tbuckley/cabot-search huggingface dataset:
DEV-12. OUTCOME AND TOXICITY OF MEDULLOBLASTOMA IN ALEXANDRIA, EGYPT: 10 YEARS EXPERIENCE
Authors: Zeyad Abdelaziz, Basmaa Elsabe, Ahmed Farhod, Amr Abdelkarim, Shady Fadel
Journal: Neuro-Oncology (2018)

Medulloblastoma is the 2nd most common CNS tumor in children. Current risk stratification into standard and high risk is based on different variables. The treatment setting and socioeconomic status could affect the outcome. We reviewed 55 patients from January 2005. Their age was from 0–20 years old. Male to female ratio was 1.5:1.18% were diagnosed less than 3 years old. CSF analysis was done in 80% of the cases during the initial state. CSF positivity was detected in 20% of the cases. Metastasis at diagnosis was detected in 23.6% of the cases (13 patients). Most of the cases in our study (70.6%) were stratified as high risk. gross total excision was done in 61.8% of the cases (34 cases), while in 38.2 % of the cases subtotal excision was performed. Only 13 cases required ventriculoperitoneal shunt. External beam radiotherapy was received in 83% of cases (44 cases), 87% percent of patients (46 cases) received 1st line chemotherapy, 22% of them were treated by baby protocols. recurrence was documented in 31% of the cases (17 cases), overall survival was 64.7%. progressive disease was the cause of death in 84% of the cases, while uncontrolled infection was responsible for only 16% of the death cases. GTR, Standard risk, and complete response to therapy were the factors that affected the overall survival. Toxicity including hormonal deficiency (23%) and hearing loss (17,3%) were reported in this group. Developing MDT in a low middle income country setting improved the outcome of medulloblastoma patients.
QOL-48. SEIZURE IN PEDIATRIC PATIENTS WITH BRAIN TUMORS
Authors: Viviane Robert-Boire, Béatrice Desnous, Alexander Weil, Sébastien Perreault
Journal: Neuro-Oncology (2018)

Seizures are one of the most common symptoms of pediatric brain tumors. The purpose of this study was to determine seizures frequency and associated risk in pediatric patients with brain tumors. A retrospective study was conducted in a single center over a period of 13 years. Data including demographic, tumor location, pathology, extend of resection, seizure characteristics were collected. A logistic regression model was built to determine which predictors are associated with the occurrence of seizures. Among the 329 children with primary brain tumors, 62 (18.8 %) experienced seizures. Children with cortical tumors were higher at risk to present seizures than patients with infratentorial tumors (OR=96.2; 95% CI=28.8-319.2; p<0,0001). All patients with dysembryoplastic neuroepithelial tumor (DNET, 7/7) and 80% of glioneuronal tumors (8/10) experienced seizures. Twenty-nine patients had focal seizures with impaired awareness (46.8 %), while 25 had focal to bilateral tonic-clonic seizures (40.3 %), and 8 had focal aware seizures (12.9 %). Twenty-nine patients (46.8 %) were eventually seizure-free after antiepileptic drugs withdrawal, while ten patients (16.1 %) had refractory epilepsy. Our study is one of the largest cohorts of children with tumor-related seizures and brings new insight in term of seizures frequency, risk factors and evolution following treatment.
MBRS-33. RNA-SEQUENCING OF MEDULLOBLASTOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODELS ENABLES IDENTIFICATION OF BOTH TUMOR AND MICROENVIRONMENT SPECIFIC BIOMARKERS
Authors: Natalie Jäger, Sebastian Brabetz, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2018)

