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Cancer Statistics
Population in 2012: 2.0m
People newly diagnosed with cancer (excluding NMSC) / yr: 11,500
Age-standardised rate, incidence per 100,000 people/yr: 296.3
Risk of getting cancer before age 75:29.4%
People dying from cancer /yr: 5,900
Data from IARC GlobalCan (2012)
Slovenia: Cancer Organisations and Resources
Latest Research Publications from Slovenia

Slovenia: Cancer Organisations and Resources (7 links)

Latest Research Publications from Slovenia

Žigart N, Časar Z
A literature review of the patent publications on venetoclax - a selective Bcl-2 inhibitor: discovering the therapeutic potential of a novel chemotherapeutic agent.
Expert Opin Ther Pat. 2019; 29(7):487-496 [PubMed] Related Publications
INTRODUCTION: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies.
AREAS COVERED: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations,
EXPERT OPINION: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.

Rashid M, van der Horst M, Mentzel T, et al.
ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.
Nat Commun. 2019; 10(1):2213 [PubMed] Free Access to Full Article Related Publications
Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.

Maric T, Mikhaylov G, Khodakivskyi P, et al.
Bioluminescent-based imaging and quantification of glucose uptake in vivo.
Nat Methods. 2019; 16(6):526-532 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Glucose is a major source of energy for most living organisms, and its aberrant uptake is linked to many pathological conditions. However, our understanding of disease-associated glucose flux is limited owing to the lack of robust tools. To date, positron-emission tomography imaging remains the gold standard for measuring glucose uptake, and no optical tools exist for non-invasive longitudinal imaging of this important metabolite in in vivo settings. Here, we report the development of a bioluminescent glucose-uptake probe for real-time, non-invasive longitudinal imaging of glucose absorption both in vitro and in vivo. In addition, we demonstrate that the sensitivity of our method is comparable with that of commonly used

Aribal E, Mora P, Chaturvedi AK, et al.
Improvement of early detection of breast cancer through collaborative multi-country efforts: Observational clinical study.
Eur J Radiol. 2019; 115:31-38 [PubMed] Related Publications
AIM: The aim of this paper is to present baseline imaging data and the improvement that was achieved by the participating centers after applying practice-specific interventions that were identified during the course of a multicentric multinational research coordinated project.
INTRODUCTION: The incidence and mortality rates from breast cancer are rising worldwide and particularly rapidly across the countries with limited resources. Due to lack of awareness and screening options it is usually detected at a later stage. Breast cancer screening programs and even clinical services on breast cancer have been neglected in such countries particularly due to lack of available equipment, funds, organizational structure and quality criteria.
MATERIALS AND METHODS: A harmonized form was designed in order to facilitate uniformity of data collection. Baseline data such as type of equipment, number of exams, type and number of biopsy procedures, stage of cancer at detection were collected from 10 centers (9 countries: Bosnia-Herzegovina, Costa Rica, Egypt, India, North Macedonia, Pakistan, Slovenia, Turkey, Uganda) were collected. Local practices were evaluated for good practice and specific interventions such as training of professionals and quality assurance programs were identified. The centers were asked to recapture the data after a 2-year period to identify the impact of the interventions.
RESULTS: The data showed increase in the number of training of relevant professionals, positive changes in the mammography practice and image guided interventions. All the centers achieved higher levels of success in the implementation of the quality assurance procedures.
CONCLUSION: The study has encountered different levels of breast imaging practice in terms of expertise, financial and human resources, infrastructure and awareness. The most common challenges were the lack of appropriate quality assurance programs and lack of trained skilled personnel and lack of high-quality equipment. The project was able to create higher levels of breast cancer awareness, collaboration amongst participating centers and professionals. It also improved quality, capability and expertise in breast imaging particularly in centers involved diagnostic imaging.

Doma A, Škerget M, Žagar I
18F-FDG PET/CT for Staging and Evaluation of Therapy in a Patient With Unusual Hairy Cell Leukemia Presentation.
Clin Nucl Med. 2019; 44(7):e458-e460 [PubMed] Related Publications
Hairy cell leukemia is a rare hematologic malignancy characterized by splenomegaly, pancytopenia, and susceptibility to infections. We report a case of a 66-year-old man, diagnosed with hairy cell leukemia, without severe cytopenias and splenomegaly, but with an extensive pathological retroperitoneal mass and infiltration of the spleen and skeletal involvement. All findings were highly avid on pretreatment F-FDG PET/CT scan. Treatment response evaluation F-FDG PET/CT scan showed normalization of FDG uptake on all previously pathological sites.

