Abstract Background Intratumour heterogeneity is recognised across different tumour types and has implications for therapeutic resistance. At present, clinical practice often relies upon molecular information derived from a single biopsy of a primary or metastatic tumour. This information guides treatment choice but may not be representative of the diversity of the tumour. It is currently difficult to evaluate how effectively a single region guides treatment decisions because the formalin-fixed residual surgical sample that is not paraffin embedded for diagnostic purposes is typically thrown away. Retention and homogenisation – ‘blending’- of this residual formalin-fixed leftover tumour tissue creates a more representative sample for analysis. DNA may be extracted from this sample for sequencing. Pilot data in kidney cancer has demonstrated the potential of this methodology for robust mutational calling, accurate determination of cancer cell fraction and the ability to discern clonal from subclonal variants. Such information may be clinically relevant; for example, discerning resistant subclones prior to treatment, or identifying clonal neoantigens worth targeting with immunotherapy. Trial design In order to establish the feasibility of homogenization as a potential companion diagnostic tool, our study aims to 1) identify the proportion of primary tumour cases that have left over tissue amenable to homogenization across multiple tumour types and 2) pilot homogenization across multiple tumour types. The molecular profile of the homogenate will be compared to that obtained from the diagnostic specimen using next generation sequencing techniques. This is a prospective non-interventional study (NCT03832062). Patients undergoing surgical intervention at The Royal Marsden Hospital (NHS Foundation Trust) with leftover tumour tissue from primary breast, colorectal, gastric, pancreatic, ovarian, renal cancer and sarcoma surgeries, as well as melanoma lymph node dissections will be included in the feasibility assessment. We plan to homogenise 500 cases across different tumour types. The study opened in September 2018 and is expected to run for 2 years. Clinical trial identification NCT03832062; Release date: February 2019. Legal entity responsible for the study Royal Marsden NHS Foundation Trust. Funding Ventana Medical Systems (a subsidiary of Roche). Disclosure L. Gallegos: Full / Part-time employment: Roche. S. Hill: Full / Part-time employment: Roche. A. Barhoumi: Full / Part-time employment: Roche. S. Stanislaw: Full / Part-time employment: Roche. M. Mendoza: Full / Part-time employment: Roche. J.M.G. Larkin: Research grant / Funding (institution): Roche; Advisory / Consultancy: Roche. N. Alexander: Full / Part-time employment: Roche; Shareholder / Stockholder / Stock options: Roche. S. Turajlic: Research grant / Funding (institution): Ventana Medical Systems (subsidiary of Roche). All other authors have declared no conflicts of interest.

Abstract Background In 2017 a new PN led clinic was established for immunotherapy patients. At the 1-year mark to ensure patients were satisfied with the service provision, a patient experience survey was conducted. The survey explored if patients felt comfortable in discussing side effects with the PN and if they felt part of their treatment related decisions. Importantly patients were asked if they had confidence and trust in the PN. Methods The survey was provided to all patients whom attended the PN led clinic from May 2017 to May 2018. The survey consisted of 10 closed questions using the Likert scale, with spaces provided for personal comments. Data collection period was 1.06.18 to 29.06.18. Estimated number of patients was 10. Results Questionnaires were provided to a total of 10 patients. Three questionnaires could not be provided to 3 patients whom attended the PN led clinic as they had died. Two patients did not respond back. 6/8 patients strongly agreed (SAg) to feeling comfortable in discussing treatment related side effects and 2/8 patients agreed (Ag). This same result was found when patients were asked if they felt involved in the decisions related to their care e.g. stopping immunotherapy treatment at 2 yrs. With respect to having confidence and trust with the advice and care provided by the PN, 7 patients SAg and 1 Ag. All patients felt that they were being listened to and had the opportunity to ask questions during their consultations (7 patients SAg and 1 Ag). Reassuringly all 8 patients said that they would recommend this service to their friends and family (7 patients SAg and 1 Ag). Conclusions This survey was to ensure patients were satisfied with being reviewed by a PN and as the service was new to the melanoma unit in 2017; it was vital that the patients had the opportunity to evaluate the service provision. With this positive feedback the clinic was expanded from September 2018 and to date 36 patients have now been seen within the PN led immunotherapy clinic and another patient experience survey is due. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Abstract Background ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naive patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade. Methods In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments. Results 15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles). Conclusions ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing. Clinical trial identification NCT02446860. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK). Disclosure All authors have declared no conflicts of interest.

