Nervous System Malignancies Research Articles

Tissue Specific Expression of Neurofibromin Isoforms in Swine

Neurofibromatosis type 1 (NF1) is one of the most common monogenic disorders and affects 1 in 2,500 children. The disorder manifests in varying, complex phenotypes that include cognitive and learning dysfunction, bone and cardiovascular disorders, and an increased risk of developing benign and malignant nervous system tumors. The neurofibromin gene contains 63 exons, of which four are alternatively spliced (optionally included) within isoforms of neurofibromin transcripts that are differentially expressed in specific tissues. Recently, several swine models of NF1 have been developed in hopes that these models will recapitulate the disorder in humans better than existing rodent models and thus offer a more translational platform for the development of novel therapies. However, the normal expression patter of neurofibromin isoforms in swine is unknown. In the current study, we characterize the tissue specific expression pattern of neurofibromin in swine to enable comparisons to that known in humans.Tissue samples taken from the cortex, cerebellum, pituitary, amygdala, hippocampus, substantia nigra, optic nerve, brachial nerve, adipose, skeletal muscle, small intestine, and colon of swine were used to determine mRNA expression levels for isoforms containing each of the four known alternatively spliced exons (ASEs). Mesenchymal stem cells isolated and cultured from adipose tissue were also included in the analysis. A standard qPCR approach was first used to determine in which tissues ASEs significantly varied. Then, droplet digital PCR was used to produce a more precise analysis of ASE expression pattern in targeted tissues. The level of total neurofibromin mRNA and the relative expression of each of the four ASEs were determined in the cultured MSCs and each tissue sample. The stem cells were found to have the highest expression of total neurofibromin mRNA, while nervous tissues containing gray matter and white matter showed 2‐ and 6‐ fold lower expression, respectively. Muscle tissue showed 14‐fold lower expression. Muscle and gray matter tissues had the highest relative expression of ASE 12 (a12), while the stem cells and white matter tissues had the highest relative expression of ASE 31 (a31). Muscle showed the most relative abundance of ASE 57 (a57). The expression of a12 and a57 were negligible in stem cells. Most malignant NF1 tumors originate from white matter and in this tissue, we observed higher relative levels of a31, an ASE that is known to influence Ras activity implicated in tumorigenesis. Overarchingly, our results are concordant with known patterns of ASE expression in corresponding human tissues and provide the first characterization of neurofibromin ASE expression in swine.Support or Funding InformationThe research was supported by the Biomedical & Genomic Research Group Discretionary Fund (University of Wisconsin‐ Madison), NF North Central, NF Network, and NF Team Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging.

To characterize the adaptive behavior profile of children with neurofibromatosis type 1 (NF1) and determine its relationship to neuropsychological functioning and non-neoplastic T2-weighted hyperintense brain lesions on brain magnetic resonance imaging (MRI). In this cross-sectional study, we retrospectively reviewed neuropsychological reports from 104 children with NF1 (56 males, 48 females; mean age 10y 4mo; standard deviation [SD] 3y 4mo; range 3y 5mo-17y 6mo), and extracted data from a range of cognitive and behavioral measures, including the Adaptive Behavior Assessment System (ABAS). Brain MRI was retrospectively reviewed in 42 individuals. Adaptive Behavior Assessment System scores were continuously distributed and pathologically shifted by 0.79 to 1.26SD across Conceptual, Social, and Practical domains, and 46.5% of individuals had a composite score in the borderline or impaired range. Impairment in adaptive functioning was correlated with deficits in executive function (r=-9.543, p<0.001), externalizing problems (r=-0.366, p<0.001), and attention (r=-9.467, p=0.001). Cluster analysis revealed three distinct phenotypic subgroups, one of which exhibited normal cognitive ability, but impaired adaptive functioning, with persistent deficits in executive function, behavioral problems, and attention-deficit/hyperactivity disorder symptomatology. There was no relationship between ABAS scores and the number or location of unidentified bright objects. Adaptive functioning deficits are common among children with NF1 and are associated with impairment in other cognitive/behavioral domains, independent of general cognitive ability. Deficits in adaptive behavior are common in children with neurofibromatosis type 1 (NF1). Poor adaptive functioning is associated with impairments in executive function, externalizing behaviors, and attention, regardless of cognitive ability. The presence or location of unidentified bright objects do not predict adaptive behavior skills in children with NF1.

