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We present evaluation of junction of coplanar external beam photon fields and its portal dosimetric analysis for breast cancer with positive lymph nodes. In our work, we compared twelve patients affected by breast cancer with axillary and supraclavicular lymph nodes, using conformal external beam plans from a dosimetric point of view. 3-3 plans were prepared per patient. Three methods were used for the conformal technique to investigate the potential of lymph nodes treatment field's collimations. During the evaluation of the portal dosimetry images, it was concluded that the junction plane at isocenter appeared as a discrete coldline, when fitted the regional field with or without collimation manually and by the software. However, the coverage of the isocenter plane is strongly influenced by the linear accelerator and the fitted field edges. Based on our results, in order to avoid uncertainties arising from field junctions and the overdosed areas of the target volume, it is more appropriate to choose another advanced irradiation technique such as intensity-modulated radiation therapy.

Introduction: Heterogenous clinical manifestations, overlapping phenotypes and complex genetic backgrounds are common in patients with endocrine tumors. There are no comprehensive recommendations for genetic testing and counselling of these patients compared to other hereditary cancer syndromes. The application of multigene panel testing is common in clinical genetic laboratories, but their performance for patients with endocrine tumors has not been assessed., Methods: As a national reference center, we prospectively tested the diagnostic utility and cost-efficiency of a multigene panel covering 113 genes representing genetic susceptibility for solid tumors. 1279 patients (including 96 cases with endocrine tumors) were evaluated between October 2021 and December 2022 who were suspected to have hereditary tumor syndromes., Results: The analytical performance of the hereditary cancer panel was suitable for diagnostic testing. Clinical diagnosis was confirmed in 24% (23/96); incidental findings in genes not associated with the patient's phenotype were identified in 5% (5/96). A further 7% of pathogenic/likely pathogenic variants were detected in genes with potential genetic susceptibility roles but currently no clear clinical consequence. Cost-benefit analysis showed that the application of a more comprehensive gene panel in a diagnostic laboratory yielded a shorter turnaround time and provided additional genetic results with the same cost and workload., Discussion: Using comprehensive multigene panel results in faster turnaround time and cost-efficiently identifies genetic alterations in hereditary endocrine tumor syndromes. Incidentally identified variants in patients with poor prognoses may serve as a potential therapeutic target in tumors where therapeutic possibilities are limited., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The pathogenic/likely pathogenic (P/LP) variant detection rate and profile of PALB2 , the third most important breast cancer gene, may vary between different populations., Methods: PALB2 was analyzed in peripheral blood samples of three independent cohorts: prospectively between September 2021 and March 2023 (i) in 1280 consecutive patients with breast and/or ovarian cancer (HBOC), (ii) in 568 patients with other cancers (controls), and retrospectively, (iii) in 191 young breast cancer (<33 years, yBC) patients. These data were compared with data of 134,187 non-cancer individuals retrieved from the Genome Aggregation Database., Results: Altogether, 235 cases (235/1280; 18.3%) carried at least one P/LP variant in one of the HBOC susceptibility genes. P/LP PALB2 variants were identified in 18 patients (1.4%; 18/1280) in the HBOC and 3 cases (1.5%; 3/191) in the yBC group. In the control group, only one patient had a disease-causing PALB2 variant (0.17%; 1/568) as a secondary finding not related to the disease, which was similar (0.15%; 205/134,187) in the non-cancer control group. The NM&#95;024675.4:c.509&#95;510delGA variant was the most common among our patients (33%; 6/18). We did not find a significant difference in the incidence of PALB2 disease-causing variants according to age; however, the median age of tumor onset was lower in PALB2 P/LP carriers versus wild-type patients (44 vs. 48 years). In our cohort, the odds ratio for breast cancer risk in women with PALB2 P/LP variants was between 8.1 and 9.3 compared to non-HBOC cancer patients and the non-cancer population, respectively., Conclusions: PALB2 P/LP variants are not uncommon among breast and/or ovarian cancer patients. Their incidence was the same in the two breast cancer cohorts studied but may occur rarely in patients with non-breast/ovarian cancer. The c.509&#95;510delGA variant is particularly common in the studied Hungarian patient population.

