Healthy immigrant effect in non-European Union immigrants in Portugal: after a decade of (non-)integration!

OBJECTIVES: The aim of the study was to characterise the existence of the healthy immigrant effect (HIE; better health initially, worsening with an increase in the length of residence) in a big city from a Western European country, particularly in a non-European Union immigrant population. STUDY DESIGN: This is a cross-sectional study. METHODS: We used data from the National Health Survey 2014 to compare the health status of the immigrant and Portuguese populations with different lengths of residence. After descriptive statistics, binary logistic regressions models, with adjusted levels and 95% confidence intervals, were used. RESULTS: Immigrants were healthier than the Portuguese population (<10 years: odds ratio [OR] = 0.07; 95% confidence interval [CI] = [0.01; 0.51]; ≥10 years: OR = 0.62; 95% CI = [0.19; 2.03]), but had an increased likelihood of suffering from chronic diseases and risk behaviours with the increase in their length of stay in Portugal. After living in Portugal for more than 10 years, the immigrants showed no statistical difference in the main health indicators. CONCLUSIONS: There was a tendency for the health status of immigrants to deteriorate over 10 years of residence in Portugal. To better understand the reasons behind the HIE, specific and tailored studies must be developed.

Elevated soluble TNFα levels and upregulated TNFα mRNA expression in purified peripheral blood monocyte subsets associated with high-grade hepatocellular carcinoma.

BACKGROUND: Chronic inflammation is involved in the initiation and progression of various cancers, including liver cancer. The current study focuses on the characterization of the peripheral immune response in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patients, before and after surgical procedure, in order to assess the effect of tumor resection in the immune system homeostasis and to determine possible prognostic factors associated with high-grade tumors. We developed a whole-blood assay to monitor immune alterations and functional competence of peripheral monocytes in a group of 10 healthy individuals (HG), in 20 HCC patients and 8 CCA patients, by multi-color flow cytometry, qRT-PCR, and ELISA techniques. RESULTS: The qRT-PCR analysis showed an upregulation of TNFα expression by classical and intermediate monocytes purified from HCC patients presenting tumors in grade G3-G4 as compared to G1-G2 HCC patients. Moreover, ELISA assay confirmed elevated serum levels of TNFα in G3-G4 compared to G1-G2 HCC patients. A significant decrease of circulating non-classical monocytes was detected in both CCA and HCC patients before and after surgical procedure. In addition, a functional defect in circulating classical and intermediate monocytes was observed in both groups of cancer patients when compared to the HG, with partial recovery after the surgical intervention. CONCLUSIONS: This integrated analysis permitted the identification of altered functional competence of monocyte subsets in CCA and HCC patients. In addition, our results point to a potential role of TNFα as a prognostic peripheral biomarker in HCC patients, indicating the presence of high-grade tumors that should be further validated.

Preventing HIV under financial constraints: The 2011-12 reform of the Portuguese HIV/AIDS Programme.

The national HIV/AIDS Programme has been a core health programme in Portugal, and has led the country's response to the HIV epidemics since the 1980s. In 2011, the Portuguese Government reorganised central services and reformed all vertical programmes, including the HIV/AIDS Programme. This paper describes the main features of that reform and analyses selected outcomes, as well as how those financial constraints affected the response to HIV/AIDS. Despite some transitory cuts in spending, the National Programme for HIV/AIDS Infection was able to successfully expand testing and prevention interventions. Strategic partnerships with non-governmental and community-based organisations were crucial to continue delivering adequate HIV testing services and reaching most-at-risk groups. Scaling-up access to pre-exposure prophylaxis (PrEP), improving access and adherence to antiretroviral therapy, and continuously promoting access to HIV testing services and HIV self-testing are the main challenges that the National Programme for HIV/AIDS Infection will face in the upcoming years.

Evidence-based radiography: A new methodology or the systematisation of an old practice?

