Evaluation of PET quantitation accuracy among multiple discovery IQ PET/CT systems via NEMA image quality test

Introduction: Quantitative imaging biomarkers are becoming usual in oncology for assessing therapy response. The harmonization of image quantitation reporting has become of utmost importance due to the multi-center trials increase. The NEMA image quality test is often considered for the evaluation of quantitation and is more accurate with a radioactive solid phantom that reduces variability. The goal of this project is to determine the level of variability among imaging centers if acquisition and imaging protocol parameters are left to the center's preference while all other parameters are fixed including the scanner type. Methods: A NEMA-IQ phantom filled with radioactive Ge-68 solid resin was imaged in five clinical sites throughout Europe. Sites reconstructed data with OSEM and BSREM algorithms applying the sites' clinical parameters. Images were analyzed according with the NEMA-NU2-2012 standard using the manufacturer-provided NEMA tools to calculate contrast recovery (CR) and background variability (BV) for each sphere and the lung error (LE) estimation. In addition, a F-18-filled NEMA-IQ phantom was also evaluated to obtain a gauge for variability among centers when the sites were provided with identical specific instructions for acquisition and reconstruction protocol (the aggregate of data from 12 additional sites is presented). Results: The data using the Ge-68 solid phantom showed no statistical differences among different sites, proving a very good reproducibility among the PET center models even if dispersion of data is higher with OSEM compared to BSREM. Furthermore, BSREM shows better CR and comparable BV, while LE is slightly reduced. Two centers exhibit significant differences in CR and BV values for the F-18 NEMA NU2-2012 experiments; these outlier results are explained. Conclusion: The same PET system type from the various sites produced similar quantitative results, despite allowing each site to choose their clinical protocols with no restriction on data acquisition and reconstruction parameters. BSREM leads to lower dispersion of quantitative data among different sites. A solid radioactive phantom may be recommended to qualify the sites to perform quantitative imaging

Monitoring and evaluation of breast cancer screening programmes : Selecting candidate performance indicators

In the scope of the European Commission Initiative on Breast Cancer (ECIBC) the Monitoring and Evaluation (M&E) subgroup was tasked to identify breast cancer screening programme (BCSP) performance indicators, including their acceptable and desirable levels, which are associated with breast cancer (BC) mortality. This paper documents the methodology used for the indicator selection. The indicators were identified through a multi-stage process. First, a scoping review was conducted to identify existing performance indicators. Second, building on existing frameworks for making well-informed health care choices, a specific conceptual framework was developed to guide the indicator selection. Third, two group exercises including a rating and ranking survey were conducted for indicator selection using pre-determined criteria, such as: relevance, measurability, accurateness, ethics and understandability. The selected indicators were mapped onto a BC screening pathway developed by the M&E subgroup to illustrate the steps of BC screening common to all EU countries. A total of 96 indicators were identified from an initial list of 1325 indicators. After removing redundant and irrelevant indicators and adding those missing, 39 candidate indicators underwent the rating and ranking exercise. Based on the results, the M&E subgroup selected 13 indicators: screening coverage, participation rate, recall rate, breast cancer detection rate, invasive breast cancer detection rate, cancers > 20 mm, cancers ≤10 mm, lymph node status, interval cancer rate, episode sensitivity, time interval between screening and first treatment, benign open surgical biopsy rate, and mastectomy rate. This systematic approach led to the identification of 13 BCSP candidate performance indicators to be further evaluated for their association with BC mortality

Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance

<p>Abstract</p> <p>Background</p> <p>Subsets of cells with stem-like properties have been previously isolated from human epithelial cancers and their resistance to apoptosis-inducing stimuli has been related to carcinoma recurrence and treatment failure. The aim of this study was to investigate the mechanisms of resistance to apoptosis-inducing agents of cells with stem-like properties in both normal and malignant human epithelia.</p> <p>Methods</p> <p>Cells isolated from fresh human head and neck carcinomas (n = 11), cell lines derived from head and neck, prostate and breast human carcinomas (n = 7), and from normal human oral mucosa (n = 5), were exposed to various apoptosis-inducing stimuli (UV, Tumour Necrosis Factor, Cisplatin, Etoposide, and Neocarzinostatin). Flow cytometry for CD44 and epithelial-specific antigen (ESA) expression, colony morphology, tumour sphere formation and rapid adherence assays were used to identify the subset of cells with stem-like properties. Apoptosis, cell cycle and expression of various cell cycle checkpoint proteins were assessed (Western Blot, qPCR). The role of G2-checkpoint regulators Chk1 and Chk2 was investigated by use of debromohymenialdisine (DBH) and siRNA.</p> <p>Results</p> <p>In both cancer biopsies and carcinoma cell lines a subset of CD44^highcells showed increased clonogenicity, a significantly lower rate of apoptosis, and a significantly higher proportion of cells in the G2-phase of the cell cycle. An inverse correlation between the percentage of cells in G2-phase and the rate of apoptosis was found. Pulse-chase with iododeoxyuridine (IdU) demonstrated that CD44^highcarcinoma cells spent longer time in G2, even in un-treated controls. These cells expressed higher levels of G2 checkpoint proteins, and their release from G2 with BDH or Chk1 siRNA increased their rate of apoptosis. Low passage cultures of normal keratinocytes were also found to contain a subset of CD44^highcells showing increased clonogenicity, and a similar pattern of G2-block associated with apoptotic resistance.</p> <p>Conclusions</p> <p>These data indicate that both normal and malignant human epithelial cells with stem-like properties show greater resistance to apoptosis associated with extended G2 cell cycle phase, and that this property is not a consequence of neoplastic transformation. Targeting G2 checkpoint proteins releases these cells from the G2-block and makes them more prone to apoptosis, implying an opportunity for improved therapeutic approaches.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Role of HIF-1 and NF-κB Transcription Factors in the Modulation of Transferrin Receptor by Inflammatory and Anti-inflammatory Signals*

Inflammation generates various changes in body iron homeostasis, including iron sequestration in the reticuloendothelial system with ensuing hypoferremia and anemia of chronic disease. Increased iron accumulation is caused by hepcidin-mediated down-regulation of the iron export protein ferroportin and higher iron uptake. However, enhanced iron acquisition by macrophages cannot be accounted for by the previously reported transferrin receptor (TfR1) down-regulation in macrophages exposed to lipopolysaccharide (LPS)/interferon γ (IFNγ) because it impairs a major iron uptake mechanism. Because TfR1 is up-regulated by the hypoxia-inducible factor (HIF-1), we investigated the effect of inflammatory and anti-inflammatory signals on HIF-1-mediated TfR1 gene expression. Exposure of mouse macrophages (RAW 264.7 and J774A.1 cells or peritoneal macrophages) to LPS/IFNγ up-regulated NF-κB, which in turn rapidly and transiently activated HIF-1-dependent TfR1 expression and iron uptake. Activation of an anti-inflammatory pathway by pre-exposure to the adenosine A2A receptor agonist CGS21680 prevented the inducing effect of LPS/IFNγ on HIF-1 and TfR1 expression by inhibiting NF-κB activity, whereas treatment with CGS21680 alone increased HIF-1-mediated TfR1 expression by means of an NF-κB-independent signaling pathway. In conclusion, an interplay of the HIF-1 and NF-κB pathways controls TfR1 transcription in inflammation. The consequent changes in TfR1 expression may be involved in modulating iron retention in inflammatory macrophages, thus possibly contributing to the development of hypoferremia in the early phases preceding the down-regulation of macrophage ferroportin by hepcidin

Surgical Navigation in Mandibular Reconstruction: Accuracy Evaluation of an Innovative Protocol

