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Purpose: The CONSORT extension for patient reported outcomes (PROs) aims to improve reporting, but guidance on the optimal integration with clinical data is lacking. This study examines in detail the reporting of PROs and clinical data from randomized controlled trials (RCTs) in gastro-intestinal cancer to inform design and reporting of combined PRO and clinical data from trials to improve the ‘take home’ message for clinicians to use in practice. Materials and Methods: The case study was undertaken in gastro-intestinal cancer trials. Well-conducted RCTs reporting PROs with validated instruments were identified and categorized into those combining PRO and clinical data in a single paper, or those separating data into linked primary and supplemental papers. Qualitative methods were developed to examine reporting of the critical interpretation of the trial results (trial exegesis) in the papers in relation of the PRO and clinical outcomes and applied to each publication category. Results were used to inform recommendations for practice. Results: From 1917 screened abstracts, 49 high quality RCTs were identified reported in 36 combined and 15 linked primary and supplemental papers. In-depth analysis of manuscript text identified three categories for understanding trial exegesis: where authors reported a “detailed”, “general”, or absent PRO rationale and integrated interpretation of clinical and PRO results. A total of 11 (30%) and 6 (16%) combined papers reported “detailed” PRO rationale and integrated interpretation of results although only 2 (14%) and 1 (7%) primary papers achieved the same standard respectively. Supplemental papers provide better information with 11 (73%) and 3 (20%) achieving “detailed” rationale and integrated interpretation of results. Supplemental papers, however, were published a median of 20 months after the primary RCT data in lower impact factor journals (median 16.8 versus 5.2). Conclusion: It is recommended that single papers, with detailed PRO rationale and integrated PRO and clinical data are published to optimize trial exegesis. Further work to examine whether this improves the use of PRO data to inform practice is needed. [ABSTRACT FROM AUTHOR]

Background: Distant metastasis or local recurrence after primary tumour resection remain a major clinical problem. The anaesthetic technique used during oncologic surgery is suggested to influence the metastatic process. While awaiting the results of ongoing randomised controlled trials (RCTs), we have analyzed the evidence regarding the influence of anaesthetic drugs on experimental tumour metastasis in animal studies. Methods: PubMed and Embase were searched until April 21st, 2015. Studies were included in the systematic review when they 1) assessed the effect of an anaesthetic drug used in clinical practice on the number or incidence of metastasis in animal models with experimental cancer, 2) included an appropriate control group, and 3) presented unique data. Results: 20 studies met the inclusion criteria (published between 1958–2010). Data on number of metastases could be retrieved from 17 studies. These studies described 41 independent comparisons, 33 of which could be included in the meta-analysis (MA). The incidence of metastases was studied in 3 unique papers. From these 3 papers, data on 7 independent comparisons could be extracted and included in the MA. Locally administered local anaesthetics appear to decrease the number of metastases (SMD -6.15 [-8.42; -3.88]), whereas general anaesthetics (RD: 0.136 [0.045, 0.226]), and more specifically volatile anaesthetics (SMD 0.54 [0.24; 0.84]), appear to increase the number and risk of metastases in animal models for cancer. Conclusions: Anaesthetics influence the number and incidence of metastases in experimental cancer models. Although more high quality experimental research is necessary, based on the currently available evidence from animal studies, there is no indication to suggest that locally administered local anaesthetics are harmful during surgery in cancer patients. Volatile anaesthetics, however, might increase metastasis in animal models and clinical trials investigating this possibly harmful effect should receive priority. The results of our systematic review in animal studies are broadly consistent with clinical reports that anaesthetic technique does seem to affect the tumour metastasis process. [ABSTRACT FROM AUTHOR]

Many different physiological processes affect the growth of malignant lesions and their response to therapy. Each of these processes is spatially and genetically heterogeneous; dynamically evolving in time; controlled by many other physiological processes, and intrinsically random and unpredictable. The objective of this paper is to show that all of these properties of cancer physiology can be treated in a unified, mathematically rigorous way via the theory of random processes. We treat each physiological process as a random function of position and time within a tumor, defining the joint statistics of such functions via the infinite-dimensional characteristic functional. The theory is illustrated by analyzing several models of drug delivery and response of a tumor to therapy. To apply the methodology to precision cancer therapy, we use maximum-likelihood estimation with Emission Computed Tomography (ECT) data to estimate unknown patient-specific physiological parameters, ultimately demonstrating how to predict the probability of tumor control for an individual patient undergoing a proposed therapeutic regimen. [ABSTRACT FROM AUTHOR]

Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the “maximum dose in minimum time” principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient’s life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor’s proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme. [ABSTRACT FROM AUTHOR]

Background: Cancer and Diabetes Mellitus (DM) are leading causes of death worldwide and the prevalence of both is escalating. People with co-morbid cancer and DM have increased morbidity and premature mortality compared with cancer patients with no DM. The reasons for this are likely to be multifaceted but will include the impact of hypo/hyperglycaemia and diabetes therapies on cancer treatment and disease progression. A useful step toward addressing this disparity in treatment outcomes is to establish the impact of cancer treatment on diabetes control. Aim: The aim of this review is to identify and analyse current evidence reporting glycaemic control (HbA1c) during and after cancer treatment. Methods: Systematic searches of published quantitative research relating to comorbid cancer and type 2 diabetes mellitus were conducted using databases, including Medline, Embase, PsychINFO, CINAHL and Web of Science (February 2017). Full text publications were eligible for inclusion if they: were quantitative, published in English language, investigated the effects of cancer treatment on glycaemic control, reported HbA1c (%/mmols/mol) and included adult populations with diabetes. Means, standard deviations and sample sizes were extracted from each paper; missing standard deviations were imputed. The completed datasets were analysed using a random effects model. A mixed-effects analysis was undertaken to calculate mean HbA1c (%/mmols/mol) change over three time periods compared to baseline. Results: The available literature exploring glycaemic control post-diagnosis was mixed. There was increased risk of poor glycaemic control during this time if studies of surgical treatment for gastric cancer are excluded, with significant differences between baseline and 12 months (p < 0.001) and baseline and 24 months (p = 0.002). Conclusion: We found some evidence to support the contention that glycaemic control during and/or after non-surgical cancer treatment is worsened, and the reasons are not well defined in individual studies. Future studies should consider the reasons why this is the case. [ABSTRACT FROM AUTHOR]