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is a common genetic predisposition to cancer due to germline mutations in genes affecting DNA mismatch repair. Due to mismatch repair deficiency, developing tumors are characterized by microsatellite instability (MSI-H), high frequency of expressed neoantigens and good clinical response to immune checkpoint inhibitors. Granzyme B (GrB) is the most abundant serine protease in the granules of cytotoxic T-cells and natural killer cells, mediating anti-tumor immunity. However, recent results confirm a diverse range of physiological functions of GrB including that in extracellular matrix remodelling, inflammation and fibrosis. In the present study, our aim was to investigate whether a frequent genetic variation of GZMB , the gene encoding GrB, constituted by three missense single nucleotide polymorphisms (rs2236338, rs11539752 and rs8192917) has any association with cancer risk in individuals with LS. In silico analysis and genotype calls from whole exome sequencing data in the Hungarian population confirmed that these SNPs are closely linked. Genotyping results of rs8192917 on a cohort of 145 individuals with LS demonstrated an association of the CC genotype with lower cancer risk. In silico prediction proposed likely GrB cleavage sites in a high proportion of shared neontigens in MSI-H tumors. Our results propose the CC genotype of rs8192917 as a potential disease-modifying genetic factor in LS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Grolmusz, Nagy, Likó, Butz, Pócza, Bozsik, Papp, Oláh and Patócs.)

Due to the profound difference in radiosensitivity of patients and various side effects caused by this phenomenon, a radiosensitivity marker is needed. Prediction by a marker may help personalise the treatment. In this study, we tested chromosomal aberrations (CA) of in vitro irradiated blood as predictor of pulmonary function decrease of nonsmall cell lung cancer (NSCLC) patients and also compared it with the CAs in the blood of irradiated patients. Peripheral blood samples were taken from 45 lung cancer patients before stereotactic radiotherapy (SBRT) and immediately after the last fraction and 3, 6, 9, 12, 15, 18, 21, and 24 months later. Respiratory function measurements were performed at the same time. Diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1s), and FEV1s/FVC (FEV1%) were monitored. Metaphase preparations of lymphocytes were made with standard procedures, and chromosome aberrations were analysed. In our cohort, the 36-month local relapse-free survival was 97.4%, and the distant metastasis-free survival was 71.5% at 36 months. There was no change in the mean of the pulmonary function tests (PFTs) after the therapy. However, there was a considerable variability between the patients. Therefore, we subtracted the baseline and normalised the PFT values. There were significant decreases at 12-24 months in relative FEV1s and relative FEV1%. The tendentious decrease of the PFTs could be predicted by the in vitro chromosome aberration data. We also found connections between the in vitro and in vivo CA values (i.e., dicentrics plus rings after 3 Gy irradiation predicts dicentric-plus-ring value directly after the radiotherapy/V 54 Gy ( p  = 0.001 24.2%)). We found that-after further validation-chromosome aberrations resulted from in vitro irradiation before radiotherapy can be a predictive marker of pulmonary function decrease after lung irradiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kocsis, Farkas, Bajcsay, Kun-Gazda, Lövey, Ostoros, Pócza, Herein, Ladányi, Székely, Markóczy, Takácsi-Nagy, Polgár and Juranyi.)

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pócza, Grolmusz, Papp, Butz, Patócs and Bozsik.)

In treatment planning of small-sized lung tumors treated with stereotactic body radiotherapy (SBRT) in Eclipse treatment planning system with the Normal tissue objective (NTO) tool sharp dose gradients beyond the target volume can be achived. NTO has 5 variable parameters, so it is difficult to know which settings are optimal. The purpose of this study was to characterize the effects of changing NTO parameters on lung SBRT dose distributions. Ten lung SBRT cases were replanned using different NTO parameters. Dose calculation was performed using AAA and AXB algorithms as well. Differences between AAA and AXB plans were statistically significant. Plans were evaluated based on plan quality metrics. According to this analysis the fall-off of 0.15 and the priority of 500 have satisfied our institutional criteria best. Using NTO during planning is recommended in clinical practice.

