accuracy of DCP for distinguishing HCC from various controls was 6.2–9.7% higher than that of AFP. In cohort B, which comprised 447 subjects, including patients with HCC, LC, and chronic hepatitis B as well as HC, the accuracy of DCP was further elevated (12.3–20.67% higher than that of AFP). The superiority of DCP to AFP was more profound in the surveillance of early HCC [AUC 0.837 (95% CI: 0.771–0.903) vs. 0.650 (0.555–0.745)] and AFP-negative HCC [AUC: 0.856 (0.798–0.914)] and in discriminating HCC from LC (accuracy: 92.9% vs.64.71%). Higher DCP levels were associated with worse clinical behaviors and shorter disease-free survival. DCP not only is complementary to AFP in identifying AFP-negative HCC and in excluding AFP-positive non-HCC (liver cirrhosis), but also demonstrates improved performance in HCC surveillance, early diagnosis, treatment response and recurrence monitoring in the HBV-related population. [ABSTRACT FROM AUTHOR]

Introduction: Screening for prostate cancer remains controversial because of conflicting results from the two major trials: The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). Objective: Meta-analyze and meta-regress the available PSA screening trials. Methods: We performed a living systematic review and meta-regression of the reduction in prostate cancer mortality as a function of the duration of screening provided in each trial. We searched PubMed, Web of Science, the Cochrane Registry, and references lists from previous meta-analyses to identify randomized trials of PSA screening. We followed PRISMA guidelines and qualified strength of evidence with a GRADE Profile. Results: We found 6 trials, but excluded one that also screened with trans-rectal ultrasound. We considered each ERSPC center as a separate trial. When pooling together all 11 trials we found no significant benefit from screening; however, the heterogeneity was 28.2% (95% CI: 0% to 65%). Heterogeneity was explained by variations in the duration of serial screening (I2 0%; 95% CI: 0% to 52%). When we analyzed the subgroup of trials that added more than 3 years of screening (range 3.2 to 3.8) we found a significant benefit for screening with risk ratio 0.78 (95% CI 0.65–0.94; I2 = 0%; 95% CI: 0% to 69%) and a number needed to invite for screening of 1000. We downgraded the quality of evidence to moderate due to our retrospective identification of subgroups and limited data on control group screening. Conclusions: Adequate duration of screening reduces mortality from prostate cancer. The benefit, while small, compares favorably with screening for other cancers. Our projections are limited by the moderate quality of evidence. [ABSTRACT FROM AUTHOR]

Objective: Meningioma of the cranio-cervical junction is a rare diagnosis and demand a thorough surgical planning as radical excision of these tumors is difficult. In this context recurrence is most likely due to regrowth of residual tumor. The aim of this study was to evaluate the clinical course of patients operated for craniocervical meningioma (CCM) and to investigate the histological features of these tumors and their impact on recurrence rate. Methods: All patients who were operated for CCM at our institution between 2003 and 2012 were identified. Presenting symptoms, MRI findings, surgical approaches and recurrence rate were reviewed retrospectively using medical charts. Histological features of the included tumors were studied focusing on subtypes and MIB-1 immunoreactivity and compared with MIB-1 immunoreactivity in an age and gender-matched control group of patients with supratentorial meningioma. Results: 18 patients with CCM with a mean age of 56.2 years and median follow-up of 60 months were included in the study. Sensory or motor deficit was the most frequent presenting symptom followed by neck pain and lower cranial nerve palsy. Simpson grade II resection was achieved in 16 patients and Simpson grade III resection in two patients. Mortality, morbidity and recurrence rates were 16.7%, 5.5% and 5.5%, respectively. According to the WHO-grading all were found to be grade I meningiomas. Histological subtypes included meningotheliomatous (10), transitional (2), fibrillar (2), angiomatous (3) and secretory (1) meningioma. The mean MIB-1 labeling index in the study group was significantly higher than in the control group, (7.2% and 3.6%, respectively), p < 0.05. There was no correlation between MIB-1 levels and tumor recurrence. Conclusions: CCM seems to have a benign character. Despite a significantly higher MIB-1 index, a high rate of recurrence was not observed. Therefore, approaches with high morbidity are not justified. Nevertheless, in view of the challenging approaches with limited access to the lesion, CCM should be considered a distinctive clinical subgroup. [ABSTRACT FROM AUTHOR]

