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Clinical Oncology

APRIL 30, 2020

[Hormone replacement therapy in cancer survivors – Review of the literature]

DELI Tamás, OROSZ Mónika, JAKAB Attila

[Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as a side effect of their oncotherapy, experience the cessation of gonadal function, leading to premature ovarian insuffi ciency, with disturbing vasomotor symtoms and long-term negative cardiovascular and skeletal effects. Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women’s Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude defi nitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Yet, the oncologic risk of HRT is extremely diffi cult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies. We group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: ’HRT is advanageous’ (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); ’HRT is neutral’ (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); ’HRT is relatively contraindicated’ for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); ’HRT is diasadvantageous and thus contraindicated’ (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).]

Clinical Oncology

APRIL 30, 2020

[Tumor induction by chemotherapy]

[Without chemotherapy, the fi ve-year survival rate of detected cancers would be between 0 and 15%, depending on the tumor, and between 17 and 85% with current therapy. Several warnings call attention to the dangers of chemotherapy-induced side effects, most notably the potential for tumor-inducing ability, which can affect 5-10% of patients who have recovered beyond fi ve years. Some systematically applied drugs used in chemotherapy (alkylating agents, etoposide, arsenic trioxide) are able to cause mutations in healthy cells of the patients, increasing the likelihood that the mutated cells will start a later (secondary) tumor formation. In addition to mutagenic effects, some chemotherapeutic agents exert their effects on normal myeloid and epithelial cells of the body, which, by altering the tissue microenvironment, create the potential for malignant transformation. Tumor-associated macrophages (TAMs), which can alter gene expression patterns by tumor cell secreted factors and promote the survival and invasiveness of tumor cells by pro-carcinogenic signals, are very important in this process. It is of utmost importance that doctors, pharmacists, technicians and nurses working with cancer-causing materials do not come into direct contact with dangerous substances and wear appropriate protective equipment.]

Clinical Oncology

FEBRUARY 28, 2020

[Non-surgical treatment of ovarian cancer]

PIKÓ Béla, LACZÓ Ibolya,, MARIK László

[The primary surgery with an optimal cytoreduction is an essential step during the treatment of the epithelial ovarian cancer because it determines the effectiveness of other therapeutic options as well. Immediately after the surgery a cytostatic infusion typically 40-42.5 degrees Celsius is pumped directly to the abdomen. During the systemic therapy the main point is the 6 months progression free survival because beyond this time the disease could be considered as platinum sensitive, inside this time as platinum refracter or resistant disease. The cytostatic treatment improved during the years from the alkylating agents through the platinum derivates to the administration of paclitaxel with several combinations of them and with more and more signifi cant results and less side effects. The most signifi cant targeted agents are the angiogenesis inhibitors (mainly the bevacizumab) and the PARP-inhibitors which prevents DNA repairs. In order to a PARP-inhibitor could be administered a platinum sensitivity is required while BRCA mutation not. Recently there are promising clinical researches with immunotherapy as well. The main benefi t of the hormonal therapy is the tolerability. Besides the signifi cant improvement in the systemic agents the role of radiotherapy is more and more decreasing, however the treatment of the whole peritoneal surface – mainly with the modern radiation techniques – could be an alternative solution for the chemotherapy. The palliative irradiation which relieve the symptoms could extend the drug-free period and the combination of radiation and chemotherapy could provide further possibilities.]

Lege Artis Medicinae

OCTOBER 21, 2020

[Gene modified immune cells: New weapons not exclusively against cancer]

SZÖŐR Árpád

[The oncological breakthrough of the last decade was the application of CD19-specific CAR T cells in different hematologic diseases. Experience gained by clinical trials, coupled with investments of the private stakeholders and the pharmaceutical industry resulted not only in commercial release to the public of already developed CAR T cell products, but drew the atten­tion of many researchers to the potentials of new type immune cells, and their non-oncological administration. This study aims to present briefly those preclinical applications, which approved successfully the administration of CAR T cells in autoimmune and infectious diseases.]

