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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]

The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC. [ABSTRACT FROM AUTHOR]

Background: The incidence and/or diagnosis of a major disease may activate weight change. Patterns of weight change associated with diagnoses have not been systematically documented. Methods: We use data on adults ages 30+ in the National Health and Nutrition Examination Survey (NHANES) from 1999–2014. Self-reported current weight and weight one year prior are used to estimate percent weight change in the last year. We use self-reported data on arthritis, diabetes, cancer, cardiovascular disease, liver conditions, and respiratory disease diagnoses to compare weight change among individuals never diagnosed with these conditions, individuals diagnosed 0–1 years ago, and individuals diagnosed 2+ years ago. Multinomial logistic regressions adjust for the presence of multiple conditions. Results: 17.7% of the adult population experienced weight loss of 5.0% or more in the year prior to survey. Individuals diagnosed with any of the conditions were less likely to maintain their weight than those without a diagnosis. Arthritis, diabetes, cancer, cardiovascular disease, and liver conditions were associated with net weight loss, whereas respiratory diseases were associated with higher probabilities of both losing and gaining weight. Among those losing 10% or more, 56.7% had been diagnosed with one of the conditions. Cancer was associated with the highest probability of unintentional weight loss and diabetes with the highest probability of intentional weight loss. Conclusions: Disease-associated weight changes leave a distinct imprint on patterns of weight change in the population. Individuals losing at least 10% of their weight in the last year have likely been diagnosed with one of the six conditions. [ABSTRACT FROM AUTHOR]

Background: Although the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS. Methods: Comparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites. Results: The best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20βDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2). Conclusion: PCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability. [ABSTRACT FROM AUTHOR]

ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms. In addition, we investigated the impact of proofreading capabilities of different DNA polymerases on ASXL1 c.1934dupG somatic mutation using conventional Sanger sequencing, another common method for ASXL1 genotyping. Our results confirm that ASXL1 c.1934dupG can be detected as a technical artifact, which can be overcome by the use of appropriate enzymes and library preparation methods. A systematic study of serial samples from 30 patients show that ASXL1 c.1934dupG is a somatic mutation in haematological neoplasms including MDS, AML, MPN and MDS/MPN and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for persistent/relapsing disease. [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]

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) “A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)”, was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials. [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]

Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses (‘gained’ genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative meta-analysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease. [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]

Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs. [ABSTRACT FROM AUTHOR]

Background and aims: Transjugular intrahepatic portosystemic shunts (TIPS) are used in patients with cirrhosis for the prevention of variceal rebleeding. Methods: We retrospectively evaluated re-bleeding rate, patency, mortality, and transplant-free survival (TFS) in cirrhotic patients receiving TIPS implantation for variceal bleeding between 1994–2014. Results: 286 patients received TIPS (n = 119 bare metal stents, n = 167 polytetrafluorethylene (PTFE)-covered stents) for prevention of variceal re-bleeding. Mean age was 55.1 years, median MELD was 11.8, and the main etiology of cirrhosis was alcoholic liver disease (70%). Median follow-up was 821 days. 67 patients (23%) experienced at least one re-bleeding event. Patients with PTFE-TIPS were at significantly lower risk for variceal re-bleeding than patients with bare metal stents (14% vs. 37%, OR:0.259; p<0.001) and had less need for stent revision (21% vs. 37%; p = 0.024). Patients with PTFE stent grafts showed lower mortality than patients with bare stents after 1 year (19% vs. 31%, p = 0.020) and 2 years (29% vs. 40%; p = 0.041) after TIPS implantation. Occurrence of hepatic encephalopathy after TIPS was similar between groups (20% vs. 24%, p = 0.449). Conclusions: PTFE-TIPS were more effective at preventing variceal re-bleeding than bare metal stents due to better patency. Since this tended to translate in improved survival, only covered stents should be implemented for bleeding prophylaxis when TIPS is indicated. [ABSTRACT FROM AUTHOR]