Background: The recently adopted Sustainable Development Goals call for the end of poverty and the equitable provision of healthcare. These goals are often at odds, however: health seeking can lead to catastrophic spending, an outcome for which cancer patients and the poor in resource-limited settings are at particularly high risk. How various health policies affect the additional aims of financial wellbeing and equity is poorly understood. This paper evaluates the health, financial, and equity impacts of governmental and charitable policies for surgical oncology in a resource-limited setting. Methods: Three charitable platforms for surgical oncology delivery in Uganda were compared to six governmental policies aimed at improving healthcare access. An extended cost-effectiveness analysis using an agent-based simulation model examined the numbers of lives saved, catastrophic expenditure averted, impoverishment averted, costs, and the distribution of benefits across the wealth spectrum. Findings: Of the nine policies and platforms evaluated, two were able to provide simultaneous health and financial benefits efficiently and equitably: mobile surgical units and governmental policies that simultaneously address surgical scaleup, the cost of surgery, and the cost of transportation. Policies that only remove user fees are dominated, as is the commonly employed short-term “surgical mission trip”. These results are robust to scenario and sensitivity analyses. Interpretation: The most common platforms for increasing access to surgical care appear unable to provide health and financial risk protection equitably. On the other hand, mobile surgical units, to date an underutilized delivery platform, are able to deliver surgical oncology in a manner that meets sustainable development goals by improving health, financial solvency, and equity. These platforms compare favorably with policies that holistically address surgical delivery and should be considered as countries strengthen health systems. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is one of the leading causes of cancer deaths in both sexes in the world. Improvement of existing therapy modalities and implementing new ones in order to improve survival of patients with colorectal cancer represents a great challenge for medicine. The aim of this paper was to assess the impact that adding bevacizumab to chemotherapy has on survival in patients with metastatic colorectal cancer, compared to the use of chemotherapy alone. Methods: Hazard ratios (HRs) with their 95% confidence intervals (CI) were determined from the studies and pooled. Two-sided p values were reported and considered to indicate statistical significance if less than 0.05. Results: A total of 12 studies that meet the inclusion criteria were identified in the literature search, 3 phase II studies and 9 phase III studies. Based on the random effects meta-analysis, a statistically significant improvement was identified for both overall survival (HR = 0.84; 95% CI: 0.74–0.94; p = 0.003) and progression free survival (HR = 0.64; 95% CI: 0.55–0.73; p<0.00001) in patients with metastatic colorectal cancer when bevacizumab was added to chemotherapy, compared to chemotherapy treatment alone. Conclusion: The findings of this meta analysis confirm the benefit of adding bevacizumab to chemotherapy in terms of survival and progression free survival, but the magnitude of this effect is not consistent throughout the included studies. This suggests the need for further research of interaction of bevacizumab with chemotherapeutic agents as well as recognition of patients’ characteristics important for the treatment selection criteria. [ABSTRACT FROM AUTHOR]

Purpose: This paper identifies predictors of recovery trajectories of quality of life (QoL), health status and personal wellbeing in the two years following colorectal cancer surgery. Methods: 872 adults receiving curative intent surgery during November 2010 to March 2012. Questionnaires at baseline, 3, 9, 15, 24 months post-surgery assessed QoL, health status, wellbeing, confidence to manage illness-related problems (self-efficacy), social support, co-morbidities, socio-demographic, clinical and treatment characteristics. Group-based trajectory analyses identified distinct trajectories and predictors for QoL, health status and wellbeing. Results: Four recovery trajectories were identified for each outcome. Groups 1 and 2 fared consistently well (scores above/within normal range); 70.5% of participants for QoL, 33.3% health status, 77.6% wellbeing. Group 3 had some problems (24.2% QoL, 59.3% health, 18.2% wellbeing); Group 4 fared consistently poorly (5.3% QoL, 7.4% health, 4.2% wellbeing). Higher pre-surgery depression and lower self-efficacy were significantly associated with poorer trajectories for all three outcomes after adjusting for other important predictors including disease characteristics, stoma, anxiety and social support. Conclusions: Psychosocial factors including self-efficacy and depression before surgery predict recovery trajectories in QoL, health status and wellbeing following colorectal cancer treatment independent of treatment or disease characteristics. This has significant implications for colorectal cancer management as appropriate support may be improved by early intervention resulting in more positive recovery experiences. [ABSTRACT FROM AUTHOR]

Background: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. Objectives: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. Methods: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. Results: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. Conclusions and Implications: The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. Systematic Review Protocol Number: CRD42015014145 [ABSTRACT FROM AUTHOR]

Objective: Lung cancer is the most common type of cancer around the world, and it represents the main cause of death in the USA. Surgical treatment is the optimal therapeutic strategy for resectable non-small cell lung cancer. The principal factor for long-term survival after complete resection is the anatomic extension of the neoplasm. However, other factors also have adverse effects on operative mortality, and influence long-term outcome. In this paper we propose an algorithmic solution for the estimation of 5-years survival rate in lung cancer patients undertaking pulmonary resection. Materials and methods: We address the issue of survival analysis through decision-making techniques based on fuzzy and soft set theories. We develop an expert system based on clinical and functional data of lung cancer resections in patients with cancer that can be used to predict the survival of patients. Results: The evaluation of surgical risk in patients undertaking pulmonary resection is a primary target for thoracic surgeons. Lung cancer survival is influenced by many factors. The computational performance of our algorithm is critically analyzed by an experimental study. The correct survival classification is achieved with an accuracy of 79.0%. Our novel soft-set based criterion is an effective and precise diagnosis application for the determination of the survival rate. [ABSTRACT FROM AUTHOR]