Therapies for medulloblastoma, a highly malignant pediatric brain tumor, often impose debilitating effects on the developing child, highlighting the need for molecularly targeted treatments with reduced toxicity. Therapies aimed at tumor-intrinsic mechanisms have translated to limited success thus far. More effective therapeutic strategies may also need to target elements of the tumor microenvironment. Current understanding about the medulloblastoma microenvironment is limited, particularly its cellular composition. To identify genes and biomarkers that compose the medulloblastoma microenvironment, we performed whole-transcriptome sequencing and bioinformatics analyses of 16 patient-derived orthotopic medulloblastoma xenografts (PDOXs), comprising all four medulloblastoma subgroups and matching primary tumors, as well as early and late passages for some models. PDOXs were generated by intracranial injection of human tumor cells into the brain of NSG-mice. In PDOXs, mouse stroma supports human cancer cells. Therefore, the transcriptome of PDXs is composed of a mixture of human RNAs (deriving from tumor cells) and mouse RNAs (deriving from stroma) and a species-specific alignment approach allows for the simultaneous study of both tumor and microenvironment specific signals. The majority of genes differentially expressed between the primary tumors and PDOXs are significantly down-regulated in the human fraction of PDOX RNA-seq data, while being expressed in the mouse fraction, confirming that the human stroma is replaced by murine stromal cells. As additional proof-of-concept, these down-regulated genes are highly enriched for immune response-related genes and collagens. Expression of various growth factor genes, for example IGF2, known to play a role in medulloblastoma tumorigenesis, appears to be of stromal origin.
HGG-04. PERICYTE-DERIVED PERIOSTIN IS CRUCIAL FOR NEO-VESSEL FORMATION IN GLIOMA
Authors: Changbin Zhu, Ihsan Chrifi, Yang Zhao, Johan Kros, Caroline Cheng, Jie Ma
Journal: Neuro-Oncology (2018)

Glioblastoma, as the most malignant type, is characterized by robust angiogenesis. In previous study, periostin is one of the highest enriched extracellular matrix components. The latest study pointed that the origin of periostin was glioma initiating cell and associated with glioma progression and prognosis. While, the continuous staining pattern of periostin in tissues which indicated a pericyte-like phenotype did not go parallel with the glioma initiating cell origin. We aim to confirm pericyte is the major source of periostin as well as its functions in pericyte in the angiogenesis of glioblastoma. To this aim, with the support of TCGA and CGGA database, immunostaining and western blot was used to define periostin expressing cells. Further, knocking down periostin in pericyte was followed by 3D-tube formation assay, migration assay to assess the POSTN-mediated pericyte function. Periostin expressing cells majorly displayed the phenotype of mural cells with co-expression of PDGFRB, a well-known pericyte marker. Cells with periostin knockdown displayed a diminished vascular formation when co-cultured with endothelial cells in 3D-tube formation assay. Mechanistically, pericyte with periostin knockdown expressed lower abundance of pro-angiogenic factors mainly via the PDGFB-PDGFRB axis and further affected the activation of intracellular JNK pathway. In addition, the migration of pericyte was attenuated by periostin knockdown mainly via the aberrant modulation of focal adhesion kinase together with the insufficient expression of vinculin. Periositn, as expressed by pericyte, is essential in mediating glioma angiogenesis through various molecular mechanisms. Targeting periostin or its related pathways would be valuable in developing novel therapeutic regimens for GBM patients.
Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways
Authors: Narcis I. Popescu, Robert Silasi, Ravi S. Keshari, Alanson Girton, Tarea Burgett, Sacha S. Zeerleder, David Gailani, Andras Gruber, Florea Lupu, K. Mark Coggeshall
Journal: Blood (2018)
Diagnosis of alpha1-antitrypsin deficiency not just in severe COPD
Authors: A. Nuñez, M. Barrecheguren, E. Rodríguez, M. Miravitlles, C. Esquinas
Journal: Pulmonology (2018)

Alpha1-antitrypsin deficiency (AATD) is a well known genetic risk factor for pulmonary disease and is the most frequent hereditary disease diagnosed in adults. Despite being one of the most common hereditary diseases, AATD remains under-diagnosed because of its variable clinical presentation and the poor knowledge of this disease by physicians. With the aim of identifying clinical differences that could influence early diagnosis, we compared two groups of six AATD Pi*ZZ patients with different lung function severity and clinical expression at diagnosis. On comparing the two groups, we observed a younger mean age at diagnosis and more exacerbations in the severe group, but the percentage of smokers did not statistically differ between the two groups. Our results suggest that AATD continues being a disease suspected on younger patients with a worse lung function. In addition these findings confirm the clinical variability of the disease and that there are still unknown factors that contribute to its development. Therefore, early diagnosis may modify the prognosis of this disease.
Pre- and post-treatment body weight and prognosis in a multiethnic cohort of breast cancer patients.
Authors: Lihua Shang, Nora T. Jaskowiak, Donald Hedeker, Olufunmilayo I. Olopade, Dezheng Huo
Journal: Journal of Clinical Oncology (2018)