Vivoda Tomšič M, Bisdas S, Kovač V, et al.
Dynamic contrast-enhanced MRI of malignant pleural mesothelioma: a comparative study of pharmacokinetic models and correlation with mRECIST criteria.
Cancer Imaging. 2019; 19(1):10 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic malignancy that is difficult to cure. Dynamic contrast-enhanced (DCE) MRI is a functional imaging technique used to analyze tumor microvascular properties and to monitor therapy response. Purpose of this study was to compare two tracer kinetic models, the extended Tofts (ET) and the adiabatic approximation tissue homogeneity model (AATH) for analysis of DCE-MRI and examine the value of the DCE parameters to predict response to chemotherapy in patients with MPM.
METHOD: This prospective, longitudinal, single tertiary radiology center study was conducted between October 2013 and July 2015. Patient underwent DCE-MRI studies at three time points: prior to therapy, during and after cisplatin-based chemotherapy. The images were analyzed using ET and AATH models. In short-term follow-up, the patients were classified as having disease control or progressive disease according to modified response evaluation criteria in solid tumors (mRECIST) criteria. Receiver operating characteristic curve analysis was used to examine specificity and sensitivity of DCE parameters for predicting response to therapy. Comparison tests were used to analyze whether derived parameters are interchangeable between the two models.
RESULTS: Nineteen patients form the study population. The results indicate that the derived parameters are not interchangeable between the models. Significant correlation with response to therapy was found for AATH-calculated median pre-treatment efflux rate (k
CONCLUSION: Both models show potential in predicting response to therapy in MPM. High pre-treatment k

Cabeçadas J, Martinez D, Andreasen S, et al.
Lymphomas of the head and neck region: an update.
Virchows Arch. 2019; 474(6):649-665 [PubMed] Related Publications
The field of haematopathology is rapidly evolving and for the non-specialized pathologist receiving a specimen with the possibility of a lymphoid malignancy may be a daunting experience. The coincidence of the publication, in 2017, of the WHO monographies on head and neck and haematopoietic and lymphoid tumours prompted us to write this review. Although not substantially different from lymphomas elsewhere, lymphomas presenting in this region pose some specific problems and these are central to the review. In addition, differences in subtype frequency and morphological variations within the same entity are discussed. The difficulty in diagnosis related to some specimens led us to briefly mention common subtypes of systemic lymphomas presenting in the head and neck region.

Malod-Dognin N, Petschnigg J, Windels SFL, et al.
Towards a data-integrated cell.
Nat Commun. 2019; 10(1):805 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
We are increasingly accumulating molecular data about a cell. The challenge is how to integrate them within a unified conceptual and computational framework enabling new discoveries. Hence, we propose a novel, data-driven concept of an integrated cell, iCell. Also, we introduce a computational prototype of an iCell, which integrates three omics, tissue-specific molecular interaction network types. We construct iCells of four cancers and the corresponding tissue controls and identify the most rewired genes in cancer. Many of them are of unknown function and cannot be identified as different in cancer in any specific molecular network. We biologically validate that they have a role in cancer by knockdown experiments followed by cell viability assays. We find additional support through Kaplan-Meier survival curves of thousands of patients. Finally, we extend this analysis to uncover pan-cancer genes. Our methodology is universal and enables integrative comparisons of diverse omics data over cells and tissues.

Lokar K, Zagar T, Zadnik V
Estimation of the Ecological Fallacy in the Geographical Analysis of the Association of Socio-Economic Deprivation and Cancer Incidence.
Int J Environ Res Public Health. 2019; 16(3) [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Ecological deprivation indices at the level of spatial units are often used to measure and monitor inequalities in health despite the possibility of ecological fallacy. For the purpose of this study, the European Deprivation Index (EDI) was used, which is based on Townsend theorization of relative deprivation. The Slovenian version of EDI (SI-EDI) at the aggregated level (SI-EDI-A) was calculated to the level of the national assembly polling stations. The SI-EDI was also calculated at the individual level (SI-EDI-I) by the method that represents a methodological innovation. The degree of ecological fallacy was estimated with the Receiver Operating Characteristics (ROC) curves. By calculating the area under the ROC curve, the ecological fallacy was evaluated numerically. Agreement between measuring deprivation with SI-EDI-A and SI-EDI-I was analysed by graphical methods and formal testing. The association of the socio-economic status and the cancer risk was analysed in all first cancer cases diagnosed in Slovenia at age 16 and older in the period 2011⁻2013. Analysis was done for each level separately, for SI-EDI-I and for SI-EDI-A. The Poisson regression model was implemented in both settings but adapted specifically for aggregated and individual data. The study clearly shows that ecological fallacy is unavoidable. However, although the association of cancer incidence and socio-economic deprivation at individual and aggregated levels was not the same for all cancer sites, the results were very similar for the majority of investigated cancer sites and especially for cancers associated with unhealthy lifestyles. The results confirm the assumptions from authors' previous research that using the level of the national assembly polling stations would be the acceptable way to aggregate data when explaining inequalities in health in Slovenia in ecological studies.

