BACKGROUND: Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. METHODS: In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. RESULTS: In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5-101.8, versus 104.4, 95% CI: 100.4-108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6-4.3, versus 4.5, 95% CI: 4.1-4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). CONCLUSIONS: Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. CLINICAL TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, NCT00330447.

• Klíčová slova
• Antineoplastic agents, Child development, Follow-up studies, High risk, Infant, Pregnancy, Prenatal exposure delayed effects,
• MeSH
• diastola účinky léků   MeSH
• dítě MeSH
• dospělí MeSH
• inteligence účinky léků   MeSH
• lidé MeSH
• nádorové komplikace v těhotenství farmakoterapie   radioterapie   MeSH
• paměť účinky léků   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• protinádorové látky škodlivé účinky   MeSH
• těhotenství MeSH
• vývoj dítěte účinky léků   účinky záření   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové látky MeSH

An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies. Recent large-scale sequencing by International Genome Consortium and Paediatric Cancer Genome Project has further shown that the genetic and epigenetic repertoire of driver mutations in specific childhood malignancies differs from more common adult-type malignancies. To bring about much needed change, a Paediatric Platform, ACCELERATE, was proposed in 2013 by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents and the European Society for Paediatric Oncology. The Platform, comprising multiple stakeholders in paediatric oncology, has three working groups, one with responsibility for promoting and developing high-quality MoA-informed paediatric drug development programmes, including specific measures for adolescents. Key is the establishment of a freely accessible aggregated database of paediatric biological tumour drug targets to be aligned with an aggregated pipeline of drugs. This will enable prioritisation and conduct of early phase clinical paediatric trials to evaluate these drugs against promising therapeutic targets and to generate clinical paediatric efficacy and safety data in an accelerated time frame. Through this work, the Platform seeks to ensure that potentially effective drugs, where the MoA is known and thought to be relevant to paediatric malignancies, are evaluated in early phase clinical trials, and that this approach to generate pre-clinical and clinical data is systematically pursued by academia, sponsors, industry, and regulatory bodies to bring new paediatric oncology drugs to front-line therapy more rapidly.

• Klíčová slova
• Mechanism of action, Paediatric oncology, Targeted cancer drug development,
• MeSH
• cílená molekulární terapie metody   MeSH
• databáze faktografické MeSH
• dítě MeSH
• farmaceutický průmysl metody   MeSH
• hodnocení léčiv MeSH
• lékařská onkologie metody   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• objevování léků metody   MeSH
• protinádorové látky terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové látky MeSH

BACKGROUND: Organometallic compounds are chemical substances containing a carbon-metal bond. From a biological point of view, these compounds are generally considered to be toxic for living organisms. They may exert therapeutic potential, especially as anticancer or antimicrobial drugs. Their structural variability and usually uncharged and mostly lipophilic character are particularly advantageous properties. Platinum derivatives (predominately cisplatin) are the most proven advantageous agents in the medical field. The success of cisplatin has led the scientific community to focus on the synthesis of other organometallic compounds with improved anti-tumour effects and lower cytotoxicity towards healthy tissues. Close attention is focused on compounds bearing atoms of iron, titanium or ruthenium. PURPOSE: Here, we focus on summarising a description of the most important compounds containing iron, titanium or ruthenium atoms in their structure, showing potential application in cancer treatment including the mechanism of action for some of the most commonly studied compounds. The reported structures were used successfully in preclinical studies including animal models and progressed to various stages of human clinical trials. Despite the fail-ure of some of these compounds, there are still several candidates which are expected to progress to the late stages of the clinical trials either alone or as part of combined chemotherapy. Ruthenium-containing substances in particular show high potential for utilisation in cancer treatment due to low cytotoxicity associated with the ability to block neoangiogenesis and metastasis development.

• Klíčová slova
• cancer, chemother­apy, drugs, organometallic compounds, ruthenium, titanium,
• MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• organokovové sloučeniny terapeutické užití   MeSH
• prognóza MeSH
• protinádorové látky terapeutické užití   MeSH
• vyvíjení léků * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• organokovové sloučeniny MeSH
• protinádorové látky MeSH

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.

• Klíčová slova
• Clinical trials, Drug development, Epigenetics, MYCN, Neuroblastoma, Phase I, Preclinical testing,
• MeSH
• cílená molekulární terapie metody   trendy   MeSH
• dítě MeSH
• experimentální terapie metody   trendy   MeSH
• inhibitory proteinkinas izolace a purifikace   terapeutické užití   MeSH
• kongresy jako téma MeSH
• lékařská onkologie metody   organizace a řízení   trendy   MeSH
• lidé MeSH
• nádory mozku farmakoterapie   patologie   MeSH
• neuroblastom farmakoterapie   patologie   MeSH
• objevování léků metody   organizace a řízení   trendy   MeSH
• pediatrie metody   organizace a řízení   trendy   MeSH
• protinádorové látky izolace a purifikace   terapeutické užití   MeSH
• vyvíjení léků * metody   organizace a řízení   trendy   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH

INTRODUCTION: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. OBJECTIVE: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. CONCLUSION: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings.