Predicting novel microRNA (miRNA)-disease associations is clinically significant due to miRNAs’ potential roles of diagnostic biomarkers and therapeutic targets for various human diseases. Previous studies have demonstrated the viability of utilizing different types of biological data to computationally infer new disease-related miRNAs. Yet researchers face the challenge of how to effectively integrate diverse datasets and make reliable predictions. In this study, we presented a computational model named Laplacian Regularized Sparse Subspace Learning for MiRNA-Disease Association prediction (LRSSLMDA), which projected miRNAs/diseases’ statistical feature profile and graph theoretical feature profile to a common subspace. It used Laplacian regularization to preserve the local structures of the training data and a L1-norm constraint to select important miRNA/disease features for prediction. The strength of dimensionality reduction enabled the model to be easily extended to much higher dimensional datasets than those exploited in this study. Experimental results showed that LRSSLMDA outperformed ten previous models: the AUC of 0.9178 in global leave-one-out cross validation (LOOCV) and the AUC of 0.8418 in local LOOCV indicated the model’s superior prediction accuracy; and the average AUC of 0.9181+/-0.0004 in 5-fold cross validation justified its accuracy and stability. In addition, three types of case studies further demonstrated its predictive power. Potential miRNAs related to Colon Neoplasms, Lymphoma, Kidney Neoplasms, Esophageal Neoplasms and Breast Neoplasms were predicted by LRSSLMDA. Respectively, 98%, 88%, 96%, 98% and 98% out of the top 50 predictions were validated by experimental evidences. Therefore, we conclude that LRSSLMDA would be a valuable computational tool for miRNA-disease association prediction. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate whether the endocervical brush (ECB) is better accepted by patients and health care providers for endocervical evaluation when compared to the endocervical curette (ECC), without a decrease in the quality of sampling. Methods: Two hundred patients with cervical dysplasia were randomized at the colposcopy clinic of the University Hospital of Geneva into two groups according to technique. Patients and physicians’ preference regarding the technique as well as the quality of samples were assessed. ECB samples were analyzed using both cytological (cell block) and histologic analysis, while ECC samples were analyzed using standard histologic analysis. Results: Of the 200 patients, 89 were randomized to ECC, 101 to ECB and 10 were excluded due to incomplete information or cervical stenosis. Physicians preferred ECB against ECC, classifying it more frequently as an easy technique (94.1% vs.61.4%, p<0.001). Physicians more frequently evaluated the ECB as little or not uncomfortable for patients (28.7% vs.10.2%, p<0.001), though patients themselves didn’t express a preference for either technique. From a quality standpoint, the brush allowed for a better quality of samples, with a lower rate of inadequate samples (2.0% vs 14.3%, p = 0.002) and greater amount of material. Conclusion: Endocervical sampling using ECB seems to be easier to perform and provides better quality samples. ECB can therefore be an acceptable alternative to ECC in standard practice. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Novel biomarkers for prostate cancer (PCa) diagnosis and prognosis are necessary to improve the accuracy of current ones employed in clinic. We performed a retrospective study between the association of several polymorphisms in the main genes involved in the synthesis and metabolism of sex hormones and PCa risk and aggressiveness. A total of 311 Caucasian men (155 controls and 156 patients) were genotyped for 9 SNPs in AR, CYP17A1, LHCGR, ESR1 and ESR2 genes. Diagnostic PSA serum levels, Gleason score, tumor stage, D´Amico risk and data of clinical progression were obtained for patients at the moment of the diagnosis and after 54 months of follow-up. Chi-squared test were used for comparisons between clinical variables groups, logistic regression for clinical variables associations between SNPs; and Kaplan–Meier for the association between SNPs and time to biochemical progression. We found 5 variants (CYP17A1) rs743572, rs6162, rs6163; (LHCGR) rs2293275 and (ESR2) rs1256049 that were statistically significant according to clinical variables (PSA, D´Amico risk and T stage) on a case-case analysis. Moreover, the presence of and alleles in rs743572 and rs6162 respectively, increase the risk of higher PSA levels (>10 ng/μl). With respect to D´Amico risk rs743572 (), rs6162 () and rs6163 () were associated with an increased risk; and last, and genotypes for rs6163 were associated with a shorter biochemical recurrence free survival (BRFS) in patients with radical prostatectomy. In multigene analysis, several variants in SNPs rs2293275, rs6152, rs1062577, rs6162, rs6163, rs1256049 and rs1004467 were described to be associated with a more aggressiveness in patients. However, none of the selected SNPs show significant values between patients and controls. In conclusion, this study identified inherited variants in genes CYP17A1, LHCGR and ESR2 related to more aggressiveness and/or a poor progression of the disease. According to this study, new promise PCa biomarkers for clinical management could be included in these previous SNPs. [ABSTRACT FROM AUTHOR]