Flattening filter free mode (FFF) has been introduced in radiotherapy during the past decades, however, not much has been reported on its radiobiological effect. The purpose of our study was to compare the radiobiological effects of flattening filter and flattening filter free photon beams on chromosomal aberrations in peripheral blood lymphocytes. In our study the blood of the same healthy donor was irradiated with linear accelerator using both conventional flattening filter (FF) and FFF photon beams at dose rate of 3.57-23.08 Gy/min, using 6 or 10 MV. The dose-response calibration curves for dicentric + ring chromosomes induced by irradiation were fitted with linear-quadratic model. CABAS (Chromosomal Aberration Calculation Software) was used to prepare the curves. The coefficients and equations of the curves were calculated and compared with the results of other authors. We found significant differences in the number of aberrations at different irradiation parameters. Based on our results, FFF mode has a 10-20% higher biological effect than FF mode. These results can be used during radiotherapy or to estimate the biological doses in case of an accidental exposure to radiation.

The aim of the study was to compare the different stereotactic treatment plans and dose calculation algorithms for small targets with film dosimetry in anthropomorphic phantom. Treatment plans were prepared for multiple targets with single setup isocenter. Plans for three different irradiation techniques were generated using conformal arc with four non-coplanar arcs, RapidArc with two coplanar full arcs and RapidArc with four non-coplanar arcs in the Varian Eclipse v13.7.16 TPS. Conformal arc and RapidArc plans were calculated using AAA, Acuros XBDm and XBDw algorithms. Conformity index, gradient index and dose maximum were calculated for all PTVs. All measurements were made on the Varian TrueBeam linear accelerator. Comparison between computed and measured dose distributions was performed with gamma evaluation criteria of 3%, 3 mm; 3%, 1 mm and 2%, 2 mm. According to our results, the Eclipse AAA and AXB algorithms provide accurate dose distributions for homogeneous cranial irradiation.

The clinical relevance of the BRCA2 C-terminal stop codon variants is controversial. The pathogenic role of the germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent probands diagnosed with HBOC and in 122,209 cancer patients reported earlier. Loss-of-heterozygosity (LOH) in tumor samples and allelic imbalance in RNA extracted from peripheral blood cells were investigated. Neither c.10095delinsGAATTATATCT or c.9976A>T variants showed significant association with clinicopathological parameters or elevated risk for HBOC-associated tumors. Lung cancer was more prevalent in families carrying the c.9976A>T variant compared to pathogenic BRCA1 or BRCA2 carrier families. An increased prevalence of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. An increased risk for familial pancreatic, lung and upper aero-digestive tract cancers was confirmed in the validation set. Regarding BRCA2 C-terminal variants, no linkage with other pathogenic BRCA2 variants, no LOH in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort.

Lung cancer is known for its outstanding incidence and mortality rates. One of the cornerstones of the treatment of this disease is radiation therapy. A remarkable development was observed in this field through the latest decades. Intensity-modulated and image-guided radiotherapy (IMRT and IGRT) are now widely accessible in Hungarian centers, and should be increasingly applied in case of thoracic irradiations as well. Application of modern radiotherapy techniques in the treatment of lung cancer allows better clinical results and lower rates of side effects. In this work the authors give an overview of this above mentioned development regarding different clinical stages.

Introduction The purpose of the study was to compare the results of gamma value based film analysis according to the used type of self-developer film and software product. Material and methods The films were irradiated with different treatment techniques such as 3D conformal and intensity modulated radiotherapy with static and rotational delivery. Stereotactic plans with conformal and intensity modulated arc techniques, using coplanar and non-coplanar beam setup were also evaluated. The data of irradiated film were compared with the planned planar dose distribution exported from the treatment planning system. Three film analysis software programs were evaluated: PTW Mephysto (PTW), FilmQA Pro (FQP) and radiohromic.com(RC). Both EBT2 and EBT3 types of films were examined. The comparisons of dose distributions were performed with gamma analysis using 10% cut-off level. Results The results of the gamma analysis for larger fields were between 78.3% and 98.3%, 75.7% and 100%, 80.2% and 98.8% with PTW, FQP and RC, respectively. The results of evaluation in case of stereotactic measurements were 76.8%-99.2% for PTW, 95.7%-100% for FQP and 91.2%-99.9% for RC. Conclusions All the three software programs are suitable for calibrating and evaluating films, performing gamma analysis, and can be used for patient specific quality assurance measurements. There is no direct connection between gamma passing rate and absolute accuracy or software quality, it is just a feature of the software. The interpretation of own results has to be defined on an institutional level according to given workflow and preliminary results.