Background: The only curative treatment for pancreatic adenocarcinoma is radical surgical resection. Because of the special anatomic features of pancreatic neck, the selection of optimal surgical procedure for treatment of adenocarcinoma of pancreatic neck has always been a dilemma for surgeons. In this paper, we aim to investigate whether different surgical procedures can affect prognosis in the patient with adenocarcinoma of pancreatic neck. Methods: We used the surveillance, epidemiology, and end results database to review patients with adenocarcinoma of pancreatic neck diagnosed between 1998 and 2015. We calculated overall survival (OS) and cancer-specific survival (CSS) of these patients using Kaplan-Meier analysis and Cox regression model. Results: Overall, 1443 patients were included in the study, with 12.5% treated with surgical resection. Among them, 30 (18.8%) patients underwent distal pancreatectomy (DP), 105 (65.6%) patients underwent pancreatoduodenectomy (PD), and 25 (15.6%) patients underwent total pancreatectomy (TP). Patients underwent DP were older than these underwent TP (70.5±10.7 vs. 62.2±14.1, P = 0.027). Patients underwent TP had higher percentages of nodal metastasis (N1 stage) than these underwent DP (68.0% vs. 34.5%, P = 0.014). The surgical procedures did not significantly affect either OS times (P = 0.924) or CSS times (P = 0.786) in Kaplan-Meier analysis, even if in any subgroup of AJCC stage. The multivariate Cox regression model showed that types of surgery were not associated with OS and CSS. Higher tumor grade and AJCC stage are independent prognostic factors for OS and CSS. No radiotherapy was associated with a worse CSS (HR 1.610, 95% CI 1.016–2.554, P = 0.043). Conclusion: Different surgical procedures did not affect prognosis in the patients with adenocarcinoma of pancreatic neck. TP should be performed in carefully selective patients in high-volume pancreatic centers. [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]

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]

Introduction: Successful breast conserving cancer surgeries come along with tumor free resection margins and account for cosmetic outcome. Positive margins increase the likelihood of tumor recurrence. Intra-operative fluorescence molecular imaging (IFMI) aims to focus surgery on malignant tissue thus substantially lowering the presence of positive margins as compared with standard techniques of breast conservation (ST). A goal of this paper is to assess the incremental number of surgeries and costs of IFMI vs. ST. Methods: We developed a decision analytical model and applied it for an early evaluation approach. Given uncertainty we considered that IFMI might reduce the proportion of positive margins found by ST from all to none and this proportion is assumed to be reduced to 10% for the base case. Inputs included data from the literature and a range of effect estimates. For the costs of IFMI, respective cost components were added to those of ST. Results: The base case reduction lowered number of surgeries (mean [95% confidence interval]) by 0.22 [0.15; 0.30] and changed costs (mean [95% confidence interval]) by €-663 [€-1,584; €50]. A tornado diagram identified the Diagnosis Related Group (DRG) costs, the proportion of positive margins of ST, the staff time saving factor and the duration of frozen section analysis (FSA) as important determinants of this cost. Conclusions: These early results indicate that IFMI may be more effective than ST and through the reduction of positive margins it is possible to save follow-up surgeries–indicating further health risk–and to save costs through this margin reduction and the avoidance of FSA. [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]

In the scientific literature, spin refers to reporting practices that distort the interpretation of results and mislead readers so that results are viewed in a more favourable light. The presence of spin in biomedical research can negatively impact the development of further studies, clinical practice, and health policies. This systematic review aims to explore the nature and prevalence of spin in the biomedical literature. We searched MEDLINE, PreMEDLINE, Embase, Scopus, and hand searched reference lists for all reports that included the measurement of spin in the biomedical literature for at least 1 outcome. Two independent coders extracted data on the characteristics of reports and their included studies and all spin-related outcomes. Results were grouped inductively into themes by spin-related outcome and are presented as a narrative synthesis. We used meta-analyses to analyse the association of spin with industry sponsorship of research. We included 35 reports, which investigated spin in clinical trials, observational studies, diagnostic accuracy studies, systematic reviews, and meta-analyses. The nature of spin varied according to study design. The highest (but also greatest) variability in the prevalence of spin was present in trials. Some of the common practices used to spin results included detracting from statistically nonsignificant results and inappropriately using causal language. Source of funding was hypothesised by a few authors to be a factor associated with spin; however, results were inconclusive, possibly due to the heterogeneity of the included papers. Further research is needed to assess the impact of spin on readers’ decision-making. Editors and peer reviewers should be familiar with the prevalence and manifestations of spin in their area of research in order to ensure accurate interpretation and dissemination of research. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis in China. Chemotherapy now is one of the most frequently used treatments for patients with ESCC in middle or late stage, however the effects were often limited by increased chemoresistance or treatment toxicity. So it is urgent to find new drugs to treat ESCC patients. Metformin with low cost and toxicity has proved to have anti-cancer effects in numerous cancers, while its role and mechanism in ESCC has seldom been studied. In the present study, we found that metformin exhibited not only an anti-proliferation ability in a dose and time dependent manner but also a proapoptosis effect in a dose dependent manner in ESCC cell line KYSE450. Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline. What’s more, no obvious toxic reactions were observed. To further explore the underlying mechanism, we found that metformin treatment could significantly damp the expression of 4EBP1 and S6K1 in KYSE 450 cells in vitro and in vivo, furthermore, the p-4EBP1 and p-S6K1 expression in KYSE 450 cells were also inhibited greatly in vitro and in vivo. During the therapy of cancer, in order to overcome side effects, combination therapy was often used. In this paper, we demonstrated that metformin potentiated the effects of cisplatin via inhibiting cell proliferation and promoting cell apoptosis. Taken together, metformin owned the potential anti-cancer effect on ESCC in monotherapy or was combined with cisplatin and these results laid solid basis for the use of metformin in ESCC. [ABSTRACT FROM AUTHOR]