Zakelj MN, Prevc A, Kranjc S, et al.
Electrochemotherapy of radioresistant head and neck squamous cell carcinoma cells and tumor xenografts.
Oncol Rep. 2019; 41(3):1658-1668 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Electrochemotherapy is an established local ablative method used for the treatment of different tumor types, including tumors of the head and neck area. Clinical studies have demonstrated a lower response rate of tumors that recur in pre‑irradiated area. The aim of the present study was to explore the response of experimentally induced radioresistant cells and tumors to electrochemotherapy with cisplatin or bleomycin. The radioresistant cells (FaDu‑RR) were established by fractionated irradiation of parental human squamous cell carcinoma cell line, FaDu. We compared the 2 cell lines in response to chemotherapy and electrochemotherapy with cisplatin or bleomycin in vitro and in vivo. Using specific mass spectrometry‑based analytical methods we determined the difference in the uptake of chemotherapeutics in tumors after electrochemotherapy. Additionally, we compared the capacity of the cells to repair DNA double‑strand breaks (DSB) after exposure to the drugs used in electrochemotherapy with the γH2AX foci resolution determined by immunofluorescence microscopy. Our results indicate radio‑ and cisplatin cross‑resistance, confirmed with the lower response rate of radioresistant tumors after electrochemotherapy with cisplatin. On the other hand, the sensitivity to electrochemotherapy with bleomycin was similar in both cell lines and tumors. While the uptake of chemotherapeutics after electrochemotherapy was comparable in both tumor models, there was a difference between the cell lines in capacity to repair DNA DSB‑the radioresistant cells had a lower level of DSB and faster DNA repair rate after exposure to both, cisplatin or bleomycin. Due to the higher complete response rate after electrochemotherapy with bleomycin than with cisplatin, we conclude that the results favor bleomycin‑over cisplatin‑based electrochemotherapy for treatment of radioresistant tumors and/or tumors that regrow after radiotherapy.

Mendenhall WM, Strojan P, Beitler JJ, et al.
Radiotherapy for parapharyngeal space tumors.
Am J Otolaryngol. 2019 Mar - Apr; 40(2):289-291 [PubMed] Related Publications
A wide variety of tumors, both benign and malignant, occur in the parapharyngeal space. Depending on histology and extent, treatment may include surgery and/or radiotherapy (RT). Herein we discuss the role of RT in the management of some of the more commonly encountered neoplasms, including salivary gland tumors, paragangliomas, schwannomas, and soft-tissue sarcomas.

Rades D, Conde-Moreno AJ, Cacicedo J, et al.
A scoring system to predict local progression-free survival in patients irradiated with 20 Gy in 5 fractions for malignant spinal cord compression.
Radiat Oncol. 2018; 13(1):257 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
BACKGROUND: Local progression-free survival (LPFS = stable or improved motor function/resolution of paraplegia during RT without in-field recurrence following RT) is important when treating metastatic spinal cord compression (MSCC). An instrument to estimate LPFS was created to identify patients appropriately treated with short-course RT instead of longer-course RT plus/minus decompressive surgery.
METHODS: In 686 patients treated with 20 Gy in 5 fractions alone, ten characteristics were retrospectively analyzed for LPFS including age, interval between tumor diagnosis and RT of MSCC, visceral metastases, other bone metastases, primary tumor type, gender, time developing motor deficits, pre-RT gait function, number of vertebrae affected by MSCC, and performance score. Characteristics significantly (p < 0.05) associated with LPFS on multivariate analyses were incorporated in the scoring system. Six-month LPFS rates for significant characteristics were divided by 10, and corresponding points were added.
RESULTS: On multivariate analyses, visceral metastases (p < 0.001), tumor type (p = 0.009), time developing motor deficits (p < 0.001) and performance score (p = 0.009) were associated with LPFS and used for the scoring system. Scores for patients ranged between 24 and 35 points. Three groups were designed: 24-28 (A), 29-31 (B) and 32-35 (C) points. Six-month LPFS rates were 46, 69 and 92%, 12-month LPFS rates 46, 63 and 83%. Median survival times were 2 months (61% died within 2 months), 4 months and ≥ 11 months (median not reached).
CONCLUSIONS: Most group A patients appeared sub-optimally treated with 20 Gy in 5 fractions. Patients with survival prognoses ≤2 months may be considered for best supportive care or single-fraction RT, those with prognoses ≥3 months for longer-course RT plus/minus upfront decompressive surgery. Many group B and most group C patients achieved long-time LPFS and appeared sufficiently treated with 20 Gy in 5 fractions. However, based on previous data, long-term survivors may benefit from longer-course RT.

