ABSTRACT
AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Subject(s)
Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Chromosomes, Human, Pair 14/genetics , Glioma/genetics , Glioma/pathology , DNA Methylation , Female , Humans , Male , Monosomy , Neurocytoma/genetics , Neurocytoma/pathology , Oligodendroglioma/genetics , Oligodendroglioma/pathologyABSTRACT
BACKGROUND AND PURPOSE: In addition to the 4 histopathologically defined entities of medulloblastoma, 4 distinct genetically defined subgroups have been included in the World Health Organization classification of 2016. The smallest subgroup is the medulloblastoma with activated wingless pathway. The goal of this study was to identify a typical MR imaging morphology in a larger number of pediatric patients with wingless pathway medulloblastoma. MATERIALS AND METHODS: From January 2001 to October 2017, of 75 patients with histologically confirmed and molecularly subgrouped wingless pathway medulloblastomas recruited to the German Pediatric Brain Tumor (HIT) trials, 38 patients (median age, 12.8 ± 4.6 years at diagnosis; 24 [63.2%] female) had preoperative imaging that passed the entry criteria for this study. Images were rated by the local standardized imaging criteria of the National Reference Center of Neuroradiology. Additionally, a modified laterality score was used to determine tumor localization and extension. RESULTS: Twenty-eight of 38 (73.7%) were primary midline tumors but with a lateral tendency in 39.3%. One extensively eccentric midline tumor was rated by the laterality score as in an off-midline position. Five tumors were found in the cerebellopontine angle; 3, in the deep white matter; and 2, in a cerebellar hemisphere. Leptomeningeal dissemination was rare (11.5%). In 60.5%, intratumoral blood-degradation products were found, and 26.3% showed cysts with blood contents. CONCLUSIONS: According to our observations, wingless pathway medulloblastomas are not preferentially off-midline tumors as postulated in previous studies with smaller wingless pathway medulloblastoma cohorts. Dense intratumoral blood-degradation products and cysts with blood contents are frequently found and might help to differentiate wingless pathway medulloblastoma from other medulloblastoma subtypes.
Subject(s)
Cerebellar Neoplasms/diagnostic imaging , Cerebellar Neoplasms/genetics , Medulloblastoma/diagnostic imaging , Medulloblastoma/genetics , Wnt Signaling Pathway/genetics , Adolescent , Cerebellar Neoplasms/pathology , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Male , Medulloblastoma/pathology , Mutation , Retrospective Studies , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors has revealed a number of distinct entities and has led to the term "CNS-primitive neuroectodermal tumors" being removed from the 2016 World Health Organization classification. The purpose of this study was to describe the MR imaging findings of histologically diagnosed primitive neuroectodermal tumors and pineoblastomas and correlate them with molecular diagnoses and outcomes. MATERIALS AND METHODS: Histologically diagnosed primitive neuroectodermal tumors and pineoblastomas were enrolled in this Children's Oncology Group Phase III trial, and molecular classification was retrospectively completed using DNA methylation profiling. MR imaging features were systematically studied and correlated with molecular diagnoses and survival. RESULTS: Of the 85 patients enrolled, 56 met the inclusion criteria, in whom 28 tumors were in pineal and 28 in nonpineal locations. Methylation profiling revealed a variety of diagnoses, including pineoblastomas (n = 27), high-grade gliomas (n = 17), embryonal tumors (n = 7), atypical teratoid/rhabdoid tumors (n = 3), and ependymomas (n = 2). Thus, 39% overall and 71% of nonpineal tumor diagnoses were discrepant with histopathology. Tumor location, size, margins, and edema were predictors of embryonal-versus-nonembryonal tumors. Larger size and ill-defined margins correlated with poor event-free survival, while metastatic disease by MR imaging did not. CONCLUSIONS: In nonpineal locations, only a minority of histologically diagnosed primitive neuroectodermal tumors are embryonal tumors; therefore, high-grade glioma or ependymoma should be high on the radiographic differential. An understanding of molecularly defined tumor entities and their relative frequencies and locations will help the radiologist make more accurate predictions of the tumor types.