Objective: The adenoma detection rate (ADR) varies widely between physicians, possibly due to patient population differences, hampering direct ADR comparison. We developed and validated a prediction model for adenoma detection in an effort to determine if physicians’ ADRs should be adjusted for patient-related factors. Materials and methods: Screening and surveillance colonoscopy data from the cross-sectional multicenter cluster-randomized Endoscopic Quality Improvement Program-3 (EQUIP-3) study (NCT02325635) was used. The dataset was split into two cohorts based on center. A prediction model for detection of ≥1 adenoma was developed using multivariable logistic regression and subsequently internally (bootstrap resampling) and geographically validated. We compared predicted to observed ADRs. Results: The derivation (5 centers, 35 physicians, overall-ADR: 36%) and validation (4 centers, 31 physicians, overall-ADR: 40%) cohort included respectively 9934 and 10034 patients (both cohorts: 48% male, median age 60 years). Independent predictors for detection of ≥1 adenoma were: age (optimism-corrected odds ratio (OR): 1.02; 95%-confidence interval (CI): 1.02–1.03), male sex (OR: 1.73; 95%-CI: 1.60–1.88), body mass index (OR: 1.02; 95%-CI: 1.01–1.03), American Society of Anesthesiology physical status class (OR class II vs. I: 1.29; 95%-CI: 1.17–1.43, OR class ≥III vs. I: 1.57; 95%-CI: 1.32–1.86), surveillance versus screening (OR: 1.39; 95%-CI: 1.27–1.53), and Hispanic or Latino ethnicity (OR: 1.13; 95%-CI: 1.00–1.27). The model’s discriminative ability was modest (C-statistic in the derivation: 0.63 and validation cohort: 0.60). The observed ADR was considerably lower than predicted for 12/66 (18.2%) physicians and 2/9 (22.2%) centers, and considerably higher than predicted for 18/66 (27.3%) physicians and 4/9 (44.4%) centers. Conclusion: The substantial variation in ADRs could only partially be explained by patient-related factors. These data suggest that ADR variation could likely also be due to other factors, e.g. physician or technical issues. [ABSTRACT FROM AUTHOR]