Šterbenc A, Maver PJ, Poljak M
Recent advances in prophylactic human papillomavirus (HPV) vaccination: a review of key literature published between September 2017 and September 2018.
Acta Dermatovenerol Alp Pannonica Adriat. 2018; 27(4):193-201 [PubMed] Related Publications
Prophylactic human papillomavirus (HPV) vaccines represent a revolutionary approach in preventing and potentially eliminating HPV-related cancers. Overwhelming real-life data are confirming the high efficacy and exceptional safety profile of all three prophylactic HPV vaccines currently available, which was previously shown in pivotal clinical trials. In this review, we summarized and discussed in our opinion the most influential peer-reviewed literature published between September 2017 and September 2018; that is, during the 2017/2018 school year in Slovenia. We mainly focus on publications on progress and the development of novel prophylactic HPV vaccines, efficacy clinical trials evaluating various dosing schemes and HPV vaccination of alternative populations, and studies contributing to the mounting evidence for the real-life effectiveness of prophylactic HPV vaccines from several countries with successfully implemented HPV vaccination programs. In addition, we present the most important safety data from large population-based cohorts evaluating potential adverse events, briefly describe the most notable HPV vaccine-related crises, and provide insight into various responses by healthcare authorities that have resulted in markedly different outcomes in the vaccination perception of the general population and, consequently, HPV vaccine uptake. Finally, global disparities in access to HPV vaccines reveal substantial gender and socioeconomic inequity that must be overcome to achieve a large population impact of HPV vaccines worldwide.

Pisanu ME, Maugeri-Saccà M, Fattore L, et al.
Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma.
J Exp Clin Cancer Res. 2018; 37(1):318 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
BACKGROUND: Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs.
METHODS: SCD1 gene expression data of melanoma patients were downloaded from TCGA and correlated with disease progression by bioinformatics analysis and confirmed on patient's tissues by qRT-PCR and IHC analyses. The effects of combination of BRAF/MEKi and the SCD1 inhibitor MF-438 were monitored by spheroid-forming and proliferation assays on a panel of BRAF-mutated melanoma cell lines grown in 3D and 2D conditions, respectively. SCD1, YAP/TAZ and stemness markers were evaluated in melanoma cells and tissues by qRT-PCR, WB and Immunofluorescence.
RESULTS: We first observed that SCD1 expression increases during melanoma progression. BRAF-mutated melanoma 3D cultures enriched for CSCs overexpressed SCD1 and were more resistant than 2D differentiated cultures to BRAF and MEK inhibitors. We next showed that exposure of BRAF-mutated melanoma cells to MAPK pathway inhibitors enhanced stemness features by upregulating the expression of YAP/TAZ and downstream genes but surprisingly not SCD1. However, SCD1 pharmacological inhibition was able to downregulate YAP/TAZ and to revert at the same time CSC enrichment and resistance to MAPK inhibitors.
CONCLUSIONS: Our data underscore the role of SCD1 as prognostic marker in melanoma and promote the use of SCD1 inhibitors in combination with MAPK inhibitors for the control of drug resistance.

Šekoranja D, Boštjančič E, Salapura V, et al.
Primary aneurysmal bone cyst with a novel SPARC-USP6 translocation identified by next-generation sequencing.
Cancer Genet. 2018; 228-229:12-16 [PubMed] Related Publications
Aneurysmal bone cyst (ABC) is a benign but locally aggressive, mostly pediatric neoplasm, with characteristic USP6 gene rearrangement that distinguishes it from a secondary ABC and other primary bone tumors. With the advent of next-generation sequencing (NGS) technology, several hitherto unknown USP6 fusion partners have been identified in ABC. Accordingly, we present a case of an 18-year-old male with a solid sub-periosteal primary ABC in the diaphysis of the left femur. Using an NGS-based assay, we identified SPARC-USP6 fusion, which has not previously been described in ABC. Including our case, the list of currently known USP6 fusion partners in primary ABC include: CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3 and THRAP3.

