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Robustly predicting outcome for cancer patients from gene expression is an important challenge on the road to better personalized treatment. Network-based outcome predictors (NOPs), which considers the cellular wiring diagram in the classification, hold much promise to improve performance, stability and interpretability of identified marker genes. Problematically, reports on the efficacy of NOPs are conflicting and for instance suggest that utilizing random networks performs on par to networks that describe biologically relevant interactions. In this paper we turn the prediction problem around: instead of using a given biological network in the NOP, we aim to identify the network of genes that truly improves outcome prediction. To this end, we propose SyNet, a gene network constructed ab initio from synergistic gene pairs derived from survival-labelled gene expression data. To obtain SyNet, we evaluate synergy for all 69 million pairwise combinations of genes resulting in a network that is specific to the dataset and phenotype under study and can be used to in a NOP model. We evaluated SyNet and 11 other networks on a compendium dataset of >4000 survival-labelled breast cancer samples. For this purpose, we used cross-study validation which more closely emulates real world application of these outcome predictors. We find that SyNet is the only network that truly improves performance, stability and interpretability in several existing NOPs. We show that SyNet overlaps significantly with existing gene networks, and can be confidently predicted (~85% AUC) from graph-topological descriptions of these networks, in particular the breast tissue-specific network. Due to its data-driven nature, SyNet is not biased to well-studied genes and thus facilitates post-hoc interpretation. We find that SyNet is highly enriched for known breast cancer genes and genes related to e.g. histological grade and tamoxifen resistance, suggestive of a role in determining breast cancer outcome. [ABSTRACT FROM AUTHOR]

Anxiety and depression can be heightened among individuals living with chronic diseases. Identifying these individuals is necessary for ensuring they are provided with adequate support. Traditional tools such as clinical interviews or symptom checklists are not always feasible to implement in practice. Robust single-item questions may be a useful alternative. This study aimed to measure agreement, sensitivity, specificity, positive predictive value and negative predictive value of a single-item question about anxiety and depression compared to the widely used Hospital Anxiety and Depression Scale (HADS). A cross-sectional survey of 2,811 people with cancer attending 19 treatment centres in Australia. Patients were approached in the waiting room prior to an outpatient clinic appointment and invited to complete a pen and paper survey. Participants completed the HADS as well as 2 single-items asking if they have felt anxious or depressed in the last week. The single-items for anxiety and depression each demonstrated moderate levels of sensitivity (0.78 for anxiety; 0.63 for depression) and specificity (0.75 for anxiety; 0.84 for depression) against the relevant HADS subscale. Positive predictive values were moderate (0.53 for anxiety and 0.52 for depression) while negative predictive values were high for both single-item questions (0.90 for anxiety and 0.89 for depression). The single-item measures of anxiety and depression may be useful to rule out individuals who do not require further psychological assessment or intervention for anxiety and depression. Further research is needed to explore whether these findings generalise to other chronic diseases. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. Methods: A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio’s (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). Results: Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). Conclusions: In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy. [ABSTRACT FROM AUTHOR]

The primary goal of precision medicine is to minimize side effects and optimize efficacy of treatments. Recent advances in medical imaging technology allow the use of more advanced image analysis methods beyond simple measurements of tumor size or radiotracer uptake metrics. The extraction of quantitative features from medical images to characterize tumor pathology or heterogeneity is an interesting process to investigate, in order to provide information that may be useful to guide the therapies and predict survival. This paper discusses the rationale supporting the concept of radiomics and the feasibility of its application to Non-Small Cell Lung Cancer in the field of radiation oncology research. We studied 91 stage III patients treated with concurrent chemoradiation and adaptive approach in case of tumor reduction during treatment. We considered 12 statistics features and 230 textural features extracted from the CT images. In our study, we used an ensemble learning method to classify patients’ data into either the adaptive or non-adaptive group during chemoradiation on the basis of the starting CT simulation. Our data supports the hypothesis that a specific signature can be identified (AUC 0.82). In our experience, a radiomic signature mixing semantic and image-based features has shown promising results for personalized adaptive radiotherapy in non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Background: Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August 2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer. Methods: Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted. Results: Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta-analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64–0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53–0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73–1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95). Conclusion: Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers? [ABSTRACT FROM AUTHOR]

How can we predict the occurrence of acute kidney injury (AKI) in cancer patients based on machine learning with serum creatinine data? Given irregular and heterogeneous clinical data, how can we make the most of it for accurate AKI prediction? AKI is a common and significant complication in cancer patients, and correlates with substantial morbidity and mortality. Since no effective treatment for AKI still exists, it is important to take timely preventive measures. While several approaches have been proposed for predicting AKI, their scope and applicability are limited as they either assume regular data measured over a short hospital stay, or do not fully utilize heterogeneous data. In this paper, we provide an AKI prediction model with a greater applicability, which relaxes the constraints of existing approaches, and fully utilizes irregular and heterogeneous data for learning the model. In a cohort of 21,022 cancer patients who were registered into Korea Central Cancer Registry (KCCR) in Seoul National University Hospital between January 1, 2004 and December 31, 2013, our method achieves 0.7892 precision, 0.7506 recall, and 0.7576 F-measure in predicting whether a patient will develop AKI during the next 14 days. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second leading cause of cancer mortality by 2030. PDAC remains resistant to the majority of systemic chemotherapies. In this paper, we explore if epigenetic sensitization can improve chemotherapy response in PDAC. Multiple PDAC cell lines were tested with serial concentrations of the epigenetic modulators 5-azacitidine (Aza) and guadecitabine (SGI-110). Guadecitabine was effective at inhibiting the expression of DNA Methyltransferase 1 (DNMT1) and in decreasing cell viability at nanomolar concentrations. We also report that guadecitabine has increased efficacy following a delay period or as we reference, a ‘rest period’. Sensitization with guadecitabine improved response to the chemotherapeutic agent–Irinotecan- as measured by decreased cell viability and accompanied by an increase in caspase activity. Additional studies are needed to understand the mechanism of action. [ABSTRACT FROM AUTHOR]

Since absorption of X-ray radiation has the possibility of inducing cancerous, genetic and other diseases to patients, researches usually attempt to reduce the radiation dose. However, reduction of the radiation dose associated with CT scans will unavoidably increase the severity of noise and artifacts, which can seriously affect diagnostic confidence. Due to the outstanding performance of deep neural networks in image processing, in this paper, we proposed a Stacked Competitive Network (SCN) approach to noise reduction, which stacks several successive Competitive Blocks (CB). The carefully handcrafted design of the competitive blocks was inspired by the idea of multi-scale processing and improvement the network’s capacity. Qualitative and quantitative evaluations demonstrate the competitive performance of the proposed method in noise suppression, structural preservation, and lesion detection. [ABSTRACT FROM AUTHOR]

Gliomas are the most frequent type of primary brain tumours. Low grade gliomas (LGGs, WHO grade II gliomas) may grow very slowly for the long periods of time, however they inevitably cause death due to the phenomenon known as the malignant transformation. This refers to the transition of LGGs to more aggressive forms of high grade gliomas (HGGs, WHO grade III and IV gliomas). In this paper we propose a mathematical model describing the spatio-temporal transition of LGGs into HGGs. Our modelling approach is based on two cellular populations with transitions between them being driven by the tumour microenvironment transformation occurring when the tumour cell density grows beyond a critical level. We show that the proposed model describes real patient data well. We discuss the relationship between patient prognosis and model parameters. We approximate tumour radius and velocity before malignant transformation as well as estimate the onset of this process. [ABSTRACT FROM AUTHOR]

This paper reports the damaging effects of magnetic iron-oxide nanoparticles (MNP) on magnetically labeled cancer cells when subjected to oscillating gradients in a strong external magnetic field. Human breast cancer MDA-MB-231 cells were labeled with MNP, placed in the high magnetic field, and subjected to oscillating gradients generated by an imaging gradient system of a 9.4T preclinical MRI system. Changes in cell morphology and a decrease in cell viability were detected in cells treated with oscillating gradients. The cytotoxicity was determined qualitatively and quantitatively by microscopic imaging and cell viability assays. An approximately 26.6% reduction in cell viability was detected in magnetically labeled cells subjected to the combined effect of a static magnetic field and oscillating gradients. No reduction in cell viability was observed in unlabeled cells subjected to gradients, or in MNP-labeled cells in the static magnetic field. As no increase in local temperature was observed, the cell damage was not a result of hyperthermia. Currently, we consider the coherent motion of internalized and aggregated nanoparticles that produce mechanical moments as a potential mechanism of cell destruction. The formation and dynamics of the intracellular aggregates of nanoparticles were visualized by optical and transmission electron microscopy (TEM). The images revealed a rapid formation of elongated MNP aggregates in the cells, which were aligned with the external magnetic field. This strategy provides a new way to eradicate a specific population of MNP-labeled cells, potentially with magnetic resonance imaging guidance using standard MRI equipment, with minimal side effects for the host. [ABSTRACT FROM AUTHOR]