Importance: Decision support tools can assist people to apply population-based evidence on benefits and harms to individual health decisions. A key question is whether “personalising” choice within decisions aids leads to better decision quality. Objective: To assess the effect of personalising the content of a decision aid for prostate cancer screening using the Prostate Specific Antigen (PSA) test. Design: Randomized controlled trial. Setting: Australia. Participants: 1,970 men aged 40–69 years were approached to participate in the trial. Intervention: 1,447 men were randomly allocated to either a standard decision aid with a fixed set of five attributes or a personalised decision aid with choice over the inclusion of up to 10 attributes. Outcome Measures: To determine whether there was a difference between the two groups in terms of: 1) the emergent opinion (generated by the decision aid) to have a PSA test or not; 2) self-rated decision quality after completing the online decision aid; 3) their intention to undergo screening in the next 12 months. We also wanted to determine whether men in the personalised choice group made use of the extra decision attributes. Results: 5% of men in the fixed attribute group scored ‘Have a PSA test’ as the opinion generated by the aid, as compared to 62% of men in the personalised choice group (χ2 = 569.38, 2df, p< 0001). Those men who used the personalised decision aid had slightly higher decision quality (t = 2.157, df = 1444, p = 0.031). The men in the personalised choice group made extensive use of the additional decision attributes. There was no difference between the two groups in terms of their stated intention to undergo screening in the next 12 months. Conclusions: Together, these findings suggest that personalised decision support systems could be an important development in shared decision-making and patient-centered care. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) [ABSTRACT FROM AUTHOR]

Background: Acute lymphoblastic leukemia (ALL) is more common in children than in adults. Secondary neoplasms (SNs) in childhood ALL have been widely reported. However, only one study has demonstrated SNs in adult ALL. Because of the poorer survival of adult ALL, the incidence might be underestimated. Objective: To evaluate the incidence and risk factors of secondary solid organ neoplasms among adult and child ALL patients. Methods: Newly diagnosed ALL patients between 1997 and 2011 were recruited from the Taiwan National Health Insurance database. Those who had antecedent or combined malignancies were excluded. Standardized incidence ratios (SIRs) were analyzed to compare the risk of our cohort to general population in the same age, sex and calendar year. Risk factors for SN development were analyzed by Cox proportional hazards models. Effects of treatments were treated as time-dependent variables. Results: The 15-year cumulative incidence of SN was 1.9% and 8.4% in 1,381 child and 2,154 adult ALL patients, respectively. The SIR was significantly increased in child ALL (SIR 6.06), but not in adult ALL (SIR 1.16). The SIRs of follow-up periods were 5.14, 2.24, .87 and .71 at ≥ 10 years, 5–10 years, 1–5 years and 0–1, respectively. Overall, 15 SNs developed, and CNS tumors (SIR 11.56) were the most common type. Multivariate analysis showed that age ≥ 20 years (hazard ratio [HR] 5.04), end-stage renal disease (HR 18.98) and cranial irradiation (HR 8.12) were independent risk factors for cancer development. Conclusions: When compared with the general population, child ALL shows a increased risk of developing SNs. CNS tumors are the most common type, and cranial irradiation is an independent risk factor. With longer follow-up, the risk of SNs increases. Hence, physicians need to pay more attention on the risk of developing SNs in long-term ALL survivors with risk factors. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is both common and highly lethal and therefore new biomarkers or potential targets for treatment are needed. Loss of BRCA associated protein-1 (BAP1) expression has been found in up to a quarter of intrahepatic cholangiocarcinomas. Given the close anatomical relationship between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma, we therefore sought to investigate the frequency of loss of BAP1 expression in pancreatic ductal adenocarcinoma. Methods: The records of the department of Anatomical Pathology Royal North Shore Hospital, Sydney, Australia, were searched for cases of pancreatic ductal adenocarcinoma diagnosed between 1992 and 2014 with material available in archived formalin fixed paraffin embedded tissue blocks. Immunohistochemistry for BAP1 was performed on tissue microarray sections and if staining was equivocal or negative it was confirmed on whole sections. Negative staining for BAP1 was defined as loss of expression in all neoplastic nuclei, with preserved expression in non-neoplastic cells which acted as an internal positive control. Results: Loss of BAP1 expression was found in only 1 of 306 (0.33%) pancreatic ductal adenocarcinomas. This case was confirmed to demonstrate diffuse loss of expression throughout all neoplastic cells in multiple blocks, consistent with BAP1 loss being an early clonal event. All other cases demonstrated positive expression of BAP1. Conclusion: We conclude that, in contrast to intrahepatic cholangiocarcinoma, loss of expression of BAP1 occurs very rarely in pancreatic ductal adenocarcinoma. Therefore BAP1 inactivation is unlikely to be a frequent driver abnormality in pancreatic adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. Summary Background Data: Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over-expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. Methods: Bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, linear regression, multiple regression, and receiver operating characteristic (ROC) curve analysis. Results: Bile from 83 patients was analyzed: 42 with benign disease and 41 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower median biliary CEACAM6 levels than patients in the malignant cohort (7.5 ng/ml vs. 40 ng/ml; p = <.001). ROC curve analysis determined CEACAM6 to be a positive predictor cholangiocarcinoma with a CEACAM6 level >14 ng/ml associated with 87.5% sensitivity, 69.1% specificity, and a likelihood ratio of 2.8 (AUC 0.74). Multiple regression analysis suggested elevated alkaline phosphatase and the presence of biliary endoprostheses may influence CEACAM6 levels. Conclusion: Biliary CEACAM6 can identify patients with extrahepatic cholangiocarcinoma with a high degree of sensitivity and should be investigated further as a potential screening tool. [ABSTRACT FROM AUTHOR]