In modern market it is very important to deliver products to customers fast. That delivery can be on site or to customer's homes. In order to achieve that it is important to have enough goods stored in warehouses and prepared for delivery. It is not a good decision to clutter up warehouses with the goods because space is limited and expensive and it makes it more complicated to collect orders. Those are the reasons why it is important that number of stored goods converge to the exact number of product units that will be ordered in the future. Demand forecasting tries to solve that problem. In this work demand forecasting algorithm based on Long Short-Term Memory recurrent neural network is described and compared with demand forecasting algorithms developed by authors before.

A number of industrial wireless technologies have emerged over the last decade, promising to replace the need for wires in a variety of use cases. Except for customized time division multiple access (TDMA)-based wireless technologies that can achieve ultralow latency over a very limited area, wireless communication generally has reliability and latency issues when it comes to industrial applications. Closed loop communication requires high reliability (over 99%), limited jitter and latency, which poses a challenge especially over a wide area measuring in hundreds of meters. Extended coverage is promised with the advent of sub-GHz technologies, one of them being IEEE 802.11ah which is the only one that offers sufficient data rate for frequent bidirectional communication. Thus, we evaluated IEEE 802.11ah for low-latency time-critical control loops. We propose the network setup for adjusting the network dynamics to that of control loops, enabling limited jitter and high reliability. We explore the scalability of IEEE 802.11ah network hosting both control loops and monitoring sensors that periodically transmit measurements. Assigning the control loop end-nodes to dedicated restricted access window (RAW) slot results in over 99.99% successful deliveries. Furthermore, interpacket delay is concentrated around the cycle-time in the following or preceding beacon interval in case the beacon interval is at least half the value of the shortest cycle-time. Adjusting the beacon interval to the fastest control loop in the network ensures latency requirements at the cost of maximum achievable throughput and energy consumption.

This letter studies the stabilization of non-linear networked control systems (NCSs) where the information between plant and controller is sent over a lossy wireless multi-hop network under a carrier-sense multiple access with collision avoidance (CSMA-CA) scheme. We present a hybrid model for the overall NCS that captures time-varying transmission instants, both inter-and at-transmission behavior, packet dropouts, field device dynamics, and CSMA-CA scheduling. We then use this model to provide sufficient conditions in terms of the intensity of transmission that ensure closed-loop $ \mathcal {L}_{p}$ stability-in-expectation. In doing so, we exploit the mathematical structure of our NCS model to improve previous results in the literature.

This article presents an overview of integrability of procedural modeling techniques needed to create a complete virtual city with streets, roads, building lots, exteriors and interiors with arranged furniture. Techniques are distributed into four hierarchies: urban plan, buildings, interior and furniture. Each technique is analyzed from the aspect of control of space definition, style uniformity, automatic interaction with other hierarchies and ability to procedurally generate a result around existing content. Each paper presented in this survey contributes either as a new control feature that has a potential of integrating with other techniques of higher, lower or same level of hierarchy, or as a new important part for creating a complete procedural city from highest to lowest level of hierarchy. The paper is concluded with a discussion of strong links between each area in the chain and important challenges in procedural generation of a complete city.

Abstract Applying MIPVU (Steen et al., 2010) to the corpus of media articles about the European migrant crisis in the period from August 2015 until March 2016 in English and Bosnian/Croatian/Serbian, this paper analyzes the IMMIGRANTS ARE ANIMALS metaphor within the framework of the deliberate metaphor theory by considering the three dimensions of this metaphor, namely, the linguistic dimension of (in)directness, the conceptual parameter of conventionality, and the communicative dimension of (non)deliberateness. Specifically, the paper examines the use of the ANIMALS metaphor as a deliberate metaphor in the immigration discourse in English and Bosnian/Croatian/Serbian. The paper aims to determine to what extent and in which situations the authors of the texts tend to divert the addressee’s attention to viewing immigrants in terms of animals. Using the IDeM protocol for the identification of deliberate metaphor (Krennmayr, 2011), the paper also focuses on the rhetorical potential and the effects of the use of deliberate metaphors in the media discourse. Such metaphors are often used in the media discourse to dehumanize immigrants and consequently reduce the addressee’s empathy for them.