Background: Enhanced Recovery After Surgery (ERAS) protocol are well established in many surgical disciplines, leading to decrease in morbidity and length of hospital stay. These multi-modal protocols have been also introduced to oesophageal cancer surgery. This review aimed to evaluate current literature on ERAS in oesophageal cancer surgery and conduct a meta-analysis on primary and secondary outcomes. Methods: MEDLINE, Embase, Scopus and Cochrane Library were searched for eligible studies. We analyzed data up to May 2016. Eligible studies had to contain four described ERAS protocol elements. The primary outcome was overall morbidity. Secondary outcomes included length of hospital stay, specific complications, mortality and readmissions. Random effect meta-analyses were undertaken. Results: Initial search yielded 1,064 articles. Thorough evaluation resulted in 13 eligible articles which were analyzed. A total of 2,042 patients were included in the analysis (1,058 ERAS group and 984 treated with traditional protocols). Analysis of overall morbidity as well as complication rate did not show any significant reduction. Non-surgical complications and pulmonary complications were significantly lower in the ERAS group, RR = 0.71 95% CI 0.62–0.80, p < 0.00001 and RR = 0.75, 95% CI 0.60–0.94, p = 0.01, respectively. Meta-analysis on length of stay presented significant reduction Mean difference = -3.55, 95% CI -4.41 to -2.69, p for effect<0.00001. Conclusions: This systematic review with a meta-analysis on ERAS in oesophageal surgery indicates a reduction of non-surgical complications and no negative influence on overall morbidity. Moreover, a reduction in the length of hospital stay was presented. [ABSTRACT FROM AUTHOR]

It has been hypothesized that continuously releasing drug molecules into the tumor over an extended period of time may significantly improve the chemotherapeutic efficacy by overcoming physical transport limitations of conventional bolus drug treatment. In this paper, we present a generalized space- and time-dependent mathematical model of drug transport and drug-cell interactions to quantitatively formulate this hypothesis. Model parameters describe: perfusion and tissue architecture (blood volume fraction and blood vessel radius); diffusion penetration distance of drug (i.e., a function of tissue compactness and drug uptake rates by tumor cells); and cell death rates (as function of history of drug uptake). We performed preliminary testing and validation of the mathematical model using in vivo experiments with different drug delivery methods on a breast cancer mouse model. Experimental data demonstrated a 3-fold increase in response using nano-vectored drug vs. free drug delivery, in excellent quantitative agreement with the model predictions. Our model results implicate that therapeutically targeting blood volume fraction, e.g., through vascular normalization, would achieve a better outcome due to enhanced drug delivery. Author Summary: Cancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly, this model only requires a limited number of parameters which can all be readily assessed from standard clinical diagnostic measurements (e.g., histopathology and CT). This addresses an important challenge in current translational research and justifies further development of the model towards clinical translation. [ABSTRACT FROM AUTHOR]

Background: Gestational Trophoblastic Disease comprises a group of benign and malignant disorders that derive from the placenta. Using Leventhal’s Common-Sense Model as a theoretical framework, this paper examines illness perception in women who have been diagnosed with this disease. Methods: Thirty-one women diagnosed with Gestational Trophoblastic Disease in a hospital in Italy were asked to complete the Illness Perception Questionnaire-Revised to measure the following: illness Identity, illness opinions and causes of Gestational Trophoblastic Disease. Results: High mean scores were observed in the Emotional representations and Treatment control subscales. A significant difference emerged between hydatidiform mole patients and those with gestational trophoblastic neoplasia on the Identity subscale. A significant correlation emerged between “time since diagnosis” and the Treatment control subscale. Discussion: This study is the first to investigate illness perception in Gestational Trophoblastic Disease. From a clinical perspective the results highlight the need for multidisciplinary support programs to promote a more realistic illness perception. [ABSTRACT FROM AUTHOR]

Bibliometric indicators increasingly affect careers, funding, and reputation of individuals, their institutions and journals themselves. In contrast to author self-citations, little is known about kinetics of journal self-citations. Here we hypothesized that they may show a generalizable pattern within particular research fields or across multiple fields. We thus analyzed self-cites to 60 journals from three research fields (multidisciplinary sciences, parasitology, and information science). We also hypothesized that the kinetics of journal self-citations and citations received from other journals of the same publisher may differ from foreign citations. We analyzed the journals published the American Association for the Advancement of Science, Nature Publishing Group, and Editura Academiei Române. We found that although the kinetics of journal self-cites is generally faster compared to foreign cites, it shows some field-specific characteristics. Particularly in information science journals, the initial increase in a share of journal self-citations during post-publication year 0 was completely absent. Self-promoting journal self-citations of top-tier journals have rather indirect but negligible direct effects on bibliometric indicators, affecting just the immediacy index and marginally increasing the impact factor itself as long as the affected journals are well established in their fields. In contrast, other forms of journal self-citations and citation stacking may severely affect the impact factor, or other citation-based indices. We identified here a network consisting of three Romanian physics journals Proceedings of the Romanian Academy, Series A, Romanian Journal of Physics, and Romanian Reports in Physics, which displayed low to moderate ratio of journal self-citations, but which multiplied recently their impact factors, and were mutually responsible for 55.9%, 64.7% and 63.3% of citations within the impact factor calculation window to the three journals, respectively. They did not receive nearly any network self-cites prior impact factor calculation window, and their network self-cites decreased sharply after the impact factor calculation window. Journal self-citations and citation stacking requires increased attention and elimination from citation indices. [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: Preclinical in vivo studies using small animals are considered crucial in translational cancer research and clinical implementation of novel treatments. This is of paramount relevance in radiobiology, especially for any technological developments permitted to deliver high doses in single or oligo-fractionated regimens, such as stereotactic ablative radiotherapy (SABR). In this context, clinical success in cancer treatment needs to be guaranteed, sparing normal tissue and preventing the potential spread of disease or local recurrence. In this work we introduce a new dose-response relationship based on relevant publications concerning preclinical models with regard to delivered dose, fractionation schedule and occurrence of biological effects on non-irradiated tissue, abscopal effects. Methods: We reviewed relevant publications on murine models and the abscopal effect in radiation cancer research following PRISMA methodology. In particular, through a log-likelihood method, we evaluated whether the occurrence of abscopal effects may be related to the biologically effective dose (BED). To this aim, studies accomplished with different tumor histotypes were considered in our analysis including breast, colon, lung, fibrosarcoma, pancreas, melanoma and head and neck cancer. For all the tumors, the α / β ratio was assumed to be 10 Gy, as generally adopted for neoplastic cells. Results: Our results support the hypothesis that the occurrence rate of abscopal effects in preclinical models increases with BED. In particular, the probability of revealing abscopal effects is 50% when a BED of 60 Gy is generated. Conclusion: Our study provides evidence that SABR treatments associated with high BEDs could be considered an effective strategy in triggering the abscopal effect, thus shedding light on the promising outcomes revealed in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: To point out the advantages and drawbacks of high-dose rate brachytherapy in the treatment of mobile tongue cancer and indicate the clinical importance of modular lead-lined spacers when applying this technique to patients. Methods: First, all basic steps to construct the modular spacer are shown. Second, we simulate and evaluate the dose rate reduction for a wide range of spacer configurations. Results: With increasing distance to the source absorbed doses dropped considerably. Significantly more shielding was obtained when lead was added to the spacer and this effect was most pronounced on shorter (i.e. more clinically relevant) distances to the source. Conclusions: The modular spacer represents an important addition to the planning and treatment stages of mobile tongue cancer using HDR-ISBT. [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]