Senore C, Basu P, Anttila A, et al.
Performance of colorectal cancer screening in the European Union Member States: data from the second European screening report.
Gut. 2019; 68(7):1232-1244 [PubMed] Related Publications
OBJECTIVE: To present comparative data about the performance of colorectal cancer (CRC) screening programmes in the European Union Member States (EU MSs).
DESIGN: Cross-sectional study. We analysed key performance indicators-participation rate, positivity rate (PR), detection rate (DR) and positive predictive value for adenomas and CRC-based on the aggregated quantitative data collected for the second EU screening report. We derived crude and pooled (through a random effects model) estimates to describe and compare trends across different MSs/regions and screening protocols.
RESULTS: Participation rate was higher in countries adopting faecal immunochemical test (FIT) (range: 22.8%-71.3%) than in those using guaiac faecal occult blood test (gFOBT) (range 4.5%-66.6%), and it showed a positive correlation (ρ=0.842, p<0.001) with participation in breast cancer screening in the same areas. Screening performance showed a large variability. Compliance with referral for colonoscopy (total colonoscopy (TC)) assessment ranged between 64% and 92%; TC completion rate ranged between 92% and 99%. PR and DR of advanced adenomas and CRC were higher in FIT, as compared with gFOBT programmes, and independent of the protocol among men, older subjects and those performing their first screening.
CONCLUSIONS: The variability in the results of quality indicators across population-based screening programmes highlights the importance of continuous monitoring, as well as the need to promote quality improvement efforts, as recommended in the EU guidelines. The implementation of monitoring systems, ensuring availability of data for the entire process, together with initiatives aimed to enhance reproducibility of histology and quality of endoscopy, represent a priority in screening programmes management.

Campana LG, Edhemovic I, Soden D, et al.
Electrochemotherapy - Emerging applications technical advances, new indications, combined approaches, and multi-institutional collaboration.
Eur J Surg Oncol. 2019; 45(2):92-102 [PubMed] Related Publications
The treatment of tumors with electrochemotherapy (ECT) has surged over the past decade. Thanks to the transient cell membrane permeabilization induced by the short electric pulses used by ECT, cancer cells are exposed to otherwise poorly permeant chemotherapy agents, with consequent increased cytotoxicity. The codification of the procedure in 2006 led to a broad diffusion of the procedure, mainly in Europe, and since then, the progressive clinical experience, together with the emerging technologies, have extended the range of its application. Herein, we review the key advances in the ECT field since the European Standard Operating Procedures on ECT (ESOPE) 2006 guidelines and discuss the emerging clinical data on the new ECT indications. First, technical developments have improved ECT equipment, with custom electrode probes and dedicated tools supporting individual treatment planning in anatomically challenging tumors. Second, the feasibility and short-term efficacy of ECT has been established in deep-seated tumors, including bone metastases, liver malignancies, and pancreatic and prostate cancers (long-needle variable electrode geometry ECT), and gastrointestinal tumors (endoscopic ECT). Moreover, pioneering studies indicate lung and brain tumors as suitable future targets. A further advance relates to new combination strategies with immunotherapy, gene electro transfer (GET), calcium EP, and radiotherapy. Finally and fourth, cross-institutional collaborative groups have been established to refine procedural guidelines, promote clinical research, and explore new indications.

Petrera M, Paleari L, Clavarezza M, et al.
The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.
BMC Cancer. 2018; 18(1):1210 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
BACKGROUND: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials.
METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year.
DISCUSSION: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC.
TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; ClinicalTrial.gov Identifier: NCT03047837 . Registered on February 1, 2017.

Rich A, Baldwin D, Alfageme I, et al.
Achieving Thoracic Oncology data collection in Europe: a precursor study in 35 Countries.
BMC Cancer. 2018; 18(1):1144 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
BACKGROUND: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire.
METHODS: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months.
RESULTS: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses.
CONCLUSION: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research.

Milevoj N, Tratar UL, Nemec A, et al.
A combination of electrochemotherapy, gene electrotransfer of plasmid encoding canine IL-12 and cytoreductive surgery in the treatment of canine oral malignant melanoma.
Res Vet Sci. 2019; 122:40-49 [PubMed] Related Publications
The aim of this study was to evaluate the safety and efficacy of the combination of electrochemotherapy (ECT) with bleomycin and gene electrotransfer (GET) of plasmid encoding canine interleukin 12 (IL-12) for the treatment of canine oral malignant melanoma (OMM). Our focus was to determine the effect of the treatment on achieving local tumor control and stimulation of an antitumor immune response. Nine dogs with histologically confirmed OMM stage I to III were included in a prospective, non-randomized study. The dogs were treated with a combination of cytoreductive surgery, ECT and IL-12 GET, which was repeated up to five times, depending on the clinical response to the treatment, evaluated according to the follow-up protocol (7, 14 and 28 days after, the last treatment). One month after treatment, the objective response (OR) rate was 67% (6/9). Median survival time (MST) was 6 months and, even though the disease progressed in 8/9 patients at the end of the observation period (2 to 22 months), four animals were euthanized due to tumor-unrelated reasons. In addition, we observed a decline in the percentage of regulatory T cells (T