Context: Magnetic resonance imaging (MRI) is currently the most accurate imaging modality to assess local prostate cancer stage. Despite a growing body of evidence, incorporation of MRI images into decision-making process concerning surgical template of radical prostatectomy, is complex and still poorly understood. Objective: We sought to determine the value of MRI in preoperative planning before radical prostatectomy. Materials and methods: Systematic search through electronic PubMed, EMBASE, and Cochrane databases from 2000 up to April 2018 was performed. Only studies that used preoperative MRI in decision-making process regarding extension of resection in patients with prostate cancer, in whom radical prostatectomy was an initial form of treatment were included into analysis. Their quality was scored by Risk Of Bias In Non-Randomized Studies of Interventions system. Meta-analysis was performed to calculate the weighted summary proportion under the fixed or random effects model as appropriate and pooled effects were depicted on forest plots. Results: The results showed that the preoperative MRI led to the modification of initial surgical template in one third of cases (35%). This occurred increasingly with the rising prostate cancer-risk category: 28%, 33%, 52% in low-, intermediate- and high-risk group, respectively. Modification of neurovascular bundle-sparing surgery based on MRI appeared to have no impact on the positive surgical margin rate. The decision based on MRI was correct on average in 77% of cases and differed across prostate cancer-risk categories: 63%, 75% and 91% in low-, intermediate- and high-risk group, accordingly. Conclusions: In summary, MRI has a considerable impact on the decision-making process regarding the extent of resection during radical prostatectomy. Adaptation of MRI images by operating surgeons has at worst no significant impact on surgical margin status, however its ability to decrease the positive surgical margin rates remains unconfirmed. [ABSTRACT FROM AUTHOR]

Lung 4D computed tomography (4D-CT) plays an important role in high-precision radiotherapy because it characterizes respiratory motion, which is crucial for accurate target definition. However, the manual segmentation of a lung tumor is a heavy workload for doctors because of the large number of lung 4D-CT data slices. Meanwhile, tumor segmentation is still a notoriously challenging problem in computer-aided diagnosis. In this paper, we propose a new method based on an improved graph cut algorithm with context information constraint to find a convenient and robust approach of lung 4D-CT tumor segmentation. We combine all phases of the lung 4D-CT into a global graph, and construct a global energy function accordingly. The sub-graph is first constructed for each phase. A context cost term is enforced to achieve segmentation results in every phase by adding a context constraint between neighboring phases. A global energy function is finally constructed by combining all cost terms. The optimization is achieved by solving a max-flow/min-cut problem, which leads to simultaneous and robust segmentation of the tumor in all the lung 4D-CT phases. The effectiveness of our approach is validated through experiments on 10 different lung 4D-CT cases. The comparison with the graph cut without context constraint, the level set method and the graph cut with star shape prior demonstrates that the proposed method obtains more accurate and robust segmentation results. [ABSTRACT FROM AUTHOR]

Background: LncRNA CCAT1 is significantly overexpressed in various types of cancers, suggesting that it might be associated with prognosis and clinicopathological features in patients with cancer. Methods: A comprehensive search was performed in Pubmed, Web of Science, OVID and CNKI databases. We also retrieved articles from other sources, such as retrieving from the reference lists of relevant articles. Eligible studies were included based on defined exclusion and inclusion criteria to perform a meta-analysis. STATA 14.0 was used to estimate pooled hazard ratios (HRs) with 95% confidence interval (95% CI), the heterogeneity among studies and publication bias to judge the prognostic value. Results: A total of 1587 patients from 11 eligible studies were included in the meta-analysis. The results showed that high expression level of CCAT1 was significantly associated with shorter overall survival in cancer patients (HR 2.335, 95% CI:1.551–3.517); in the subgroup analysis, region (China or UK), sample size (more or less than 100), type of cancer (digestive or non-digestive disease) and paper quality (score more or less than 7) did not alter the association between CCAT1 expression and cancer prognosis but preoperative treatment did. And CCAT1 expression was an independent prognostic marker for overall survival in patients with cancer (pooled HR 2.195, 95%CI:1.316–3.664) using Cox multivariate analyses. The clinicopathological parameters analysis further showed that increased expression level of CCAT1 was correlated with tumor size, lymph node metastasis, TNM stage, distant metastasis, microvascular invasion and capsular formation in relevant cancers. Conclusions: The meta-analysis results from present study suggested that increased expression level of CCAT1 was associated with poor prognosis and can serve as an independent biomarker. And the expression level of CCAT1 was associated with clinicopathological features in relevant cancers. [ABSTRACT FROM AUTHOR]

Background: Personalized medicine requires accurate molecular profiling for targeted therapy decisions. Insufficient tissue yield or tumor heterogeneity frequently limits the correct tissue biomarker determination. As a noninvasive complement to traditional tissue biopsies, liquid biopsies detect and track cancer driver mutations from biofluids (e.g., blood, urine). Here we present the analytical validation of Target Selector™ ctDNA assays capable of single mutant DNA copy detection. Methods: The Target Selector ctDNA assay applies a patented Switch-Blocker technology to suppress amplification of background (wild-type) WT alleles, while allowing specific amplification of very low frequency mutant alleles. In contrast to allele specific enrichment technologies like ddPCR, one Switch-Blocker inhibits amplification of a DNA target up to 15 bp in length (e.g., one Switch-Blocker covers all KRAS exon 2, codon 12 and 13 variants). Target enrichment is achieved through a quantitative PCR reaction; subsequent DNA sequencing confirms mutation identity. Analytical validation with cancer cell line DNA was conducted by three independent operators using five instruments across five days. Results: A total of 3086 samples were tested on EGFR, BRAF and KRAS Target Selector ctDNA assays, with EGFR WT as a reference. All assays showed >99% analytical sensitivity and specificity. Single mutant copy detection is confirmed by experimental data and theoretical estimates. In the presence of 14000 WT DNA copies, limits of detection were: EGFR Del19, 0.01%; EGFR L858R, 0.02%; EGFR T790M, 0.01%; BRAF V600E, 0.01%; KRAS G12C, 0.02%. Inter- and intra-assay analyses showed r2>0.94, suggesting consistent performance among operational variables. Healthy donor samples (100 tests) showed clinical specificity at >99%. Finally, Target Selector clinical experience data of >2200 patient samples is consistent with published tissue mutation prevalence. Conclusions: Highly sensitive Target Selector ctDNA assays with single mutant copy detection and limit of detection at 0.02% or better enable accurate molecular profiling vital for disease management. [ABSTRACT FROM AUTHOR]

Radiomics studies require many patients in order to power them, thus patients are often combined from different institutions and using different imaging protocols. Various studies have shown that imaging protocols affect radiomics feature values. We examined whether using data from cohorts with controlled imaging protocols improved patient outcome models. We retrospectively reviewed 726 CT and 686 PET images from head and neck cancer patients, who were divided into training or independent testing cohorts. For each patient, radiomics features with different preprocessing were calculated and two clinical variables—HPV status and tumor volume—were also included. A Cox proportional hazards model was built on the training data by using bootstrapped Lasso regression to predict overall survival. The effect of controlled imaging protocols on model performance was evaluated by subsetting the original training and independent testing cohorts to include only patients whose images were obtained using the same imaging protocol and vendor. Tumor volume, HPV status, and two radiomics covariates were selected for the CT model, resulting in an AUC of 0.72. However, volume alone produced a higher AUC, whereas adding radiomics features reduced the AUC. HPV status and one radiomics feature were selected as covariates for the PET model, resulting in an AUC of 0.59, but neither covariate was significantly associated with survival. Limiting the training and independent testing to patients with the same imaging protocol reduced the AUC for CT patients to 0.55, and no covariates were selected for PET patients. Radiomics features were not consistently associated with survival in CT or PET images of head and neck patients, even within patients with the same imaging protocol. [ABSTRACT FROM AUTHOR]