Subject(s)
Neuroectodermal Tumors, Primitive/diagnostic imaging , Neuroectodermal Tumors, Primitive/genetics , Pinealoma/diagnostic imaging , Pinealoma/genetics , Supratentorial Neoplasms/diagnostic imaging , Supratentorial Neoplasms/genetics , Adolescent , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Child , Child, Preschool , Female , Glioma/diagnostic imaging , Glioma/genetics , Glioma/pathology , Humans , Infant , Magnetic Resonance Imaging , Male , Neoplasms, Germ Cell and Embryonal/diagnostic imaging , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/pathology , Neuroectodermal Tumors, Primitive/classification , Neuroectodermal Tumors, Primitive/pathology , Pineal Gland/diagnostic imaging , Pineal Gland/pathology , Pinealoma/pathology , Retrospective Studies , Rhabdoid Tumor/diagnostic imaging , Rhabdoid Tumor/genetics , Rhabdoid Tumor/pathology , Supratentorial Neoplasms/pathology , Teratoma/diagnostic imaging , Teratoma/genetics , Teratoma/pathology , Young AdultABSTRACT
The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .
Subject(s)
Genetic Predisposition to Disease , Li-Fraumeni Syndrome , Genes, p53/genetics , Humans , Li-Fraumeni Syndrome/genetics , Li-Fraumeni Syndrome/mortality , Li-Fraumeni Syndrome/pathologyABSTRACT
BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.
Subject(s)
Brain Neoplasms/genetics , DNA Methylation/genetics , Gene Dosage , Glioma/genetics , Transcriptome , Brain Neoplasms/complications , Computational Biology , Epigenesis, Genetic , Humans , Neoplasm Grading , Tumor Microenvironment/genetics , World Health OrganizationABSTRACT
AIMS: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. METHODS: We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. RESULTS: Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. CONCLUSIONS: This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.
Subject(s)
Astrocytoma/pathology , Brain Neoplasms/pathology , Glioblastoma/genetics , Glioma/pathology , Isocitrate Dehydrogenase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Astrocytoma/genetics , Brain Neoplasms/genetics , Glioma/genetics , Humans , Middle Aged , Mutation/genetics , Neoplasm Grading/methods , Young AdultABSTRACT
Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.
Subject(s)
Cerebellar Neoplasms/genetics , Cerebellum/embryology , Cerebellum/pathology , Medulloblastoma/genetics , Proto-Oncogene Proteins c-myc/genetics , Animals , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/pathology , Cerebellum/cytology , Cerebellum/metabolism , Disease Models, Animal , Female , Humans , Male , Medulloblastoma/metabolism , Medulloblastoma/pathology , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-myc/metabolism , TransfectionABSTRACT
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/physiology , Ataxia Telangiectasia/genetics , Neoplasm Proteins/physiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Ataxia Telangiectasia/complications , Ataxia Telangiectasia Mutated Proteins/deficiency , Ataxia Telangiectasia Mutated Proteins/genetics , Child , Child, Preschool , Chromosomes, Human/ultrastructure , Chromothripsis , DNA Repair/genetics , DNA, Neoplasm/genetics , Female , Genome, Human , Genomic Instability , Humans , In Situ Hybridization, Fluorescence , Male , Mutation , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Neoplasms/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , RNA, Neoplasm/genetics , Sequence Analysis, DNA , Sequence Analysis, RNA , Telomere Shortening/genetics , TranscriptomeABSTRACT
Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.
Subject(s)
Cerebellar Neoplasms/pathology , Chemokine CXCL2/metabolism , G-Protein-Coupled Receptor Kinase 5/metabolism , Medulloblastoma/pathology , Phosphoprotein Phosphatases/genetics , Receptors, CXCR4/genetics , Adolescent , Animals , Cell Line, Tumor , Cerebellar Neoplasms/genetics , Child , Child, Preschool , Female , G-Protein-Coupled Receptor Kinase 5/genetics , Humans , Infant , Male , Medulloblastoma/genetics , Mice , Mice, SCID , Neoplasm Invasiveness , Neoplasm Transplantation , Phosphoprotein Phosphatases/metabolism , Protein Phosphatase 2C , Receptors, CXCR4/metabolism , Signal Transduction , Young AdultABSTRACT
BACKGROUND: The coagulation system becomes activated during progression and therapy of high-grade brain tumors. Triggering tissue factor (F3/TF) and thrombin receptors (F2R/PAR-1) may influence the vascular tumor microenvironment and angiogenesis irrespective of clinically apparent thrombosis. These processes are poorly understood in medulloblastoma (MB), in which diverse oncogenic pathways define at least four molecular disease subtypes (WNT, SHH, Group 3 and Group 4). We asked whether there is a link between molecular subtype and the network of vascular regulators expressed in MB. METHODS: Using R2 microarray analysis and visualization platform, we mined MB datasets for differential expression of vascular (coagulation and angiogenesis)-related genes, and explored their link to known oncogenic drivers. We evaluated the functional significance of this link in DAOY cells in vitro following growth factor and thrombin stimulation. RESULTS: The coagulome and angiome differ across MB subtypes. F3/TF and F2R/PAR-1 mRNA expression are upregulated in SHH tumors and correlate with higher levels of hepatocyte growth factor receptor (MET). Cultured DAOY (MB) cells exhibit an up-regulation of F3/TF and F2R/PAR-1 following combined SHH and MET ligand (HGF) treatment. These factors cooperate with thrombin, impacting the profile of vascular regulators, including interleukin 1ß (IL1B) and chondromodulin 1 (LECT1). CONCLUSIONS: Coagulation pathway sensors (F3/TF, F2R/PAR-1) are expressed in MB in a subtype-specific manner, and may be functionally linked to SHH and MET circuitry. Thus coagulation system perturbations may elicit subtype/context-specific changes in vascular and cellular responses in MB.