Introduction: Proliferation and apoptosis are opposing processes by which the cell numbers are kept in a delicate balance, essential for tissue homeostasis, whereas uncontrolled growth of cells is a hallmark of cancer. Papillary thyroid cancer (PTC) is the commonest type of thyroid cancer, with some PTC following an indolent course, whereas the other ones are more aggressive. Aim: To evaluate respective contribution of proliferation and apoptosis in the tumorigenesis of PTC by automated analysis. Materials and Methods: We investigated the immunolabeling of phosphorylated histone H3 (pHH3), cyclin D1, active caspase-3, and bcl-2 in thirteen cases each of metastatic PTC, follicular variant of PTC (FVPTC), papillary microcarcinoma (PMC) and well differentiated tumor of uncertain malignant potential (WDT-UMP). FVPTC cases comprised seven encapsulated and six unencapsulated cases. Results: Proliferation, as assessed by pHH3 and cyclin D1 immunolabeling, was increased in all PTC variants, including the putative precursor lesion WDT-UMP, compared to normal thyroid tissue. pHH3 was immunolabeled in more cells of metastatic PTC than of PMC and of encapsulated FVPTC. Surprisingly, metastatic PTC and unencapsulated FVPTC also demonstrated more cleaved caspase-3 immunolabeled cells than the other types. In contrast, increased expression of bcl-2 protein was seen in normal thyroid areas, encapsulated FVPTC and PMC as compared to metastatic PTC. Metastatic PTC shows higher proliferation than other types of PTC but unexpectedly also higher apoptotic levels. Similar results were also seen with unencapsulated FVPTC, thus suggesting that unencapsulated FVPTC has a potential for adverse outcome. Bcl-2 was immunolabeled in a low percentage of cells in WDT-UMP. Conclusions: The expression of the proliferative protein pHH3 together with the apoptotic marker cleaved caspase-3 may indicate an aggressive behaviour of PTC and loss of apoptosis inhibition by bcl-2 protein can further amplify the role of these proteins in tumor progression. Both cyclin D1 and bcl-2 could prove to be interesting markers of PTC precursor lesions. Automated/digital image quantification approach helps in refining the diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Objective: Fine needle aspiration cytology (FNAC) for diagnosis of a parotid gland tumor is widely used but its sensitivity is low and non-diagnostic rate is relatively high. In contrast, core needle biopsy (CNB) has a higher sensitivity and lower rate of sampling errors but has a higher risk of injury to adjacent organs such as facial nerve than FNAC. Screening of patients with parotid gland tumors to identify cases of pleomorphic adenoma (PA) and Warthin tumor (WT) may allow CNB to be confined to patients without PA and WT. We established an algorithm for preoperative diagnosis and management of parotid gland tumor using diffusion-weighted MRI and 99mTc pertechnetate scintigraphy. This algorithm was developed with the goal of maximal reduction of the number of patients in whom CNB is required. The purpose of the study is to validate our algorithm prospectively. Methods: A prospective study was conducted in 71 cases who were newly diagnosed with parotid gland tumor and 53 cases were enrolled in the study. In the algorithm, PA (high apparent diffusion coefficient (ADC) mean≥1.5×10−3 mm2/s) and non-PA (low ADCmean<1.5×10−3 mm2/s) cases are first distinguished based on the ADCmean on diffusion-weighed MRI. Second, among suspected non-PA cases, WT and non-WT are distinguished using technetium-99m pertechnetate scintigraphy. CNB is then performed only in probable non-PA and non-WT cases. Results: Although CNB was only required in 40% (21/53) of all cases, we made a preoperative histopathological diagnosis with an accuracy of 87% (46/53) and we correctly diagnosed whether a tumor was benign or malignant with an accuracy of 96% (51/53). Preoperative surgical planning had to be changed during surgery in only one case (2%) Conclusions: Our algorithm is valuable in terms of clinical practice with highly potential for preoperative diagnosis and with less risk of CNB procedure. [ABSTRACT FROM AUTHOR]

