Miklós Garami

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Papers by Miklós Garami

Chemotherapy of Medulloblastoma in Children

InTech eBooks, Aug 23, 2011

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Mechanical Strain Increases Expression of the Brain Natriuretic Peptide Gene in Rat Cardiac Myocytes

Journal of Biological Chemistry, Oct 1, 1997

Using a device that applies cyclical strain (1 Hz) to ventricular cardiocytes cultured on collage... more Using a device that applies cyclical strain (1 Hz) to ventricular cardiocytes cultured on collagen-coated silicone elastomer surfaces, we have demonstrated straindependent increases in brain natriuretic peptide (BNP) secretion, BNP mRNA levels, and expression of a transiently transfected ؊1595 human BNP-luciferase reporter. When actinomycin D (10 M) was introduced concomitantly with the strain stimulus, the strain-induced increase in BNP mRNA was eliminated, and the decay of transcripts was identical in the control and strained cells, indicating the lack of independent effects on transcript stability. Strain-dependent ؊1595 human BNPluciferase activity was completely inhibited by chelerythrine, 2-aminopurine, genistein, and W-7 and only partially or not at all by KN-62, wortmannin, and H-89. The effects of these individual agents paralleled their effects on mitogen-activated protein kinase (MAPK) activity, but not c-Jun N-terminal kinase (JNK) activity, in the cells. Overexpression of wild-type MAPK and, to a lesser extent, JNK increased strain-dependent BNP promoter activity, whereas dominant-negative mutants of MAPK kinase, JNK kinase, or Ras completely blocked strain-dependent reporter activity. These findings provide the first demonstration that mechanical strain can increase myocardial gene expression through a transcriptional mechanism and suggest important roles for MAPK and JNK in mediating this effect.

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Supplementary Data from Genetic Aberrations Leading to MAPK Pathway Activation Mediate Oncogene-Induced Senescence in Sporadic Pilocytic Astrocytomas

Supplementary Figures S1-S3; Supplementary Tables S1-S2.

Data from Genetic Aberrations Leading to MAPK Pathway Activation Mediate Oncogene-Induced Senescence in Sporadic Pilocytic Astrocytomas

Purpose: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS)... more Purpose: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. Experimental Design: We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600Emutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. Results: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic b-galactosidase activity, low KI-67 index, and induction of p16 INK4a but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16 INK4a in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16 INK4a pathway induction following aberrant MAPK activation. Conclusions: OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas,andthe highoverall survival ofaffected patients.Clin CancerRes; 17(14); 4650-60.'2011 AACR.

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Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review

Pharmaceutics, Jan 10, 2023

Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets... more Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing unknown risks of toxicity. The therapeutic drug monitoring (TDM) of OACDs in therapeutically relevant peripheral fluid compartments is therefore essential. In this work, the available knowledge regarding exposure to OACD concentrations in these fluid spaces is summarized. A review of the literature was conducted by searching Embase, PubMed, and Web of Science for clinical research articles and case reports published between 10 May 2001 and 31 August 2022. Results show that, to date, penetration into cerebrospinal fluid has been studied especially intensively, in addition to breast milk, leukocytes, peripheral blood mononuclear cells, peritoneal fluid, pleural fluid, saliva and semen. The typical clinical indications of peripheral fluid TDM of OACDs were (1) primary malignancy, (2) secondary malignancy, (3) mental disorder, and (4) the assessment of toxicity. Liquid chromatography-tandem mass spectrometry was most commonly applied for analysis. The TDM of OACDs in therapeutically relevant peripheral fluid spaces is often indispensable for efficient and safe treatments.

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MPTH-09MOLECULAR Markers and Their Prognostic Impact in Pediatric Ependymomas

Neuro-oncology, Nov 1, 2015

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Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

Hypertension, Dec 1, 1999

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Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma

Scientific Reports, Jul 21, 2023

Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, w... more Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients' CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients' age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects. ALDH Aldehyde dehydrogenase ALT Alanine aminotransferase CPIC Clinical Pharmacogenetics Implementation Consortium GGT Gamma-glutamyltransferase CTC Common toxicity criteria CYP Cytochrome P450 INRC International Neuroblastoma Response Criteria INSS International Neuroblastoma Staging System PharmVar Pharmacogene Variation Consortium MYCN V-Myc myelocytomatosis viral related oncogene, neuroblastoma derived SNV Single nucleotide variation Neuroblastoma is one of the most prevalent solid organ malignancies in infants and young children, mainly under 5 years of age (6% of all childhood cancers), and its incidence rates vary between 3 and 15 per million children 1,2 .

