tbuckley/cabot-search huggingface dataset:
Age and RAS status to select patients with metastatic colorectal cancer (mCRC) for initial sequential versus combination therapy including fluoropyrimidines (FP), irinotecan (Iri) and bevacizumab (Bev): XELAVIRI- study
Authors: D. Modest, L. Fischer von Weikersthal, T. Decker, U. Vehling-Kaiser, J. Uhlig, M. Schenk, J. Freiberg-Richter, B. Peuser, C. Denzlinger, C. Peveling genannt Reddemann, U. Graeven, G. Schuch, I. Schwaner, A. Stahler, A. Jung, T. Kirchner, S. Held, S. Stintzing, C. Giessen-Jung, V. Heinemann
Journal: Annals of Oncology (2018)

Introduction: The XELAVIRI (AIO KRK0110) study compared upfront application of FP+BEV plus sequential escalation to IRI+ FP+ BEV (arm A) vs. initial combination therapy with FP+ IRI+ BEV (arm B) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS, primary endpoint) was not shown; Methods: Patients were stratified for age (<65, > =65<75, > =75 yrs) and molecular subgroups (RAS status). TFS as well as overall survival (OS) and 60-day mortality were evaluated in age categories by Kaplan-Meier method, log rank test and Cox regression. Results: Of the full analysis set (FAS) of 421 pts, 128 pts were <65yrs, 177 pts > =65<75 yrs and 116 pts > =75 yrs. In the FAS, age did not seem to influence TFS, but an association of (increasing) age with less OS benefit from initial combination chemotherapy was evident. This finding was pronounced in pts with RAS mutant (MT) as compared to pts with RAS wildtype (WT) mCRC. In pts with RAS WT mCRC, benefit from initial combination chemotherapy was seen in all age categories. 60-day mortality was 1.6% in pts <65yrs, 2.8% in pts > =65<75 yrs and 5.2% in pts > =75 yrs. Conclusion: This exploratory analysis suggests that age and RAS status influence benefit from combination therapy. The trend of increasing 60-day mortality in higher age-categories underlines the necessity for careful patient selection and surveillance during initiation of therapy.
Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors
Authors: Evan M. Chen, Amanda R. Quijano, Young-Eun Seo, Christopher Jackson, Alexander D. Josowitz, Seth Noorbakhsh, Andrea Merlettini, Ranjini K. Sundaram, Maria Letizia Focarete, Zhaozhong Jiang, Ranjit S. Bindra, W. Mark Saltzman
Journal: Biomaterials (2018)
DIPG-38. ID1 EXPRESSION CORRELATES WITH H3F3A K27M MUTATION AND EXTRA-PONTINE INVASION IN DIPG
Authors: Stefanie Stallard, Robert Siddaway, Zachary Miklja, Brendan Mullan, Taylor Garcia, Daniel Zamler, Katayoon Kasaian, Xuhong Cao, Bailey Anderson, Shawn Hervey-Jumper, Maria G Castro, Pedro R Lowenstein, Rajen Mody, Arul Chinnaiyan, Sriram Venneti, Cynthia Hawkins, Carl Koschmann
Journal: Neuro-Oncology (2018)

ID1 regulates transcription by interacting with bHLH transcription factors and previous work has shown that over-expression of the recurrent DIPG H3F3A K27M and ACVR1 mutations in cultured astrocytes lead to an increase in ID1 expression; this has not been validated in human DIPG. DNA (exome)/RNA sequencing of 34 DIPGs and 17 normal samples (SickKids) revealed that ID1 expression was significantly increased in tumor as compared to normal (p=0.001). ID1 expression was significantly higher in H3F3A K27M-mutated tumors as compared to normal (p=0.003), but not in ACVR1-mutated tumors. This was confirmed in an analysis of pediatric high-grade gliomas (PedcBioPortal) where ID1 expression was increased in H3F3A K27M-mutated tumors as compared to H3 wildtype (p=0.0055, n=189), but not in ACVR1-mutated tumors as compared to ACVR1 wildtype (p=0.1178, n=114). In an additional patient with DIPG at autopsy, multi-focal sequencing revealed clonal mutations in HIST1H3B K27M and ACVR1 and ID1 expression correlated with tumor size and cerebellar invasion. We identified several genes whose expression in pediatric HGG correlated with that of ID1 and which have been implicated in invasion and/or metastasis in various solid tumors. ChipSeq revealed reduced K27 me3 and elevated K27 acetylation at the ID1 locus in multiple K27M-mutant DIPG cell lines, pointing to an epigenetic control of this phenotype in H3F3A K27M-mutated DIPGs. Based on these data, we propose that epigenetically controlled upregulation of ID1 promotes DIPG invasion in H3F3A K27M-mutated DIPG and represents an optimal therapeutic target.
Із Нехворощі — у світи Присвячується 150-річчю від дня народження М.М. Лучника
Authors: M.P. Chaban, Z.I. Shevtsova, V.V. Gaponov
Journal: GASTROENTEROLOGY (2018)