Side effects caused by radiation are a limiting factor to the amount of dose that can be applied to a tumor volume. A novel method to reduce side effects in radiotherapy is the use of spatial fractionation, in which a pattern of sub-millimeter beams (minibeams) is applied to spare healthy tissue. In order to determine the skin reactions in dependence of single beam sizes, which are relevant for spatially fractionated radiotherapy approaches, single pencil beams of submillimeter to 6 millimeter size were applied in BALB/c mice ears at a Small Animal Radiation Research Platform (SARRP) with a plateau dose of 60 Gy. Radiation toxicities in the ears were observed for 25 days after irradiation. Severe radiation responses were found for beams ≥ 3 mm diameter. The larger the beam diameter the stronger the observed reactions. No ear swelling and barely reddening or desquamation were found for the smallest beam sizes (0.5 and 1 mm). The findings were confirmed by histological sections. Submillimeter beams are preferred in minibeam therapy to obtain optimized tissue sparing. The gradual increase of radiation toxicity with beam size shows that also larger beams are capable of healthy tissue sparing in spatial fractionation. [ABSTRACT FROM AUTHOR]

Background: Randomized clinical trials compare participants receiving an experimental intervention to participants receiving standard of care (SOC). If one could predict the outcome for participants receiving SOC, a trial could be designed where all participants received the experimental intervention, with the observed outcome of the experimental group compared to the prediction for those individuals. Methods: We used the CancerMath calculator to predict outcomes for participants in two large clinical trials of adjuvant chemotherapy for breast cancer: NSABPB15 and CALGB9344. NSABPB15 was the training set, and we used the modified algorithm to predict outcomes for two groups from CALGB9344: one which received standard of care (SOC) chemotherapy and one which received paclitaxel in addition. We made a prediction for each individual CALGB9344 participant, assuming each received only SOC. Results: The predicted outcome for the group which received only SOC matched what was observed in the CALGB9344 trial. In contrast, the predicted outcome for the group also receiving paclitaxel was significantly worse than what was observed for this group. This matches the conclusion of CALGB9344 that adding paclitaxel to SOC improves survival. Conclusion: This project proves that a statistical model can predict the outcome of clinical trial participants treated with SOC. In some circumstances, a predictive model could be used instead of a control arm, allowing all participants to receive experimental treatment. Predictive models for cancer and other diseases could be constructed using the vast amount of outcomes data available to the federal government, and made available for public use. [ABSTRACT FROM AUTHOR]

Many different treatments may affect the serum lipid profiles of breast cancer patients. This study analyzed serum lipid levels at different periods during treatment to observe the changes in lipid profiles during and after chemotherapy and to compare the different effects of different chemotherapy regimens on serum lipid profiles. A total of 805 patients were included in this study. We measured the lipid profiles of patients who received surgery without chemotherapy prior to the operation and at 3, 6 and 12 months after operation. In addition, in patients who underwent chemotherapy, the lipid profiles were measured prior to chemotherapy, prior to the last cycle of chemotherapy and 6 months after chemotherapy. Lipid profile measurements included total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), homocysteine (HCY), and uric acid (UA). (Neo)Adjuvant chemotherapy exerted an adverse temporary effect on lipid levels (manifested as increased TG and LDL-C levels, and decreased HDL-C levels, particularly in the adjuvant chemotherapy group) during the chemotherapy periods. However, this influence was not sustained, as the lipid profiles levels were generally restored to baseline levels 6 months after chemotherapy completion. Different age groups showed different changes in lipid levels that were influenced by chemotherapy. The younger group (20–40 years old) showed a greater increase in TC and LDL-C levels during chemotherapy than the 41-65-year-old group. Chemotherapy exerts an adverse temporary effect, and the effects of different regimens on lipid levels are similar. Furthermore, lipid profiles in younger women may be more sensitive to chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Tongue mobility has shown to be a clinically interesting parameter on functional results after tongue cancer treatment which can be objectified by measuring the Range Of Motion (ROM). Reliable measurements of ROM would enable us to quantify the severity of functional impairments and use these for shared decision making in treatment choices, rehabilitation of speech and swallowing disturbances after treatment. Method: Nineteen healthy participants, eighteen post-chemotherapy patients and seventeen post-surgery patients were asked to perform standardized tongue maneuvers in front of a 3D camera system, which were subsequently tracked and corrected for head and jaw motion. Indicators, such as the left-right tongue range and the deflection angle with the horizontal axis were extracted from the tongue trajectory to serve as a quantitative measure for the impaired tongue mobility. Results: The range and deflection angle showed an excellent intra- and interrater reliability (ICC 0.9) The repeatability experiment showed an average standard deviation of 2.5 mm to 3.5 mm for every movement, except the upward movement. The post-surgery patient group showed a smaller tongue range and higher deflection angle overall than the healthy participants. Post-chemoradiation patients showed less difference in tongue ROM compared with healthy participants. Only a few patients showed asymmetrical movement after treatment, which could not always be explained by T-stage or the side of treatment alone. Conclusion: We introduced a reliable and reproducible method for measuring the ROM and to quantify for motion impairments, that was able to show differences in tongue ROM between healthy subjects and patients after chemoradiation or surgery. Future research should focus on measuring patients with oral cancer pre- and post-treatment in combination with the collection of detailed information about the individual tongue anatomy, so that the full ROM trajectory can be used to identify changes over time and to quantify functional impairment. [ABSTRACT FROM AUTHOR]