Đokić M, Badovinac D, Petrič M, Trotovšek B
An unusual presentation of metastatic malignant melanoma causing jejuno-jejunal intussusception: a case report.
J Med Case Rep. 2018; 12(1):337 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
BACKGROUND: Small bowel intussusception in adults is rarely encountered. In most cases small bowel intussusception is caused by benign neoplastic lesions, but metastasis of cutaneous malignant melanoma causing small bowel intussusception is rare. We present such a case of jejuno-jejunal intussusception with an intraluminal metastatic lesion acting as a lead point.
CASE PRESENTATION: We present a case of a 71-year-old Caucasian man who presented with small bowel obstruction. His medical history revealed that he had had a cutaneous malignant melanoma excised 7 years earlier and underwent total laryngectomy due to a metastasis 6 years later. The disease was classified as stage IV and he was receiving immunotherapy. An emergency abdominal computed tomography scan demonstrated small bowel obstruction, most probably caused by an intraluminal lesion. An emergency laparotomy revealed an intraluminal metastatic lesion causing jejuno-jejunal intussusception. Metastasectomy of the lesion was performed and 13 days later he was discharged.
CONCLUSIONS: Jejuno-jejunal intussusception with a malignant melanoma metastasis acting as a lead point is very rare. With the gastrointestinal tract being a common location of distal metastases, a medical history of malignant melanoma treatment in cases of small bowel obstruction should raise a suspicion of possible metastatic disease. A computed tomography scan is the diagnostic modality of choice and surgery still remains the standard of care.

Minicozzi P, Van Eycken L, Molinie F, et al.
Comorbidities, age and period of diagnosis influence treatment and outcomes in early breast cancer.
Int J Cancer. 2019; 144(9):2118-2127 [PubMed] Related Publications
Survival for breast cancer (BC) is lower in eastern than northern/central Europe, and in older than younger women. We analysed how comorbidities at diagnosis affected whether selected standard treatments (STs) were given, across Europe and over time, also assessing consequences for survival/relapse. We analysed 7581 stage I/IIA cases diagnosed in 9 European countries in 2009-2013, and 4 STs: surgery; breast-conserving surgery plus radiotherapy (BCS + RT); reconstruction after mastectomy; and prompt treatment (≤6 weeks after diagnosis). Covariate-adjusted models estimated odds of receiving STs and risks of death/relapse, according to comorbidities. Pearson's R assessed correlations between odds and risks. The z-test assessed the significance of time-trends. Most women received surgery: 72% BCS; 24% mastectomy. Mastectomied patients were older with more comorbidities than BCS patients (p < 0.001). Women given breast reconstruction (25% of mastectomies) were younger with fewer comorbidities than those without reconstruction (p < 0.001). Women treated promptly (45%) were younger than those treated later (p = 0.001), and more often without comorbidities (p < 0.001). Receiving surgery/BCS + RT correlated strongly (R = -0.9), but prompt treatment weakly (R = -0.01/-0.02), with reduced death/relapse risks. The proportion receiving BCS + RT increased significantly (p < 0.001) with time in most countries. This appears to be the first analysis of the influence of comorbidities on receiving STs, and of consequences for outcomes. Increase in BCS + RT with time is encouraging. Although women without comorbidities usually received STs, elderly patients often received non-standard less prompt treatments, irrespective of comorbidities, with increased risk of mortality/relapse. All women, particularly the elderly, should receive ST wherever possible to maximise the benefits of modern evidence-based treatments.

Khajanchi S, Perc M, Ghosh D
The influence of time delay in a chaotic cancer model.
Chaos. 2018; 28(10):103101 [PubMed] Related Publications
The tumor-immune interactive dynamics is an evergreen subject that continues to draw attention from applied mathematicians and oncologists, especially so due to the unpredictable growth of tumor cells. In this respect, mathematical modeling promises insights that might help us to better understand this harmful aspect of our biology. With this goal, we here present and study a mathematical model that describes how tumor cells evolve and survive the brief encounter with the immune system, mediated by effector cells and host cells. We focus on the distribution of eigenvalues of the resulting ordinary differential equations, the local stability of the biologically feasible singular points, and the existence of Hopf bifurcations, whereby the time lag is used as the bifurcation parameter. We estimate analytically the length of the time delay to preserve the stability of the period-1 limit cycle, which arises at the Hopf bifurcation point. We also perform numerical simulations, which reveal the rich dynamics of the studied system. We show that the delayed model exhibits periodic oscillations as well as chaotic behavior, which are often indicators of long-term tumor relapse.