INTRODUCTION: Evidence based radiography (EBR) is the logical development of evidence based practice applied to radiography. The aim of this study was to investigate the opinion of a cohort of Portuguese radiographers in Southern Portugal working in public hospitals regarding evidence based practice (EBP), namely about the levels of knowledge about EBR, how they access information and how they use it within daily practice. METHODS: A self-administered questionnaire was applied to a sample of 40 radiographers in the Portuguese region of Algarve. This questionnaire was validated for Portuguese speakers using the translation-retranslation method. RESULTS: The final response rate was 69% (40/58). Results suggest that most radiographers trained EBR during their undergraduate training. Although, no statistically significant correlations were found in the practice of EBR against participant gender, age, training, career level, reading papers and workplace. The most frequent reason to read papers is the "interest" to do so, and national professional journals are read more often. It was found that radiographers that read scientific papers more frequently know more about research (p = 0.005), understand the importance of research for the professional activity (p = 0.023), and know more on how to conduct research papers (p = 0.034). CONCLUSION: EBR within radiography is not yet well established, and radiographers' have varying viewpoints. Radiographers that read scientific papers more frequently understand better the philosophy behind this concept but it is very important to deepen the knowledge on this area. IMPLICATIONS FOR PRACTICE: When practicing radiography based on the best available scientific knowledge, professionals are ensuring the best for patients and for profession. To achieve this, and before taking any action, it is important to evaluate the current situation, and this research presents a way to do so.

Functional and Phenotypic Characterization of Tumor-Infiltrating Leukocyte Subsets and Their Contribution to the Pathogenesis of Hepatocellular Carcinoma and Cholangiocarcinoma.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most common primary liver malignancies whose outcome is influenced by the immune response. In the present study, we evaluated the tumor-infiltrating leukocyte (TIL) populations in 21 HCC patients and 8 CCA patients by flow cytometry immediately after the surgical procedure. Moreover, CD4+ T cells, CD8+ T cells, monocytes, and macrophages were purified by cell sorting for further analysis of gene expression by quantitative reverse-transcription polymerase chain reaction. Regarding tumor-infiltrating macrophages, we observed a significantly higher expression of markers associated with M2 phenotype and a higher expression of PD-L1 in patients with HCC in comparison to CCA. In addition, for HCC patients, we found a significant increase in the expression of CD200R in macrophages from tumors that were in grade G3-G4 as compared to tumors in grade G1-G2. Besides, a significantly higher frequency of tumor-infiltrating lymphocytes, CD8+CD56+ T cells, and natural killer cells was detected in HCC biopsies in comparison to CCA. In summary, this study has revealed functional and phenotypic differences in TIL cell subpopulations between CCA and HCC, as well as among different histopathological grades and tumor aggressiveness degrees, and it has provided evidence to better understand the tumor immune microenvironment of CCA and HCC.

Functional Impairment of Circulating FcεRI+ Monocytes and Myeloid Dendritic Cells in Hepatocellular Carcinoma and Cholangiocarcinoma Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most common primary liver malignancies whose outcome is influenced by the immune response. METHODS: In this study, we have functionally characterized, by flow cytometry, circulating myeloid dendritic cells (mDCs) and FcεRI+ monocytes in a group of healthy individuals (n = 10) and in a group of patients with HCC (n = 19) and CCA (n = 8), at the time point of the surgical resection (T0) and once the patient had recovered from surgery (T1). Moreover, we proceeded to a more in depth phenotypic characterization of the FcεRI+ monocyte subpopulation. RESULTS: A significant decrease in the frequency of TNFα producing FcεRI+ monocytes and mDCs in HCC and CCA patients when compared to the group of healthy individuals was observed, and a close association between FcεRI+ monocytes and mDCs dysfunction was identified. In addition, the phenotypic characteristics of FcεRI+ monocytes from healthy individuals strongly suggest that this population drives to mDCs, which matches with the fact that both populations are functionally affected. CONCLUSIONS: The frequency and the function of circulating mDCs and FcεRI+ monocytes are affected in both HCC and CCA patients, and FcεRI+ monocytes could represent those fated to become mDCs. © 2019 International Clinical Cytometry Society.

Targeted alpha therapy using Radium-223: From physics to biological effects.