Dynamic network biomarkers (DNB) can identify the critical state or tipping point of a disease, thereby predicting rather than diagnosing the disease. However, it is difficult to apply the DNB theory to clinical practice because evaluating DNB at the critical state required the data of multiple samples on each individual, which are generally not available, and thus limit the applicability of DNB. In this study, we developed a novel method, i.e., single-sample DNB (sDNB), to detect early-warning signals or critical states of diseases in individual patients with only a single sample for each patient, thus opening a new way to predict diseases in a personalized way. In contrast to the information of differential expressions used in traditional biomarkers to “diagnose disease”, sDNB is based on the information of differential associations, thereby having the ability to “predict disease” or “diagnose near-future disease”. Applying this method to datasets for influenza virus infection and cancer metastasis led to accurate identification of the critical states or correct prediction of the immediate diseases based on individual samples. We successfully identified the critical states or tipping points just before the appearance of disease symptoms for influenza virus infection and the onset of distant metastasis for individual patients with cancer, thereby demonstrating the effectiveness and efficiency of our method for quantifying critical states at the single-sample level. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the relationship between visual score of emphysema and homology-based emphysema quantification (HEQ) and evaluate whether visual score was accurately predicted by machine learning and HEQ. Materials and methods: A total of 115 anonymized computed tomography images from 39 patients were obtained from a public database. Emphysema quantification of these images was performed by measuring the percentage of low-attenuation lung area (LAA%). The following values related to HEQ were obtained: nb0 and nb1. LAA% and HEQ were calculated at various threshold levels ranging from −1000 HU to −700 HU. Spearman’s correlation coefficients between emphysema quantification and visual score were calculated at the various threshold levels. Visual score was predicted by machine learning and emphysema quantification (LAA% or HEQ). Random Forest was used as a machine learning algorithm, and accuracy of prediction was evaluated by leave-one-patient-out cross validation. The difference in the accuracy was assessed using McNemar’s test. Results: The correlation coefficients between emphysema quantification and visual score were as follows: LAA% (−950 HU), 0.567; LAA% (−910 HU), 0.654; LAA% (−875 HU), 0.704; nb0 (−950 HU), 0.552; nb0 (−910 HU), 0.629; nb0 (−875 HU), 0.473; nb1 (−950 HU), 0.149; nb1 (−910 HU), 0.519; and nb1 (−875 HU), 0.716. The accuracy of prediction was as follows: LAA%, 55.7% and HEQ, 66.1%. The difference in accuracy was statistically significant (p = 0.0290). Conclusion: LAA% and HEQ at −875 HU showed a stronger correlation with visual score than those at −910 or −950 HU. HEQ was more useful than LAA% for predicting visual score. [ABSTRACT FROM AUTHOR]

Background: Research has shown that women with disabilities face additional challenges in accessing and using healthcare services compared to non-disabled women. However, relatively little is known about the utilisation of cancer screening services for women with disabilities. This study addresses this gap by examining the utilisation of the Papanicolaou test and mammography for disabled women in Chile. Methods: We used cross-sectional data, taken from a 2015 nationally-representative survey. Initially, we employed logistic regressions to test for differences in utilisation rates for the Papanicolaou test (66,281 observations) and the mammogram (35,294 observations) between disabled and non-disabled women. Next, logistic regressions were used to investigate the demographic, socioeconomic, and health-related factors affecting utilisation rates for cancer screening services for disabled women (sample sizes: 5,823 observations for the Papanicolaou test and 5,731 observations for the mammogram). Results: Disabled women were less likely to undergo screening tests than non-disabled women. For the Papanicolaou test and mammography, the multivariable regression models showed that living in rural areas, having higher education, being affiliated with a private health insurance company, giving a good health self-assessment score, and being under medical treatment for other illnesses were associated with higher utilisation rates. On the other hand, being single, inactive with regard to employment, and having a better income were linked with lower utilisation. While utilisation rates for both disabled and non-disabled women have increased since 2006, the utilisation disparity has slightly increased. Conclusions: This study shows the influence of various factors in the utilisation rates of preventive cancer screening services for disabled women. To develop effective initiatives targeting inequalities in the utilisation of cancer screening tests, it is important to move beyond an exclusively single-disease approach and acknowledge the complexity of the patient population. [ABSTRACT FROM AUTHOR]

The encoded transcript of the Maestro—Male-specific Transcription in the developing Reproductive Organs (MRO) gene exhibits sexual dimorphic expression during murine gonadal development. The gene has no homology to any known gene and its expression pattern, protein function or structure are still unknown. Previously, studying gene expression in human ovarian cumulus cells, we found increased expression of MRO in lean-type Polycystic Ovarian Syndrome (PCOS) subjects, as compared to controls. In this study, we examined the MRO splice variants and protein expression pattern in various human tissues and cells. We found a differential expression pattern of the MRO 5’-UTR region in luteinized granulosa-cumulus cells and in testicular tissues as compared to non-gonadal tissues. Our study also shows a punctate nuclear expression pattern and disperse cytoplasmic expression pattern of the MRO protein in human granulosa-cumulus cells and in testicular germ cells, which was later validated by western blotting. The tentative and unique features of the protein hampered our efforts to gain more insight about this elusive protein. A better understanding of the tissue-specific MRO isoforms expression patterns and the unique structure of the protein may provide important insights into the function of this gene and possibly to the pathophysiology of PCOS. [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]

