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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.]

Clinical Neuroscience

SEPTEMBER 30, 2020

[Prognostic significance of invasion in glioblastoma]


[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

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

[Practical use of meta-analyses in predicting disease risk, outcome, and therapy response in breast cancer]

KAHÁN Zsuzsanna, TARI Gergely, ENYEDI Márton, HARACSKA Lajos

[Germinal BRCA status infl uences patient care both in early and advanced/metastatic breast cancer. Ideally, the patient should make the decision on the type of surgery or the avoidance of radiotherapy being aware of the BRCA status; based on the most recent clinical studies, this knowledge may infl uence the type of chemotherapy in the neoadjuvant, adjuvant, or metastatic setting or may raise the use of emerging targeted therapies. DNA-targeting cytostatic agents, mostly platinum agents and PARP inhibitors that act by inducing synthetic lethality, provide specifi c therapies in BRCA-mutant cases. The optimum place and sequence of these specifi c agents in treatment, however, are not known yet. International guidelines promote BRCA testing for the specifi cation of treatment strategy in all HER2-negative advanced/metastatic breast cancer cases (NCCN) or at least in all cases when, based on certain predictors, the presence of mutations is likely (ESMO). Recently, the methods employed for BRCA testing have improved immensely and are widely available through the services of various providers. For the identifi cation of the mutation, sequencing of the whole genes is needed, which can be achieved faster and more cost-effi ciently using next-generation sequencing (NGS) platforms compared to previous methods. It is the responsibility of the physician to consider the possibility of BRCA mutations and to raise the issue of BRCA testing to the patient if the family history, the age, previous malignant disease(s) of the patient, or the cancer features are suggestive of genetic risk.]

Clinical Oncology

FEBRUARY 20, 2019

[Liquid biopsy in clinical oncology – fine-tuning precision medicine]

PRISKIN Katalin, PINTÉR Lajos, JAKSA Gábor, PÓLYA Sára, KAHÁN Zsuzsa, SÜKÖSD Farkas, HARACSKA Lajos

[The classical method of genetically characterising a tumour requires tissue biopsy with which a small sample is removed from the affected organ. This sample represents the tumour in the further analyses. However, the localised nature of sample collection limits representative characterisation. The so-called circulating tumour DNA, isolated from blood plasma after a simple sample collection, potentially enables the oncological analysis of all tumour tissues carrying genetic alterations that can be identifi ed as markers. In order to maximally exploit the potentials of circulating tumour DNA, we must adjust the analytical tools to its specifi c features. The preanalytical handling and storage of the sample signifi cantly infl uences its further usability. In order to be able to detect a potential mutation in a mostly wild-type background, the development of new, specifi c methods is needed, most of which are based on next-generation sequencing techniques. In the past decades, the pronounced decrease in the costs of such techniques led to an accumulation of an immense amount of genetic information on tumorigenesis. Due to the development of sequencing technologies, the turnaround times of tests also decreased enabling their employment in routine care besides research. Starting from our research, this can be realised via three approaches: technological development, the implementation of our already existing diagnostic methods in liquid biopsy, and the construction of well-planned disease-specifi c gene panels. Based on international trends and our experience in serum diagnostics, we are certain that liquid biopsy will become a central pillar of oncological screening and precision oncology in the near future.]

Clinical Neuroscience

JULY 30, 2019

Cerebral cavernous malformation type 1 with retinal blood vessel tortuosity and KRIT1 gene mutation

KALMÁR Tibor, MARÓTI Zoltán, VADVÁRI Árpád, HALMOSI Ágnes, KÁLOVITS Ferenc, KÁLMÁN Bernadette

Cerebral cavernous malformations (CCMs) represent a relatively rare and heterogeneous clinical entity with mutations identified in three genes. Both sporadic and familial forms have been reported. We present a young female patient with episodic paresthesia and headaches, but without acute neurological deficits. Her mother had a hemorrhaged cavernoma surgically removed 21 years ago. Cranial magnetic resonance imaging revealed multiple cavernous malformations in the size of a few millimeters and the ophthalmologic exam detected retinal blood vessel tortuosity in the proband. Targeted exome sequencing analysis identified a nonsense mutation in exon 16 of the KRIT1 gene, which resulted in a premature stop codon and a truncated protein underlying the abnormal development of cerebral and retinal blood vessels. This mutation with pathogenic significance has been reported before. Our case points to the importance of a thorough clinical and molecular work up despite the uncertain neurological complaints, since life style recommendations, imaging monitoring and genetic counseling may have major significance in the long term health of the patient.