• Klíčová slova
• Cancer therapeutics, European Paediatric regulation, Paediatric oncology drug development,
• MeSH
• dítě MeSH
• lékařská onkologie metody   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• vyvíjení léků MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause another type of kidney fibrosis with malignant transformation of the urothelium, called Balkan Endemic Nephropathy (BEN). The compound predominantly responsible for the nephropathy and urothelial cancer of AA, is aristolochic acid I (AAI) which is a genotoxic mutagen after metabolic activation The activation pathway involves reduction of the nitro group to a cyclic N-acylnitrenium ion that can form covalent DNA adducts. These specific DNA adducts have been detected in experimental animals exposed to AAI, and in urothelial tissues from AAN patients. In rodent tumours induced by AAI, 7-(deoxyadenosin-N(6)-yl)aristolactam I was the most abundant DNA adduct formed and associated with activation of ras oncogenes through a characteristic transversion mutation. Such A:T-->T:A mutations have been identified in TP53 of urothelial tumour DNA of an AAN patient and in several patients suffering from BEN along with specific AA-DNA adducts. Understanding which enzymes are involved in AAI activation to species forming DNA adducts and/or detoxification to its O-demethylated metabolite aristolochic acid Ia (AAIa) is important in order to assess susceptibility to this carcinogen. METHODS AND RESULTS: A literature search. CONCLUSIONS: The most important human enzymes activating AAI by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 (CYP) 1A2 and renal microsomal NADPH:CYP reductase as well as cyclooxygenase which is highly expressed in urothelial tissue. However, the contribution of most of these enzymes to the development of AAN and BEN diseases is still unclear. Hepatic CYP enzymes were found to detoxify AAI to AAIa in mice, and thereby protect the kidney from injury. CYP enzymes of the 1A subfamily seem to play a major role in this process in mouse liver. Likewise, among human CYP enzymes, CYP1A1 and 1A2 were found to be the most efficient enzymes participating in AAI oxidation to AAIa in vitro. Nevertheless, which CYPs are the most important in this process in both animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AAI to species responsible for induction of urothelial cancer in humans remains still to be resolved.

• MeSH
• adukty DNA metabolismus   MeSH
• aktivace enzymů MeSH
• biotransformace MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• kyseliny aristolochové farmakokinetika   toxicita   MeSH
• ledviny účinky léků   MeSH
• lidé MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa metabolismus   MeSH
• nemoci ledvin chemicky indukované   MeSH
• urologické nádory chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adukty DNA MeSH
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• kyseliny aristolochové MeSH
• NADPH-cytochrom c-reduktasa MeSH

Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

• Klíčová slova
• Neuroblastoma, clinical trials, drug development, phase I, preclinical testing,
• MeSH
• časové faktory MeSH
• cílená molekulární terapie MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• neuroblastom farmakoterapie   patologie   MeSH
• preklinické hodnocení léčiv metody   MeSH
• prognóza MeSH
• protinádorové látky škodlivé účinky   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové látky MeSH

Cancer is viewed as a genetic disease. According to the currently accepted model of carcinogenesis, several consequential mutations in oncogenes or tumor suppressor genes are necessary for cancer development. In this model, mutated DNA sequence is transcribed to mRNA that is finally translated into functionally aberrant protein. mRNA is viewed solely as an intermediate between DNA (with 'coding' potential) and protein (with 'executive' function). However, recent findings suggest that (m)RNA is actively regulated by a variety of processes including nonsense-mediated decay, alternative splicing, RNA editing or RNA interference. Moreover, RNA molecules can regulate a variety of cellular functions through interactions with RNA, DNA as well as protein molecules. Although, the precise contribution of RNA molecules by themselves and RNA-regulated processes on cancer development is currently unknown, recent data suggest their important role in carcinogenesis. Here, we summarize recent knowledge on RNA-related processes and discuss their potential role in cancer development.

• MeSH
• alternativní sestřih MeSH
• editace RNA MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• modely genetické MeSH
• nádory genetika   patologie   MeSH
• regulace genové exprese * MeSH
• RNA interference MeSH
• stabilita RNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• messenger RNA MeSH

The mammary gland is a complex organ that begins development early in gestation and constantly changes in size, shape and function from the time of puberty to menopause. The earliest stages of embryogenesis appear to be independent of steroid hormones, whereas after the 15th week breast structure is largely influenced by a variety of hormones. In most females, further breast development begins at puberty under the influence of cyclical estrogen and progesterone secretion. This process may continue into the 20s and it is enhanced by pregnancy. Growth and transcription factors contribute to the reciprocal stromal-epithelial interactions in growth, development and tumorogenesis of the mammary gland. From the embryological point of view the morphology of both mammary ductal and lobular cells results from the same developmental process. Numerous data suggest the existence of self-renewing, pluripotent mammary stem cells but their molecular characteristics and differentiation pathways are unknown. The extensive research currently being done in molecular biology and pathology, cancer genomics and proteomics will hopefully contribute to further elucidation of all the genetic and environmental factors involved in the development, differentiation, and involution of the mammary gland and this may give insight into the etiopathogenesis, early detection, treatment, and potential prevention of breast cancer.

• MeSH
• lidé MeSH
• nádory prsu patofyziologie   MeSH
• prsy embryologie   růst a vývoj   MeSH
• růstové látky fyziologie   MeSH
• transkripční faktory fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• růstové látky MeSH
• transkripční faktory MeSH

BACKGROUND: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. METHODS: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. RESULTS: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64). CONCLUSION: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction.

• Klíčová slova
• behaviors, demographics, epidemiology, head and neck cancer, laryngeal cancer, model, oral cancer, oropharyngeal cancer, risk, risk prediction,
• MeSH
• dospělí MeSH
• hodnocení rizik MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• nádory hlavy a krku * epidemiologie   MeSH
• rizikové faktory MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• validační studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Spojené království epidemiologie   MeSH