Background: To enhance risk stratification for Wilms tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols. Methods: Patients(6 months-18 years) with unilateral WT were selected from prospective SIOP 93–01 and 2001 studies(1993–2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy(yes/no), stage, histology and tumour volume at surgery. Results: 5631 patients were included; median age was 3.4 years(IQR: 2–5.1). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85%(95%CI 83.5–85.5) and 93%(95%CI 92.0–93.4). Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age(linear trend P<0.001). Using previously described age categories, EFS was lower for patients aged 2-4(HR 1.34, P = 0.02), 4-10(HR 1.83, P<0.0001) and 10–18 years(HR 1.74, P = 0.01) as compared to patients aged 6 months-2 years. OS was lower for patients 4–10 years(HR 1.67, P = 0.01) and 10–18 years(HR 1.87, P = 0.04), but not for 2–4 years(HR 1.29, P = 0.23). Higher stage, histological risk group and tumour volume were independent adverse prognostic factors. Conclusion: Although optimal age cutoffs could not be identified, we demonstrated the prognostic significance of age as well as previously described cutoffs for EFS (2 and 4 years) and OS (4 years) in children with WT treated with pre-operative chemotherapy. These findings encourage the consideration of age in the design of future SIOP-RTSG protocols. [ABSTRACT FROM AUTHOR]

Purpose: mARC (modulated arc) is the arc therapy technique provided by Siemens. The present study analyses the dose distributions and treatment times corresponding to preoperative rectal cancer mARC treatments. The results are compared to those corresponding to 3D-CRT plans. Methods: The plans of 30 patients, each having one mARC and one 3D-CRT plan, were evaluated. Every plan was calculated on a sequential two-phase treatment scheme with prescription doses of 45 Gy in the initial phase and 5.4 Gy in the boost phase. Dosimetric parameters and mean DVHs corresponding to the PTVs and OARs were assessed for both techniques. Results: All mARC plans were considered valid for treatment and yielded a highly significant improvement in the CI over 3D-CRT plans (p <0.001). They also showed statistically significant advantage on the parameters D98%, D95% and D2% of the high dose PTV. Regarding the OARs, mARC plans showed reductions in the mean dose of 3.5 Gy in the bladder and greater than 4 Gy in the femoral heads. Considering the small bowel, the mARC plans resulted in a 2.7 Gy mean reduction in the mean dose and lower irradiated volumes over the entire dose range. Conclusions: Arc therapy plans with the mARC technique for preoperative rectal cancer treatment in a sequential two-phase treatment scheme provide important advantages in the PTVs and OARs. mARC plans show superior protection of the femoral heads, bladder and small bowel, similar to the results found with other more widespread arc therapy techniques. [ABSTRACT FROM AUTHOR]

Objective: We conducted this meta-analysis to assess the effectiveness of parathyroid gland autotransplantation in preserving parathyroid function during thyroid surgery for thyroid neoplasms. Methods: We conducted a search by using PubMed, Embase, and the Cochrane Library electronic databases for studies that were published up to January 2019. The reference lists of the retrieved articles were also reviewed. Two authors independently assessed the methodological quality and extracted the data. A random-effects model was used to calculate the overall combined risk estimates. Publication bias was evaluated with a funnel plot using Egger’s and Begg’s tests. Results: A total of 25 independent studies involving 10,531 participants were included in the meta-analysis. Compared with patients who did not undergo parathyroid gland autotransplantation, the overall pooled relative risks for patients who underwent parathyroid gland autotransplantation were 1.75 (95% CI: 1.51–2.02, p<0.001) for postoperative hypoparathyroidism, 1.72 (95% CI: 1.45–2.05, p<0.001) for protracted hypoparathyroidism, 1.06 (95% CI: 0.44–2.58, p = 0.894) and 0.71 (95% CI: 0.22–2.29, p = 0.561) for biochemical hypoparathyroidism and biochemical hypocalcemia at 6 months postoperatively, respectively, and 1.89 (95% CI: 1.33–2.69, p<0.001) and 0.22 (95% CI: 0.09–0.52, p = 0.001) for biochemical hypoparathyroidism and biochemical hypocalcemia at 12 months postoperatively, respectively. The pooled relative risks for patients who underwent one parathyroid gland autotransplantation and patients who underwent two or more parathyroid gland autotransplantations were 1.71 (95% CI: 1.25–2.35, p = 0.001) and 2.22 (95% CI: 1.43–3.45, p<0.001) for postoperative hypoparathyroidism, 1.09 (95% CI: 0.59–2.01, p = 0.781) and 0.55 (95% CI: 0.16–1.87, p = 0.341) for hypoparathyroidism at 6 months postoperatively compared with those of patients who did not undergo parathyroid gland autotransplantation. Conclusions: Parathyroid gland autotransplantation is significantly associated with increased risk of postoperative and protracted hypoparathyroidism, and the number of autoplastic parathyroid glands is positively correlated with the incidence of postoperative hypoparathyroidism. [ABSTRACT FROM AUTHOR]