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using 18F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as 18F-Fluorocholine (18F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer 18F-FCH/18F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to 18F-FCH and 18F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The 18F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in 18F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by 18F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of 18F-FCH/ 18F-FDG-PET imaging in this study, while the false-positive caused by 18F-FCH can be eliminated. Dual tracer 18F-FCH/18F-FDG PET imaging has the potential to improve the visualization of low grade glioma. 18F-FCH delineates tumor areas and the tumor can be identified by subtracting the 18F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To quantitatively assess the value of dual-energy CT (DECT) in differentiating malignancy and benignity of solitary pulmonary nodules. Materials and Methods: Sixty-three patients with solitary pulmonary nodules detected by CT plain scan underwent contrast enhanced CT scans in arterial phase (AP) and venous phase (VP) with spectral imaging mode for tumor type differentiation. The Gemstone Spectral Imaging (GSI) viewer was used for image display and data analysis. Region of interest was placed on the relatively homogeneous area of the nodule to measure iodine concentration (IC) on iodine-based material decomposition images and CT numbers on monochromatic image sets to generate spectral HU curve. Normalized IC (NIC), slope of the spectral HU curve (λHU) and net CT number enhancement on 70keV images were calculated. The two-sample t-test was used to compare quantitative parameters. Receiver operating characteristic curves were generated to calculate sensitivity and specificity. Results: There were 63 nodules, with 37 malignant nodules (59%) and 26 benign nodules (41%). NIC, λHU and net CT number enhancement on 70keV images for malignant nodules were all greater than those of benign nodules. NIC and λHU had intermediate to high performances to differentiate malignant nodules from benign ones with the areas under curve of 0.89 and 0.86 respectively in AP, 0.96 and 0.89 respectively in VP. Using 0.30 as a threshold value for NIC in VP, one could obtain sensitivity of 93.8% and specificity of 85.7% for differentiating malignant from benign solitary pulmonary nodules. These values were statistically higher than the corresponding values of 74.2% and 53.8% obtained with the conventional CT number enhancement. Conclusions: DECT imaging with GSI mode provides more promising value in quantitative way for distinguishing malignant nodules from benign ones than CT enhancement numbers. [ABSTRACT FROM AUTHOR]