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$Research paper thumbnail of Long-term survival and cure fraction estimates for childhood cancer in Europe (EUROCARE-6): results from a population-based study$

Long-term survival and cure fraction estimates for childhood cancer in Europe (EUROCARE-6): results from a population-based study

The Lancet Oncology

Real-world performance analysis of a novel computational method in the precision oncology of pediatric tumors

World Journal of Pediatrics

Background The utility of routine extensive molecular profiling of pediatric tumors is a matter o... more Background The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods. Digital drug assignment (DDA) is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers, targets, and targeted agents. DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial. The aim of this study was to evaluate the utility of DDA in pediatric oncology. Methods Between 2017 and 2020, 103 high-risk pediatric cancer patients (< 21 years) were involved in our precision oncology program, and samples from 100 patients were eligible for further analysis. Tissue or blood samples were analyzed by whole-exome (WES) or targeted panel sequencing and other m...

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Germline MUTYH mutations and high‐grade gliomas: Novel evidence for a potential association

Genes, Chromosomes and Cancer

There is growing body of evidence supporting the role of germline mutations in the pathogenesis o... more There is growing body of evidence supporting the role of germline mutations in the pathogenesis of pediatric central nervous system (CNS) tumors, and the widespread use of next‐generation sequencing (NGS) panels facilitates their detection. Variants of the MUTYH gene are increasingly recognized as suspected germline background of various extraintestinal malignancies, besides their well‐characterized role in the polyposis syndrome associated with biallelic mutations. Using a multigene NGS panel (Illumina TruSight Oncology 500), we detected one H3 G34V‐ and one H3 K27M‐mutant pediatric high‐grade diffuse glioma, in association with c.1178G>A (p.G393D) and c.916C>T (p.R306C) MUTYH variants, respectively. Both MUTYH mutations were germline, heterozygous and inherited, according to the subsequent genetic testing of the patients and their first‐degree relatives. In the H3 K27M‐mutant glioma, amplifications affecting the 4q12 region were also detected, in association with KDR‐PDGFRA,...

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

Neuro-Oncology, 2021

Background Only few data are available on treatment-associated behavior of distinct rare CNS embr... more Background Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. Methods Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. Results DNA methylation profiling of “CNS-PNET” classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 ot...

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Prognostic factors in stage 4 neuroblastoma treated with busulphan-melphalan: Report from the European HR-NBL1/Siopen trial

Journal of Clinical Oncology, 2016

10527Background: Evaluation of prognostic factors in high risk stage 4 neuroblastoma (HRNBL) pati... more

A longevity study with enhancer substances (selegiline, BPAP) detected an unknown tumor-manifestation-suppressing regulation in rat brain

Life Sciences, 2017

Aims: First proof to show that (−)‐deprenyl/selegiline (DEP), the first selective inhibitor of MA... more Aims: First proof to show that (−)‐deprenyl/selegiline (DEP), the first selective inhibitor of MAO‐B, later identified as the first &bgr;‐phenylethylamine (PEA)‐derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)‐1‐(1‐benzofuran‐2‐yl)‐N‐propylpentane‐2‐amine (BPAP), the tryptamine‐derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer‐sensitive brain regulations. Main methods: Longevity study disclosing the operation of tumor‐manifestation‐suppressing (TMS) regulation in rat brain. Immonohistochemical identification of a fibromyxosarcoma in rats. Experiments with human medulloblastoma cell lines. Analysis of the mechanism of action of enhancer substances. Key findings: Whereas 20/40 saline‐treated rats manifested a fibromyxosarcoma, in groups of rats treated with 0.001 mg/kg DEP: 15/40 rats; with 0.1 mg/kg DEP: 11/40 rats (P < 0.01); with 0.0001 mg/kg BPAP: 8/40 rats (P < 0.001); with 0.05 mg/kg BPAP: 7/40 rats (P < 0.01) manifested the tumor. Experiments with human medulloblastoma cell lines, HTB‐186 (Daoy); UW‐228‐2, showed that BPAP was devoid of direct cytotoxic effect on tumor cells, and did not alter the direct cytotoxic effectiveness of temozolomide, cisplatin, etoposide, or vincristine. Interaction with distinct sites on vesicular monoamine‐transporter‐2 (VMAT2) is the main mechanism of action of the enhancer substances which clarifies the highly characteristic bi‐modal, bell‐shaped concentration‐effect curves of DEP and BPAP. Significance: Considering of the safeness of the enhancer substances and the finding that DEP and BPAP, specific markers of unknown enhancer sensitive brain regulations, detected the operation of an enhancer‐sensitive TMS‐regulation in rat brain, it seems reasonable to test in humans low dose DEP or BPAP treatment against the spreading of a malignant tumor.