WED 244 CSF cytology alone is unable to predict CNS neoplastic process

Incidence of both primary and secondary central nervous system (CNS) malignancies are increasing, yet detection and diagnosis of which remains challenging. Neurological examination, CSF cytology and neuroimaging each offer diagnostic value, however, individually, each method has relatively low sensitivity. CSF cytology is often routinely requested as part of the diagnostic work-up. Therefore, we reviewed the value of CSF cytology in predicting CNS neoplastic process.We systematically analysed 296 patients who had had CSF cytology. All consecutive patients over the last 2 years were included. The 12 patients positive for CSF cytology were also found to have concurrent; clinical findings (92%), radiological findings (92%), or both (83%). In no patient CNS malignancy was identified by CSF cytology alone. Additionally, only 7 of the 12 CSF positive cases were collected by means of lumbar puncture, the rest were carried out during neurosurgical procedures.We conclude that if there is neither clinical findings nor abnormal neuroimaging, assessing CSF cytology does not contribute towards diagnosis of CNS malignancy. Yield of CSF cytology is high when both clinical and radiological evidence are present. Where neuroimaging is normal but suspicion remains, the low sensitivity of the CSF-cytology would make it a weak corroborator to exclude malignancy.

Oral Manifestation of Neurofibromatosis Type I: a Case Report

Neurofibromatosis is a hereditary condition with at least 8 identified forms; neurofibromatosis type I is the most common. The type I form is characterized by multiple café-au-lait spots and cutaneous neurofibromas, freckles in the axillary and inguinal regions, a brownish spot on the iris, skeletal dysplasias, benign and malignant nervous system tumor growth, and usually a first-degree relative with the same condition. A 35-year-old woman presented with café-au-lait spots and multiple cutaneous neurofibromas, with the oral manifestation as nodules in the palate, alveolar ridge, buccal mucosa, and tongue. A panoramic radiography analysis did not show any change. The histological evaluation of an incisional biopsy of the palate lesion was compatible with the neurofibromatosis diagnosis. Due to difficulty in swallowing caused by the palate lesion, it was surgically removed and a histological evaluation confirmed the diagnosis. The patient continues to be under follow-up with the oral medicine team.

DACH1 inhibits glioma invasion and tumor growth via the Wnt/catenin pathway.

Background/aimGlioma is the most common and malignant nervous system tumor and is associated with high-grade malignancy and high recurrence. The mammalian Dachshund1 (DACH1) is a recognized anti-tumor site and has low expression in several malignant tumors, including glioma. We designed and conducted this study to further determine the mechanism of DACH1 in glioma.Patients and methodsThe data collected from specimens of patients with glioma from GSE16011 and REMBRANDT databases were analyzed. The effect of DACH1 on proliferation, migration, and invasion of U87 and U251 cell lines was analyzed in vitro. The symbol targets of the Wnt/β-catenin pathway were also evaluated through Western blot.ResultsDACH1 deficiency was found in glioma tissues, and the DACH1 level was negatively correlated with the tumor malignancy. DACH1 overexpression inhibited the tumor proliferation, migration, and invasion. High expression of DACH1 also dampened the Wnt/β-catenin pathway, and the activation of the Wnt/β-catenin pathway partly led to the limited proliferation in glioma cells.ConclusionDownregulation of DACH1 was related to the malignancy and poor prognosis of patients with glioma, and DACH1 overexpression inhibited the tumor proliferation via the Wnt/β-catenin pathway. These findings might assist in the discovery of novel potential diagnostic and therapeutic targets for DACH1, thereby reducing the malignancy and recurrence of glioma.