Subject(s)
Angiogenic Proteins/genetics , Blood Coagulation/genetics , Cerebellar Neoplasms/blood supply , Cerebellar Neoplasms/genetics , Gene Expression Profiling , Intercellular Signaling Peptides and Proteins/metabolism , Medulloblastoma/blood supply , Medulloblastoma/genetics , Neovascularization, Pathologic , Thrombin/metabolism , Angiogenic Proteins/metabolism , Cell Line, Tumor , Cerebellar Neoplasms/blood , Cerebellar Neoplasms/pathology , Data Mining , Databases, Genetic , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Hedgehog Proteins/metabolism , Hepatocyte Growth Factor/metabolism , Humans , Intercellular Signaling Peptides and Proteins/genetics , Medulloblastoma/blood , Medulloblastoma/pathology , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , RNA, Messenger/metabolism , Receptor, PAR-1/genetics , Receptor, PAR-1/metabolism , Signal Transduction , Thromboplastin/genetics , Thromboplastin/metabolismABSTRACT
Recent advances in genomic technologies have allowed for tremendous progress in our understanding of the biology underlying medulloblastoma, a malignant childhood brain tumor. Consensus molecular subgroups have been put forth by the pediatric neuro-oncology community and next-generation genomic studies have led to an improved description of driver genes and pathways somatically altered in these subgroups. In contrast to the impressive pace at which advances have been made at the level of the medulloblastoma genome, comparable studies of the epigenome have lagged behind. Complementary data yielded from genomic sequencing and copy number profiling have verified frequent targeting of chromatin modifiers in medulloblastoma, highly suggestive of prominent epigenetic deregulation in the disease. Past studies of DNA methylation-dependent gene silencing and microRNA expression analyses further support the concept of medulloblastoma as an epigenetic disease. In this Review, we aim to summarize the key findings of past reports pertaining to medulloblastoma epigenetics as well as recent and ongoing genomic efforts linking somatic alterations of the genome with inferred deregulation of the epigenome. In addition, we predict what is on the horizon for medulloblastoma epigenetics and how aberrant changes in the medulloblastoma epigenome might serve as an attractive target for future therapies.
Subject(s)
Cerebellar Neoplasms/genetics , Epigenesis, Genetic , Genotype , Medulloblastoma/genetics , Child , Epigenomics , HumansABSTRACT
Osteonecrosis is a frequent complication after treatment for childhood leukemia and other steroid-based therapies. The success rate of core decompression surgery is limited. Therefore, we evaluated relevant biological characteristics of human multipotent mesenchymal stromal cells (MSCs) in vitro. MSCs cultured under low-oxygen tensions showed decreased proliferation and differentiation into bone. However, these MSCs secreted significant amounts of vascular endothelial-derived factor in the presence of interferon-gamma. These in vitro results with potential effects on neovascularization and bone regeneration as well as findings in animal models prompted us to treat five patients with steroid-induced osteonecrosis of the femur by core decompression surgery and instillation of expanded autologous MSCs. Within 3 weeks of culture, sufficient numbers of MSCs were generated using animal protein-free culture conditions. No chromosomal aberrations were detected by matrix-based comparative genomic hybridization. Application of MSCs during core decompression was feasible and safe. Median follow-up is 16 months and the patients in this pilot study reported clinical improvement. Formation of mineralized bone in the osteonecrotic cavity was proven by computed tomography. Taken together, MSCs display biological properties that may add to the efficiency of surgical treatment in osteonecrosis and should be evaluated in larger patient cohorts.