It is estimated that approximately 24% of the US population has at least one tattoo. However, tattoo ink ingredients include heavy metals (high atomic number Z) that are not regulated, which can cause skin reactions. This study investigates the dosimetric effects in surface dose due to high-Z elements in tattoo ink under electron beam irradiation. Four commercially available tattoo ink colors, black, red, yellow, and blue were chosen. The elemental composition of the tattoo ink samples was analyzed using X-ray Fluorescence (XRF). An ultrathin-window parallel plate ion chamber was used to measure the surface dose perturbation (ratio of ionizations with and without tattoo ink) for 6 − 20 MeV electron beams. The elemental concentration in the tattoo ink samples showed high-Z elements, with Z ranging from 11 to 92. The dose perturbation ranged from 1.4% up to 6% for the yellow ink for the 6 MeV electron beam, with similar values across the rest of the electron energies, whereas the black, red, and blue inks presented up to 3% dose perturbation for the same range of energies. Based on this initial study, we conclude that commercially available tattoo inks contain large amounts of high-Z metals that may contribute to dose perturbation. Therefore treatment of superficial lesions with electron beams in a tattooed area should be monitored for signs of early skin reaction during radiation therapy treatments. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of death caused by malignant tumors. PD-L1(programmed cell death protein-1) has shown tremendous achievement in treating NSCLC. We sought to find the relationship between CTCs in the pulmonary vein and postoperative PFS, besides we detected PD-L1 in CTCs. Method: We enrolled 112 NSCLC patients. CTC tests were performed at four time points (preoperative, pulmonary vein, intraoperative and postoperative) on every NSCLC patient who received surgery. The RNA of PD-L1 was tested by FISH. The levels of the PD-L1 mRNA and protein in tissue samples were detected. Results: The CTCs in the PV were the highest (P< 0.001), and CTCs in the PPA were the lowest (P< 0.001). The PFS in the group with PV CTCs≥ 16/5 ml was shorter than that in the group with PV CTCs< 16/5 ml (11.1 months vs 21.2 months, respectively; P< 0.001). The PFS in the group with PPA CTCs≥ 3/5 ml was shorter than that in the group with CTCs< 3/5 ml (14.8 months vs 20.7 months, respectively; P< 0.001). The CTCs in stage I were lower than those in stage II-IV (P = 0.025). No linear relationship was found between the CTCs and tumor size (P> 0.05) or LN metastasis (P> 0.05). In total, fifty-two (50.5%) patients had positive PD-L1 expression in CTC. In PD-L1-positive CTC patients, the value of PD-L1 tissue expression was higher than that in PD-L1-negative CTC patients (P = 0.0153). Conclusion: CTCs in the pulmonary vein can be an effective prognosis indicator of NSCLC patients. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. Methods: A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients’ baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. Results: Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. Conclusions: TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option. [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]

Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the ‘in-silico twins’ of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits. [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]

Introduction: The aim of this randomized controlled trial was to investigate if remote ischemic preconditioning (RIPC) reduced platelet aggregation and increased fibrinolysis in cancer patients undergoing surgery and thereby reduced the risk of thrombosis. Materials and methods: Head and neck cancer patients undergoing tumor resection and microsurgical reconstruction were randomized 1:1 to RIPC or sham intervention. RIPC was administered intraoperatively with an inflatable tourniquet by four cycles of 5-min upper extremity occlusion and 5-min reperfusion. The primary endpoint was collagen-induced platelet aggregation measured with Multiplate as area-under-the-curve on the first postoperative day. Secondary endpoints were markers of primary hemostasis, secondary hemostasis, and fibrinolysis. Clinical data on thromboembolic and bleeding complications were prospectively collected at 30-day follow-up. An intention-to-treat analysis was performed. Results: Sixty patients were randomized to RIPC (n = 30) or sham intervention (n = 30). No patients were lost to follow-up. The relative mean [95% confidence interval] collagen-induced platelet aggregation was 1.26 [1.11;1.40] in the RIPC group and 1.17 [1.07;1.27] in the sham group on the first postoperative day reported as ratios compared with baseline (P = 0.30). Median (interquartile range) 50% fibrin clot lysis time was 517 (417–660) sec in the RIPC group and 614 (468–779) sec in the sham group (P = 0.25). The postoperative pulmonary embolism rate did not differ between groups (P = 1.0). Conclusions: RIPC did not influence hemostasis and fibrinolysis in head and neck cancer patients undergoing surgery. RIPC did not reduce the rate of thromboembolic complications. [ABSTRACT FROM AUTHOR]

Objective: To investigate morbidity for patients after the primary surgical management of cervical cancer in low and middle-income countries (LMIC). Methods: The Pubmed, Cochrane, the Cochrane Central Register of Controlled Trials, Embase, LILACS and CINAHL were searched for published studies from 1st Jan 2000 to 30th June 2017 reporting outcomes of surgical management of cervical cancer in LMIC. Random-effects meta-analytical models were used to calculate pooled estimates of surgical complications including blood transfusions, ureteric, bladder, bowel, vascular and nerve injury, fistulae and thromboembolic events. Secondary outcomes included five-year progression free (PFS) and overall survival (OS). Findings: Data were available for 46 studies, including 10,847 patients from 11 middle income countries. Pooled estimates were: blood transfusion 29% (95%CI 0.19–0.41, P = 0.00, I2 = 97.81), nerve injury 1% (95%CI 0.00–0.03, I2 77.80, P = 0.00), bowel injury, 0.5% (95%CI 0.01–0.01, I2 = 0.00, P = 0.77), bladder injury 1% (95%CI 0.01–0.02, P = 0.10, I2 = 32.2), ureteric injury 1% (95%CI 0.01–0.01, I2 0.00, P = 0.64), vascular injury 2% (95% CI 0.01–0.03, I2 60.22, P = 0.00), fistula 2% (95%CI 0.01–0.03, I2 = 77.32, P = 0.00,), pulmonary embolism 0.4% (95%CI 0.00–0.01, I2 26.69, P = 0.25), and infection 8% (95%CI 0.04–0.12, I2 95.72, P = 0.00). 5-year PFS was 83% for laparotomy, 84% for laparoscopy and OS was 85% for laparotomy cases and 80% for laparoscopy. Conclusion: This is the first systematic review and meta-analysis of surgical morbidity in cervical cancer in LMIC, which highlights the limitations of the current data and provides a benchmark for future health services research and policy implementation. [ABSTRACT FROM AUTHOR]