Diagnosis and Management Pathway for High Grade Central Nervous System (CNS) Malignancies

Diagnosis and Management Pathway for High Grade Central Nervous System (CNS) Malignancies

Cancer exosomes in cerebrospinal fluid

Cancer cells secrete extracellular vesicles (EVs), including exosomes, which contain a varied cargo of tumour-specific genetic material such as DNA, mRNA and miRNA. EVs possess the ability to manipulate various functional and pathological characteristics of the donor and recipient cells, in addition to facilitating modifications of the tumour microenvironment, firstly during disease progression and also in response to clinical treatment. ‘Liquid biopsy’ platforms, such as blood based tests for monitoring cancer progression and response to therapeutics, have been part of oncologic care for decades. However, further development of biofluid-based methodologies is required as an important step not only in tumour characterization and the ongoing monitoring of the disease, but also as a basis for creating novel therapies for treating cancer patients. Cerebrospinal fluid (CSF) is another accessible body fluid which can provide an overview of the pathological state of central nervous system (CNS) malignancies such as gliomas. Glioma cells are known to secrete EVs, including exosomes, and CSF is recognized as a route for the potential seeding of invasive cells of CNS tumours. This suggests that CSF-derived exosomes are a promising source of biomarkers that not only have the capacity to mirror the genetic diversity within a tumour at any one time, but to also enable the longitudinal measurements for monitoring genetic changes in the tumour during treatment without the need for repeated tissue biopsies. In this review, we examine the current scientific literature on our current understanding of exosomes in glioma and the relevance of CSF-derived exosomes in this disease.

A cellular platform to enable targeted brain delivery of T cells to glioblastoma.

2053 Background: Poor T cell homing hinders the development of effective cell therapy for central nervous system (CNS) malignancies. Lessons learnt from inflammatory brain diseases can give insight into how to overcome the blood brain barrier (BBB) blockade created by cancer. Activated Leukocyte Cell Adhesion Molecule (ALCAM; CD166) is a pathological adhesion molecule upregulated in the endothelium of a number of inflammatory/infiltrative CNS diseases, such as multiple sclerosis. Antibodies blocking ALCAM decrease leukocyte access to the brain and are currently being tested in a clinical trial for MS. Methods: We studied the difference in the dynamic signature of adhesion molecules in the “anergic” brain tumor endothelium and that of infiltrative brain conditions. Consequently, we mapped the ALCAM minimal binding region to domain 3 (D3) of CD6 and created an artificial molecule with the intent of creating a novel cellular platform to reverse endothelial anergy, through ALCAM specific binding. Results: GBM endothelium fails to launch the second wave of adhesion molecules necessary for firm T leukocyte capture and effective BBB transmigration. Engineered D3 on the T cell crosslinked to ALCAM on endothelial cells in proximity ligation assays (PLA; &lt; 40nm) during TEM. Under shear stress, D3 T cells showed a global improved ALCAM specific trafficking kinetics: higher capture on ALCAM+ endothelium, rolling with slower velocity, and better TEM. In an ex vivo model of BBB, D3 T cells exhibited higher transmigratory ability. We discovered that signaling through the D3 endodomain phosphorylated pZAp70 recruiting Talin that enables LFA-1 (ICAM-ligand) open confirmation, mediating effective TEM. Lastly, in an orthotopic model of GBM, D3 T cells homed more and accumulated at the tumor site compared to NT controls. And, testing Her2 CAR T cells on D3 platform showed an advantageous homing after IV administration which was reflected in tumor control and better survival. Conclusions: We created a cellular platform that enables targeted brain delivery of T cells. This platform serves as a gateway to the effective cellular therapeutics for brain malignancies but potentially as a delivery system for complex biologics for other pathological conditions.

Dissecting Clinical Heterogeneity in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder in which affected children and adults are predisposed to the development of benign and malignant nervous system tumors. Caused by a germline mutation in the NF1 tumor suppressor gene, individuals with NF1 are prone to optic gliomas, malignant gliomas, neurofibromas, and malignant peripheral nerve sheath tumors, as well as behavioral, cognitive, motor, bone, cardiac, and pigmentary abnormalities. Although NF1 is a classic monogenic syndrome, the clinical features of the disorder and their impact on patient morbidity are variable, even within individuals who bear the same germline NF1 gene mutation. As such, NF1 affords unique opportunities to define the factors that contribute to disease heterogeneity and to develop therapies personalized to a given individual (precision medicine). This review highlights the clinical features of NF1 and the use of genetically engineered mouse models to define the molecular and cellular pathogenesis of NF1-associated nervous system tumors.