With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 (223Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with 223Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical.

Adjunctive yoga v. health education for persistent major depression: a randomized controlled trial.

BACKGROUND: The objective of this study was to determine whether hatha yoga is an efficacious adjunctive intervention for individuals with continued depressive symptoms despite antidepressant treatment. METHOD: We conducted a randomized controlled trial of weekly yoga classes (n = 63) v. health education classes (Healthy Living Workshop; HLW; n = 59) in individuals with elevated depression symptoms and antidepressant medication use. HLW served as an attention-control group. The intervention period was 10 weeks, with follow-up assessments 3 and 6 months afterwards. The primary outcome was depression symptom severity assessed by blind rater at 10 weeks. Secondary outcomes included depression symptoms over the entire intervention and follow-up periods, social and role functioning, general health perceptions, pain, and physical functioning. RESULTS: At 10 weeks, we did not find a statistically significant difference between groups in depression symptoms (b = -0.82, s.e. = 0.88, p = 0.36). However, over the entire intervention and follow-up period, when controlling for baseline, yoga participants showed lower levels of depression than HLW participants (b = -1.38, s.e. = 0.57, p = 0.02). At 6-month follow-up, 51% of yoga participants demonstrated a response (⩾50% reduction in depression symptoms) compared with 31% of HLW participants (odds ratio = 2.31; p = 0.04). Yoga participants showed significantly better social and role functioning and general health perceptions over time. CONCLUSIONS: Although we did not see a difference in depression symptoms at the end of the intervention period, yoga participants showed fewer depression symptoms over the entire follow-up period. Benefits of yoga may accumulate over time.

Oxidative Stress, DNA, Cell Cycle/Cell Cycle Associated Proteins and Multidrug Resistance Proteins: Targets of Human Amniotic Membrane in Hepatocellular Carcinoma.

The anticancer effects of human amniotic membrane (hAM) have been studied over the last decade. However, the action mechanisms responsible for these effects are not fully understood until now. Previously results reported by our team proved that hAM is able to induce cytotoxicity and cell death in hepatocellular carcinoma (HCC), a worldwide high incident and mortal cancer. Therefore, this experimental study aimed to investigate the cellular targets of hAM protein extracts (hAMPE) in HCC through in vitro studies. Our results showed that hAMPE is able to modify oxidative stress environment in all HCC cell lines, as well as its cell cycle. hAMPE differently targets deoxyribonucleic acid (DNA), P21, P53, ß-catenin and multidrug resistance (MDR) proteins in HCC cell lines. In conclusion, hAMPE has several targets in HCC, being clear that the success of this treatment depends of a personalized therapy based on the biological and genetic characteristics of the tumor.

Selective cytotoxicity and cell death induced by human amniotic membrane in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a worldwide high incidence and mortality. For this reason, it is essential to invest in new therapies for this type of cancer. Our team already proved that human amniotic membrane (hAM) is able to inhibit the metabolic activity of several human cancer cell lines, including HCC cell lines. Taking into account the previously performed work, this experimental study aimed to investigate the pathways by which hAM protein extracts (hAMPEs) act on HCC. Our results showed that hAMPE reduce the metabolic activity, protein content and DNA content in a dose- and time-dependent manner in all HCC cell lines. This therapy presents selective cytotoxicity, since it was not able to inhibit a non-tumorigenic human cell line. In addition, hAMPE induced cell morphology alterations in all HCC cell lines, but death type is cell line dependent, as proved by in vitro and in vivo studies. In conclusion, hAMPE have a promising role in HCC therapy, since it is capable of inducing HCC cytotoxicity and cell death.

Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment.