Subject(s)
Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Osteonecrosis/therapy , Stromal Cells/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adolescent , Adult , Alkaline Phosphatase/metabolism , Bone Marrow Cells/metabolism , Bone Regeneration , Cell Differentiation , Cell Hypoxia , Child , Chromosomal Instability , Comparative Genomic Hybridization , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Follow-Up Studies , Humans , Immunophenotyping , Male , Osteonecrosis/metabolism , Pilot Projects , Radioimmunoassay , Tomography, X-Ray Computed , Young AdultSubject(s)
Arteriosclerosis/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Ticlopidine/analogs & derivatives , Clopidogrel , Drug Costs , Drug Interactions , Drug Monitoring , Humans , Patient Education as Topic , Platelet Activation/drug effects , Platelet Aggregation Inhibitors/economics , Platelet Aggregation Inhibitors/pharmacology , Ticlopidine/economics , Ticlopidine/pharmacology , Ticlopidine/therapeutic useABSTRACT
Urinary incontinence is one chronic health problem that many older adults experience. Assessment is the first step in approaching a urinary elimination problem and forms the basis for determining potential management modalities. The bladder diary, one type of fluid intake and output record, is helpful in describing an individual's voiding pattern and is an integral component of urinary assessment. Bladder diaries also can be used to evaluate the effectiveness of interventions initiated to manage incontinence. This article describes the procedure for using bladder diaries within the context of a research study conducted with residents of retirement settings.
Subject(s)
Geriatric Nursing/methods , Nursing Assessment/methods , Nursing Records/standards , Self Care/methods , Urinary Incontinence/nursing , Urinary Incontinence/physiopathology , Urination , Aged , Aged, 80 and over , Female , Housing for the Elderly , Humans , Male , Middle Aged , Nursing Evaluation Research , Urinary Incontinence/prevention & control , UrodynamicsABSTRACT
PURPOSE: This study examines the effects of a sodium hyaluronate-based bioresorbable membrane (Seprafilm) on tumor implantation at surgical wound and laparoscopic trocar sites. METHODS: GW-39, an established human colon cancer line carried in immunocompetent golden Syrian hamsters was used as the experimental model. Under general anesthesia, a 2-cm midline incision was made to allow placement of four 5-mm abdominal trocars. Hamsters were then randomly assigned to preSeprafilm, postSeprafilm, and control (no Seprafilm) groups. In the preSeprafilm group 0.5 ml of a 5 percent (vol/vol) suspension of the GW-39 tumor cells (approximately 1.675 x 10(6) cells) was injected into the abdomen of each hamster via midline incision. Trocars were removed, the wounds were closed, and 1 cm2 of Seprafilm was placed on the peritoneal surface of each trocar site. In the postSeprafilm group the membrane was placed at each site before injection of tumor cells. The control group did not receive Seprafilm. The animals were killed after seven weeks, and the abdominal wound sites were excised. Sites without gross tumor underwent histologic evaluation. RESULTS: One hundred thirty-two animals were randomly assigned to the three groups. The preSeprafilm group had an 87 percent tumor implantation rate. The postSeprafilm group had a 90 percent tumor implantation rate. The control group had an 88 percent tumor implantation rate. Chi squared analysis demonstrated that these total tumor implant rates and mean tumor mass were similar at all wound sites and between groups. No toxicity was observed in any of the experimental groups. CONCLUSIONS: Sodium hyaluronate-based bioresorbable membrane (Seprafilm) does not influence GW-39 human colon cancer implantation at abdominal wound sites in this hamster model.
Subject(s)
Abdomen/surgery , Biocompatible Materials/therapeutic use , Colonic Neoplasms/pathology , Membranes, Artificial , Neoplasm Seeding , Animals , Chi-Square Distribution , Cricetinae , Follow-Up Studies , Humans , Hyaluronic Acid , Laparoscopes , Male , Neoplasm Transplantation , Prospective Studies , Random Allocation , Tumor Cells, CulturedABSTRACT
BACKGROUND AND OBJECTIVES: Pneumoperitoneum increases the trocar-site tumor implantation rate using a human colon cancer cell line in a hamster model. The purpose of this study was to determine whether local treatment of trocar sites with potential tumoricidal agents can inhibit tumor implantation after pneumoperitoneum. METHODS: GW-39 human colon cancer cells (0.5 ml of 2.5% v/v; 8.0 x 10(5) cells) were injected throughout the abdomen of 133 Golden Syrian hamsters through a midline incision. The animals were randomized to receive either untreated 5-mm trocars in each abdominal quadrant (group I control, n = 49), trocars dipped in 10% povidone-iodine (group II, n = 53), or trocars coated with 1% silver sulfadiazine (group III, n = 51). The midline wounds were also coated with the respective agents before closing. Pneumoperitoneum was then maintained at 10 mmHg for 10 min, after which the trocar wounds were closed. In group II, the trocar sites were treated with a coat of povidone-iodine after the trocars were withdrawn and before closing. Gross and microscopic tumor implants were analyzed at 7 weeks postoperatively. RESULTS: The rate of tumor cell implantation at trocar sites was reduced from 93% (172/184) in the control group to 75% (126/168) and 78% (141/180) in groups II and III, respectively (P < 0.0001). Fewer palpable tumors were detected in groups II and III (40% and 23%, respectively) than in the control group (72%, P < 0.0001). Mean tumor mass in group III (0.4+/-0.1 g), but not in group II (1.0+/-0.2 g), was significantly less than that in the control group (1.3+/-0.1 g, P < 0.01). Overall tumor involvement of the larger midline wound was similar for all groups (I = 80%, II = 79%, III = 71%). However, palpable tumors were identified more frequently in group I (67%) than in groups II and III (43%, P < 0.05; 22%, P < 0.01, respectively). CONCLUSION: Pretreatment of abdominal wounds with povidone-iodine or silver sulfadiazine can reduce tumor implantation after pneumoperitoneum in a hamster model.