$Research paper thumbnail of Randomized phase II study of carboplatin and irinotecan or irinotecan in 1–21 year old patients with refractory solid tumors$

Randomized phase II study of carboplatin and irinotecan or irinotecan in 1–21 year old patients with refractory solid tumors

Journal of Clinical Oncology, 2004

8559 Background: Carboplatin and irinotecan have been shown to be active in pediatric tumors. MET... more 8559 Background: Carboplatin and irinotecan have been shown to be active in pediatric tumors. METHODS The primary objective of this non-comparative, randomized study is to estimate the response rate of carboplatin AUC 4 mg/ml*min every 21 days in combination with irinotecan 12 mg/m2/day daily × 10 days every 21 days, with growth factor support (Arm A), and irinotecan 20 mg/m2/day daily × 10 days every 21 days(Arm B) in children with refractory solid tumors. The Arm A dose and schedule were determined by a prior phase I study (2003 AACR abst. #3567). One hundred and fifty-one patients were randomized and stratified by site of the primary tumor (non-CNS or CNS) and 148 were treated- 46 non-CNS and 28 CNS on Arm A, and 47 non-CNS and 27 CNS on Arm B. Non-CNS tumor types included osteosarcoma 19 (20%), rhabdomyosarcoma (RMS) 16 (17%), neuroblastoma 15 (16%), Wilm's tumor 12 (13%), sarcomas 9 (10%), retinoblastoma 5 (5%), Ewing's sarcoma 3 (3%), and others 15 (16%). CNS tumor types included gliomas (all grades) 24 (44%), medulloblastoma 10 (18%), ependymoma 9 (16%), and others 11 (20%). RESULTS Grade 3-4 non-hematologic toxicities in Arm A and B included infection/febrile neutropenia in 45% and 35% of patients, diarrhea in 41% and 42%, vomiting in 35% and 35%, abdominal pain/cramping in 23% and 18%, and nausea in 14% and 23%, respectively. Additional grade 3-4 non-hematologic toxicities in patients with CNS primary tumors on Arm A and B included seizures in 21% and 30% of patients, headache in 21% and 26%, ataxia in 21% and 7%, and motor neuropathy in 21% and 26%, respectively. Grade 3-4 hematologic toxicities in Arm A and B included thrombocytopenia in 20% and 3% of patients, neutropenia in 19% and 9%, and anemia in 24% and 14%, respectively. On Arm A, confirmed partial responses (PR) occurred in 2 patients (pineoblastoma and astrocytoma) and 38 patients had stable disease (SD). On Arm B, there was a confirmed complete response (CR) (neuroblastoma), and 3 PRs (RMS-2, peripheral neuroectodermal tumor). SD was noted in 35 patients. In both arms, several unconfirmed responses in evolution have been classified as SD. CONCLUSION Final results will be presented at the meeting. [Table: see text].

Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial

Journal of Clinical Oncology, 2011

2 Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimen... more 2 Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS). Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m2 in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m2/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m2day or 4x200mg/m2/day*], melphalan [3x70mg/m2/day or 3x60mg/m2/day*. *reduced if ...

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Trends and territorial inequalities of incidence and survival of childhood leukaemia and their relations to socioeconomic status in Hungary, 1971-2015

European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), Jan 18, 2017

The Hungarian Childhood Cancer Registry, a population-based national registry of the Hungarian Pa... more The Hungarian Childhood Cancer Registry, a population-based national registry of the Hungarian Paediatric Haemato-Oncology Network founded in 1971, monitors the incidence and mortality of childhood cancer. Our aims were to carry out a longitudinal study to investigate the trends and spatial inequalities of incidence and survival of leukaemia, and the association between survival and deprivation in Hungary. All cases of childhood leukaemia and myelodysplasia were analysed (3157 cases, 1971-2015, age: 0-14 years). Time trends and the annual percentage change in direct standardized incidence and mortality were assessed. Survival and association with deprivation were assessed using the Kaplan-Meier method and Cox regression. Incidence rates of leukaemia (23.5-56.0/million) increased with an average annual percent change (AAPC) of 1%, determined by an increase in the incidence of acute lymphoblastic leukaemia (14.6-39.2/million, AAPC: 1.25%). Kaplan-Meier analysis showed a significant im...

Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data

Neuro-Oncology, 2016

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Inoperábilis agytumorok sugárkezelése gyermekkorban

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Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

The Lancet. Oncology, Jan 13, 2015

Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood canc... more Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Transcriptional analyses id...

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