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.

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 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.

Abstract Background An optimal adjuvant treatment of HER2 positive breast cancer includes the initiation of trastuzumab within 6 months after the surgery. However, due to limited resources and waiting lists, this timeframe is often exceeded in developing countries. We previously reported short-term outcomes of a time-optimal versus delayed postoperative initiation of trastuzumab in women with HER2 positive, non-metastatic, neoadjuvant naive breast cancer. Here, we report an extended follow-up, summarizing outcomes of our cohorts. Methods We included 223 consecutive women with surgically treated, non-metastatic, neoadjuvant naive, HER2 positive breast cancer from 2009 to 2011, from four institutions in Bosnia and Herzegovina. Patients were assigned to a time-optimal group (TOG), or a delayed group 1 (DG1), or a delayed group 2 (DG2), depending on whether their adjuvant trastuzumab was initiated 6 months, or 6-12 months, or more than 12 months after the surgery, respectively. A cut-off point for the follow-up was January 2019. We compared clinical outcomes between the groups, taking into account lymph node status. Results The patient’s median age was 55 (range 27-80) years. Mean follow-up period was 67 (range 4-109) months. Node-negative disease was found in 38.6% patients overall. 37% (TOG) patients received trastuzumab within 6 months, while 41% (DG1) received it within 6-12, and 22% (DG2) more than 12 months after their surgery. A higher number of node negative patients was found in the DG2 group compared to the TOG and DG1 groups (48%, 35%, and 36% respectively). 5-year DFS rate was 70.73% (TOG), 67.03% (DG1), and 62.00% (DG2). The OS rate was 78.05% (TOG), 75.82% (DG1), and 74.00% (DG2). Conclusions From the above, a conclusion can be made that patients with time-optimal initiation of adjuvant trastuzumab therapy had a higher 5-year DFS and OS rate compared to the delayed treatment initiation groups. Results of the DG1 and the DG2 group indicate that trastuzumab therapy shows a persistent benefit even if administered with a delay. Higher DFS and OS rates in the DG2 group could be explained by a higher number of node-negative low-risk, patients in this group. Legal entity responsible for the study The authors. Funding Roche. Disclosure S. Beslija: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. T. Ceric: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. B. Hasanbegovic: Advisory / Consultancy: Roche. A. Pasic: Advisory / Consultancy: Merck; Advisory / Consultancy: Sanofi. All other authors have declared no conflicts of interest.

Metastatic Leydig cell tumors (LCT) are rare, difficult to treat malignancies without known underlying molecular-genetic events. We profiled 27 LCT cases using NGS and immunohistochemistry. Our study identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in LCT. TOP1 and AR expressions may guide decisions on chemo- and/or hormone therapy for selected individual patients. Objective: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular–genetic events. An index case of metastatic LCT showed an LDLR–TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs. Patients and Methods: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry. Results: TERT gene fusions were detected only in testicular metastatic LCTs, in 3 of 7 successfully analyzed cases (RMST:TERT,LDLR:TERT, and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in 1 metastatic tumor without a TERT fusion. Five primary (4 testicular and 1 ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1, and SS18 genes. At the protein level, 4 of 7 metastatic and 6 of 10 primary testicular LCTs overexpressed Topo1. Androgen receptor was overexpressed in 10 of 13 primary testicular tumors and 2 of 5 metastatic testicular LCTs (without detectable ARv7 messenger RNA or ARv7 protein). Only 1 metastatic testicular LCT exhibited a high tumor mutational burden; all tested cases were microsatellite instability stable and did not express programmed cell death ligand 1. Conclusions: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic LCTs. Topo1 and androgen receptor may guide decisions on chemotherapy and/or hormone therapy for selected individual patients.