Introduction: Diabetes is the fastest growing chronic diseases worldwide and in Bosnia and Herzegovina. International standards for diabetes care have recognized the crucial role of pharmacists in diabetes management. Community pharmacists can provide services beyond medication dispensing inducing patient identification, assessment, education, referral, monitoring and behavioral counseling. Pharmacists’ attitudes toward diabetes are generally positive but do not correlate with the degree of their involvement in diabetes management and frequency of providing diabetes-related services varied throughout countries. Aim: To measure pharmacists’ attitude toward diabetes management and to identify pharmacy services that are currently provided to patients with diabetes. Material and Methods: We have conducted a descriptive, cross-sectional survey-based study among pharmacists from Bosnia and Herzegovina attending on of the conferences in May 2018. Majority of pharmacist attending such conferences are from community pharmacies across the whole country considering surveyed sample was representative. The questionnaire contained 3 different sections: a) participants’ demographics, b) measured participants’ attitude toward diabetes using the DAS-3 to measure participants’ degree of agreement to 33 diabetes-related statements, on a 5-point Likert type scale and c) a list of possible diabetes patient support activities that could be delivered by pharmacists based on authors experience and available literature. Results: The majority of respondents (86,5%) were female and 53,8% work in private owned pharmacies. Interest in diabetes was indicated by 94,2% while 59,6% completed special diabetes continuing education in the past. All the respondents expressed positive attitudes in all DAS-3 with no significant difference between overall DAS-3 and subscale values. Provided services differ but mainly drug oriented and partially include comorbidity counseling. Conclusion: Pharmacists had positive attitudes toward diabetes but they provided limited diabetes-related services to patients. Additional special education is needed.

The purpose of the credit scoring process is the classification of the loan as default or non-default trying to reduce the risk for financial institutions. Paper aims to illustrate the implementation of a credit scoring model using boosting techniques. Specifically, the proposed solution is implemented using XGBoost algorithm discussing the role of hyperparameter tuning and feature selection in result optimization. Data used for obtaining performance scores is real-world data provided by a microfinance institution based in Bosnia and Herzegovina. Results suggest that significant optimization of XGBoost may be performed, yet, the model fails to outperform typically recommended approaches for solving credit scoring problem. Given that, it is suggested that although boosting techniques are increasingly being relied upon, it is unaccountable to make a decision without understanding the specificity of data and questioning whether other techniques are more suitable.

Abstract Background Neuroendocrine carcinoma of the uterine cervix (NEC) is a rare cervical malignancy, accounting for 0.9% of all cervical carcinomas. Cervical NEC is a high-grade cancer with an aggressive clinical course and poor outcome. Given that no target therapy has been approved yet for NEC, we explored novel targetable biomarkers in a large cohort of NEC of the cervix. Methods Sixty-two NEC of the cervix were profiled for biomarkers of targeted therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), tropomyosin receptor kinases (NTRK1/2/3 gene fusions), and immune checkpoint inhibitors (PD-L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays. Results The study included 36 primary and 26 metastatic cervical NEC. The mean patient’s age was 43.6 years (range, 24-82 years). DLL3 expression was observed in 81% of the cases with 49% of cases expressing diffusely (≥50% of positive cancer cells) DLL3 protein. DLL3 expression was inversely correlated with commonly observed mutations: PIK3CA (7/47) (p = 0.018) and PTEN mutations (5/40) (p = 0.006). Other frequently seen mutations (TP53 17%, KRAS 11% and CTTNB1 5%) were not associated with DLL3 expression. PD-L1 expression, high TMB and MSI-H were seen in single cases. Although NTRK protein expression was observed in 21% of the cases, none of these had confirmatory NTRK gene fusions. TROP-2 and FOLR1 were negative in all tested cases. Conclusions DLL3 protein and PIK3CA/PTEN pathway genes may be potential therapeutic targets for a substantial proportion of the patients NEC of the cervix. Based on I-O biomarkers status, the patients with cervical NEC are less likely to benefit from immune checkpoint inhibitors. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure D. Arguello: Full / Part-time employment: Caris Life Sciences. E. Contreras: Full / Part-time employment: Caris Life Sciences. Z. Gatalica: Full / Part-time employment: Caris Life Sciences. All other authors have declared no conflicts of interest.

Receiver functions are sensitive to sharp seismic velocity variations with depth and are commonly used to constrain crustal thickness. The H–κ stacking method of Zhu & Kanamori is often used to constrain both the crustal thickness (H) and ${V_P}$/${V_S}$ ratio ($\kappa $) beneath a seismic station using P-to-s converted waves (Ps). However, traditional H–κ stacks require an assumption of average crustal velocity (usually ${V_P}$). Additionally, large amplitude reverberations from low velocity shallow layers, such as sedimentary basins, can overprint sought-after crustal signals, rendering traditional H–$\ \kappa $ stacking uninterpretable. We overcome these difficulties in two ways. When S-wave reverberations from sediment are present, they are removed by applying a resonance removal filter allowing crustal signals to be clarified and interpreted. We also combine complementary Ps receiver functions, Sp receiver functions, and the post-critical P-wave reflection from the Moho (SPmp) to remove the dependence on an assumed average crustal ${V_P}$. By correcting for sediment and combining multiple data sets, the crustal thickness, average crustal P-wave velocity and crustal ${V_P}$/${V_S}$ ratio is constrained in geological regions where traditional H–$\ \kappa $ stacking fails, without making an initial P-wave velocity assumption or suffering from contamination by sedimentary reverberations.