Depletion of thymopoietin inhibits proliferation and induces cell cycle arrest/apoptosis in glioblastoma cells.

BackgroundGlioblastoma (GBM) is the most malignant nervous system tumor with an almost 100 % recurrence rate. Thymopoietin (TMPO) has been demonstrated to be upregulated in various tumors, including lung cancer, breast cancer, and so on, but its role in GBM has not been reported. This study was aimed to determine the role of TMPO in GBM.MethodsPublicly available Oncomine dataset analysis was used to explore the expression level of TMPO in GBM specimens. Then the expression of TMPO was knocked down in GBM cells using lentiviral system, and the knockdown efficacy was further validated by real-time quantitative PCR and western blot analysis. Furthermore, the effects of TMPO silencing on GBM cell proliferation and apoptosis were examined by MTT, colony formation, and flow cytometry analysis. Meanwhile, the expression of apoptotic markers caspase-3 and poly(ADP-ribose) polymerase (PARP) were investigated by western blot analysis.ResultsThis study observed that the expression of TMPO in GBM specimens was remarkably higher than that in normal brain specimens. Moreover, knockdown of TMPO could significantly inhibit cell proliferation and arrest cell cycle progression at the G2/M phase. It also found that TMPO knockdown promoted cell apoptosis by upregulation of the cleavage of caspase-3 and PARP protein levels which are the markers of apoptosis.ConclusionsThe results suggested TMPO might be a novel therapeutic target for GBM.

Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity

Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/- mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/- mice. Collectively, these findings suggest that disrupting 5-HT6 receptor-neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.

Pattern of malignancies in children

Objectives:To describe the patterns of childhood cancers in Hadhramout Sector, Yemen between January 2002 and December 2014.Methods:This descriptive retrospective study was based on secondary data from Hadhramout Cancer Registry, Hadhramout, Yemen. All Yemeni children under age of 15 years, who were diagnosed with cancer were included. The International Childhood Cancer Classification system was used to categorize cancer types.Results:A total of 406 childhood cancers of both gender <15 years of age were reported. These represented 8.5% of all cases registered. The mean age was 7.34 ± 4.18 years. There were 240 males (59.1%) and 166 females (40.9%) with a male to female ratio of 1.4:1. Calculated incidence of cancer in children in this population is 1.9 per 100,000. The predominant age group was 5-9 years (35%) followed by 10-14 years (33.7%), and 0-4 years group (31%). The most common group of malignancies were hematological malignancies accounting for 47% of cases, followed by nervous system malignancies (15%). The most frequently reported cancer types were lymphoma (24%), leukemia (23%), carcinoma (13.1%), and central nervous system (CNS) tumors (11.6%).Conclusions:There is a lower frequency of childhood cancer in Hadhramout Sector when compared with developed countries. The most common cancers among children were lymphoma, leukemia, carcinoma, and CNS tumors.

Dissecting dysfunctional crosstalk pathways regulated by miRNAs during glioma progression.

Glioma is a malignant nervous system tumor with a high fatality rate and poor prognosis. MicroRNAs (miRNAs) are important post-transcriptional modulators of glioma initiation and progression. Tumor progression often results from dysfunctional co-operation between pathways regulated by miRNAs. We therefore constructed a glioma progression-related miRNA-pathway crosstalk network that not only revealed some key miRNA-pathway patterns, but also helped characterize the functional roles of miRNAs during glioma progression. Our data indicate that crosstalk between cell cycle and p53 pathways is associated with grade II to grade III progression, while cell communications-related pathways involving regulation of actin cytoskeleton and adherens junctions are associated with grade IV glioblastoma progression. Furthermore, miRNAs and their crosstalk pathways may be useful for stratifying glioma and glioblastoma patients into groups with short or long survival times. Our data indicate that a combination of miRNA and pathway crosstalk information can be used for survival prediction.

Metronomic Chemotherapy: Seems Prowess to Battle against Cancer in Current Scenario.