Background: Hydronephrosis is a common finding in patients with bladder cancer. The aim of the study was to appraise the prognostic value of preoperative hydronephrosis in bladder cancer patients undergoing radical cystectomy. Methods: We conducted a literature search using PubMed and Embase databases in Aug 2018. Summary hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed-effect or random-effects models. The primary endpoint was overall survival (OS). Secondary endpoints were cancer-specific survival (CSS) and recurrence-free survival (RFS). Results: Overall, 13 studies published between 2008 and 2018 including 4,820 patients were selected for the meta-analysis. The age of bladder cancer patients ranged from 27 to 90.4 years, and the overall proportion of males was 72.5%. Preoperative hydronephrosis was reported in 27.4% of patients. The pooled HR was statistically significant for OS (HR, 1.36; 95% CI [1.20–1.55]) and CSS (HR, 1.64; 95% CI [1.33–2.02]), with no heterogeneity among the enrolled studies. Patients with bilateral hydronephrosis showed a poorer CSS compared to those with no hydronephrosis (HR 5.43, 95% CI [3.14–9.40]). However, there was no difference in CSS between no hydronephrosis and unilateral hydronephrosis groups (HR 1.35, 95% CI [0.84–2.14]). Despite a tendency towards poorer RFS (HR, 1.27; 95% CI [0.96–1.96]), the results demonstrated no significant association between presence of preoperative hydronephrosis and RFS after radical cystectomy. Conclusion: This meta-analysis indicates that preoperative hydronephrosis is significantly associated with poorer OS and CSS after radical cystectomy for patients with bladder cancer. Preoperative hydronephrosis has a stronger effect on CSS in patients with bilateral hydronephrosis. The presence of preoperative hydronephrosis not only predicts prognosis, but may also help to identify patients who benefit the most from neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The narrative surrounding the management of potentially resectable pancreatic cancer is complex. Surgical resection is the only potentially curative treatment. However resection rates are low, the risk of operative morbidity and mortality are high, and survival outcomes remain poor. The aim of this study was to create a prognostic Bayesian network that pre-operatively makes personalized predictions of post-resection survival time of 12months or less and also performs post-operative prognostic updating. Methods: A Bayesian network was created by synthesizing data from PubMed post-resection survival analysis studies through a two-stage weighting process. Input variables included: inflammatory markers, tumour factors, tumour markers, patient factors and, if applicable, response to neoadjuvant treatment for pre-operative predictions. Prognostic updating was performed by inclusion of post-operative input variables including: pathology results and adjuvant therapy. Results: 77 studies (n = 31,214) were used to create the Bayesian network, which was validated against a prospectively maintained tertiary referral centre database (n = 387). For pre-operative predictions an Area Under the Curve (AUC) of 0.7 (P value: 0.001; 95% CI 0.589–0.801) was achieved accepting up to 4 missing data-points in the dataset. For prognostic updating an AUC 0.8 (P value: 0.000; 95% CI:0.710–0.870) was achieved when validated against a dataset with up to 6 missing pre-operative, and 0 missing post-operative data-points. This dropped to AUC: 0.7 (P value: 0.000; 95% CI:0.667–0.818) when the post-operative validation dataset had up to 2 missing data-points. Conclusion: This Bayesian network is currently unique in the way it utilizes PubMed and patient level data to translate the existing empirical evidence surrounding potentially resectable pancreatic cancer to make personalized prognostic predictions. We believe such a tool is vital in facilitating better shared decision-making in clinical practice and could be further developed to offer a vehicle for delivering personalized precision medicine in the future. [ABSTRACT FROM AUTHOR]

Objectives: Disutility allows to identify how much population values intervention-related harms contributing to knowledge on the benefits/harms ratio of cancer screening programs. This systematic review evaluates disutility related to cancer screening applying a utility theory framework. Methods: Using a predefined protocol, Embase, Medline Ovid, Web of Science, Cochrane, Google scholar and supplementary sources were systematically searched. The framework grouped disutilities associated with breast, cervical, lung, colorectal, and prostate cancer screening programs into the screening, diagnostic work up, and treatment phases. We assessed the quality of included studies according to the relevance to target population, risk of bias, appropriateness of measure and the time frame. Results: Out of 2840 hits, we included 38 studies, of which 27 measured (and others estimated) disutilities. Around 70% of studies had medium to high-level quality. Measured disutilities and Quality Adjusted Life Years loss were 0–0.03 and 0–0.0013 respectively in screening phases. Both disutilities and Quality Adjusted Life Years loss had similar ranges in diagnostic work up (0–0.26), and treatment (0.09–0.27) phases. We found no measured disutilities available for lung cancer screening and—little evidence for disutilities in treatment phase. Almost 40% of the estimated disutility values were above the range of measured ones. Conclusions: Cancer screening programs led to low disutities related to screening phase, and low to moderate disutilities related to diagnostic work up and treatment phases. These disutility values varied by the measurement instrument applied, and were higher in studies with lower quality. The estimated disutility values comparing to the measured ones tended to overestimate the harms. [ABSTRACT FROM AUTHOR]

Background: The risk of recurrence of solitary plasmacytoma (SP)/progression to MM is well established, but patient, imaging and treatment factors influencing risk of progression require further evaluation. Methods: This is a retrospective analysis of 66 SP patients (23 UK, 43 Brazil) diagnosed 1989–2016. Patient baseline characteristics were recorded. The incidence of progression to MM was calculated, including biochemical and imaging findings and the treatment modality received. Survival estimates were determined by Kaplan-Meier analyses. Results: With a median follow-up of 53.6 months the 5 year overall survival (OS) was 90.7% (95%CI 79–96%). The median progression free survival (PFS) from diagnosis was 61 months. Cumulative incidence of progression to MM was 49.9% at 5 years (95% CI 35.6–62.6%) and was significantly higher with bone plasmacytoma (47.2%, 95%CI 31.9–61.1%), than an extramedullary location (8.3%, 95%CI 0.4–32.3%, Gray test p = 0.0095)). The majority of patients with solitary bony plasmacytoma (SBP) received radiotherapy (RT) (51/53, 96.2%) whereas most extramedullary cases were treated with surgical resection (7/13, 53.8%). A small proportion of SBP patients received additional upfront chemotherapy, with 5/6 in remission after a median follow-up (FU) of 10 years. The diagnostic yield of surveillance functional FU imaging without other indications of relapse/progression was low. The positive predictive value of functional FU imaging was high but with a low negative predictive value, especially in cases of suspected relapse/progression. Conclusion: Our data suggests functional imaging should be used if clinical suspicion of relapse/progression, rather than a routine surveillance tool, and upfront adjuvant chemotherapy is worthy of prospective evaluation. [ABSTRACT FROM AUTHOR]

Introduction: Intraoperative software assistance is gaining increasing importance in laparoscopic and robot-assisted surgery. Within the user-centred development process of such systems, the first question to be asked is: What information does the surgeon need and when does he or she need it? In this article, we present an approach to investigate these surgeon information needs for minimally invasive partial nephrectomy and compare these needs to the relevant surgical computer assistance literature. Materials and methods: First, we conducted a literature-based hierarchical task analysis of the surgical procedure. This task analysis was taken as a basis for a qualitative in-depth interview study with nine experienced surgical urologists. The study employed a cognitive task analysis method to elicit surgeons' information needs during minimally invasive partial nephrectomy. Finally, a systematic literature search was conducted to review proposed software assistance solutions for minimally invasive partial nephrectomy. The review focused on what information the solutions present to the surgeon and what phase of the surgery they aim to support. Results: The task analysis yielded a workflow description for minimally invasive partial nephrectomy. During the subsequent interview study, we identified three challenging phases of the procedure, which may particularly benefit from software assistance. These phases are I. Hilar and vascular management, II. Tumour excision, and III. Repair of the renal defects. Between these phases, 25 individual challenges were found which define the surgeon information needs. The literature review identified 34 relevant publications, all of which aim to support the surgeon in hilar and vascular management (phase I) or tumour excision (phase II). Conclusion: The work presented in this article identified unmet surgeon information needs in minimally invasive partial nephrectomy. Namely, our results suggest that future solutions should address the repair of renal defects (phase III) or put more focus on the renal collecting system as a critical anatomical structure. [ABSTRACT FROM AUTHOR]