Aim: the purpose of this work is to present an innovative protocol for virtual planning and surgical navigation in post-oncological mandibular reconstruction through fibula free flap. In order to analyze its applicability, an evaluation of accuracy for the surgical protocol has been performed. Methods: 21 patients surgically treated for mandibular neoplasm have been included in the analysis. The Brainlab Vector Vision 3.0&reg; software for surgical navigation has been used for preoperative surgical planning and intra-operative navigation. A post-operative accuracy evaluation has been performed matching the position of mandibular landmarks between pre-operative and post-operative CT scans. Results: the maximal discrepancy observed was included between &minus;3.4 mm and +3.2 mm, assuming negative values for under correction and positive values for overcorrection. An average grade of accuracy included between 0.06 &plusmn; 0.58 mm and 0.43 &plusmn; 0.68 mm has been observed for every mandibular landmark examined, except for mandibular angles that showed a mean discrepancy value included between 1.36 &plusmn; 1.73 mm and 1.46 &plusmn; 1.02 mm when compared to preoperative measurements. Conclusion: a satisfying level of accuracy has been observed in the protocol presented, which appears to be more versatile if compared to closed custom-made systems. The technique described may represent a valid option for selected patients, but it cannot be considered for routine activity because of the complexity of the method, the mobility of the jaw, the necessity of surgical navigator and the long surgical learning curve that is required

The Comprehensive Facial Injury (CFI) Score Is an Early Predictor of the Management for Mild, Moderate and Severe Facial Trauma

Identifying groups of patients with homogeneous characteristics and comparable outcomes improves clinical activity, patients&rsquo; management, and scientific research. This study aims to define mild, moderate, and severe facial trauma by validating two cut-off values of the Comprehensive Facial Injury (CFI) score and describing their foreseeable clinical needs to create a useful guide in patient management, starting from the first evaluation. The individual CFI score, overall surgical time, and length of hospitalization are calculated for a sample of 1400 facial-injured patients. Receiver Operating Characteristic (ROC) analysis and the corresponding Area Under the Curve (AUC) is tested, and a CFI score &ge;4 is selected to discriminate patients undergoing surgical management under general anesthesia (Positive Predictive Value, PPV of 91.4%), while a CFI score &ge;10 is selected to identify patients undergoing major surgical procedures (Negative Predictive Value, NPV of 91.7%). These results are enhanced by the consensual trend of Length of Stay outcome. The use of the CFI score allows us to distinguish between the &ldquo;Mild facial trauma&rdquo; with a low risk of hospitalization for surgical treatment, the &ldquo;Moderate facial trauma&rdquo; with a high probability of surgical treatment, and the &ldquo;Severe facial trauma&rdquo; that requires long-lasting surgery and hospital stay, with an increased incidence of Intensive Care Unit admission

Single-Isocenter Linac-Based Radiosurgery for Brain Metastases with Coplanar Arcs: A Dosimetric and Clinical Analysis

The efficacy of linac-based SRS/fSRS treatments using the single-isocenter coplanar FFF-VMAT technique for both single and multiple BM was investigated. Seventy patients (129 BM) treated with 15–21 Gy in 1 (n = 59) or 27 Gy in 3 (n = 11) fractions were analyzed. For each fraction, plans involving the intra-fractional errors measured by post-treatment CBCT were recalculated. The relationships of BM size, distance-to-isocenter, and barycenter shift with the difference in target coverage were evaluated. Clinical outcomes were assessed using logistic regression and Kaplan-Meier analysis. The median delivery time was 3.78 min (range, 1.83–9.25). The median post-treatment 3D error was 0.5 mm (range, 0.1–2.7) and the maximum rotational error was 0.3° (range, 0.0–1.3). In single BM patients, the GTV D95% was never reduced by >5%, whereas PTV D95% reductions >1% occurred in only 11 cases (29%). In multiple BM patients, dose deficits >5% and >1% occurred in 2 GTV (2%) and 34 PTV (37%), respectively. The differences in target coverage showed a moderate-to-strong correlation only with barycenter shift. Local failure of at least one treated BM occurred in 13 (21%) patients and the 1-year and 2-year local control rates for all lesions were 94% and 90%, respectively. The implemented workflow ensured that the degradation of target and brain dose metrics in delivered treatments was negligible. Along with encouraging clinical outcomes, these findings warrant a reduction in the PTV margins at our institution