Metronomic chemotherapy is an emerging method of chemotherapy. Metronomic 'lowdose' chemotherapy regimen induces tumour dormancy and reduces cancer resistance against anticancer drugs. It tends to improve overall success rate of cancer chemotherapy than conventional cyclical regimen. The aim of this systemic review was to provide comprehensive data of metronomic chemotherapy trials, regimens used and it's outcome in cancer therapeutics. Fifty chemotherapy trial data were searched sequentially from web. The main sources were official website of Clinical trial forum, USA and Clinical Trial Registry India (CTRI). Evidence on efficacy and safety of such metronomic chemotherapy trials was gathered from various data published in Medline, New England Journal of Medicine (NEJM), Lancet Oncology and other journals with high credentials. As a result of our search, out of 50 trials including breast -15(30%), colon-, 5(10%) ovarian -5(10%), prostate-5(10%) and others including haematologic, soft tissue and nervous system malignancies -20 (50%). Twenty seven trials showed favourable, 20 trials showed equivocal outcome and 3 trials reported unfavourable outcome. Overall comparison showed definitive statistical significance for using metronomic regimen (p-0.05). It can be concluded that metronomic chemotherapy regimen seems convincing beneficial to induce tumour remission and survival at a higher than conventional regimen. More metanalyses are needed to frame common metronomic chemotherapeutic regimen.

Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1.

Ankylosing spondylitis (AS) is a systemic disease primarily characterized by the inflammation of sacroiliac joints and axial skeleton. Neurofibromatosis type 1 (NF1) is a multisystem genetic disease which is characterized by cutaneous findings, most importantly café-au-lait spots and axillary freckling, by skeletal dysplasia, and by the growth of both benign and malignant nervous system neoplasms, most notably benign neurofibromas. In this case report, we present a 43-year-old male with AS and NF1.

IMPS-18OVERCOMING TGFβ-MEDIATED SUPPRESSION OF NK CELL CYTOTOXICITY IN MEDULLOBLASTOMA

Medulloblastoma is the most common pediatric central nervous system (CNS) malignancy, with generally favorable outcomes depending on the molecular subtype. However, current therapies have significant long-term neurologic morbidities, and recurrent/relapsed disease portends a dismal prognosis. Therefore, novel, innovative, and safe therapies are needed. Immune cell therapy is an appealing, targeted approach, and NK cells have shown activity against some adult CNS tumors. However, NK cell adoptive cell therapy may be susceptible to the immunosuppressive effects of TGFβ, either produced by the tumor or the surrounding microenvironment. We have developed a robust expansion platform that yields NK cells in sufficient numbers and cyotoxic potency for therapy. We now seek to overcome TGFβ-mediated suppression to enhance NK cell cytotoxicity for CNS tumors. We show that expanded NK cells are highly cytotoxic against medulloblastoma cell lines, but have diminished cytotoxicity toward medulloblastoma in the presence of soluble TGFβ. The decrease in cytotoxicity correlates with a decrease in NKG2D expression on the expanded NK cells, as has been described for freshly-obtained peripheral blood NK cells. However, we also show that NK cells can be expanded in the presence of TGFβ without affecting their proliferative rate, and that the presence of TGFβ alters the CD16 and KIR expression profile, while maintaining NKG2D levels. Furthermore, NK cells that are expanded in the presence of TGFβ are resistant to the immunosuppressive effects of additional TGFβ. We are also exploring genetic and pharmacologic approaches to generating TGFβ-resistance. Understanding the mechanisms of NK cell immunosuppression by medulloblastoma may lead to a better understanding of the disease, and improved pre-clinical models and clinical trials of NK cell adoptive therapy for medulloblastoma and other pediatric CNS malignancies.