We investigated whether use of American College of Radiology thyroid imaging report and data system (ACR TIRADS) in combination with K-RAS mutation status may facilitate risk stratification of patients with cytological Bethesda Category III and IV thyroid nodules. Ultrasonographic, cytological, and histopathological diagnoses were retrospectively correlated with K-RAS mutation status in a series of 43 cytologically indeterminate thyroid nodules (CITNs) that were referred for surgical excision. K-RAS mutations were detected in 8/43 (18.6%) fine-needle aspiration (FNA) samples as against 11/43 (25.6%) surgical specimens. ACR TIRADS level (TR) TR3 lesions had a malignancy risk of 40%; the K-RAS mutation rate in FNA samples and surgical specimens of category TR3 lesions was 40% and 60%, respectively. K-RAS mutation-positive malignancy was significantly more frequently detected in follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) lesions than that in atypia or follicular lesion of undetermined significance (AUS/FLUS) (P<0.01). Combined use of ACR TIRADS (TR5 as the diagnostic threshold) and K-RAS mutation status helped identify 83.3% (10/12) malignant nodules (58.6% specificity, 45.5% positive predictive value, 89.5% negative predictive value, and 65.9% accuracy). CITNs with ACR TIRADS category TR3 showed an unexpectedly high risk of malignancy. K-RAS mutation-positive FN/SFN nodules have a 50% risk of malignancy and surgery should be recommended. Combined use of ACR TIRADS and K-RAS mutation may facilitate risk-stratification of patients with CITNs. The high negative predictive value (NPV) for malignancy seems sufficient to allow conservative management of patients with active surveillance. [ABSTRACT FROM AUTHOR]

Eukaryotic elongation factor 1 alpha 2 (eEF1A2) is a translation factor selectively expressed by heart, skeletal muscle, nervous system and some specialized cells. Its ectopic expression relates with tumorigenesis in several types of human cancer. No data are available about the role of eEF1A2 in Triple Negative Breast Cancers (TNBC). This study investigated the relation between eEF1A2 protein levels and the prognosis of TNBC. A total of 84 TNBC diagnosed in the period 2002–2011 were included in the study. eEF1A2 protein level was measured in formalin-fixed paraffin-embedded tissues by immunohistochemistry in a semi-quantitative manner (sum of the percentage of positive cells x staining intensity) on a scale from 0 to 300. Cox regression assessed the association between eEF1A2 levels and disease-free survival (DFS) and breast cancer-specific survival (BCSS). Elevated values of eEF1A2 were associated with older age at diagnosis (p = 0.003), and androgen receptors positivity (p = 0.002). At univariate Cox analysis, eEF1A2 levels were not significantly associated with DFS and BCSS (p = 0.11 and p = 0.08, respectively) whereas adjusting for stage of disease, elevated levels of eEF1A2 protein resulted associated with poor prognosis (HR = 1.05, 95% CI: 1.01–1.11, p = 0.04 and HR = 1.07, 95% CI: 1.01–1.14, p = 0.03 for DFS and BCSS, respectively). This trend was confirmed analyzing negative versus positive samples by using categorized scores. Our data showed a negative prognostic role of eEF1A2 protein in TNBC, sustaining further investigations to confirm this result by wider and independent cohorts of patients. [ABSTRACT FROM AUTHOR]

Background: The global burden of cervical cancer remains high with the highest morbidity and mortality rates reported in developing countries. Hyperthermia as a chemo- and radiosensitiser has shown to improve treatment outcomes. This is an analysis of the local control results at six months post-treatment of patients enrolled in an ongoing study investigating the effects of the addition of modulated electro-hyperthermia (mEHT) to chemoradiotherapy for the treatment of HIV-positive and -negative cervical cancer patients in a low-resource setting. Methods: This ongoing Phase III randomised controlled trial, conducted at a state hospital in Johannesburg, South Africa, was registered with the appropriate ethics committee. After signing an informed consent, participants with FIGO stages IIB to IIIB squamous cell carcinoma of the cervix were randomised to receive chemoradiotherapy with/without mEHT using a secure online random-sampling tool (stratum: HIV status) accounting for age and stage. Reporting physicians were blind to treatment allocation. HIV-positive participants on antiretroviral treatment, or with a CD4 count >200cell/μL were included. mEHT was administered 2/weekly immediately before external beam radiation. The primary end point is local disease control (LDC) and secondary endpoints are toxicity; quality of life analysis; and two year survival. We report on six month LDC, including nodes visualised in the radiation field on 18F-FDG PET/CT (censored for six month survival), and six month local disease free survival (LDFS) (based on intention to treat). Trial status: Recruitment closed (ClinicalTrials.gov: NCT03332069). Results: 271 participants were recruited between January 2014 and November 2017, of which 210 were randomised for trial and 202 were available for analysis at six months post-treatment (mEHT: n = 101; Control: n = 101). Six month LDFS was higher in the mEHT Group (n = 39[38.6%]), than in the Control Group (n = 20[19.8%]); p = 0.003). LDC was also higher in the mEHT Group (n = 40[45.5%]) than the Control Group (n = 20[24.1%]); (p = 0.003). Conclusion: Our results show that mEHT is effective as a chemo-radiosensitiser for cervical cancer, even in high risk a patients and resource-constrained settings. [ABSTRACT FROM AUTHOR]

Background: Recent literature has suggested that tumor sidedness in colorectal cancer (CRC) is an independent prognostic and potentially predictive marker of survival. The aims of the study were to determine the prognostic significance of tumor sidedness in colorectal cancer patients undergoing primary tumor resection and to assess associated tumor biology. Methods: A total of 3281 consecutive patients who underwent surgical resection of their primary CRC from January 1998 to December 2012 were analyzed for association with tumor biologic factors and with overall survival. Metastatic patients were excluded from analysis. Results: Left sided CRCs were associated with a number of additional key prognostic markers including BRAFV600E wildtype status (P<0.001), mismatch repair proficiency (p<0.001), absence of peritumoral lymphocytic response (p = 0.001), high lymphocyte-to-monocyte ratio (p<0.001) and low neutrophil-to-lymphocyte ratio (p<0.001). In primary analysis with 3067 patients, there was no statistical difference in sidedness in the univariate analysis (p = 0.291). Three further subgroup analyses were performed. In the first subgroup, only stage III patients were analyzed. In the second, patients with mismatch repair deficiency were removed. In the third, additional clinicopathologic variables known to be independently prognostic were added into analysis. In all three subgroup analyses tumor sidedness was not an independent prognostic marker. Conclusions: Tumor sidedness was not an independent prognostic marker of CRC. However, right sided CRCs were associated with several key independent prognostic markers supporting a hypothesis that tumor sidedness is a surrogate for other biomarkers. [ABSTRACT FROM AUTHOR]

Background: Prognostic models based on individual patient characteristics can improve treatment decisions and outcome in the future. In many (radiomic) studies, small size and heterogeneity of datasets is a challenge that often limits performance and potential clinical applicability of these models. The current study is example of a retrospective multi-centric study with challenges and caveats. To highlight common issues and emphasize potential pitfalls, we aimed for an extensive analysis of these multi-center pre-treatment datasets, with an additional 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan acquired during treatment. Methods: The dataset consisted of 138 stage II-IV non-small cell lung cancer (NSCLC) patients from four different cohorts acquired from three different institutes. The differences between the cohorts were compared in terms of clinical characteristics and using the so-called ‘cohort differences model’ approach. Moreover, the potential prognostic performances for overall survival of radiomic features extracted from CT or FDG-PET, or relative or absolute differences between the scans at the two time points, were assessed using the LASSO regression method. Furthermore, the performances of five different classifiers were evaluated for all image sets. Results: The individual cohorts substantially differed in terms of patient characteristics. Moreover, the cohort differences model indicated statistically significant differences between the cohorts. Neither LASSO nor any of the tested classifiers resulted in a clinical relevant prognostic model that could be validated on the available datasets. Conclusion: The results imply that the study might have been influenced by a limited sample size, heterogeneous patient characteristics, and inconsistent imaging parameters. No prognostic performance of FDG-PET or CT based radiomics models can be reported. This study highlights the necessity of extensive evaluations of cohorts and of validation datasets, especially in retrospective multi-centric datasets. [ABSTRACT FROM AUTHOR]