Background: There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19–9 (CA 19–9) is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies. Methods: CA 19–9, carcinoembryonic antigen (CEA), C-reactive protein, albumin, insulin growth factor-1 (IGF-1) and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls. Results: The combination of CA 19–9, IGF-1 and albumin resulted in a combined area under the curve (AUC) of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19–9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients. Conclusions: Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: Liver metastasis is a common phenomenon in breast cancer patients. Hepatic lesions detected in breast cancer patients may be easily misdiagnosed as metastatic sites, rather than being treated as primary foci. This descriptive study aims to investigate the clinicopathological characteristics of second primary hepatocellular carcinoma in breast cancer patients and to infer in which circumstances liver biopsy is needed. Methods: Eighty-one consecutive breast cancer patients with hepatic lesions admitted to our department were retrospectively studied and analyzed from January 2009 to March 2014 according to Warren and Gates’ criteria for second primary cancers. Results: Second primary hepatocellular carcinoma was observed in sixteen of seventy eight patients with breast cancer. There was a significant difference in HBV status between the second HCC group and liver metastases group (P<0.0001). There was no significant difference in age (P = 0.2254) and family history (P = 0.1160) between second primary HCC and metastases group. Two of these patients had synchronous second primary hepatocellular carcinoma and the remaining fourteen patients had metachronous second primary HCC. All sixteen patients were infected with hepatitis, including hepatitis virus B and C, or resolved HBV infection. Conclusions: Breast cancer patients with either HBV infection or resolved HBV infection, regardless of an elevated AFP level, may receive liver biopsy to avoid unnecessary and inappropriate treatments for metastasis. Awareness of second primary HCC in breast cancer patients needs to be emphasized. [ABSTRACT FROM AUTHOR]

Background: Interval cancers are primary breast cancers diagnosed in women after a negative screening test and before the next screening invitation. Our aim was to evaluate risk factors for interval cancer and their subtypes and to compare the risk factors identified with those associated with incident screen-detected cancers. Methods: We analyzed data from 645,764 women participating in the Spanish breast cancer screening program from 2000–2006 and followed-up until 2009. A total of 5,309 screen-detected and 1,653 interval cancers were diagnosed. Among the latter, 1,012 could be classified on the basis of findings in screening and diagnostic mammograms, consisting of 489 true interval cancers (48.2%), 235 false-negatives (23.2%), 172 minimal-signs (17.2%) and 114 occult tumors (11.3%). Information on the screening protocol and women's characteristics were obtained from the screening program registry. Cause-specific Cox regression models were used to estimate the hazard ratios (HR) of risks factors for interval cancer and incident screen-detected cancer. A multinomial regression model, using screen-detected tumors as a reference group, was used to assess the effect of breast density and other factors on the occurrence of interval cancer subtypes. Results: A previous false-positive was the main risk factor for interval cancer (HR = 2.71, 95%CI: 2.28–3.23); this risk was higher for false-negatives (HR = 8.79, 95%CI: 6.24–12.40) than for true interval cancer (HR = 2.26, 95%CI: 1.59–3.21). A family history of breast cancer was associated with true intervals (HR = 2.11, 95%CI: 1.60–2.78), previous benign biopsy with a false-negatives (HR = 1.83, 95%CI: 1.23–2.71). High breast density was mainly associated with occult tumors (RRR = 4.92, 95%CI: 2.58–9.38), followed by true intervals (RRR = 1.67, 95%CI: 1.18–2.36) and false-negatives (RRR = 1.58, 95%CI: 1.00–2.49). Conclusion: The role of women's characteristics differs among interval cancer subtypes. This information could be useful to improve effectiveness of breast cancer screening programmes and to better classify subgroups of women with different risks of developing cancer. [ABSTRACT FROM AUTHOR]

Background and Objectives: In previous studies, obesity (measured according to the body mass index) has correlated inconsistently with the risk of biopsy-measured prostate cancer, and specifically high-grade prostate cancer. This meta-analysis aimed to clarify these correlations. Methods: A comprehensive literature search of the MEDLINE and EMBASE databases was conducted for relevant studies published through January 2014. The pooled estimates of odds ratios (OR) and confidence intervals (CI) were computed, and the meta-analysis was performed with the STATA software according to a random effects approach. Results: A total of 11 studies that included 29,464 individuals were identified. A 5-kg/m2 increase in body mass index was associated with a 15% (OR, 1.15; 95% CI, 0.98–1.34) higher risk of prostate cancer detection and a 37% (OR, 1.37; 95% CI, 1.19–1.57) higher risk of high-grade prostate cancer detection at biopsy. There were no differences among the results of studies conducted in the USA, Europe or Asia. We also found that studies that had adjusted for prostate-specific antigen levels, digital rectal examination results, and prostate volumes obtained positive significant outcomes (OR, 1.27; 95% CI, 1.12–1.44), whereas studies that did not adjust for the above-mentioned confounding variables obtained negative results (OR, 0.92; 95% CI, 0.68–1.25). Moreover, the positive correlation between body mass index and the detection of both prostate cancer and high-grade diseases tended to be stronger as the number of biopsy cores increased. Conclusion: The present meta-analysis demonstrated that a high body mass index correlated positively with prostate cancer detection, especially high-grade prostate cancer detection. The adoption of a modified and possibly more aggressive biopsy strategy was suggested for obese populations. [ABSTRACT FROM AUTHOR]