Retinoblastoma and uveal melanoma are fast spreading eye tumors usually diagnosed by using 2D Fundus Image Photography (Fundus) and 2D Ultrasound (US). Diagnosis and treatment planning of such diseases often require additional complementary imaging to confirm the tumor extend via 3D Magnetic Resonance Imaging (MRI). In this context, having automatic segmentations to estimate the size and the distribution of the pathological tissue would be advantageous towards tumor characterization. Until now, the alternative has been the manual delineation of eye structures, a rather time consuming and error-prone task, to be conducted in multiple MRI sequences simultaneously. This situation, and the lack of tools for accurate eye MRI analysis, reduces the interest in MRI beyond the qualitative evaluation of the optic nerve invasion and the confirmation of recurrent malignancies below calcified tumors. In this manuscript, we propose a new framework for the automatic segmentation of eye structures and ocular tumors in multi-sequence MRI. Our key contribution is the introduction of a pathological eye model from which Eye Patient-Specific Features (EPSF) can be computed. These features combine intensity and shape information of pathological tissue while embedded in healthy structures of the eye. We assess our work on a dataset of pathological patient eyes by computing the Dice Similarity Coefficient (DSC) of the sclera, the cornea, the vitreous humor, the lens and the tumor. In addition, we quantitatively show the superior performance of our pathological eye model as compared to the segmentation obtained by using a healthy model (over 4% DSC) and demonstrate the relevance of our EPSF, which improve the final segmentation regardless of the classifier employed. [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 aims: The psychometric hepatic encephalopathy score (PHES) is the “gold standard” for minimal hepatic encephalopathy (MHE) diagnosis. Some reports suggest that some cirrhotic patients “without” MHE according to PHES show neurological deficits and other reports that neurological alterations are not homogeneous in all cirrhotic patients. This work aimed to assess whether: 1) a relevant proportion of cirrhotic patients show neurological deficits not detected by PHES; 2) cirrhotic patients with mild neurological deficits are a homogeneous population or may be classified in sub-groups according to specific deficits. Methods: Cirrhotic patients “without” (n = 56) or “with” MHE (n = 41) according to PHES and controls (n = 52) performed psychometric tests assessing attention, concentration, mental processing speed, working memory and bimanual and visuomotor coordination. Heterogeneity of neurological alterations was analysed using Hierarchical Clustering Analysis. Results: PHES classified as “with” MHE 42% of patients. Around 40% of patients “without” MHE according to PHES fail two psychometric tests. Oral SDMT, d2, bimanual and visuo-motor coordination tests are failed by 54, 51, 51 and 43% of patients, respectively. The earliest neurological alterations are different for different patients. Hierarchical clustering analysis shows that patients “without” MHE according to PHES may be classified in clusters according to the tests failed. In some patients coordination impairment appear before cognitive impairment while in others concentration and attention deficits appear before. Conclusions: PHES is not sensitive enough to detect early neurological alterations in a relevant proportion of cirrhotic patients. Oral SDMT, d2 and bimanual and visuo-motor coordination tests are more sensitive. The earliest neurological alterations are different in different cirrhotic patients. These data also have relevant clinical implications. Patients classified as “without MHE” by PHES belonging to clusters 3 and 4 in our study have a high risk of suffering clinical complications, including overt HE and must be diagnosed and clinically followed. [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]