Purpose: Portal vein thrombosis (PVT) is generally recognized as a prognostic factor in HCC. Our purpose is to assess and compare the survival of patients with PVT and without PVT, after Y-90 Trans-Arterial Radio-Embolization (TARE) of unresectable HCC, unresponsive to other loco-regional treatments. Materials and methods: Between November 2005 and November 2012, Y-90 resin-based TARE was performed in an IRB-approved prospective protocol, on 89 patients with unresectable HCC. 33/89 patients had PVT, the remaining 56 were resistant-to-cTACE or underwent TARE as a downstaging therapy. All patients were studied with Multi-Detector Computed Tomography (MDCT), angiography, 99mTc-MAA-scintigraphy and liver biopsy. Gastro-duodenal artery was embolized in most cases. Proton-Pump Inhibitors were administered to prevent gastritis and ulcers. χ2 test with Yates correction and log rank test were used to compare the two proportions and Kaplan-Meier survival curves, respectively. Results: The average activity administered was 1.7 ± 0.4 GBq. After the treatment, CTCAE grade 2 adverse events occurred in 46% (41/89) patients: in particular, fever and abdominal pain were found in 25 and 16 patients, respectively. No major side-effect was observed. According to mRECIST criteria, partial response or complete response was found in 70% of patient three months after the treatment, and in 90.5% nine months after the treatment. No significant difference was found in survival of patients with PVT compared to those without PVT (p-value = 0.672). A complete regression of PVT was observed in almost half patients (13/27, 48.1%). Conclusions: Portal vein invasion does not affect survival in advanced stage HCC-patients undergoing TARE using Y-90 resin-based microspheres. Y90 procedure is associated with regression of portal vein tumor thrombus. [ABSTRACT FROM AUTHOR]

Background: Low-grade gliomas cause significant neurological morbidity by brain invasion. There is no universally accepted objective technique available for detection of enlargement of low-grade gliomas in the clinical setting; subjective evaluation by clinicians using visual comparison of longitudinal radiological studies is the gold standard. The aim of this study is to determine whether a computer-assisted diagnosis (CAD) method helps physicians detect earlier growth of low-grade gliomas.Methods and Findings: We reviewed 165 patients diagnosed with grade 2 gliomas, seen at the University of Alabama at Birmingham clinics from 1 July 2017 to 14 May 2018. MRI scans were collected during the spring and summer of 2018. Fifty-six gliomas met the inclusion criteria, including 19 oligodendrogliomas, 26 astrocytomas, and 11 mixed gliomas in 30 males and 26 females with a mean age of 48 years and a range of follow-up of 150.2 months (difference between highest and lowest values). None received radiation therapy. We also studied 7 patients with an imaging abnormality without pathological diagnosis, who were clinically stable at the time of retrospective review (14 May 2018). This study compared growth detection by 7 physicians aided by the CAD method with retrospective clinical reports. The tumors of 63 patients (56 + 7) in 627 MRI scans were digitized, including 34 grade 2 gliomas with radiological progression and 22 radiologically stable grade 2 gliomas. The CAD method consisted of tumor segmentation, computing volumes, and pointing to growth by the online abrupt change-of-point method, which considers only past measurements. Independent scientists have evaluated the segmentation method. In 29 of the 34 patients with progression, the median time to growth detection was only 14 months for CAD compared to 44 months for current standard of care radiological evaluation (p < 0.001). Using CAD, accurate detection of tumor enlargement was possible with a median of only 57% change in the tumor volume as compared to a median of 174% change of volume necessary to diagnose tumor growth using standard of care clinical methods (p < 0.001). In the radiologically stable group, CAD facilitated growth detection in 13 out of 22 patients. CAD did not detect growth in the imaging abnormality group. The main limitation of this study was its retrospective design; nevertheless, the results depict the current state of a gold standard in clinical practice that allowed a significant increase in tumor volumes from baseline before detection. Such large increases in tumor volume would not be permitted in a prospective design. The number of glioma patients (n = 56) is a limitation; however, it is equivalent to the number of patients in phase II clinical trials.Conclusions: The current practice of visual comparison of longitudinal MRI scans is associated with significant delays in detecting growth of low-grade gliomas. Our findings support the idea that physicians aided by CAD detect growth at significantly smaller volumes than physicians using visual comparison alone. This study does not answer the questions whether to treat or not and which treatment modality is optimal. Nonetheless, early growth detection sets the stage for future clinical studies that address these questions and whether early therapeutic interventions prolong survival and improve quality of life. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this registry study was to analyze the long-term safety and effectiveness of recombinant human growth hormone (rhGH) in South Korean pediatric patients (≥2 years of age) with growth hormone deficiency GHD) of idiopathic or organic etiology, idiopathic short stature, Turner syndrome, small for gestational age and chronic renal failure. Methods: The study patients were followed-up till two years after the epiphyseal closure, with visits scheduled every six months. The outcome measures included the incidence of adverse events (AEs, in particular, neoplasia, glucose intolerance and hypothyroidism), as well as height standard deviation score (Ht SDS) and annual height velocity. The results of the interim analysis of a 5-year accumulated data for 2,024 patients (7,342 patient-years, PY) are presented. Results: A total of 14 neoplasms were diagnosed (191/100,000 PY); 7 out of 9 malignancies were recurrent craniopharyngioma found in patients with organic GHD. Seven cases of glucose intolerance (95/100,000 PY) and 22 cases of hypothyroidism (300/100,000 PY) were detected; about half of the cases (4 and 10 cases each) were considered to be related with rhGH treatment. Most of the growth-retarded patients showed continuous improvement in Ht SDS, with the most prominent effect observed within a year of treatment initiation. The beneficial effect of rhGH on Ht SDS gain was maintained for 2–4 years. Conclusions: The incidence of AEs of interest in rhGH-treated patients was low, and most of the neoplasms were benign and/or non-related to rhGH. Most patients benefited from the therapy in terms of height increment. [ABSTRACT FROM AUTHOR]

Objectives: Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) is increasing in incidence. Although HPV+ OPSCC has favorable prognosis, 10 to 25% of HPV+ OPSCCs eventually recur. We sought to evaluate the feasibility of detection of HPV16 E6/E7 expression in Circulating Tumor Cells (CTCs) and its utility as a prognostic tool in HPV16-associated OPSCC. Materials and methods: We developed a highly sensitive RT-qPCR assay for HPV mRNA expression in EpCAM(+) CTCs. In 22 patients with early stage and locally advanced OPSCC we evaluated HPV16 E6/E7 expression in the EpCAM(+) CTC fraction at baseline and at the end of concurrent chemoradiotherapy. HPV status in pre-therapy formalin-fixed paraffin-embedded (FFPE) tumor biopsies was assessed by p16 immunohistochemistry and polymerase chain reaction (PCR) and double positives were subjected to Real-time qPCR assay for detection of HPV16, 18 and 31 types. Results: Fourteen of 22 OPSCC (63.6%) were HPV DNA+/p16+. Among HPV+/p16+ patients, 10 patients (71.4%) were HPV16 DNA+. HPV16 E6/E7(+) CTCs were detected in 3 of 10 patients (30%) at baseline and 4 of 9 patients (44.4%) at the end-of-treatment, all of which were p16+/HPV16 DNA+. Survival analysis showed a significantly higher risk for disease relapse (p = 0.001) and death (p = 0.005) in patients with HPV16 E6/E7(+) baseline CTCs. Conclusion: Detection of HPV E6/E7(+) CTCs might be a useful noninvasive test in liquid biopsy samples for determination of a clinically relevant HPV infection in HPV+ OPSCC. Combined interpretation of HPV E6/E7(+) CTCs with UICC staging data may lead to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease. [ABSTRACT FROM AUTHOR]