Cancer during pregnancy and the postpartum period: A population‐based study

The purpose of this study was to assess patterns of cancer occurrence during pregnancy and the postpartum period. This was a register-based study using data from the Swedish Multi-Generation Register and the National Cancer Register from 1963 to 2007. Pregnancy-associated cancer (PAC) was defined as a malignancy detected during pregnancy or within 2 years of delivery and was assessed in 7 time windows: pregnancy, trimesters 1-3, 0-6 months, 7-12 months, and second year postpartum. Population incidence rates by 5-year age groups and periods were used to estimate the expected number of PACs for each site. The observed versus the expected (O/E) number of cases was estimated with 95% confidence intervals (CI). The 3 most common malignancies during pregnancy were melanoma (n = 232), breast (n = 139) and cervical cancer (n = 139). With a slightly different rank order, these cancers are also the most common in women of childbearing age. The number of observed cases during pregnancy was lower than expected for all cancers, with a combined O/E ratio for all sites of 0.46 (95% CI, 0.43-0.49). The O/E ratio was close to 1 during all postpartum intervals, including 0-6 months (0.93; 95% CI, 0.88-0.98), 7-12 months (0.96; 95% CI, 0.91-1.01), and during the second year after delivery (0.95; 95% CI, 0.92-0.99). The rate of cancer during pregnancy was lower than expected for all sites, a finding that could not be explained entirely by delayed diagnosis. A rebound in the number of observed cases after delivery was restricted to melanoma, nervous system malignancies, and breast and thyroid cancer.

High-resolution 400K oligonucleotide array comparative genomic hybridization analysis of neurofibromatosis type 1-associated cutaneous neurofibromas

Neurofibromatosis type 1 (NF1) is a genetic disorder where affected individuals develop benign or malignant nervous system tumors. To date, NF1 is caused by mutations in the NF1 tumor suppressor gene located at chromosome band 17q11.2. In this study, we aimed to characterize novel recurrent regional chromosomal imbalances and tumor-related candidate genes in NF1-associated cutaneous neurofibromas. Nine cutaneous neurofibromas from NF1 patients were screened for recurrent chromosomal imbalances using high-resolution 400K oligonucleotide array comparative genomic hybridization (aCGH). All the cases exhibited at least one sub-microscopic abnormality. Regions of recurrent chromosomal imbalances in a least one third of cases were loss of 1q13.2 (33%, FAM19A3), 1q21.1 (44%, RABGAP1L), 2q37.1 (56%, INPP5D), 3p25.1 (67%, CHCHD4), 4p15.32 (56%, FGFBP1), 5q11.2 (56%, ARL15), 6q22.31 (56%, NKAIN2), 6q22.33 (67%, ARHGAP18), 6q25.1 (67%, UST), 7q13 (56%, ADCY1), 12q13.13 (44%, KRT71), 19q13.32 (56%, GRLF1), and 20p11.21 (56%, NLP) and gain of 2p23.3 (76%, C2orf53), 8q22.3 (44%, ODF1) and 8q24.3 (67%, ARC). Several chromosomal imbalances, including loss of 7q11.23, 13q14.1, 14q32.13, 17p12, and 17q11.2 were detected at a lower frequency. We also confirmed that these chromosomal imbalances were not detected in the patient-matched lymphocyte DNAs. Amongst the 6 tumor-related candidate genes (RABGAP1L, ADCY1, SLIT2, GRLF1, UST, and ARC) identified in the regions of recurrent chromosomal imbalances, the gene expression changes of UST (down-regulation) and ARC (up-regulation) were found to be significantly associated with copy number alterations. The novel recurrent chromosomal imbalances and the altered expression levels of the tumor-related candidate genes may be associated with the development of NF1-associated benign cutaneous neurofibromas.

Impact of Comorbidities on Length of Stay and Mortality in Hospitalized Patients with Cancer and Febrile Neutropenia