Glioblastomas are the most common primary brain tumours. They are known for their highly aggressive growth and invasion, leading to short survival times. Treatments for glioblastomas commonly involve a combination of surgical intervention, chemotherapy, and external beam radiation therapy (XRT). Previous works have not only successfully modelled the natural growth of glioblastomas in vivo, but also show potential for the prediction of response to radiation prior to treatment. This suggests that the efficacy of XRT can be optimized before treatment in order to yield longer survival times. However, while current efforts focus on optimal scheduling of radiotherapy treatment, they do not include a similarly sophisticated spatial optimization. In an effort to improve XRT, we present a method for the spatial optimization of radiation profiles. We expand upon previous results in the general problem and examine the more physically reasonable cases of 1-step and 2-step radiation profiles during the first and second XRT fractions. The results show that by including spatial optimization in XRT, while retaining a constant prescribed total dose amount, we are able to increase the total cell kill from the clinically-applied uniform case. [ABSTRACT FROM AUTHOR]

Background: Few randomized controlled trials have assessed the effects of laughter therapy on health-related quality of life (QOL) in cancer patients. This study aimed to evaluate these effects as an exploratory endpoint in cancer patients as part of a randomized controlled trial conducted at a single institution in Japan. Methods: The Initiative On Smile And CAncer (iOSACA) study was an open-label randomized controlled trial conducted in 2017 in which participants aged 40–64 years with cancer were randomly assigned to either an intervention group (laughter therapy) or control group (no laughter therapy). Each participant in the intervention group underwent a laughter therapy session once every two weeks for seven weeks (total of four sessions). Each session involved a laughter yoga routine followed by Rakugo or Manzai traditional Japanese verbal comedy performances. We assessed QOL as a secondary endpoint in this intention-to-treat population using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The questionnaire was completed at baseline (Week 0) and at Weeks 3 and 7. Mixed-effects models for repeated measures were developed to compare time-dependent changes in each QOL domain from baseline between the intervention and control groups. Results: Four participants retracted consent and one participant was retrospectively excluded from analysis due to unmet inclusion criteria. The analysis was conducted using 56 participants, with 26 in the intervention group and 30 in the control group. Questionnaire completion rates were high (>90%), with similar QOL scores reported at baseline in both groups. The mixed-effects models showed that the intervention group had significantly better cognitive function and less pain than the control group for a short period. Conclusion: Laughter therapy may represent a beneficial, noninvasive complementary intervention in the clinical setting. Further studies are needed to verify the hypotheses generated from this exploratory study. [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]

Purpose: Electron radiotherapy is a labor-intensive treatment option that is complicated by the need for field shaping blocks. These blocks are typically made from casting Cerrobend alloys containing lead and cadmium. This is a highly toxic process with limited precision. This work aims to provide streamlined and more precise electron radiotherapy by 3D using printing techniques. Methods: The 3D printed electron cutout consists of plastic shells filled with 2 mm diameter tungsten ball bearings. Five clinical Cerrobend defined field were compared to the planned fields by measuring the light field edge when mounted in the electron applicator on a linear accelerator. The dose transmitted through the 3D printed and Cerrobend cutouts was measured using an IC profiler ion chamber array with 6 MeV and 16 MeV beams. Dose profiles from the treatment planning system were also compared to the measured dose profiles. Centering and full width half maximum (FWHM) metrics were taken directly from the profiler software. Results: The transmission of a 16MeV beam through a 12 mm thick layer of tungsten ball bearings agreed within 1% of a 15 mm thick Cerrobend block (measured with an ion chamber array). The radiation fields shaped by ball bearing filled 3D printed cutout were centered within 0.4 mm of the planned outline, whereas the Cerrobend cutout fields had shift errors of 1–3 mm, and shape errors of 0.5–2 mm. The average shift of Cerrobend cutouts was 2.3 mm compared to the planned fields (n = 5). Beam penumbra of the 3D printed cutouts was found to be equivalent to the 15 mm thick Cerrobend cutout. The beam profiles agreed within 1.2% across the whole 30 cm profile widths. Conclusions: This study demonstrates that with a proper quality assurance procedure, 3D-printed cutouts can provide more accurate electron radiotherapy with reduced toxicity compared to traditional Cerrobend methods. [ABSTRACT FROM AUTHOR]

Many complex diseases such as cancer are associated with multiple pathological manifestations. Moreover, the therapeutics for their treatments often lead to serious side effects. Thus, it is needed to develop multi-indication therapeutics that can simultaneously target multiple clinical indications of interest and mitigate the side effects. However, conventional one-drug-one-gene drug discovery paradigm and emerging polypharmacology approach rarely tackle the challenge of multi-indication drug design. For the first time, we propose a one-drug-multi-target-multi-indication strategy. We develop a novel structural systems pharmacology platform 3D-REMAP that uses ligand binding site comparison and protein-ligand docking to augment sparse chemical genomics data for the machine learning model of genome-scale chemical-protein interaction prediction. Experimentally validated predictions systematically show that 3D-REMAP outperforms state-of-the-art ligand-based, receptor-based, and machine learning methods alone. As a proof-of-concept, we utilize the concept of drug repurposing that is enabled by 3D-REMAP to design dual-indication anti-cancer therapy. The repurposed drug can demonstrate anti-cancer activity for cancers that do not have effective treatment as well as reduce the risk of heart failure that is associated with all types of existing anti-cancer therapies. We predict that levosimendan, a PDE inhibitor for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments and systems biology analyses confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to predict cancer cell-line’s and a patient’s response to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe, effective, and precision multi-indication anti-cancer therapy. This study demonstrates the potential of structural systems pharmacology in designing polypharmacology for precision medicine. It may facilitate transforming the conventional one-drug-one-gene-one-disease drug discovery process and single-indication polypharmacology approach into a new one-drug-multi-target-multi-indication paradigm for complex diseases. [ABSTRACT FROM AUTHOR]