Background: Irreversible Electroporation (IRE) is a novel image-guided tissue ablation technology that induces cell death via very short but strong pulsed electric fields. IRE has been shown to have preserving properties towards vessels and nerves and the extracellular matrix. This makes IRE an ideal candidate to treat prostate cancer (PCa) where other treatment modalities frequently unselectively destroy surrounding structures inducing severe side effects like incontinence or impotence. We report the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time. Material and findings: The patient cohort consisted of low (25), intermediate (88) and high-risk cancers (312). All had multi-parametric magnetic resonance imaging, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE. Patients were treated either focally (123), sub-whole-gland (154), whole-gland (134) or for recurrent disease (63) after previous radical prostatectomy, radiation therapy, etc. Adverse effects were mild (19.7%), moderate (3.7%) and severe (1.4%), never life-threatening. Urinary continence was preserved in all cases. IRE-induced erectile dysfunction persisted in 3% of the evaluated cases 12 months post treatment. Mean transient IIEF-5-Score reduction was 33% within 12-month post IRE follow-up and 15% after 12 months. Recurrences within the follow-up period occurred in 10% of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals). Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6% (CI95: 1.8–16.93) for Gleason 6, 14.6% (CI95: 8.8–23.7) for Gleason 7 and 39.5% (CI95: 23.5–61.4) for Gleason 8–10. Conclusion: The results indicate comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment. The data also shows that IRE, besides focal therapy of early PCa, can also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore. [ABSTRACT FROM AUTHOR]

There are various methods of fixation for anterior pelvic ring fractures. We report our experience with modified pedicle screw-rod fixation (MPSRF) via a minimally invasive method. Fourteen patients with anterior pelvic ring fracture were treated by internal fixation (conventional plate fixation, n = 7; MPSRF, n = 7). Intraoperative blood loss, operative time, post-operative fracture reduction grading by radiography, and complication rates were compared and statistically analyzed. Patients treated with MPSRF had a shorter operative time (-36 min, P = 0.378) and significantly less blood loss (-264 ml, P = 0.026) than patients in the conventional plate fixation group. Postoperative radiological evaluations were similar between the groups (P > 0.05). The complication rate was lower in the MPSRF group (1/7 patients) than in the plate fixation group (2/7 patients). Modified pedicle screw-rod fixation is a viable treatment for anterior pelvic ring fixation and can reduce blood loss. [ABSTRACT FROM AUTHOR]

Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04–0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy. [ABSTRACT FROM AUTHOR]

Purpose: Perfusion and diffusion magnetic resonance imaging (MRI) provide important biomarkers for brain tumor analysis. Our aim was to investigate if regions of increased perfusion or tumor with restricted diffusion on the immediate post-operative MRI examination would be predictive of time to tumor progression in patients with high-grade gliomas. Materials and methods: Twenty-three patients with high-grade gliomas were retrospectively analyzed. We measured the perfusion at the resection area and evaluated the presence or absence of the restricted diffusion in residual tumor masses. The associations of the perfusion, diffusion and contrast enhancement (delayed static enhancement (DSE)) characteristics with time to tumor progression were statistically calculated. We also evaluated if the location of the tumor progression was concordant to the areas of the elevated perfusion, tumor type restricted diffusion and enhancement. Results: Patients with >200 days to progression are more likely to have no elevated relative cerebral blood volume (rCBV) ratio (p = 0.0004), no tumor restriction (p = 0.024), and no DSE (p = 0.052). The elevated mean rCBV ratio (p<0.001) and tumor type restricted diffusion (p = 0.002) were significantly associated with a higher risk of progression. All cases with rCBV ratio of >1.5 progressed in 275 days or earlier. Tumors tended to progress at the area where patients with post-operative MRIs showed elevated perfusion (p = 0.006), tumor-type restricted diffusion (p = 0.005) and DSE (p = 0.008). Conclusions: Post-operative analysis of rCBV, tumor type restricted diffusion and enhancement characteristics are predictive of time to progression, risk of progression and where tumor progression is likely to occur. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NAC) is used in patients with breast cancer to reduce tumor focus, metastatic risk, and patient mortality. Monitoring NAC effects is necessary to capture resistant patients and stop or change treatment. The existing methods for evaluating NAC results have some limitations. The aim of this study was to assess the tumor response at an early stage, after the first doses of the NAC, based on the variability of the backscattered ultrasound energy, and backscatter statistics. The backscatter statistics has not previously been used to monitor NAC effects. Methods: The B-mode ultrasound images and raw radio frequency data from breast tumors were obtained using an ultrasound scanner before chemotherapy and 1 week after each NAC cycle. The study included twenty-four malignant breast cancers diagnosed in sixteen patients and qualified for neoadjuvant treatment before surgery. The shape parameter of the homodyned K distribution and integrated backscatter, along with the tumor size in the longest dimension, were determined based on ultrasound data and used as markers for NAC response. Cancer tumors were assigned to responding and non-responding groups, according to histopathological evaluation, which was a reference in assessing the utility of markers. Statistical analysis was performed to rate the ability of markers to predict the final NAC response based on data obtained after subsequent therapeutic doses. Results: Statistically significant differences (p<0.05) between groups were obtained after 2, 3, 4, and 5 doses of NAC for quantitative ultrasound markers and after 5 doses for the assessment based on maximum tumor dimension. Statistical analysis showed that, after the second and third NAC courses the classification based on integrated backscatter marker was characterized by an AUC of 0.69 and 0.82, respectively. The introduction of the second quantitative marker describing the statistical properties of scattering increased the corresponding AUC values to 0.82 and 0.91. Conclusions: Quantitative ultrasound information can characterize the tumor's pathological response better and at an earlier stage of therapy than the assessment of the reduction of its dimensions. The introduction of statistical parameters of ultrasonic backscatter to monitor the effects of chemotherapy can increase the effectiveness of monitoring and contribute to a better personalization of NAC therapy. [ABSTRACT FROM AUTHOR]

We present an approach for fully automatic urinary bladder segmentation in CT images with artificial neural networks in this study. Automatic medical image analysis has become an invaluable tool in the different treatment stages of diseases. Especially medical image segmentation plays a vital role, since segmentation is often the initial step in an image analysis pipeline. Since deep neural networks have made a large impact on the field of image processing in the past years, we use two different deep learning architectures to segment the urinary bladder. Both of these architectures are based on pre-trained classification networks that are adapted to perform semantic segmentation. Since deep neural networks require a large amount of training data, specifically images and corresponding ground truth labels, we furthermore propose a method to generate such a suitable training data set from Positron Emission Tomography/Computed Tomography image data. This is done by applying thresholding to the Positron Emission Tomography data for obtaining a ground truth and by utilizing data augmentation to enlarge the dataset. In this study, we discuss the influence of data augmentation on the segmentation results, and compare and evaluate the proposed architectures in terms of qualitative and quantitative segmentation performance. The results presented in this study allow concluding that deep neural networks can be considered a promising approach to segment the urinary bladder in CT images. [ABSTRACT FROM AUTHOR]

Background: Surgical indications for rectal neuroendocrine tumors with potential lymph node metastasis remain controversial. Although accurate preoperative diagnosis of nodal status may be helpful for treatment strategy, scant data about clinical values of lymph node size have been reported. The aim of this retrospective study was to investigate the relationship between lymph node size and lymph node metastasis. Methods: Participants comprised 102 patients who underwent rectal resection with total mesenteric excision or tumor-specific mesenteric excision and in some cases additional lateral pelvic lymph node dissection for rectal neuroendocrine tumor between June 2005 and September 2016. All lymph nodes from specimens were checked and measured. Results: Pathological lymph node metastasis was confirmed in 37 patients (36%), including 6 patients (5.8%) with lateral pelvic lymph node metastasis. A total of 1169 lymph nodes in the mesorectum were retrieved from all specimens, with 78 lymph nodes (6.7%) showing metastasis. Mean length (long-axis diameter) of metastatic lymph nodes in the mesorectum was 4.31 mm, significantly larger than that of non-metastatic lymph nodes (2.39 mm, P<0.01). The optimal cut-off of major axis length for predicting mesorectal lymph node metastasis was 3 mm. We could predict lymph node metastasis in only 7 patients (21%) from preoperative multidetector-row computed tomography. Conclusions: Metastatic lymph nodes were small, so predicting lymph node metastasis from preoperative computed tomography is difficult. Alternative modalities with a scan width less than 3 mm may be needed to predict lymph node metastasis of rectal NET with low cost and labour requirements. [ABSTRACT FROM AUTHOR]