Clinical Neuroscience

SEPTEMBER 30, 2020

[Prognostic significance of invasion in glioblastoma]

SZIVÓS László, VIRGA József, HORTOBÁGYI Tibor, ZAHUCZKY Gábor, URAY Iván, JENEI Adrienn, BOGNÁR László, ÁRKOSY Péter, KLEKNER Álmos

[Glioblastoma is the most common malignant CNS tumor, its surgical removal is hindered by the tumors invasive nature, while current anti-tumor therapies show limited effectiveness – mean overall survival is 16-24 months. Some patients show minimal response towards standard oncotherapy, however there are no routinely available prognostic and predictive markers in clinical practice to identify the background of mentioned differences in prognosis. This research aims to identify the prognostic significance of invasion-related extracellular (ECM) components. Patient groups with different prognoses were created (OS: group A <16 months, group B > 16 months), and internationally recognized prognostic markers (IDH1 mutation and MGMT promoter hyper-methylation) were tested in the flash-frozen tumor samples. Furthermore, the mRNA levels of 46 invasion-related ECM molecules were measured. Clinical data of the patients who have been operated on at the University of Debrecen Clinical Center Department of Neurosurgery and treated at the Department of Clinical Oncology showed no significant differences except for survival data (OS and PFS), and reoperation rate. All samples were IDH wild type. MGMT promoter hypermethylation rate showed significant differences (28.6% vs 68.8%). The expressional pattern of the invasion-related ECM molecules, i.e. the invasion spectrum also showed major differences, integrin β2, cadherin-12, FLT4/VEGFR-3 and versican molecules having signficantly different mRNA levels. The accuracy of the inivasion spectrum was tested by statistical classifier, 83.3% of the samples was sorted correctly, PPV was 0.93. The difference found in the reoperation rate when comparing different prognostic groups aligns with literature data. MGMG promoter region methylation data in Hungarian samples has not been published yet, and further confirming current knowledge urges the implementation of MGMT promoter analysis in clinical practice. Studying the invasion spectrum provides extra information on tumors, as a prognostic marker it helps recognizing more aggressive tumors, and calls attention to the necessity of using anti-invasive agents in GBM therapies in the future.]

Clinical Neuroscience

JULY 30, 2020

Extraskeletal, intradural, non-metastatic Ewing’s sarcoma. Case report

OTTÓFFY Gábor, KOMÁROMY Hedvig

Intracranial localization of Ewing’s sarcoma is considerably very rare. Herein, we present clinical and neuroimaging findings regarding a 4-year-old boy with intracranial Ewing’s sarcoma. He was born prematurely, suffered intraventricular haemorrhage, posthaemorrhagic hydrocephalus developed, and a ventriculoperitoneal shunt was inserted in the newborn period. The patient endured re­gular follow ups, no signs of shunt malfunction nor increased intracranial pressure were observed. The last neuroima­ging examination was performed at 8 months of age. Upon reaching the age of 4 years, repeated vomiting and focal seizures began, and symptoms of increased intracranial pressure were detected. A brain MRI depicted a left frontoparietal space-occupying lesion infiltrating the superior sagittal sinus. The patient underwent a craniotomy resulting in the total excision of the tumour. The histological examination of the tissue revealed a small round blue cell tumour. The diagnosis was confirmed by the detection of EWSR1 gene translocation with FISH (fluorescent in situ hybridization). No additional metastases were detected during the staging examinations. The patient was treated in accordance to the EuroEwing 99 protocol. Today, ten years onward, the patient is tumour and seizure free and has a reasonably high quality of life.