Large genomic rearrangements (LGRs) affecting one or more exons of BRCA1 and BRCA2 constitute a significant part of the mutation spectrum of these genes. Since 2004, the National Institute of Oncology, Hungary, has been involved in screening for LGRs of breast or ovarian cancer families enrolled for genetic testing. LGRs were detected by multiplex ligation probe amplification method, or next-generation sequencing. Where it was possible, transcript-level characterization of LGRs was performed. Phenotype data were collected and analyzed too. Altogether 28 different types of LGRs in 51 probands were detected. Sixteen LGRs were novel. Forty-nine cases were deletions or duplications in BRCA1 and two affected BRCA2 . Rearrangements accounted for 10% of the BRCA1 mutations. Three exon copy gains, two complex rearrangements, and 23 exon losses were characterized by exact breakpoint determinations. The inferred mechanisms for LGR formation were mainly end-joining repairs utilizing short direct homologies. Comparing phenotype features of the LGR-carriers to that of the non-LGR BRCA1 mutation carriers, revealed no significant differences. Our study is the largest comprehensive report of LGRs of BRCA1/2 in familial breast and ovarian cancer patients in the Middle and Eastern European region. Our data add novel insights to genetic interpretation associated to the LGRs., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases., Competing Interests: The authors declare no conflict of interest.

The aim of this study was to investigate the radiobiological effects of flattening filter (FF) and flattening filter-free (FFF) modes of linear electron accelerators and to understand whether there is any difference between the effects of these modes. We evaluated the number of chromosome aberrations following irradiation of lymphocytes from healthy volunteers with X-ray photons at two energy levels, 6 and 10 MV; the dose rate ranged between 5.50 and 23.08 Gy/min and absorbed doses ranged between 0.5 and 8 Gy. A 60Co curve was employed for comparison. Metaphases from the lymphocyte cultures were prepared using standard cytogenetic techniques and chromosome analysis was performed. Our results allow the performance of biodosimetry at higher energies and doses than the currently used reference dosimetry. We observed significant differences in aberration frequencies when different irradiation techniques were used. FFF mode has a higher radiobiological effect than the FF mode. Linear-quadratic dose response calibration curves were constructed and relative biological effectiveness (RBE) values were calculated. Average RBE values using 6 MV (5.50 Gy/min) as a reference radiation were 1.28 for 60Co γ irradiation, 1.11 for 6 FFF and 0.79-0.92 for 10 FFF. Since there are compelling differences between radiation modalities in cases of hypofractionation, these results may be even more important in a therapeutic situation. In case of an accidental overdose of a patient, use of the appropriate calibration curves for biodosimetry are also essential for quantifying the overdose., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Aim: The aim of this study was to investigate normal tissue sparing through dosimetric parameters of normal tissue volumes using different irradiation techniques for conventional (CFRT) and simultaneously integrated boost (SIB) schedules., Background: Several dose-escalation studies for localized prostate cancer (PCa) have shown advanced biochemical relapse-free (bRFS) rates and also better local control for higher total doses using either CFRT or SIB schedules. Besides the most important organs-at-risk, absorbed dose reduction of other surrounding normal tissues are also preferable. In order to analyse the normal tissue sparing, dosimetric parameters of different normal tissue volumes were examined., Materials and Methods: Treatment plans for 15 high risk prostate cancer patients were created using RapidArc (RA), Sliding Window (SW) IMRT and 4-field box (3D-CRT) technique. In order to evaluate normal tissue sparing, the volume of pelvic region was divided into six normal tissue cylinders with 1 cm wall thickness, located in each other., Results: All plans met the criteria of target coverage (V95%>95%). All techniques provided the same results for OARs except 3D-CRT for rectum and bilateral femoral heads. The values of V5, V10 and V15 increased in cases which included RapidArc technique and decreased for V20 and V30., Conclusions: The dosimetric parameters for the cylindrical normal tissue volumes show that using RapidArc technique gives equal or slightly better normal tissue sparing and SIB provided the same normal tissue sparing as CFRT planned with RapidArc., (© 2019 Greater Poland Cancer Centre. Published by Elsevier B.V. All rights reserved.)