Colorectal cancer is still a major health problem worldwide. Based on the most recent released data by the World Health Organization GLOBOCAN in 2012, colorectal cancer is the third most prevalent type of cancer in males and the second in females. In 1999, it was published the first report showing evidence of a strong correlation between diet and cancer incidence, being its positive or negative impact intimately linked to dietary patterns. A diet rich in fiber is associated with a low risk of developing colorectal cancer. The fermentation of the dietary fiber by intestinal microflora results in production of butyrate, which plays a plurifunctional role on the colonocytes, and it has also been reported as a chemopreventive agent. However, there are limited studies focusing its anti-cancer potential. Here, we review the recent new insights that focus butyrate and its role in colorectal cancer prevention and treatment, from its synthesis, metabolism, and transport, through its involvement on several cancer-related signaling pathways, to the novel existing approaches for its clinical use.

Lung cancer: the immune system and radiation.

Lung cancer has a known relationship with smoking and is one of the leading causes of cancer-related death worldwide. Although the number of studies discussing lung cancer is vast, treatment efficacy is still suboptimal due to the wide range of factors that affect patient outcome. This review aims to collect information on lung cancer treatment, specially focused on radiation therapy. It also compiles information regarding the influence of radiotherapy on the immune system and its response to tumour cells. It evaluates how immune cells react after radiation exposure and the influence of their cytokines in the tumour microenvironment. The literature analysis points out that the immune system is a very promising field of investigation regarding prognosis, mostly because the stromal microenvironment in the tumour can provide some information about what can succeed in the future concerning treatment choices and perspectives. T cells (CD4+ and CD8+), interleukin-8, vascular endothelial growth factor and transforming growth factor-ß seem to have a key role in the immune response after radiation exposure. The lack of large scale studies means there is no common consensus in the scientific community about the role of the immune system in lung cancer patients treated with radiotherapy. Clarification of the mechanism behind the immune response after radiation can lead to better treatments and better quality life for patients.

Extinction retention and fear renewal in a lifetime obsessive-compulsive disorder sample.

Obsessive-compulsive disorder (OCD), like other illnesses with prominent anxiety, may involve abnormal fear regulation and consolidation of safety memories. Impaired fear extinction memory (extinction recall, ER) has been shown in individuals with current symptoms of OCD [1]. However, contrary to expectations, the only previous study investigating this phenomenon showed a positive correlation between extinction recall abilities and OCD symptomology (i.e., as OCD symptoms worsened, extinction memory improved). The purpose of the current study was to determine if patients with a lifetime diagnosis of OCD (not necessarily currently symptomatic) also demonstrate impairments in extinction memory, and the relationship between OCD symptomology and extinction memory in this type of sample. In addition, we also examined fear renewal, which has never been investigated in an OCD sample. We enrolled 37 patients with OCD, the majority of whom were on serotonin reuptake inhibitors, and 18 healthy control participants in a 2-day paradigm assessing fear conditioning and extinction (Day 1) and extinction retention and renewal (Day 2). Skin conductance responses (SCRs) were the dependent measure. Results, as in the prior study, indicated that the only between-group difference was impaired ER in OCD patients relative to controls. Contrary to our prediction, OCD symptom severity was not correlated with the magnitude of extinction recall. There were no differences in fear renewal between OCD patients and controls.

Effect of amniotic membrane proteins in human cancer cell lines: an exploratory study.

Human amniotic membrane (hAM) has recently drawn attention as an upcoming anti-cancer therapy. Regarding the strategies which have already investigated, little is known about hAM protein extracts (hAMPE) effect on cancer. So, this work aims to study the effect of hAMPE in metabolic activity of several human cancer cell lines. hAMPE were mechanically obtained, thus avoiding the effect of detergents and other reagents commonly used in protein extraction under the cell lines studied. After quantification of proteins in hAMPE, their effect on the metabolic activity of 21 human cancer cell lines was assessed by 3-(4,5-dimethylthia-zolyl-2)2,5-diphenyltetrazolium bromide (MTT) assay. Our results indicate that there is an inhibition of metabolic activity until 25 and 50% in two and seven cell lines, respectively. Five cell lines proved to be very sensitive to hAMPE, being its metabolic activity more than 50% inhibited. Our results show that hAMPE can inhibit the metabolic activity of some human cancer cell lines. However, research about this cell line-dependent response to hAMPE becomes indispensable.

Beyond the limits of oxygen: effects of hypoxia in a hormone-independent prostate cancer cell line.