Purpose: Standard radiological/topographical classifications of gliomas often do not reflect the real extension of the tumor within the lobar-cortical anatomy. Furthermore, these systems do not provide information on the relationship between tumor growth and the subcortical white matter architecture. We propose the use of an anatomically standardized grid system (the Brain-Grid) to merge serial morphological magnetic resonance imaging (MRI) scans with a representative tractographic atlas. Two illustrative cases are presented to show the potential advantages of this classification system. Methods: MRI scans of 39 patients (WHO grade II and III gliomas) were analyzed with a standardized grid created by intersecting longitudinal lines on the axial, sagittal, and coronal planes. The anatomical landmarks were chosen from an average brain, spatially normalized to the Montreal Neurological Institute (MNI) space and the Talairach space. Major white matter pathways were reconstructed with a deterministic tracking algorithm on a reference atlas and analyzed using the Brain-Grid system. Results: In all, 48 brain grid voxels (areas defined by 3 coordinates, axial (A), coronal (C), sagittal (S) and numbers from 1 to 4) were delineated in each MRI sequence and on the tractographic atlas. The number of grid voxels infiltrated was consistent, also in the MNI space. The sub-cortical insula/basal ganglia (A3-C2-S2) and the fronto-insular region (A3-C2-S1) were most frequently involved. The inferior fronto-occipital fasciculus, anterior thalamic radiation, uncinate fasciculus, and external capsule were the most frequently associated pathways in both hemispheres. Conclusions: The Brain-Grid based classification system provides an accurate observational tool in all patients with suspected gliomas, based on the comparison of grid voxels on a morphological MRI and segmented white matter atlas. Important biological information on tumor kinetics including extension, speed, and preferential direction of progression can be observed and even predicted with this system. This novel classification can easily be applied to both prospective and retrospective cohorts of patients and increase our comprehension of glioma behavior. [ABSTRACT FROM AUTHOR]

Objective: The objective is to present a proof-of-concept of a semi-automatic method to reduce hippocampus segmentation time on magnetic resonance images (MRI). Materials and methods: FAst Segmentation Through SURface Fairing (FASTSURF) is based on a surface fairing technique which reconstructs the hippocampus from sparse delineations. To validate FASTSURF, simulations were performed in which sparse delineations extracted from full manual segmentations served as input. On three different datasets with different diagnostic groups, FASTSURF hippocampi were compared to the original segmentations using Jaccard overlap indices and percentage volume differences (PVD). In one data set for which back-to-back scans were available, unbiased estimates of overlap and PVD were obtained. Using longitudinal scans, we compared hippocampal atrophy rates measured by manual, FASTSURF and two automatic segmentations (FreeSurfer and FSL-FIRST). Results: With only seven input contours, FASTSURF yielded mean Jaccard indices ranging from 72(±4.3)% to 83(±2.6)% and PVDs ranging from 0.02(±2.40)% to 3.2(±3.40)% across the three datasets. Slightly poorer results were obtained for the unbiased analysis, but the performance was still considerably better than both tested automatic methods with only five contours. Conclusions: FASTSURF segmentations have high accuracy and require only a fraction of the delineation effort of fully manual segmentation. Atrophy rate quantification based on completely manual segmentation is well reproduced by FASTSURF. Therefore, FASTSURF is a promising tool to be implemented in clinical workflow, provided a future prospective validation confirms our findings. [ABSTRACT FROM AUTHOR]

The current research study is concerned with the automated differentiation between histopathological slides from colon tissues with respect to four classes (healthy tissue and cancerous of grades 1, 2 or 3) through an optimized ensemble of predictors. Six distinct classifiers with prediction accuracies ranging from 87% to 95% are considered for the task. The proposed method of combining them takes into account the probabilities of the individual classifiers for each sample to be assigned to any of the four classes, optimizes weights for each technique by differential evolution and attains an accuracy that is significantly better than the individual results. Moreover, a degree of confidence is defined that would allow the pathologists to separate the data into two distinct sets, one that is correctly classified with a high level of confidence and the rest that would need their further attention. The tandem is also validated on other benchmark data sets. The proposed methodology proves to be efficient in improving the classification accuracy of each algorithm taken separately and performs reasonably well on other data sets, even with default weights. In addition, by establishing a degree of confidence the method becomes more viable for use by actual practitioners. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to assess the estimated “per patient” total cost for a single Oncologic Italian Cancer Center participating in a multicenter clinical trial with new anticancer biological agents using the activity-based costing (ABC) methodology. Methodology: Nine randomized phase 3 clinical trials employing biological agents at the National Cancer Institute of Napoli, Italy, were analyzed to indentify “per patient” costs of each trial, according to the ABC methodology. The average consumption of resources for a patient completing the entire planned treatment was estimated for each trial. Through interviews of the personnel (doctors, nurses and technicians) and by analyses of the clinical trials protocols, the main activities of the 9 clinical trials were identified and, for each trial, the complete health care pathway of the patients and the treatment programmes were minutely reconstructed. Drug costs were not included because provided by Sponsors. Principal findings: The average costs of the pre-study, treatment, monitoring, follow-up, audit, and administrative activities accounted for 2.357, 4.783, 700, 372, 1.263, and 9 Euro, respectively. The average total cost estimated for all “per patient” activities, including overhead costs, was 11.379 Euro. Staff costs accounted for € 5.988, while costs of diagnostic test accounted for 3.494 Euro. Clinical trials with immunotherapeutic drugs accounted for higher costs (+601 Euro as oncological staff costs, +1.318 Euro as intermediate services cost and +384 Euro as overheads). Conclusions: The average total cost estimated for all “per patient” activities of a clinical trial with new anticancer biological agents was 11.379 Euro using the ABC methodology. [ABSTRACT FROM AUTHOR]

Objectives: To explore the existence and importance of mental images of cancer among people with head and neck cancers with a focus on the perceived origins and meaning of mental images, their development over time, and their relationship to illness beliefs. Methods: A longitudinal qualitative study consisting of 44 in-depth semi-structured interviews with 25 consecutive, newly-diagnosed head and neck cancer patients. Participants were invited to draw their images during the interviews. Follow-up interviews occurred after treatment completion. Analysis drew upon the principles of Interpretative Phenomenological Analysis (IPA). Results: Many participants had mental images of their cancer which appeared to both embody and influence their beliefs about their illness, and affect their emotional response. For those who held them, mental images appeared to constitute an important part of their cognitive representation (understanding) of their illness. For some, their images also had a powerful emotional impact, being either reassuring or frightening. Images often appeared to originate from early clinical encounters, and remained fairly stable throughout treatment. Images could be conceptualised as ‘concrete’ (the perceived reality) and/or ‘similic’ (figurative). Patients’ images reflected the perceived meaning, properties or ‘intent’ of the cancer–that is beliefs concerning the disease’s identity, consequences and prognosis (likelihood of cure or control). Conclusions: People with head and neck cancer may develop a mental image of their disease, often generated early within clinical encounters, which can both reflect and influence their understanding of the cancer. Such images tend to be stable over time. We theorise that careful use of images in early consultations could avoid or minimise some distress, including fears of outcome or recurrence. Concrete or similic images and language could be employed later to change perceptions and reduce distress. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the dosimetric accuracy of respiratory gated volumetric modulated arc therapy (VMAT) for lung stereotactic body radiation therapy (SBRT) under simulation conditions similar to the actual clinical situation using patient-specific lung phantoms and realistic target movements. Methods: Six heterogeneous lung phantoms were fabricated using a 3D-printer (3DISON, ROKIT, Seoul, Korea) to be dosimetrically equivalent to actual target regions of lung SBRT cases treated via gated VMAT. They were designed to move realistically via a motion device (QUASAR, Modus Medical Devices, Canada). Using the lung phantoms and a homogeneous phantom (model 500–3315, Modus Medical Devices), film dosimetry was performed with and without respiratory gating for VMAT delivery (TrueBeam STx; Varian Medical Systems, Palo Alto, CA, USA). The measured results were analyzed with the gamma passing rates (GPRs) of 2%/1 mm criteria, by comparing with the calculated dose via the AXB and AAA algorithms of the Eclipse Treatment Planning System (version 10.0.28; Varian Medical Systems). Results: GPRs were greater than the acceptance criteria 80% for all film measurements with the stationary and homogeneous phantoms in conventional QAs. Regardless of the heterogeneity of phantoms, there were no significant differences (p > 0.05) in GPRs obtained with and without target motions; the statistical significance (p = 0.031) was presented between both algorithms under the utilization of heterogeneous phantoms. Conclusions: Dosimetric verification with heterogeneous patient-specific lung phantoms could be successfully implemented as the evaluation method for gated VMAT delivery. In addition, it could be dosimetrically confirmed that the AXB algorithm improved the dose calculation accuracy under patient-specific simulations using 3D printed lung phantoms. [ABSTRACT FROM AUTHOR]