Досліджено життєвий шлях, професійну й громадську діяльність земського лікаря Михайла Мусійовича Лучника (1868–?). Понад десять років він очолював Катеринославську колонію для душевнохворих, був громадським діячем, просвітянином, делегатом археологічного з’їзду, садівником, аматором театру, кооператором і експертом на престижній сільськогосподарській, промисловій і кустарній виставці в Катеринославі 1910 року.
Genetic polymorphisms and PG1/PG2 and G17 levels can predict gastric carcinoids in autoimmune atrophic chronic gastritis patients
Authors: R. Cannizzaro, R. Magris, S. Maiero, M. Fornasarig, M. De Zorzi, G. Zanette, C. Mazzon, E. Canton, A. Steffan, V. Canzonieri, V. De Re
Journal: Annals of Oncology (2018)

Introduction: Autoimmune Chronic Atrophic Gastritis (ACAG) is epidemiologically and biologically linked to the development of gastric carcinoids type I (GCs) and gastric adenocarcinoma. ACAG is often associated to multiple autoimmune disorders. The aim of the study was to evaluate the incidence of GCs development and to discover potential diagnostic markers related to GCs in patients (pts) with ACAG. Methods: 141 pts with ACAG were enrolled between years 2006-2017 and endoscopy was performed. Pepsinogen I (PG1), Pepsinogen II (PG2) and Gastrin 17 (G17) serum levels were quantified using an enzyme-linked immune-sorbent assay kit. Serum levels of PGs and G17 were used to discriminate among pts with ACAG and pts affected by GCs in univariate and in multivariate analysis. A panel of genetic polymorphisms of PG2 gene and miRNA, that are known to modulate PG2 expression (rs9471643 C/G; rs6458238 A/G; rs8111742 A/G; rs121224 C/G; rs1002765 A/G; TATA-BOX length), was tested by real time PCR. Results: Out of the 141 ACAG pts (26 M, 115 F; mean age 54,5), 21 (15%) (4M, 17F) presented GCs. A secondary autoimmune disorder was displayed by 98 pts (69,5%) and autoimmune thyroiditis was the most frequent (61,9%). A statistically significant difference in PG1/PG2 and G17 levels was found between ACAG pts with or without GCs (r=-0,3768 95% CI-0,5499 to -0,1726 p = 0,0005). Although it is known that PG2 levels correlate with Helicobacter Pylori (HP) infection in our series of ACAG and GCs and ACAG pts there wasn't a statistical significant difference nor in number of HP positive (+) pts nor in IgG anti HP load (HP+ GCs pts 17,6%, HP+ ACAG pts 30,2%; GCs pts IgG anti HP mean 19,42 SD: ±27,71, ACAG pts IgG anti HP mean 33,43 SD: ±41,43 p=ns). Among the 6 genetic polymorphisms, we found that rs8111742 A/G, rs121224 C/G were associated to a difference in serum PG2 levels and GCs (p = 0,0016 and p = 0,0051). No significant differences were found between pts with thyroiditis and GCs and pts without thyroiditis and with GCs (6,3% and 8,5% p = 0,07). Conclusion: GCs are often diagnosed incidentally during endoscopy. We found a higher association between GCs type I and ACAG than data present in literature and of interest we found a statistically significant difference in PG1/PG2 and G17 levels between ACAG pts with or without GCs. The identification of a different level of PGs ratio and G17 in GCs-positive ACAG could be proposed as a potential indicative marker for a further endoscopic targeted evaluation for GCs in ACAG pts.
MBCL-09. SALVAGE THERAPY FOR CHILDHOOD MEDULLOBLASTOMA: A SINGLE CENTER EXPERIENCE
Authors: Michelle Kameda-Smith, Alick Wang, Noora Abdulhadi, Ashley Adile, Olufemi Ajani, Blake Yarascavitch, Forough Farrokhyar, Petrelli Tina, Constantine Samaan, Cheryl Alyman, Sheila Singh, Adam Fleming
Journal: Neuro-Oncology (2018)