1501 Background: Although pre-diagnosis obesity was found to be associated with worse outcomes in breast cancer patients, few studies have been conducted on weight change after diagnosis. African Americans have higher prevalence of obesity than other racial/ethnic populations, but it is unclear if obesity prevalence could explain mortality disparity between African Americans and whites. Methods: Data on body mass index (BMI) prior to, during, or after treatment were available in 3061 breast cancer patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), including 1662 whites, 1183 African Americans and 216 other ethnicities. Multilevel random effects models were used to examine changes in body weight or BMI over time. Cox models were used to investigate the impacts of BMI on overall survival and disease-free survival. Results: At diagnosis, half of African Americans (51.5%) were obese, compared with 27.0% in whites. After 6 months, 1 year, 2 years, and 4 years from diagnosis, African Americans on average have lost 0.73 kg, 1.05 kg, 1.29 kg, and 2.47 kg, respectively (P < 0.0001), while there were only small weight changes in whites ( < 0.31 kg). The impact of pre-treatment BMI on survival was stronger for estrogen receptor (ER) positive patients (hazard ratio [HR] 1.20 per 5 kg/m2, 95% confidence interval [CI]: 1.06-1.36; p = 0.005) than for ER negative patients (HR 1.06 per 5 kg/m2, 95% CI: 0.90-1.24; p = 0.52). African Americans had a 90% higher mortality risk relative to white patients after adjusting for age, stage and other clinical factors (HR 1.90, 95% CI: 1.41-2.55). Further adjusting for BMI at diagnosis, the HR for African Americans changed to 1.81 (95% CI: 1.34-2.43). In the landmark analysis of patients who were followed > 2 years, the multivariable HR for African Americans was 1.64 (95% CI: 1.05-2.58) without adjusting for post-treatment BMI and 1.55 (95% CI: 0.97-2.48) after adjusting for post-treatment BMI. Similar results were observed in the analysis of disease-free survival. Conclusions: African American patients had higher obesity prevalence but had substantial weight loss during and after treatment. The impact of BMI on survival differs by ER status.
IMMU-16. CHARACTERIZING TUMOR-IMMUNE INTERACTIONS IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Nicole Lieberman, Heather Kovar, Kole DeGolier, Amira Davis, Virginia Hoglund, Jeffrey Stevens, Conrad Winter, Gail Deutsch, Nicholas Vitanza, Sarah Leary, Courtney Crane
Journal: Neuro-Oncology (2018)

Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal brain tumor diagnosed in approximately 300 children in the US each year. Radiation modestly extends patient survival and provides temporary relief from symptoms, however, surgical resection is impossible due to the tumor’s location in the brainstem, and no chemotherapeutics have shown any efficacy; death generally occurs less than a year after diagnosis. Due to its ability to specifically eliminate tumor cells while leaving healthy tissue intact, immunotherapy could be a major breakthrough in the treatment of DIPG. As a first step towards the rational development of DIPG-specific cellular immunotherapy, we have characterized the immune microenvironment of DIPG tumors using IHC analysis of TMAs and Nanostring transcript analysis of frozen tumor samples. In contrast to pediatric and adult high-grade cortical gliomas (HGGs), DIPGs exhibit minimal infiltration with CD163+ myeloid cells or CD8+ T cells, consistent with their low mutational burden. Furthermore, unlike adult HGGs in particular, DIPG tumors had low levels of classical immunosuppressive factors including PD-L1, TGFβ, and IL-10. To directly examine the effects of DIPG cells on immune cells, we co-cultured primary tumor cells with immune cells from healthy donors. DIPG tumor cells did not polarize macrophages towards a pro-tumor phenotype, while U87 adult GBM cells did. Furthermore, DIPG cells did not slow T cell proliferation or prevent IFNγ production, while U87 cells did. Together, this suggests that although DIPG tumors are not inducing an immune response, adoptively transferred anti-tumor immune cells will not need to overcome an immunosuppressive microenvironment.
Cost-effectiveness of biomarker testing for treatment choices in advanced non-small cell lung carcinoma: impact of diagnostic strategies and their turnaround times
Authors: Sandrine Loubière, Fabrice Barlesi, Pascale Missy, Franck Morin, Pascal Auquier, Jacques Cadranel
Journal: European Respiratory Journal (2018)