Purpose: To exploit the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI when evaluating the therapeutic response of gastrointestinal stromal tumors (GIST) to Imatinib in a mouse model. Materials and Methods: Mice with xenografts bearing cells from the GIST-T1 cell line were randomly divided into a treated group receiving Imatinib and a control group. DWMRI scans with 14 b-values (0–1500 s/mm2) were performed before and after treatment (days 1, 3 and 7). IVIM related parameters perfusion fractions (fp) and perfusion-related diffusion coefficients (D*) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the DWMRI signal decay. The mean changes from baseline to each post-treatment time point for each measurement (ΔADC, Δfp and ΔD*) were calculated. The differences of mean changes between the two groups were tested for statistical significance. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. Results: Increases in ADC of the treated group were higher than those of the control group after treatment, whereas statistical significances were not observed. Compared to the control group, D* in the treated group decreased significantly (ΔD*treated = -41%, -49%, and -49% with P = 0.0001, 0.0001 and 0.0001), and fp increased significantly (Δfptreated = 79%, 82% and 110%, with P = 0.001, 0.0001 and P = 0.0007) on days 1, 3 and 7 after treatment. Histopathological analyses demonstrated different tumor tissue characteristics between the treated and control groups. Conclusion: IVIM measurements may serve as more sensitive imaging biomarkers than ADC when assessing GIST response to Imatinib as early as one day after treatment. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common non-cutaneous cancer in male subjects and the second leading cause of cancer-related death in developed countries. The necessity of a non-invasive technique for the diagnosis of PCa in early stage has grown through years. Proton magnetic resonance spectroscopy (1H-MRS) and proton magnetic resonance spectroscopy imaging (1H-MRSI) are advanced magnetic resonance techniques that can mark the presence of metabolites such as citrate, choline, creatine and polyamines in a selected voxel, or in an array of voxels (in MRSI) inside prostatic tissue. Abundance or lack of these metabolites can discriminate between pathological and healthy tissue. Although the use of magnetic resonance spectroscopy (MRS) is well established in brain and liver with dedicated software for spectral analysis, quantification of metabolites in prostate can be very difficult to achieve, due to poor signal to noise ratio and strong J-coupling of the citrate. The aim of this work is to develop a software prototype for automatic quantification of citrate, choline and creatine in prostate. Its core is an original fitting routine that makes use of a fixed step gradient descent minimization algorithm (FSGD) and MRS simulations developed with the GAMMA libraries in C++. The accurate simulation of the citrate spin systems allows to predict the correct J-modulation under different NMR sequences and under different coupling parameters. The accuracy of the quantifications was tested on measurements performed on a Philips Ingenia 3T scanner using homemade phantoms. Some acquisitions in healthy volunteers have been also carried out to test the software performance in vivo. [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]

Background and Purpose: To evaluate the ability of IA MR perfusion to characterize meningioma blood supply. Methods: Studies were performed in a suite comprised of an x-ray angiography unit and 1.5T MR scanner that permitted intraprocedural patient movement between the imaging modalities. Patients underwent intra-arterial (IA) and intravenous (IV) T2* dynamic susceptibility MR perfusion immediately prior to meningioma embolization. Regional tumor arterial supply was characterized by digital subtraction angiography and classified as external carotid artery (ECA) dural, internal carotid artery (ICA) dural, or pial. MR perfusion data regions of interest (ROIs) were analyzed in regions with different vascular supply to extract peak height, full-width at half-maximum (FWHM), relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and mean transit time (MTT). Linear mixed modeling was used to identify perfusion curve parameter differences for each ROI for IA and IV MR imaging techniques. IA vs. IV perfusion parameters were also directly compared for each ROI using linear mixed modeling. Results: 18 ROIs were analyzed in 12 patients. Arterial supply was identified as ECA dural (n = 11), ICA dural (n = 4), or pial (n = 3). FWHM, rCBV, and rCBF showed statistically significant differences between ROIs for IA MR perfusion. Peak Height and FWHM showed statistically significant differences between ROIs for IV MR perfusion. RCBV and MTT were significantly lower for IA perfusion in the Dural ECA compared to IV perfusion. Relative CBF in IA MR was found to be significantly higher in the Dural ICA region and MTT significantly lower compared to IV perfusion. [ABSTRACT FROM AUTHOR]