Cervical lymph node evaluation by clinical ultrasound is a non-invasive procedure used in diagnosing nodal status, and when combined with fine-needle aspiration cytology (FNAC), provides an effective method to assess nodal pathologies. Development of high-frequency ultrasound (HF US) allows real-time monitoring of lymph node alterations in animal models. While HF US is frequently used in animal models of tumor biology, use of HF US for studying cervical lymph nodes alterations associated with murine models of head and neck cancer, or any other model of lymphadenopathy, is lacking. Here we utilize HF US to monitor cervical lymph nodes changes in mice following exposure to the oral cancer-inducing carcinogen 4-nitroquinoline-1-oxide (4-NQO) and in mice with systemic autoimmunity. 4-NQO induces tumors within the mouse oral cavity as early as 19 wks that recapitulate HNSCC. Monitoring of cervical (mandibular) lymph nodes by gray scale and power Doppler sonography revealed changes in lymph node size eight weeks after 4-NQO treatment, prior to tumor formation. 4-NQO causes changes in cervical node blood flow resulting from oral tumor progression. Histological evaluation indicated that the early 4-NQO induced changes in lymph node volume were due to specific hyperproliferation of T-cell enriched zones in the paracortex. We also show that HF US can be used to perform image-guided fine needle aspirate (FNA) biopsies on mice with enlarged mandibular lymph nodes due to genetic mutation of Fas ligand (Fasl). Collectively these studies indicate that HF US is an effective technique for the non-invasive study of cervical lymph node alterations in live mouse models of oral cancer and other mouse models containing cervical lymphadenopathy. [ABSTRACT FROM AUTHOR]

Aim: To verify if detailed analysis of temporal enhancement patterns on contrast enhanced ultrasound (CEUS) may help differentiate intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) in cirrhosis. Methods: Thirty three ICC and fifty HCC in cirrhosis were enrolled in this study. The contrast kinetics of ICC and HCC was analyzed and compared. Results: Statistical analysis did not reveal significant difference between ICC and HCC in the time of contrast first appearance and arterial peak maximum time. ICC displayed much earlier washout than that of HCC (47.93±26.45 seconds vs 90.86±31.26 seconds) in the portal phase, and most ICC (87.9%) showed washout before 60 seconds than HCC (16.0%). Much more ICC (78.8%) revealed marked washout than HCC (12.0%) while most HCC (88.0%) showed mild washout or no washout in late part of the portal phase (90–120 seconds). Twenty six out of thirty three ICC (78.8%) demonstrated both early washout(<60seconds) and marked washout in late part of the portal phase, whereas, only six of fifty HCC (12.0%)showed these temporal enhancement features (p = 0.000).When both early washout and marked washout in the portal phase are taken as diagnostic criterion for ICC, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 78.8%,88.0%,81.3%,86.3%,and 84.3% respectively by CEUS. Conclusions: Analysis of detailed temporal enhancement features on CEUS is helpful differentiate ICC from HCC in cirrhosis.If a nodule in cirrhotic liver displays hyper-enhancement in the arterial phase followed by early and marked washout in the portal phase, the nodule is highly suspicious of ICC rather than HCC. [ABSTRACT FROM AUTHOR]