We would like to thank A. Uguen for his correspondence with comments on our article [1]. In this prospective cohort study, the maximum cost for the diagnosis of advanced non-small cell lung cancer (NSCLC) was estimated to be 620 EUR, including EGFR/KRAS/ALK testing. In 52% of the patients in the "at least one biomarker status known", the diagnostic strategy included EGFR/KRAS and ALK testing simultaneously, incurring a mean cost around 550 EUR. In 32% of the "at least one biomarker status known" group, the diagnostic strategy consisted first of a molecular analysis for KRAS with simultaneous immunohistochemistry (IHC) ALK testing, and second a targeted analysis for EGFR, followed by an additional validation by fluorescence in situ hybridisation assay for ALK IHC positive cases, for example at the time of second-line treatment initiation. For those patients, the total cost of the diagnostic strategy was estimated to be 616 EUR. All costs were based on reimbursed prices provided by the French Ministry of Health. Costs and turnaround-time impact of biomarker testing for treatment choices in advanced NSCLC in the NGS era <http://ow.ly/16BV30k8Soz>
DIPG-12. PALLIATIVE TREATMENT FOR DIPG (DIFFUSE INTRINSIC PONTINE GLIOMA) AT KOBE CHILDREN’S HOSPITAL IN JAPAN
Authors: Atsufumi Kawamura, Junji Koyama, Nobuyuki Akutsu, Mai Azumi
Journal: Neuro-Oncology (2018)

Brain stem glioma is common pediatric brain tumor that accounts for 8~20% of them and diffuse intrinsic pontine glioma (DIPG) is the majority. The consensus treatment is radiotherapy but prognosis is very poor, thus most of the cases indicate tumor death and the average survival period is about a year. In most cases, neurosurgeon would be the first specialist doctor whom the family consult with and give the great influence to them. Therefore, it is necessary for us to lead the treatment and also palliative treatment in brain tumor care team at our institute. This report reflects our experience of palliative treatment for 19 DIPG cases in 265 central nervous system tumor from 2010 to 2017. All cases underwent irradiation with Temozoromide (TMZ) and one case has received re-radiation when symptoms and signs got worse after the first radiotherapy. Ventriculo-peritoneal shunt was placed in 5cases which indicated hydrocephalus caused by growth of tumor. The average survival period was 11.7 months and the last place for 6 cases were home, 10 cases were hospital and one was the hospice for childhood terminal disease. As for the administration period, under 1 day was 2 cases, under 5 days was 5, under one month was one and over a month was 2. To keep QOL for DIPG children, it is necessary to make the decision at appropriate time to be able to select the advanced treatments.
TBIO-15. UTILIZING A HISTOLOGY-SPECIFIC SEQUENCING ALGORITHM FOR PRECISION NEURO-ONCOLOGY
Authors: Prajwal Rajappa, Uday Maachani, Rohan Bareja, Kenneth Wang, Andrea Sboner, Caitlin Hoffman, Mark Souweidane, Olivier Elemento, David Pisapia, Jeffrey Greenfield
Journal: Neuro-Oncology (2018)