Prunk Zdravković T, Zdravković B, Lunder M, Ferk P
The effect of micro-sized titanium dioxide on WM-266-4 metastatic melanoma cell line.
Bosn J Basic Med Sci. 2019; 19(1):60-66 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Titanium dioxide (TiO2) is widely used as an inorganic UV-filter in cosmetic products; however, it has been classified as possibly carcinogenic to humans. While numerous studies demonstrated cytotoxic and genotoxic effects of nano-sized TiO2 in different cell lines, including human skin cells, studies investigating the effects of micro-TiO2 on human keratinocytes and melanocytes, in healthy and cancer cells, are scarce. Adenosine triphosphate (ATP) binding cassette subfamily B member 5 (ABCB5) is a plasma membrane protein known for its role in the tumorigenicity, progression, and recurrence of melanoma. Here, we investigated the effect of micro-TiO2 (average particle size ≤5 µm) on the metabolic activity, cytotoxicity and ABCB5 mRNA expression in metastatic melanoma cells. Metastatic melanoma cell line WM-266-4 was treated with different concentrations of micro-TiO2 for different incubation times to obtain dose- and time-dependent responses. Untreated WM-266-4 cells, cultured under the same conditions, were used as control. The cell metabolic activity was determined by MTT assay. Cytotoxicity of micro-TiO2 was analyzed by lactate dehydrogenase (LDH) cytotoxicity assay. The ABCB5 mRNA expression in melanoma cells was analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR). After 120 hours of exposure to micro-TiO2 the metabolic activity of melanoma cells decreased, especially at the two highest micro-TiO2 concentrations. Comparably, the cytotoxicity of micro-TiO2 on melanoma cells increased after 48 and 120 hours of exposure, in a time-dependent manner. The ABCB5 mRNA expression in micro-TiO2-treated melanoma cells also decreased significantly after 24 and 48 hours, in a time-dependent manner. Overall, our results suggest inhibitory effects of micro-TiO2 on the metabolic activity and ABCB5 mRNA expression in metastatic melanoma cells, indicating its potential use as an anticancer agent.

Kaasa S, Loge JH, Aapro M, et al.
Integration of oncology and palliative care: a Lancet Oncology Commission.
Lancet Oncol. 2018; 19(11):e588-e653 [PubMed] Related Publications
Full integration of oncology and palliative care relies on the specific knowledge and skills of two modes of care: the tumour-directed approach, the main focus of which is on treating the disease; and the host-directed approach, which focuses on the patient with the disease. This Commission addresses how to combine these two paradigms to achieve the best outcome of patient care. Randomised clinical trials on integration of oncology and palliative care point to health gains: improved survival and symptom control, less anxiety and depression, reduced use of futile chemotherapy at the end of life, improved family satisfaction and quality of life, and improved use of health-care resources. Early delivery of patient-directed care by specialist palliative care teams alongside tumour-directed treatment promotes patient-centred care. Systematic assessment and use of patient-reported outcomes and active patient involvement in the decisions about cancer care result in better symptom control, improved physical and mental health, and better use of health-care resources. The absence of international agreements on the content and standards of the organisation, education, and research of palliative care in oncology are major barriers to successful integration. Other barriers include the common misconception that palliative care is end-of-life care only, stigmatisation of death and dying, and insufficient infrastructure and funding. The absence of established priorities might also hinder integration more widely. This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care. Integration raises new research questions, all of which contribute to improved clinical care. When and how should palliative care be delivered? What is the optimal model for integrated care? What is the biological and clinical effect of living with advanced cancer for years after diagnosis? Successful integration must challenge the dualistic perspective of either the tumour or the host, and instead focus on a merged approach that places the patient's perspective at the centre. To succeed, integration must be anchored by management and policy makers at all levels of health care, followed by adequate resource allocation, a willingness to prioritise goals and needs, and sustained enthusiasm to help generate support for better integration. This integrated model must be reflected in international and national cancer plans, and be followed by developments of new care models, education and research programmes, all of which should be adapted to the specific cultural contexts within which they are situated. Patient-centred care should be an integrated part of oncology care independent of patient prognosis and treatment intention. To achieve this goal it must be based on changes in professional cultures and priorities in health care.

Hochmair MJ, Morabito A, Hao D, et al.
Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study.
Future Oncol. 2018; 14(27):2861-2874 [PubMed] Related Publications
AIM: To assess outcomes in patients with EGFR mutation-positive (Del19, L858R) non-small-cell lung cancer receiving sequential afatinib and osimertinib in a real-world clinical setting. Materials & methods: In this retrospective, observational, multicenter study, patients (n = 204) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months prior to data entry. Primary outcome was time on treatment.
RESULTS: Overall median time on treatment was 27.6 months (90% CI: 25.9-31.3), 30.3 months (90% CI: 27.6-44.5) in Del19-positive patients and 46.7 months (90% CI: 26.8-not reached) in Asians. The 2-year overall survival was 78.9%.
CONCLUSION: In real-world clinical practice, sequential afatinib and osimertinib facilitates prolonged, chemotherapy-free treatment in patients with T790M acquired resistance, and is a potentially attractive strategy, especially for Del19-positive tumors.

