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The majority of haematological malignancies represent sporadic diseases, but hereditary entities with predisposing genetic alterations have also been described. Diseases of the myeloid and lymphoid cell lineages with genetic predispositions are associated with heterogeneous clinical manifestations, with many symptoms being specific for certain cytogenetic and molecular aberrations. Apart from the myeloid predisposition syndromes with clear Mendelian inheritance patterns, cases with ambiguous predisposing factors are also known, but their role in hereditary leukemogenesis is still poorly understood. The presence of these genetic lesions is usually associated with an increased risk of familial malignancies and often leads to familial disease aggregation. Lymphoid malignancies often lack the disease-associated germline pathogenic variants, with their propensity to familial aggregation being most likely explained by their complex genotype serving as a hereditary base to many sporadic diseases. The heterogeneous clinical features and the large number of potentially affected genes tend to make the diagnosis of hereditary haematological malignancies difficult, however the elevated familial risk caused by predisposing genetic alterations underlines the importance of testing for individuals and families with genetic susceptibility.In the past few years there is an emerging need for clinical genetics counseling in the case of malignant diseases as well. For these reasons a novel professional recommendation has been developed for oncogenetic counseling, whose publication is in progress. In nearly 10% of childhood cancers there is an underlying tumor predisposition syndrome, but this value is thought to be underestimated. AEB071 in vitro Due to the treatment of these cancers and the risk of a possible new developing tumor, genetic counseling is strongly recommended in these children, to establish a correct diagnosis and to evaluate the tumor risk of family members. In this article we summarize the indication for genetic counseling referral in the case of childhood cancers, in which we especially have to pay attention to family anamnesis, the pathology of the tumor, multiple primary tumors, congenital anomalies and dysmorphic features, as well as excessive treatment toxicity.Inherited colorectal cancer syndromes account for 6-10% of all cases. The diagnosis of the polypoid forms is easier due to their phenotypes, compared to the non-polypoid cases. The evaluation of the MSI/MMR status of the already developed colorectal cancer cases could help in the recognition and screening of the latter forms. This screening method is much more sensitive than that solely based on family anamnestic data. The MSI/MMR status of the tumor also could help in adjuvant or palliative treatment planning, therefore it is recommended in all colorectal cancer cases. Here we review the available information regarding the inherited colorectal cancer syndromes, and the role of MSI/MMR status in the management of colorectal cancers.The technical developments lead to revolution and speed-up of molecular genetic diagnostics of hereditary cancer syndromes. In those apparently sporadic, solid tumors where the chance of inheritance is higher than 10%, the molecular genetic analysis is indicated. Nowadays these tests are performed using next generation sequencing technologies which allow parallel testing of multiple genes. However, in well-defined cancer syndromes where the clinical presentation clearly suggests the diagnosis and the disease is monogenic, targeted testing is still recommended. Clinical indication of molecular genetic testing and its interpretation is a complex procedure; all steps are regulated. Beside ethical and legal aspects both the laboratory, bioinformatic steps and the interpretation of the results require strong supervision and control. The current review summarizes the genetic alterations responsible for hereditary cancer syndromes and molecular genetic methods which are used during diagnostics in everyday practice.Germinal or somatic mutations of the BRCA genes may serve as therapeutic targets. Deficient functioning of the BRCA genes render the cancer vulnerable to such therapeutic interventions as chemotherapy with DNA-targeted agents and PARP inhibitors targeting DNA repair capacity. Although BRCA mutations may be detected in a large variety of cancers, the mentioned specific therapies are efficient in the so called BRCA-associated cancers only including ovarian, breast, pancreatic, prostate cancers and the rare uterine sarcomas. While in ovarian and prostate carcinomas both germinal and somatic, in breast and pancreatic cancers exclusively germinal, and in uterine sarcomas mostly somatic mutations specify the tumor as BRCA-dependent; platinum-sensitivity in ovarian cancer may replace BRCA testing by indicating the presence of frequent DNA repair deficiency. Platinum-based chemotherapy is frequently efficient in BRCA-dependent cancers, while PARP inhibitors yet registered for ovarian, breast and pancreatic cancers bring paradigm change in the treatment of ovarian cancer and provide an additional treatment option of the others.Cancer susceptibility but not specific cancer types can be inherited. This susceptibility(ies) is due to inherited germline mutations of key genes of the controllers of genome integrity, translational control, the cell cycle regulation or even the tumor vascularization. Cancer susceptibility can be manifested in various forms of specific syndromes, each associated with different alterations of genes. Most of these genes are tumor suppressors, and the mutations affect one or both alleles. Interestingly, inherited mutations of oncogenes resulting in cancer susceptibility are much rarer, typically affect only one allele, and the inheritance is dominant. However, cancer susceptibility is influenced not only by high penetrance gene defects but also by inherited low penetrance gene mutations, complicating the effective identification of affected individuals and their families.BACKGROUND The Vaxxas high-density microarray patch (HD-MAP) consists of a high density of microprojections coated with vaccine for delivery into the skin. Microarray patches (MAPs) offer the possibility of improved vaccine thermostability as well as the potential to be safer, more acceptable, easier to use, and more cost-effective for the administration of vaccines than injection by needle and syringe (N&S). Here, we report a phase I trial using the Vaxxas HD-MAP to deliver a monovalent influenza vaccine that was to the best of our knowledge the first clinical trial to evaluate the safety, tolerability, and immunogenicity of lower doses of influenza vaccine delivered by MAPs. METHODS AND FINDINGS HD-MAPs were coated with a monovalent, split inactivated influenza virus vaccine containing A/Singapore/GP1908/2015 H1N1 haemagglutinin (HA). Between February 2018 and March 2018, 60 healthy adults (age 18-35 years) in Melbourne, Australia were enrolled into part A of the study and vaccinated with either HD-MAPs delivering 15 μg of A/Singapore/GP1908/2015 H1N1 HA antigen (A-Sing) to the volar forearm (FA); uncoated HD-MAPs; intramuscular (IM) injection of commercially available quadrivalent influenza vaccine (QIV) containing A/Singapore/GP1908/2015 H1N1 HA (15 μg/dose); or IM injection of H1N1 HA antigen (15 μg/dose).
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