Clinical Neuroscience

MAY 30, 2020

[The long-term follow-up of enzyme replacement treatment in late onset Pompe disease]

MOLNÁR Mária Judit, BORSOS Beáta, VÁRDI Visy Katalin, GROSZ Zoltán, SEBÕK Ágnes, DÉZSI Lívia, ALMÁSSY Zsuzsanna, KERÉNYI Levente, JOBBÁGY Zita, JÁVOR László, BIDLÓ Judit

[Pompe disease (PD) is a rare lysosomal disease caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme due to mutations in the GAA gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes. Clinically, the disease has been classically classified in infantile and childhood/adult forms. Presently cc. close to 600 mutations distributed throughout the whole gene have been reported. The c.-32-13T>G splice mutation that is very common in patients of Caucasian origin affected by the childhood/adult form of the disease, with an allelic frequency close to 70%. Enzyme replacement treatment (ERT) is available for the patients with Pompe disease (Myozyme). In this paper, we are presenting the long term follow up of 13 adult onset cases treated more than 5 years. The longest follow up was 15 years. To evaluate the treatment efficacy, the 6 minutes walking test (6MWT) and the respiratory functions were monitored annually. The analysis revealed that at the beginning of ERT for 3-4 years the 6MWT had been generally increasing, then it declined, and after 10 years it was lower in 77% of the cases than it had been at the start of the treatment. In 23% of the cases the 6MWT increased during the follow up time. Only one of the patients become wheelchair dependent during the follow-up period. The respiratory function showed similar results especially in supine position. A high degree of variability was observed among patients in their responses to the treatment, which only partially associated with the antibody titer against the therapeutic protein. The efficacy of the ERT was associated with the type of the disease causing mutation, the baseline status of the disease, the lifestyle and the diet of the patient. The long-term follow up of the patients with innovative orphan drugs is necessary to really understand the value of the treatment and the need of the patients.]

Clinical Oncology

APRIL 10, 2019

[Current views on the male breast cancer]

BAKI Márta

[Breast cancer in men is a rare disease, and accounts for only 1% of all diagnosed breast cancers. Hungarian incidence by available data much higher. The greatest risk factor of male breast cancer the elevated estrogen concentration in the body. Genetic disorders, as a Klinefelter syndrome and estrogen exposures and other metabolic changes might cause the male breast cancer. Symptom duration is longer than female population and the male breast cancers diagnosed in older ages and advanced stages. Frequency of BRCA2 mutation is probably 10% among male patients. The most common type is invasive ductal carcinoma with estrogen and progesterone receptor positivity. Diagnostic, surgical, radiation procedures and chemotherapy probably same as female breast cancer. The guidelines recommend as in adjuvant and curative setting the tamoxifen and other selective estrogen receptor modulators treatment. By large nation based registry the survival rate is different from male and female breast cancers. New biomarkers, genetic changes are under investigation to understand munch better the male breast cancer.]

Clinical Oncology

FEBRUARY 20, 2019

[Molecular subtypes and the evolution of treatment decisions in metastatic colorectal cancer]

RODRIGO Dienstmann, RAMON Salazar, JOSEP Tabernero

[Colorectal cancer (CRC) has clinically-relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations defi ne a population refractory to EGFR monoclonal antibodies, BRAFV600E mutations associate with poor outcome under standard therapies and response to targeted inhibitors in combinations, while HER2 amplifi cations confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to EGFR monoclonal antibodies have been described with signifi cant overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers refl ect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable (MSI) or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, while tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratifi ed development of novel immunotherapy combinations. In this manuscript we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.]

Clinical Oncology

FEBRUARY 20, 2019

[P53 – the suppressor]

KOPPER László

[Our basic nature requere cells quantity and quality to perform differenciate activity. p53 has the responsibility for quick out those cells who carries molecular failures in DNA avoiding transfer mutations into doughter cells. If the DNA-repair insuffi cient p53s with on apoptosis. Whe p53 is mutated the phenotypes are different in a wide range due to the heterogenity of the DNA damages, and also the expression pattern of a suppressor protein. With the increasing amout the damaged DNA the genomic instability elevates D the risk to development of tumors. It is linict mutated gene could be a promosing tr, 10t for therapy. So far the attempts have little value for the clinic.]