Luzar B, Martin B, Fisher C, Calonje E
Cutaneous malignant glomus tumours: applicability of currently established malignancy criteria for tumours occurring in the skin.
Pathology. 2018; 50(7):711-717 [PubMed] Related Publications
Glomus tumours (GTs) have traditionally been classified into benign GTs, GTs with uncertain malignant potential and malignant GTs, based on a combination of criteria such as size of the tumour, degree of nuclear atypia and the level of mitotic activity. Several of the proposed grading criteria are difficult, or even impossible to apply for GTs occurring in the skin. The aim of the study was to analyse the applicability of the currently established GT malignancy criteria for tumours occurring in the skin and to establish their prognostic significance. A total of 25 benign cutaneous GTs, 11 new cutaneous malignant GTs and 36 cutaneous malignant GTs previously published in the literature were studied. We analysed the following clinicopathological features and correlated them with disease outcome: age, sex, site, size, depth of invasion, degree of nuclear atypia, mitotic activity, growth pattern, vascular invasion, spindle-cell morphology and tumoural necrosis. Of all the clinicopathological parameters analysed, only tumoural necrosis was found by univariate analysis (p = 0.001) to be associated with adverse biological behaviour, and none by multivariate analysis. Multivariate statistical analysis failed to detect any clinicopathological features predictive of the disease outcome (e.g., local recurrence, development of metastatic spread and/or death of disease) in cutaneous malignant GTs. Furthermore, the currently established malignancy criteria for cutaneous GTs can be difficult to apply, mainly due to their smaller size. Likewise, counting mitotic activity per 50 high power fields can often not be accomplished in GTs occurring at superficial locations. Complete excision of these tumours coupled with long-term follow-up is the mainstay of treatment for cutaneous malignant GTs. The results of our study also suggest that cutaneous malignant GTs follow a more indolent clinical course than their deep soft tissue counterparts.

Bolatti EM, Hošnjak L, Chouhy D, et al.
High prevalence of Gammapapillomaviruses (Gamma-PVs) in pre-malignant cutaneous lesions of immunocompetent individuals using a new broad-spectrum primer system, and identification of HPV210, a novel Gamma-PV type.
Virology. 2018; 525:182-191 [PubMed] Related Publications
Genus Gammapapillomavirus (Gamma-PV) is the most diverse and largest clade within the Papillomaviridae family. A novel set of degenerate primers targeting the E1 gene was designed and further used in combination with the well-known CUT PCR assay to assess HPV prevalence and genus distribution in a variety of cutaneous samples from 448 immunocompetent individuals. General HPV, Gamma-PV and mixed infections prevalence were significantly higher in actinic keratosis with respect to benign and malignant neoplasms, respectively (p = 0.0047, p = 0.0172, p = 0.00001). Gamma-PVs were significantly more common in actinic keratosis biopsies than Beta- and Alpha-PVs (p = 0.002). The full-length genome sequence of a novel putative Gamma-PV type was amplified by 'hanging droplet' long-range PCR and cloned. The novel virus, designated HPV210, clustered within species Gamma-12. This study provides an additional tool enabling detection of HPV infections in skin and adds new insights about possible early roles of Gamma-PVs in the development of cutaneous malignant lesions.

Sova M, Saso L
Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review.
Drug Des Devel Ther. 2018; 12:3181-3197 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
A major cell defense mechanism against oxidative and xenobiotic stress is mediated by the Nrf2/Keap1 signaling pathway. The Nrf2/Keap1 pathway regulates gene expression of many cytoprotective and detoxifying enzymes, thus playing a pivotal role in maintaining redox cellular homeostasis. Many diseases including cancer have been closely related to impaired Nrf2 activity. Targeting Nrf2 and modulating its activity represents a novel modern strategy for cancer chemoprevention and therapy. In this review, different design strategies used for the development of Nrf2 modulators are described in detail. Moreover, the main focus is on important and recently developed Nrf2 activators and inhibitors, their in vitro and in vivo studies, and their potential use as chemopreventive agents and/or cancer therapeutics.

Byrne J, Alessi D, Allodji RS, et al.
The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer.
Eur J Cancer. 2018; 103:238-248 [PubMed] Related Publications
BACKGROUND: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF.
METHODS: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public.
RESULTS: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors.
CONCLUSIONS: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.

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