Clinical Neuroscience

JANUARY 30, 2019

[Multiple ischemic stroke in Osler-Rendu-Weber disease]

SALAMON András, FARAGÓ Péter, NÉMETH Viola Luca, SZÉPFALUSI Noémi, HORVÁTH Emese, VASS Andrea, BERECZKY Zsuzsanna, TAJTI János, VÉCSEI László, KLIVÉNYI Péter, ZÁDORI Dénes

[Hereditary hemorrhagic teleangiectasia (HHT, Osler-Rendu-Weber disease) is an autosomal dominantly inherited disorder caused by the mutation of several possible genes and characterized by malformations of the arteriovenous system in multiple organs. The clinical diagnosis is based on the Curaçao criteria ((1) spontaneous, recurrent epistaxis; (2) teleangiectasias in characteristic sites (lips, oral cavity, nose, fingers); (3) visceral lesions (gastrointestinal, pulmonary, cerebral, spinal); (4) affected first degree relative). The aim of this study is to present the first genetically confirmed Hungarian case of hereditary hemorrhagic teleangiectasia with multiple ischemic strokes. Our 70-year-old woman has been suffering from severe epistaxis since her childhood and presented gastrointestinal bleeding during her adulthood as well. The characteristic skin lesions developed in the 5th decade of life. She was admitted to our department with loss of consciousness and fluctuating speech and swallowing problems. MRI of the brain supplemented with angiography revealed multiple arteriovenous malformations and multiple subacute ischemic lesions. The EEG demonstrated slowing of electric activity in the left frontal lobe. The neuropsychological assessment showed deficits in anterograde memory and executive functions. The diagnostic work-up for other characteristic alterations identified an arteriovenous malformation in the left lung. The genetic analysis demonstrated a heterozygous mutation in the 7th exon of the ENG gene at position 834 resulting in a thymine duplication and an early stop codon by a frame shift. The present case is largely similar to those already described in literature and draws the attention to the importance of multidisciplinary collaboration in the care of HHT patients.]

Lege Artis Medicinae

JUNE 20, 2018

[Treatment of EGFR mutant lung adenocarcinoma after progression]

BOGOS Krisztina

[Precision medicine proposes the personalization of health services in order to make the best individual decisions about the interventions and treatments for the patient. Molecular genetic diagnostic tests help to select the appropriate therapy, so-called targeted therapy. In the case of extensive lung cancer with EGFR mutation, EGFR tyrosine kinase inhibitors are immediately applicable; they are very effective and can reach long-term remission of the disease. However, resistance mutation can develop during the treatment, which causes the progression of the disease; therefore change of therapy is needed. In our case, we show the possibility of targeted treatment beyond the progression, emphasizing the importance of detecting resistance mutation. ]

Clinical Oncology

DECEMBER 10, 2016

[Defi ciency of DNA-repair]


[The cell uses the DNA to keep those information, which are vital to function properly. It is essential to maintain the integrity of the DNA, the stability of the genome. Since DNA damages, caused by external or internal factors, are continuously produced, DNA-repair mechanisms should be ready to identify and eliminate the damages. Either the repair system is successful and the cell can continue its duty, or, if the damages are unrepaired, the programed cell death (apoptosis) is activated according to the rule, that it is prohibited to transfer genomic/epigenomic damages into the daughter cells. It is true that the severness of the damages are not the same. The most important is the identifi cation and repair of those damages which can make genomic instability increasing the risk of cancer development. This may happen when the repair system is insuffi cient, sometimes due to inherited mutations (e.g. BRCA1 mutations can increase the risk of breast cancer, ovarian cancer etc.). Among the damages the DNA double strand breaks are rather common, and also, that the breaks are intended to be repaired in most cases. However, if such repair fails, the cell, here the cancer cell, due to the overhelming damages will dye. This phenomenon is the synthetic lethality. An example: „cooperation” of inherited BRCA1 mutation and PARP-inhibition, can lead to clinical response using PARP inhibitors, as oliparib. New agents and clinical trials intend to take advantage from synthetic lethality.]