Children diagnosed with medulloblastoma (MB) that are refractory to upfront therapy or experience recurrence have very poor prognoses. Reports of phase I and II studies for these children exist, but these therapies bear significant treatment related morbidity and mortality. A retrospective review of children diagnosed with a pediatric MB from 2002-2015 from the McMaster Pediatric Brain Tumour Study Group (PBTSG) captured a number of pediatric recurrent MB. Over the 13-year period, 31 children with a histological diagnosis of MB were treated. Thirteen children had recurrent or treatment refractory MB. The 2-year event-free survival (EFS) and overall survival (OS) of our cohort was 67.7% and 80.6% respectively. The mean time to recurrence was 14.6 months. The mean follow-up for survivors of recurrent MB was 4.0 years. Ten patients recurred with disseminated leptomeningeal spread and 3 patients experienced local recurrence. In 3 of the 13 recurrent MB, the disease had significantly progressed and the patients were palliated. For the remaining children, therapy offered included surgery, radiation (CSI or CyberKnife), carboplatin, cisplatin, cyclophosphamide, etoposide, imatinib, irinotecan, methotrexate, temsirolimus, temozolamide, tipifarnib, vinblastine, and vincristine either in isolation or in varying combinations. Recurrent MB in our single centre cohort carried a poor prognosis despite administration of salvage therapy. Though there is standardization of the upfront treatment for these children, we observed great heterogeneity in the treatment of our 13 patients experiencing recurrence. A greater understanding of the biology of recurrent MB has the potential to guide salvage therapy.
Incidence of faecal occult blood test interval cancers in population-based colorectal cancer screening: a systematic review and meta-analysis
Authors: Els Wieten, Eline H Schreuders, Esmée J Grobbee, Daan Nieboer, Wichor M Bramer, Iris Lansdorp-Vogelaar, Marco J Bruno, Ernst J Kuipers, Manon C W Spaander
Journal: Gut (2018)

Objective Faecal immunochemical tests (FITs) are replacing guaiac faecal occult blood tests (gFOBTs) for colorectal cancer (CRC) screening. Incidence of interval colorectal cancer (iCRC) following a negative stool test result is not yet known. We aimed to compare incidence of iCRC following a negative FIT or gFOBT. Design We searched Ovid Medline, Embase, Cochrane Library, Science Citation Index, PubMed and Google Scholar from inception to 12 December 2017 for citations related to CRC screening based on stool tests. We included studies on FIT or gFOBT iCRC in average-risk screening populations. Main outcome was pooled incidence rate of iCRCs per 100 000 person-years (p-y). Pooled incidence rates were obtained by fitting random-effect Poisson regression models. Results We identified 7 426 records and included 29 studies. Meta-analyses comprised data of 6 987 825 subjects with a negative test result, in whom 11 932 screen-detected CRCs and 5 548 gFOBT or FIT iCRCs were documented. Median faecal haemoglobin (Hb) positivity cut-off used was 20 (range 10–200) µg Hb/g faeces in the 17 studies that provided FIT results. Pooled incidence rates of iCRC following FIT and gFOBT were 20 (95% CI 14 to 29; I 2 =99%) and 34 (95% CI 20 to 57; I 2 =99%) per 100 000 p-y, respectively. Pooled incidence rate ratio of FIT versus gFOBT iCRC was 0.58 (95% CI 0.32 to 1.07; I 2 =99%) and 0.36 (95% CI 0.17 to 0.75; I 2 =10%) in sensitivity analysis. For every FIT iCRC, 2.6 screen-detected CRCs were found (ratio 1:2.6); for gFOBT, the ratio between iCRC and screen-detected CRC was 1:1.2. Age below 60 years and the third screening round were significantly associated with a lower iCRC rate. Conclusion A negative gFOBT result is associated with a higher iCRC incidence than a negative FIT. This supports the use of FIT over gFOBT as CRC screening tool.
RONC-09. META-ANALYSIS OF THE INCIDENCE AND PATTERNS OF SECOND NEOPLASMS AFTER PHOTON CRANIOSPINAL IRRADIATION IN CHILDREN WITH MEDULLOBLASTOMA
Authors: Abhishek Bavle, Sayani Tewari, Amy Sisson, Murali Chintagumpala, Michael Anderson, Arnold Paulino
Journal: Neuro-Oncology (2018)