Given extreme tumor variability and heterogeneity in pediatric neuro-oncology, combined with often dismal prognosis for inoperable and recurrent tumors, advanced sequencing (NGS) platforms are now commonly employed to identify clinically relevant targets to augment the current standard of care. Resected tumor tissue and blood from a histologically diverse patient cohort (n=53) was allocated for various genomic platforms including whole exome sequencing (WES), RNA sequencing, and methylation profiling. If no clinically actionable alterations were found with WES, deeper sequencing was performed at the gene expression level through RNA sequencing and fusion analyses. Methyl capture (RRBS) was utilized to delineate the epigenetic landscape for discreet glial tumors such as ependymomas, high grade gliomas and infiltrative tumors such as DIPG and gliomatosis cerebri (GC). 20% of somatic alterations detected from WES had clinical utility which includes the definition of a targetable mutation or fusion, helping pathology define a specific diagnosis, aiding a clinical team in providing prognosis to a family or facilitating an N of 1 clinical trial with a patient with recurrent or inoperable CNS disease. We have attempted to refine a streamlined and personalized sequencing approach to enhance our ability to eliminate indecision over competing sequencing platforms based on tumor location, and frozen pathology. This has allowed us to deliver actionable, diagnostic and clinically relevant information to treating neuro-oncology teams at a reasonable cost and speed, while serving as a platform to consider more frequent utilization of n of 1 clinical trials.
Survival following curative indented treatment of brain metastases from colorectal cancer: A Danish population-based cohort study
Authors: A. Boysen, A. Ording, A. Astradsson, M. Høyer, K. Spindler
Journal: Annals of Oncology (2018)

Introduction: Brain metastases (BM) are an uncommon presentation of metastatic colorectal cancer (mCRC) with reported incidence of about 2-4%. Previously, the focus has been on a palliative treatment course with whole brain radiation, corticosteroids and supportive care, resulting in an expected survival of a few months. Today, there is an increased awareness towards a localized curative intended treatment approach with either surgical resection, stereotactic body radiotherapy (SBRT) or both. We examined the survival for patients treated with a localized modality for BM from CRC in a nationwide population-based study. Methods: We retrieved data from the Danish Cancer Registry and the Danish National Patient Registry (DNPR) on all patients who underwent surgery for primary CRC during 2000-2013. The study was restricted to patients undergoing surgical resection of an intracranial metastases or those receiving cranial SBRT. For patients with a surgical specimen, the adenocarcinoma histology of BM was validated by the Danish Pathology Register. Patients with other malignant disorders were excluded. Overall survival was calculated from the date of BM treatment until death from any cause. We used the Kaplan-Meier method for survival analysis and for comparison of frequencies the chi2 test. Results: A total of 38131 patients had surgery for a primary CRC and 235 patients underwent a curative intended treatment for BM, comprising resection alone (n = 158), SBRT alone (n = 51) and combined resection and SBRT (n = 26). The median age was 64.8 years (interquartile range 57.3-71.1 years) and a male/female ratio of 49.8%/50.2%. In the cohort of all patients with a resected CRC (n = 38131) rectal cancer comprised 36% compared to 49% in the cohort of BM treated patients (p < 0.001). Furthermore, 3% of patients from the full CRC cohort were registered with a surgical resection of lung metastases, compared to 12% in the group of patients treated for BM (p < 0.001), indicating a higher risk of BM in patients with rectal cancer and lung metastasis. The median survival was 0.8 years (95% CI 0.6-0.9), in the cohort of patients treated for BM (n = 235), and the 1-and 5-year overall survival were 41.7% (95% CI 35.4-47.9%) and 12.7% (95% CI 8-17.8%), respectively. Conclusion: In this national population based study, we report a median overall survival of 0.8 years for patients receiving localized treatment for BM from CRC. Rectal tumors and lung metastasis seem associated to development of BM, and a subset of highly selected patients are long term survivors with a 5-year survival of 12.7%.
Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology
Authors: Chey Loveday, Philip Law, Kevin Litchfield, Max Levy, Amy Holroyd, Peter Broderick, Zsofia Kote-Jarai, Alison M. Dunning, Kenneth Muir, Julian Peto, Rosalind Eeles, Douglas F. Easton, Darshna Dudakia, Nick Orr, Nora Pashayan, Alison Reid, Robert A. Huddart, Richard S. Houlston, Clare Turnbull
Journal: European Urology (2018)

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p = 0.0001), with the majority of familial cases (84–100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.
Effectiveness of echinocandins versus fluconazole for treatment of persistent candidemia: A time-dependent analysis
Authors: Kuan-Yin Lin, Pao-Yu Chen, Yu-Chung Chuang, Jann-Tay Wang, Hsin-Yun Sun, Wang-Huei Sheng, Yee-Chun Chen, Shan-Chwen Chang
Journal: Journal of Infection (2018)