Background: Hematologic toxicities are common side effects of cancer chemotherapy. Despite advances in supportive care, febrile neutropenia (FN) continues to represent a serious adverse event often requiring hospitalization and is associated with an increased risk of mortality. The purpose of this analysis was to investigate the impact of comorbidities and infectious complications on in-patient length of stay (LOS) and mortality in hospitalized patients with cancer and neutropenia over the past decade. Methods: Hospitalization data from the University Health Consortium database inclusive of the years 2004-2012 from 239 US medical centers were analyzed. Cancer type, presence of neutropenia, comorbidities, and infection type were based on ICD-9-CM codes recorded during hospitalization. This analysis includes adult patients with malignant disease and neutropenia. Patients undergoing bone marrow or stem cell transplantation were excluded. For patients with multiple hospitalizations, the first admission during the time period studied was utilized. Primary study outcomes included hospital length of stay (LOS≥10 days) and in-hospital mortality. Multivariate logistic regression analysis was utilized to study the impact of major comorbidities on the primary outcomes. Major comorbidities under consideration included heart, liver, lung, renal, cerebrovascular, peripheral-vascular disease, diabetes and venous thromboembolism. Results: Among 135,309 patients with cancer hospitalized with neutropenic events, one-third were age 65 years or older and 51% were male. Approximately one-quarter (24.5%) of patients experienced more than one admission with FN. The mean (median) length of stay increased progressively from 11.1 (6) days in 2004 to 12.8 (7) days in 2012. Patients with leukemia, lymphoma and central nervous system (CNS) malignancies experienced the longest mean LOS (21.4, 10.5, 10.2 days, respectively). Overall, 50,846 (37.6%) had a LOS≥10 days and 10,261 (7.6%) patients died during the hospitalization with no difference seen over the time period of observation. (P=.30). Greater rates of mortality were observed in patients with lung (11.2%) or CNS (9.3%) malignancies, and leukemia (9.3%). Infectious complications were documented in 59.5% of patients and their presence was associated with greater LOS≥10 days (48.2% vs. 22.0%) and higher mortality (11.2% vs. 2.3%). Greater LOS≥10 days (51.6% vs. 37.1%) and increased mortality (9.8% vs. 7.5%) were also observed among obese patients with cancer. Likewise, patients with multiple comorbid conditions had more prolonged hospitalizations and a greater risk of in-hospital mortality. (Table) Abstract 2601. Table Solid tumors Lymphoma LeukemiaNo. of comorbiditiesNo. of patients% died% with LOS≥10 daysNo. of patients% died% with LOS≥10 daysNo. of patients% died% with LOS≥10 days017,8580.911.28,1890.617.010,3950.853.5118,1723.417.97,7512.626.611,3803.463.2214,2508.927.25,3868.141.08,6039.769.937,49918.038.42,86118.455.25,04022.877.742,70525.151.41,06033.670.52,00438.183.1≥ 560235.262.327839.980.657749.087.0All patients*61,0867.022.625,5256.632.237,9999.265.4 LOS – length of stay; * 10,699 patients with other type or multiple tumors not included in the table The trend toward longer LOS and greater mortality with increased number of comorbidities persisted in multivariate analyses after adjusting for cancer type, age, gender, ethnicity and type of infection (odds ratio (OR) per +1 comorbidity increase: [mortality: OR =1.89; 95% CI: 1.85-1.92; P&lt;.0001], [LOS: OR=1.56; 95% CI: 1.54-1.58; P&lt;.0001]). Conclusions: Major medical comorbidities are common among hospitalized patients with cancer and neutropenia. Importantly, such comorbidities are associated with prolonged hospitalization and increased risk of in-hospital mortality with significantly worse outcomes in patients with lymphoma or leukemia. Greater awareness of risk factors associated with poor prognosis in cancer patients hospitalized with neutropenic complications as well as validated risk tools to better identify low risk as well high risk patients may guide more personalized cancer care, potentially improving clinical outcomes and lowering the cost of care. Disclosures Crawford: Amgen: Consultancy. Dale:Amgen: Consultancy, Honoraria, Research Funding. Lyman:Amgen: Research Funding.

Abstract IA02: Developing therapies for Ras-driven cancers

Abstract The Ras pathway is one of the most commonly deregulated pathways in cancer. However Ras-driven tumors are often refractory to conventional therapies and a clinically effective targeted therapy has not yet been developed. Moreover, in some cancers KRAS mutations are used to exclude patients from being treated with specific targeted agents. As such, developing an effective targeted therapy for Ras-driven tumors is an important endeavor. We have been focusing on developing therapies for distinct Ras-driven cancers: Nf1-mutant cancers (nervous system malignancies and melanoma) as well KRas/p53-mutant non-small cell lung cancer (NSCLC). We have been using PI3K/mTOR inhibitors as a platform to develop novel combination therapies and have identified several new combinations, a subset of which are being evaluated in the clinic. We have also been deconstructing the mechanism by which these agents cooperate, which is providing insight into developing useful biomarkers and additional drug combinations. Citation Format: Karen Cichowski. Developing therapies for Ras-driven cancers. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA02. doi: 10.1158/1557-3125.RASONC14-IA02