In this paper we present our early experience with a method for the management of respiratory motion in radiotherapy for early-stage lung cancer. Forty-six patients were irradiated with a total dose of 60 Gy. Tumor response on control CT, survival, local and distant progression as well as early and late side effects were registered. Complete and partial remission, stable and progressive disease was 17 (37.0%), 15 (32.6%), 11 (23.9%) and 3 (6.5%). Isolated local recurrence and distant metastasis appeared in 4 (8.7%) and 2 (4.3%) cases, while simultaneous local and distant progression was diagnosed in 3 (6.5%) patients. The probability of 2-year local recurrence-free, progression-free, and overall survival was 76.8%, 64.0%, and 83.2%. Grade 1 (G1) and G2 early side effects occurred at 15 (32.6%) and 3 (6.5%) patients without ≥G3 side effects. G1 and G2 late side effects were observed in 10 (21.7%) and 7 (15.2%) cases. G1-2 post-irradiation fibrosis occurred in 11 (23.9%) cases. Twenty months after the irradiation, G5 respiration failure was developed in one patient. The implemented technique of respiratory motion management for the radiotherapy of early-stage lung cancer resulted in promising local freedom from relapse and survival with favorable side effect profile. Further follow-up is needed to assess longterm side effects and survival results.

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner., Methods: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival., Findings: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084)., Interpretation: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection., Funding: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Epigenetic alterations have been implicated in cancer development. DNA methylation modulates gene expression, which is catalyzed by DNA methyltransferases (DNMTs). The objective of our study was to evaluate expression of DNMTs in medulloblastoma and analyze its correlation with clinical features. Nuclear expression of DNMT1, DNMT3A and DNMT3B was analyzed in human primary medulloblastoma of 44 patients using immunohistochemistry. Correlation of expression of DNMT levels with classical histological subtypes, novel molecular subgroups and survival of patients was analyzed. Elevated expression of DNMT1, DNMT3A and DNMT3B was observed in 63.64%, 68.18% and 72.73% of all cases, respectively. None of them showed a correlation with classical histology or survival. Concerning molecular subtypes, significantly higher expression of DNMT1 was observed in the SHH group compared to non-SHH samples (p = 0.02), but without significant difference in DNMT3A or DNMT3B levels between any subtypes. In conclusion, DNMT1, DNMT3A and DNMT3B are highly expressed in human medulloblastoma samples, suggesting that promoter hypermethylation may play a role in medulloblastoma development. Demethylation of tumor suppressor gene promoters may be considered as a possible future target in therapy of medulloblastoma.

The aim of our work is to present the imaging techniques used at the National Institute of Oncology for taking into consideration the breathing motion at radiation therapy treatment planning. Internationally recommended imaging techniques, such as 4D CT, respiratory gating and ITV (Internal Target Volume) definition were examined. The different imaging techniques were analysed regarding the delivered dose during imaging, the required time to adapt the technique, and the necessary equipment. The differences in size of PTVs (Planning Target Volume) due to diverse volume defining methods were compared in 5 cases. For 4D CT breath monitoring is crucial, which requires special equipment. To decrease the relatively high exposure of 4D CT it is possible to scan only a few predefined breathing phases. The possible positions of the tumour can be well approximated with CT scans taken in the inhale maximum, the exhale maximum and in intermediate phase. The intermediate phase can be exchanged with an ordinary CT image set, and the extreme phase CT images can be ensured by given verbal instructions for the patient. This way special gating equipment is not required. Based on these 3 breathing phases an ITV can be defined. Using this ITV definition method the margin between the CTV (Clinical Target Volume) and the PTV can be reduced by 1 cm. Using this imaging protocol PTV can be reduced by 30%. A further 10% PTV reduction can be achieved with respiratory gating. In the routine clinical practice respiratory motion management with a 3-phase CT-imaging protocol the PTV for early-stage lung cancer can be significantly reduced without the use of 4D CT and/or respiratory gating. For special, high precision treatment techniques 4D CT is recommended.