Prostate cancer (PCa) has a high incidence worldwide. One of the major causes of PCa resistance is intratumoral hypoxia. In solid tumors, hypoxia is strongly associated with malignant progression and resistance to therapy, which is an indicator of poor prognosis. The antiproliferative effect and induced death caused by doxorubicin, epirubicin, cisplatin, and flutamide in a hormone-independent PCa cell line will be evaluated. The hypoxia effect on drug resistance to these drugs, as well as cell proliferation and migration, will be also analyzed. All drugs induced an antiproliferative effect and also cell death in the cell line under study. Hypoxia made the cells more resistant to all drugs. Moreover, our results reveal that long time cell exposure to hypoxia decreases cellular proliferation and migration. Hypoxia can influence cellular resistance, proliferation, and migration. This study shows that hypoxia may be a key factor in the regulation of PCa.

Hepatocellular carcinoma and chemotherapy: the role of p53.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver. A major proportion of HCCs also present mutation of the gene that encodes p53, which confers chemoresistance. The main goal of this work is to investigate the effect of cisplatin, doxorubicin and 5-fluoruracil (5-FU) in three human HCC cell lines which differ in p53 expression. METHODS: HepG2 (expressing normal p53), HuH7 (expressing mutated p53) and Hep3B2.1-7 (not expressing p53) cell lines were cultivated in the presence of cisplatin, doxorubicin and 5-FU. Cell proliferation was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT assay). The type of cell death and Bax and Bcl2 activation were assessed by flow cytometry. RESULTS: It was found that for all of the cell lines studied, the agent that gave the most satisfactory results was doxorubicin. 5-FU demonstrated no activity in these cell lines. CONCLUSIONS: For all the cell lines studied, doxorubicin was the most satisfactory agent. In HepG2 and HuH7 cell lines, it can activate Bax with statistical significance.

Amniotic membrane: from structure and functions to clinical applications.

Amniotic membrane (AM) or amnion is a thin membrane on the inner side of the fetal placenta; it completely surrounds the embryo and delimits the amniotic cavity, which is filled by amniotic liquid. In recent years, the structure and function of the amnion have been investigated, particularly the pluripotent properties of AM cells, which are an attractive source for tissue transplantation. AM has anti-inflammatory, anti-bacterial, anti-viral and immunological characteristics, as well as anti-angiogenic and pro-apoptotic features. AM is a promoter of epithelialization and is a non-tumorigenic tissue and its use has no ethical problems. Because of its attractive properties, AM has been applied in several surgical procedures related to ocular surface reconstruction and the genito-urinary tract, skin, head and neck, among others. So far, the best known and most auspicious applications of AM are ocular surface reconstruction, skin applications and tissue engineering. However, AM can also be applied in oncology. In this area, AM can prevent the delivery of nutrients and oxygen to cancer cells and consequently interfere with tumour angiogenesis, growth and metastasis.

99mTc(I)/Re(I) tricarbonyl complexes for in vivo targeting of melanotic melanoma: Synthesis and biological evaluation.