Subject(s)
Colonic Neoplasms/pathology , Neoplasm Seeding , Pneumoperitoneum, Artificial/adverse effects , Abdominal Muscles/pathology , Animals , Cricetinae , Humans , Mesocricetus , Neoplasm Transplantation , Povidone-Iodine/therapeutic use , Tumor Cells, CulturedABSTRACT
PURPOSE: The purpose of this study was to determine the effect of excising abdominal trocar wound sites after pneumoperitoneum on the rate of trocar site tumor implantation in a hamster model. This would help determine whether tumor cells seed trocar sites during or after pneumoperitoneum. METHODS: A total of 0.5 ml of GW-39 human colon cancer cell suspension at 2.5 percent v/v (8 x 10(5) cells) was injected into the abdomens of 77 hamsters through a midline incision. Animals were subjected to ten minutes of pneumoperitoneum, after placement of four abdominal trocars, and then randomly assigned to undergo either simple suture closure or 4-mm radius trocar wound site excision at the end of the procedure. Gross and microscopic tumor implants were documented seven weeks later. RESULTS: There were three and four deaths in simple suture closure and wound site excision groups, respectively. Of the remaining 35 hamsters in each group, tumor cells implanted at 89 and 78 percent of trocar sites, respectively (P < 0.03). There was no significant difference between the two groups in tumor implantation at midline laparotomy sites. Wound site excision also resulted in fewer palpable tumors (44 vs. 61 percent; P < 0.01) and a lower tumor implantation rate (49 vs. 74 percent; P < 0.05) at all four concurrent sites compared with simple suture closure. CONCLUSIONS: Excision of laparoscopic abdominal trocar wound sites can significantly, but not completely, reduce tumor implantation rate compared with simple wound closure.
Subject(s)
Abdominal Muscles/surgery , Colectomy/instrumentation , Colonic Neoplasms/surgery , Laparoscopes , Neoplasm Seeding , Abdominal Muscles/pathology , Animals , Colonic Neoplasms/pathology , Cricetinae , Humans , Male , Mesocricetus , Neoplasm Transplantation , Pneumoperitoneum, Artificial/instrumentation , Risk FactorsABSTRACT
As the use of oxygen therapy increases, primary care providers must become familiar with numerous aspects of home oxygen therapy, and they need to identify those patients who will benefit from this therapy. A number of oxygen systems are available today. A few helpful hints aid in providing effective, efficient, quality care to these patients in the primary care clinic. It is most important that health care providers know what is required to recertify a patient for oxygen therapy and how to properly complete the Health Care Financing Administration Form 484. Periodic evaluations are required by insurance companies and Medicare. This article discusses the identification of patients who will benefit from home oxygen therapy, administration, and recertification for home oxygen therapy.
Subject(s)
Home Care Services , Lung Diseases, Obstructive/therapy , Oxygen Inhalation Therapy/methods , Aerospace Medicine , Certificate of Need , Humans , Oximetry , Oxygen Inhalation Therapy/instrumentation , Patient Education as Topic , Quality of Health CareABSTRACT
Urinary incontinence is a problem for elders in many settings, including rural residential care homes (RCHs). Behavioral techniques for the management of urinary incontinence have been successful with community-dwelling and nursing home populations. A study was undertaken to evaluate the feasibility of implementing bladder diaries and bladder training to assist RCH residents with bladder control. These techniques were found not to be successful in selected rural RCHs. The characteristics of rural RCHs are explored, and the impediments and incentives to the use of behavioral management techniques for urinary incontinence in these settings are examined.