In this study we developed, characterized and validated in vitro a functional superparagmagnetic iron-oxide based magnetic resonance contrast agent by conjugating a commercially available iron oxide nanoparticle, Molday ION Rhodamine-B Carboxyl (MIRB), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent is intended for the specific and non-invasive detection of prostate cancer cells that are PSMA positive, a marker implicated in prostate tumor progression and metastasis. The two-step carbodiimide reaction used to conjugate the antibody to the nanoparticle was efficient and we obtained an elemental iron content of 1958±611 per antibody. Immunofluorescence microscopy and flow cytometry showed that the conjugated muJ591:MIRB complex specifically binds to PSMA-positive (LNCaP) cells. The muJ591:MIRB complex reduced cell adhesion and cell proliferation on LNCaP cells and caused apoptosis as tested by Annexin V assay, suggesting anti-tumorigenic characteristics. Measurements of the T2 relaxation time of the muJ591:MIRB complex using a 400 MHz Innova NMR and a multi-echo spin-echo sequence on a 3T MRI (Achieva, Philips) showed a significant T2 relaxation time reduction for the muJ591:MIRB complex, with a reduced T2 relaxation time as a function of the iron concentration. PSMA-positive cells treated with muJ591:MIRB showed a significantly shorter T2 relaxation time as obtained using a 3T MRI scanner. The reduction in T2 relaxation time for muJ591:MIRB, combined with its specificity against PSMA+LNCaP cells, suggest its potential as a biologically-specific MR contrast agent. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of cholangiocarcinoma (CC) is challenging especially in patients with primary sclerosing cholangitis (PSC) and often delayed due to the lack of reliable markers. Angiopoietin-2 (Angpt-2) has been employed as a biomarker of angiogenesis and might be involved in tumor neoangiogenesis. Aim: To evaluate the diagnostic potential of Angpt-2 as a biomarker to detect patients with CC. Methods: Bile and serum Angpt-2 levels were measured in patients with CC (n = 45), PSC (n = 74), CC complicating PSC (CC/PSC) (n = 11) and patients with bile duct stones (n = 37) in a cross sectional study. Diagnostic accuracy of Angpt-2 was compared to carbohydrate antigen 19-9 (CA19-9). Fluorescent immunohistochemistry from human CC liver tissue samples was performed to localize the origin of Angpt-2. Results: Serum Angpt-2 concentration was significantly elevated in patients with CC compared to control patients (p<0.05). Diagnostic accuracy of Angpt-2 as determined by receiver operating characteristic (ROC) analysis resulted in a higher area under the curve (AUC) value compared to CA19-9 (AUC: 0.85 versus 0.77; 95% confidence interval (CI): 0.74–0.93 versus 0.65–0.87, respectively). Angpt-2 was also detectable in bile, but was not associated with the presence of CC. Immunohistochemistry revealed a strong induction of Angpt-2 expression in the tumor vasculature. Conclusions: Circulating Angpt-2 in serum might be a promising protein candidate locally derived from the tumor vasculature in patients with CC. Measurement of Angpt-2 in serum may be useful for diagnosis and further clinical management of patients with CC. [ABSTRACT FROM AUTHOR]

Aims: The asymptomatic nature of early-stage esophageal squamous cell carcinoma (ESCC) results in late presentation and consequent dismal prognosis This study characterized 14-3-3σ protein expression in the multi-stage development of ESCC and determined its correlation with clinical features and prognosis. Materials and Methods: Western blot was used to examine 14-3-3σ protein expression in normal esophageal epithelium (NEE), low grade intraepithelial neoplasia (LGIN), high grade intraepithelial neoplasia (HGIN), ESCC of TNM I to IV stage and various esophageal epithelial cell lines with different biological behavior. Immunohistochemistry was used to estimate 14-3-3σ protein in 110 biopsy samples of NEE, LGIN or HGIN and in 168 ESCC samples all of whom had follow-up data. Support vector machine (SVM) was used to develop a classifier for prognosis. Results: 14-3-3σ decreased progressively from NEE to LGIN, to HGIN, and to ESCC. Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3σ protein compared with non-chemoresistant ESCC cell lines and immortalized NEC. Furthermore, the downregulation of 14-3-3σ correlated significantly with histological grade (P = 0.000) and worse prognosis (P = 0.004). Multivariate Cox regression analysis indicated that 14-3-3σ protein (P = 0.016) and T stage (P = 0.000) were independent prognostic factors for ESCC. The SVM ESCC classifier comprising sex, age, T stage, histological grade, lymph node metastasis, clinical stage and 14-3-3σ, distinguished significantly lower- and higher-risk ESCC patients (91.67% vs. 3.62%, P = 0.000). Conclusions: Downregulation of 14-3-3σ arises early in the development of ESCC and predicts poor survival, suggesting that 14-3-3σ may be a biomarker for early detection of high-risk subjects and diagnosis of ESCC. Our seven-feature SVM classifier for ESCC prognosis may help to inform clinical decisions and tailor individual therapy. [ABSTRACT FROM AUTHOR]