The (99m)Tc (I) tricarbonyl complexes fac-[(99m)Tc(κ(3)-L)(CO)(3)] (Tc1-Tc6) containing N-ethylpyrrolidine and N,N-diethylethylamine groups for melanin binding, were evaluated in vitro and in vivo as radioactive probes for the targeting of melanotic melanoma. Aiming at the modification of their size, topology and lipophilicity, Tc1-Tc6 were obtained based on an S,N,O-donor bifunctional chelator (BFC) derived from cysteamine and on pyridyl- and pyrazolyl-containing N,N,O-donor BFCs. Tc1-Tc6 were chemically identified by HPLC comparison with the Re congeners (Re1-Re6) that were synthesized at the macroscopic level and fully characterized by common analytical techniques. With the exception of Tc5 and Tc6, these (99m)Tc complexes are moderately lipophilic, and bind to melanin with moderate to high affinity (23-87%). The cell uptake of Tc1-Tc6, expressed as a percentage of total activity per million cells, spanned between 0.86 and 21.02% for the melanotic B16-F1 cell line and between 0.49% and 13.58% for the amelanotic A375 cell line. In the B16-F1 cell line, Tc1, Tc3 and Tc4 showed moderate cellular uptake values (>10% at 4 h of incubation). In the amelanotic A375 cell line, only Tc4 has shown a moderate cell uptake (>10% at 4 h of incubation), with all the other compounds displaying a relatively poor uptake, i.e. inferior to 5%. Competition studies with haloperidol have shown that the involvement of sigma receptors in cellular uptake and retention is likely to occur for Tc4. Complex Tc1, stabilized with the S,N,O-donor BFC and containing a N,N-diethylethylamine group, presented the most promising biological profile for in vivo targeting of melanoma, showing a moderate tumor uptake of 2.17% ID/g at 1 h p.i in a B16-F1 melanoma-bearing mouse and rather favorable target/non-target ratios with values as high as 16.9 and 5.2 for tumor/muscle and tumor/blood ratios, respectively.

Radiolabelling of ascorbic acid: a new clue to clarify its action as an anticancer agent?

Vitamin C exists in two forms: the reduced (ascorbic acid--AA) and oxidized form (dehydroascorbic acid--DHA). This is a nutrient whose benefits are long known and widely publicized, being most of them related to its antioxidant action. As an antioxidant, the main role of vitamin C is to neutralize free radicals, reducing oxidative stress. However, some controversial studies suggest that this nutrient may have a preventive and therapeutic role in cancer disease due to their possible pro-oxidant activity, promoting the formation of reactive oxygen species that can induce cell death in cancer cells. This factor, coupled with the decrease of antioxidant enzymes and increase of decompartmentalized transition metals in tumor cells may result in the selective cytotoxicity of vitamin C and the subsequent revelation of its therapeutic potential. In this way the first purpose of this work was radioactively label the reduced form of vitamin C with Tc-99m, its quality control by HPLC and the time stability. The second purpose was to use the radioactive complex 99mTc-AA in in vitro and in vivo studies in order to evaluate its uptake by colorectal cancer cells and biodistribution in mices, respectively. The results suggest that the pharmaceutical formulation developed, which was reproducible and stable over time, was residually taken up by colorectal cancer cells. Future studies are needed to deepen our understanding about the radioactive complex 99mTc-AA and clarify the mechanisms of action of vitamin C in oncologic disease.

Tumour hypoxia and technetium tracers: in vivo studies.

INTRODUCTION: Hypoxia is a biochemical condition where reduced oxygen partial pressure at tissue level occurs. This metabolic situation can lead to resistance to radio and chemotherapy. In malignant solid tumours, hypoxia is a common characteristic, having a great impact at biological level, being of tremendous importance for complete understanding of tumour progression. OBJECTIVES: We studied the behavior of 99mTc-HL91 in vivo, using an animal model based on Balb-c nu/nu mice with a xenotransplant of the human colorectal adenocarcinoma cell line, WiDr. MATERIAL AND METHODS: In vivo studies using an animal model of xenograft on Balb/c nu/nu nude mice were carried out. This model, allowed us to evaluate the radiopharmaceutical biodistribution and to calculate tumour/muscle ratio, acquired after 99mTc-HL91 injection. We also performed ex vivo studies, using the excised tumours to access viability and to characterize the intracellular production of reactive oxygen species and the status of mitochondrial membrane potential through flow cytometry. RESULTS AND DISCUSSION: The biodistribution after 99mTc-HL91 injection showed urinary and hepatobilliary excretion in similar proportions and tumour uptake around 4.4% of administered activity. This uptake was higher at the bigger tumours. Through flow cytometry we observed that larger tumours have a higher amount of reactive oxygen species and a decrease in mitochondrial membrane potential. CONCLUSIONS: 99mTc-HL91 allowed a non-invasive evaluation of the solid tumours oxidative state by nuclear medicine functional imaging. This information can be of high importance at the pre-treatment estimation of this type of tumours.