As mammalian Target of Rapamycin (mTOR) plays role in protein synthesis and metabolism, mTOR pathway activation is involved in the pathogenesis of several types of tumors. Our aim was to elucidate its role in medulloblastoma in terms of prognosis and as a therapeutic target. Members of activated mTOR complex 1 (mTORC1) pathway, phospho-mTOR (p-mTOR) and phospho-S6 (p-S6) were examined by immunohistochemistry in formalin fixed paraffin embedded samples of 40 patients with medulloblastoma, and results were compared to clinical features and survival of patients. In proliferation assays, Daoy and UW228-2 medulloblastoma cell lines were tested by rapamycin, an mTORC1 inhibitor, and NVP-BEZ235, a dual mTOR and phosphatidylinositol 3-kinase (PI3K) inhibitor, each in monotherapy and in combination with cytostatic drugs (cisplatin, etoposide). Components of mTORC1 and mTORC2 complexes were also examined in these cell lines. Neither presence of p-mTOR (32.5 %) nor p-S6 (32.5 %) correlated with age, gender or histological subtype. In 22.5 % of cases simultaneous expression of p-mTOR and p-S6 was shown. Kaplan-Meier analysis showed inferior survival of patients expressing both marker proteins, but it was not statistically significant, probably due to low case number. UW228-2 cells had greater sensitivity to mTOR inhibitors, possibly due to its higher mTORC1 specific protein expression levels, compared to Daoy cells. In both cell lines antiproliferative effect of cytostatic drugs was significantly enhanced by mTOR inhibitors (p < 0.05). Based on our in vitro and clinicopathological studies mTOR inhibitors may have a role in the future treatment of a subset of patients with medulloblastoma.

In Hungary a new oral antiangiogenic treatment was introduced in cases of primary chemoresistant or recurrent pediatric CNS tumors, called Kieran schedule. The early results of this treatment were analyzed. From 2010 at Semmelweis University on individual decisions a daily combined per oral treatment was introduced in pediatric patients with recurrent or progressive CNS tumor (Kieran schedule: thalidomid, celecoxib, etoposid and cyclophosphamid). Efficacy of therapy was analyzed in terms of demographic data, histology, side effects and tolerability in a retrospective manner. From 2010 through 2013, twenty patients were treated with Kieran schedule (medulloblastoma: 3, ependymoma: 5, anaplastic astrocytoma: 2, GBM: 4, plexus choroideus carcinoma: 1, central primitive neuroectodermal tumor: 1, optic glioma: 2, brainstem tumor: 2). Median treatment time and median progression-free survival were 0.60 and 0.61 years, respectively. Based on the preliminary analysis of a limited cohort of patients, the therapy was efficient in those cases of medulloblastoma, ependymoma, high-grade and optic gliomas, where the expected survival time was more than 3 months at start of treatment. Side effects were slight myelosuppresion in terms of previous therapy, 16% transient ischemic attack (TIA)-like episodes. During therapy patients could live their everyday life. Kieran schedule was well-tolerable and efficient with good quality of life in certain cases of pediatric CNS tumors.

Activation-induced cell death (AICD) is initiated by T-cell receptor (TCR) restimulation of already activated and expanded peripheral T cells and is mediated through Fas/Fas ligand (FasL) interactions. Adenosine is a purine nucleoside signaling molecule, and its immunomodulatory effects are mediated by 4 G-protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In this study, we investigated the role of A(2A) receptors in regulating CD4(+) T lymphocyte AICD. Our results showed that the selective A(2A) receptor agonist CGS21680 (EC(50)=15.2-32.6 nM) rescued mouse CD4(+) hybridomas and human Jurkat cells from AICD and that this effect was reversed by the selective A(2A) receptor antagonist ZM241385 (EC(50)=2.3 nM). CGS21680 decreased phosphatidylserine exposure on the membrane, as well as the cleavage of caspase-3, caspase-8 and poly(ADP-ribose) polymerase indicating that A(2A) receptor stimulation blocks the extrinsic apoptotic pathway. In addition, CGS21680 attenuated both Fas and FasL mRNA expression. This decrease in FasL expression was associated with decreased activation of the transcription factor systems NF-kappaB, NF-ATp, early growth response (Egr)-1, and Egr-3. The antiapoptotic effect of A(2A) receptor stimulation was mediated by protein kinase A. Together, these results demonstrate that A(2A) receptor activation suppresses the AICD of peripheral T cells.