To facilitate a more widespread use of volumetric tumor segmentation in clinical studies, there is an urgent need for reliable, user-friendly segmentation software. The aim of this study was therefore to compare three different software packages for semi-automatic brain tumor segmentation of glioblastoma; namely BrainVoyagerTM QX, ITK-Snap and 3D Slicer, and to make data available for future reference. Pre-operative, contrast enhanced T1-weighted 1.5 or 3 Tesla Magnetic Resonance Imaging (MRI) scans were obtained in 20 consecutive patients who underwent surgery for glioblastoma. MRI scans were segmented twice in each software package by two investigators. Intra-rater, inter-rater and between-software agreement was compared by using differences of means with 95% limits of agreement (LoA), Dice’s similarity coefficients (DSC) and Hausdorff distance (HD). Time expenditure of segmentations was measured using a stopwatch. Eighteen tumors were included in the analyses. Inter-rater agreement was highest for BrainVoyager with difference of means of 0.19 mL and 95% LoA from -2.42 mL to 2.81 mL. Between-software agreement and 95% LoA were very similar for the different software packages. Intra-rater, inter-rater and between-software DSC were ≥ 0.93 in all analyses. Time expenditure was approximately 41 min per segmentation in BrainVoyager, and 18 min per segmentation in both 3D Slicer and ITK-Snap. Our main findings were that there is a high agreement within and between the software packages in terms of small intra-rater, inter-rater and between-software differences of means and high Dice’s similarity coefficients. Time expenditure was highest for BrainVoyager, but all software packages were relatively time-consuming, which may limit usability in an everyday clinical setting. [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]

Objective: To evaluate anti-Mullerian hormone, basal follicle stimulating hormone, luteinizing hormone, estradiol, and female age in women with recurrent miscarriage and to compare women with explained and idiopathic recurrent miscarriage. Design: Retrospective cohort study. Setting: University hospital, tertiary care center. Patients: Women with recurrent miscarriage (78 explained, 66 idiopathic). Intervention(s): None. Main Outcome Measures(s): Anti-Mullerian hormone, basal follicle stimulating hormone, luteinizing hormone, estradiol, and age. Results: Anti-Mullerian hormone and estradiol were significantly lower in women with idiopathic recurrent miscarriage (median 1.2 ng/ml, IQR 0.6–2.1, and median 36.5 pg/ml, IQR 25.8–47.3, respectively) than in women with explained recurrent miscarriage (median 2.0 ng/ml, IQR 1.1–2.7, and median 42.5 pg/ml, IQR 32.8–59.8, respectively; p<0.05). Optimized cut-off values for the prediction of idiopathic recurrent miscarriage were <39.5 pg/ml for estradiol (sensitivity: 63.3%, 95% CI: 50.9–75.1; specificity: 56.4%, 95% CI: 44.7–67.6) and <1.90 ng/ml for anti-Mullerian hormone (sensitivity: 72.7%, 95% CI: 60.4–83.0; specificity: 52.6%, 95% CI: 40.9–64.0). Conclusion: Idiopathic recurrent miscarriage was associated with lower basal estradiol and anti-Mullerian hormone levels compared to explained recurrent miscarriage. [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]

Background: Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy. Methods: 40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE ‘rim’ geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients. Results: Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ. Conclusion: Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results. [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]

Aims: There are emerging data indicating an association between PCOS (polycystic ovary syndrome) and metabolic derangements with potential impact on its clinical presentation. This study aims to evaluate the pathophysiological processes beyond PCOS with particular focus on carbohydrate metabolism, ectopic lipids and their possible interaction. Differences between the two established classifications of the disease should be additionally evaluated. Methods: A metabolic characterization was performed in 53 untreated PCOS patients as well as 20 controls including an extended oral glucose tolerance test (OGTT, to assess insulin sensitivity, secretion and ß-cell function) in addition to a detailed examination of ectopic lipid content in muscle and liver by nuclear magnetic resonance spectroscopy. Results: Women with PCOS classified by the original NIH 1990 definition showed a more adverse metabolic risk profile compared to women characterized by the additional Rotterdam 2003 phenotypes. Subtle metabolic derangements were observed in both subgroups, including altered shapes of OGTT curves, impaired insulin action and hyperinsulinemia due to increased secretion and attenuated hepatic extraction. No differences were observed for ectopic lipids between the groups. However, particularly hepatocellular lipid content was significantly related to clinical parameters of PCOS like whole body insulin sensitivity, dyslipidemia and free androgen index. Conclusions: Subtle alterations in carbohydrate metabolism are present in both PCOS classifications, but more profound in subjects meeting the NIH 1990 criteria. Females with PCOS and controls did not differ in ectopic lipids, however, liver fat was tightly related to hyperandrogenism and an adverse metabolic risk profile. [ABSTRACT FROM AUTHOR]

Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future. [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]

In a Perspective article, Sigrid Carlsson and Michael Kattan discuss Gnanapragasam and colleagues' accompanying research study on refining risk stratification in early prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Treatment strategy for early gastric cancer depends on the probability of lymph node metastasis. The aim of this study is to develop a nomogram predicting lymph node metastasis in early gastric cancer using clinicopathological factors and biomarkers. Methods: A literature review was performed to identify biomarkers related to lymph node metastasis in gastric cancer. Seven markers were selected and immunohistochemistry was performed in 336 early gastric cancer tissues. Based on the multivariable analysis, a prediction model including clinicopatholgical factors and biomarkers was developed, and benefit of adding biomarkers was evaluated using the area under the receiver operating curve and net reclassification improvement. Functional study in gastric cancer cell line was performed to evaluate mechanism of biomarker. Results: Of the seven biomarkers studied, α1 catenin and CD44v6 were significantly associated with lymph node metastasis. A conventional prediction model, including tumor size, histological type, lymphatic blood vessel invasion, and depth of invasion, was developed. Then, a new prediction model including both clinicopathological factors and CD44v6 was developed. Net reclassification improvement analysis revealed a significant improvement of predictive performance by the addition of CD44v6, and a similar result was shown in the internal validation using bootstrapping. Prediction nomograms were then constructed based on these models. In the functional study, CD44v6 was revealed to affect cell proliferation, migration and invasion. Conclusions: Overexpression of CD44v6 was a significant predictor of lymph node metastasis in early gastric cancer. The prediction nomograms incorporating CD44v6 can be useful to determine treatment plans in patients with early gastric cancer. [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]

Objective: Parents report psychological distress in association with their child's cancer. Reliable tools are needed to screen parental distress over the cancer trajectory. This study aimed to estimate the stability and repeatability of the Distress Thermometer (DT) and the Depression and Anxiety items of the Edmonton Symptom Assessment System-revised (ESAS-r-D; -A) in parents of children diagnosed with cancer. Methods: Fifty parents (28 mothers, median age = 44) of clinically stable survivors of childhood solid and brain tumours completed questionnaires about their own distress (DT, ESAS-r-D; -A, Brief Symptom Inventory-18: BSI-18, Patient Health Questionnaire-9: PHQ-9, Generalized Anxiety Disorder-7: GAD-7) and their children’s quality of life (QoL; Peds Quality of Life: PedsQL) twice, with a month interval between the two assessments. At retest, parents also evaluated life events that occurred between the two time points. Hierarchical regressions explored moderators for the temporal stability of test measures. Results: Stability estimates were ICC = .78 for the DT, .55 for the ESAS-r-D, and .47 for the ESAS-r-A. Caseness agreement between test and retest was substantial for the DT, fair for the ESAS-r-D, and slight for the ESAS-r-A. Repeatability analyses indicated that the error range for the DT was more than 2 pts below/above actual measurement, whereas it was more than 3 pts for the ESAS-r-A, and 2.5 for the ESAS-r-D. Instability of the DT could be explained by changes in children’s physical QoL, but not by other components of QoL or life events. No moderators of stability could be identified for the ESAS-r items. Conclusions: The DT appears to be a fairly stable measure when the respondent's condition is stable yet with a relatively wide error range. Fluctuations in distress-related constructs may affect the temporal stability of the DT. The lower stability of ESAS-r items may result from shorter time-lapse instructions resulting in a greater sensitivity to change. Findings support future research on the DT as a reliable instrument in caregivers. [ABSTRACT FROM AUTHOR]