Background: Non-small-cell lung cancer (NSCLC) patients often demonstrate varying clinical courses and outcomes, even within the same tumor stage. This study explores deep learning applications in medical imaging allowing for the automated quantification of radiographic characteristics and potentially improving patient stratification.Methods and Findings: We performed an integrative analysis on 7 independent datasets across 5 institutions totaling 1,194 NSCLC patients (age median = 68.3 years [range 32.5-93.3], survival median = 1.7 years [range 0.0-11.7]). Using external validation in computed tomography (CT) data, we identified prognostic signatures using a 3D convolutional neural network (CNN) for patients treated with radiotherapy (n = 771, age median = 68.0 years [range 32.5-93.3], survival median = 1.3 years [range 0.0-11.7]). We then employed a transfer learning approach to achieve the same for surgery patients (n = 391, age median = 69.1 years [range 37.2-88.0], survival median = 3.1 years [range 0.0-8.8]). We found that the CNN predictions were significantly associated with 2-year overall survival from the start of respective treatment for radiotherapy (area under the receiver operating characteristic curve [AUC] = 0.70 [95% CI 0.63-0.78], p < 0.001) and surgery (AUC = 0.71 [95% CI 0.60-0.82], p < 0.001) patients. The CNN was also able to significantly stratify patients into low and high mortality risk groups in both the radiotherapy (p < 0.001) and surgery (p = 0.03) datasets. Additionally, the CNN was found to significantly outperform random forest models built on clinical parameters-including age, sex, and tumor node metastasis stage-as well as demonstrate high robustness against test-retest (intraclass correlation coefficient = 0.91) and inter-reader (Spearman's rank-order correlation = 0.88) variations. To gain a better understanding of the characteristics captured by the CNN, we identified regions with the most contribution towards predictions and highlighted the importance of tumor-surrounding tissue in patient stratification. We also present preliminary findings on the biological basis of the captured phenotypes as being linked to cell cycle and transcriptional processes. Limitations include the retrospective nature of this study as well as the opaque black box nature of deep learning networks.Conclusions: Our results provide evidence that deep learning networks may be used for mortality risk stratification based on standard-of-care CT images from NSCLC patients. This evidence motivates future research into better deciphering the clinical and biological basis of deep learning networks as well as validation in prospective data. [ABSTRACT FROM AUTHOR]

Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG and FLI1 are critical transcriptional activators for EC-specific genes, among which microRNA-126 partially contributes to blocking the induction of EndMT. Moreover, we demonstrated that ERG and FLI1 expression is downregulated in ECs within tumors by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in ECs, and EC behavior in pathological conditions. [ABSTRACT FROM AUTHOR]

Background: Published evidence on treatment costs of breast cancer varies widely in methodology and a global systematic review is lacking. Objectives: This study aimed to conduct a systematic review to compare treatment costs of breast cancer by stage at diagnosis across countries at different levels of socio-economic development, and to identify key methodological differences in costing approaches. Data sources: MEDLINE, EMBASE, and NHS Economic Evaluation Database (NHS EED) before April 2018. Eligibility criteria: Studies were eligible if they reported treatment costs of breast cancer by stage at diagnosis using patient level data, in any language. Study appraisal and synthesis methods: Study characteristics and treatment costs by stage were summarised. Study quality was assessed using the Drummond Checklist, and detailed methodological differences were further compared. Results: Twenty studies were included, 15 from high-income countries and five from low- and middle-income countries. Eleven studies used the FIGO staging system, and the mean treatment costs of breast cancer at Stage II, III and IV were 32%, 95%, and 109% higher than Stage I. Five studies categorised stage as in situ, local, regional and distant. The mean treatment costs of regional and distant breast cancer were 41% and 165% higher than local breast cancer. Overall, the quality of studies ranged from 50% (lowest quality) to 84% (highest). Most studies used regression frameworks but the choice of regression model was rarely justified. Few studies described key methodological issues including skewness, zero values, censored data, missing data, and the inclusion of control groups to estimate disease-attributable costs. Conclusions: Treatment costs of breast cancer generally increased with the advancement of the disease stage at diagnosis. Methodological issues should be better handled and properly described in future costing studies. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC. [ABSTRACT FROM AUTHOR]

Background: Peritumoral inflammation—a response mainly involving polimorphonuclear neutrophils—has traditionally been thought protumoral in its effects. In recent years, however, a number of studies have indicated that it may play an important antitumoral role. This discrepancy has been difficult to explain. Methods and findings: This work describes a tool for simulating tumor growth that obeys the universal model of tumor growth dynamics, and shows through its use that low intensity peritumoral inflammation exerts a protumoral effect, while high intensity inflammation exerts a potent antitumoral effect. Indeed, the simulation results obtained indicate that a sufficiently strong antitumoral effect can reverse tumor growth, as has been suggested several times in the clinical literature. Conclusions: The present result indicate that an ‘immunological threshold’ must exist, marking the boundary between states in which peritumoral inflammation is either harmful or beneficial. These findings lend support to the idea that stimulating intense peritumoral inflammation could be used as a treatment against solid tumors. [ABSTRACT FROM AUTHOR]

This study investigates the impact of whole-body MRI (WB-MRI) in addition to CT of chest-abdomen-pelvis (CT-CAP) and 18F-FDG PET/CT (PET/CT) on systemic treatment decisions in standard clinical practice for patients with advanced breast cancer (ABC). WB-MRI examinations in ABC patients were extracted from our WB-MRI registry (2009–2017). Patients under systemic treatment who underwent WB-MRI and a control examination (CT-CAP or PET/CT) were included. Data regarding progressive disease (PD) reported either on WB-MRI or on the control examinations were collected. Data regarding eventual change in treatment after the imaging evaluation were collected. It was finally evaluated whether the detection of PD by any of the two modalities had induced a change in treatment. Among 910 WB-MRI examinations in ABC patients, 58 had a paired control examination (16 CT-CAP and 42 PET/CT) and were analysed. In 23/58 paired examinations, additional sites of disease were reported only on WB-MRI and not on the control examination. In 17/28 paired examinations, PD was reported only on WB-MRI and not on the control examination. In 14 out of the 28 pairs of examinations that were followed by a change in treatment, PD had been reported only on WBMRI (14/28; 50%), while stable disease had been reported on the control examination. In conclusion, WB-MRI disclosed PD earlier than the control examination (CT-CAP or PET/CT), and it was responsible alone for 50% of all changes in treatment. [ABSTRACT FROM AUTHOR]

Background: Aldehyde dehydrogenase 1A1 (ALDH1A1) encodes an enzyme that oxidizes aldehydes to their corresponding carboxylic acids. In colorectal cancer ALDH1A1 marks cancer stem cells and plays putative roles in tumor progression and drug resistance. However, the potential value of ALDH1A1 as a diagnostic marker or target for therapy remains unclear. Here, we have analyzed ALDH1A1 mRNA and protein levels in relation to clinical, histopathological and molecular tumor features in large series of human colorectal cancer. Methods: ALDH1A1 protein levels were determined by immunohistochemistry in a series of primary colorectal tumors and their corresponding liver metastases (n = 158). ALDH1A1 mRNA levels were analyzed in several large patient cohorts of colorectal cancer. ALDH1A1 mRNA and protein levels were then related to overall survival and to clinical, histopathological and molecular tumor features. Results: High levels of ALDH1A1 were associated with a poorly differentiated histology and a right-sided tumor location, but not to a mesenchymal-like molecular subtype. Liver metastases contained significantly higher levels of ALDH1A1 compared to the corresponding primary tumors. Radio- and/or chemotherapy prior to tumor resection was associated with increased ALDH1A1 levels regardless of the molecular subtype. Finally, ALDH1A1 protein expression in primary tumors and metastases correlated with shorter overall survival. Conclusions: ALDH1A1 expression is associated with features of poor prognosis, including a poorly differentiated histology and ‘right-sidedness’ of the primary tumor, and with shorter overall survival. ALDH1A1 is also highly expressed in therapy-surviving tumors and in liver metastases. These results warrant further research into the potential value of targeting ALDH1A1 in order to improve the efficacy of standard treatment and thereby preventing tumor recurrence. [ABSTRACT FROM AUTHOR]