Second neoplasms (SNs) are a well-established long-term adverse effect of radiation therapy (RT), but there is limited data regarding their incidence and location relative to the radiation field, specific to medulloblastoma (MB) survivors after craniospinal irradiation (CSI). A systematic literature review, per PRISMA, identified 6 studies reporting the incidence and locations of SNs, for 1114 patients with MB, after CSI, with median follow-up of at least 5 years. The study-specific cumulative incidence (CI) of second neoplasms (SNs), second benign neoplasms (SBNs) and second malignant neoplasms (SMNs) were standardized to a 10-year time-frame. Meta-analysis was performed using mixed and random effects models, with pooled data from selected studies, and an institutional cohort of 55 patients. The 10-year CI was 6.1% for all SNs (excluding skin cancer and leukemia), 3.1% for SBNs and 3.7% for SMNs. Sixty percent of SNs were malignant; high-grade glioma was the most common SMN (15/33; 45%) and meningioma was the most common SBN (17/24; 71%). Forty percent of SNs occurred outside the CNS, primarily outside the target, but in areas of exit RT dose. Seventy eight percent of extra-CNS tumors (18/23) were malignant, most commonly thyroid carcinoma (8/18; 44%) and bone and soft tissue sarcomas (6/18, 33%). Survivors of medulloblastoma are at risk of SNs both within and outside the CNS, in areas of exit RT dose. Studies are needed to determine whether the use of proton therapy, which has no exit RT dose, is associated with a lower incidence of SNs.
MBCL-12. METASTATIC DISEASE IN THE SUPRASELLAR AREA AT DIAGNOSIS IN MEDULLOBLASTOMA
Authors: Helen Toledano, Mika Rootman, Shalom Michowiz, Osnat Konen
Journal: Neuro-Oncology (2018)

Metastatic disease at presentation of medulloblastoma is present in approximately 30% and confers a poor prognosis. Metastases are usually spinal and occult intracranial metastases maybe overlooked. The infundibular recess of the third ventricle is a known site of metastases in various tumors particularly at relapse. The diagnostic brain and spinal imaging of all our medulloblastoma patients from 1/2007 to 12/2017 were assessed by 2 radiologists blinded to patient outcome. We collected clinical data retrospectively from the charts. Of 69 children with medulloblastoma over 11 years, 6 (8.7%) were found to have metastases in this location at presentation (male:female 1:1, mean age 8). In 1 patient the metastasis was biopsied and showed pathology identical to the primary tumor. In 1 patient the metastasis was missed at diagnosis. He was treated on an average risk protocol and subsequently relapsed in the third ventricle. In 2 patients this was a solitary area of metastasis whereas in 4 there was additional extensive spinal disease. In one patient the suprasellar metastasis was symptomatic causing the appearance of the menstrual period at age 8 leading to the diagnostic imaging. None of the others had symptoms referable to their suprasellar metastasis. One patient died due to postoperative complications and 2 died of progressive disease. 3 are still alive (range 9 months - 8 years since diagnosis) including the one who relapsed. The infundibular recess of the third ventricle is a not uncommon site of metastatsis at diagnosis of medulloblastoma and should be actively assessed.
NFM-05. CANCER STEM CELLS PROMOTE RELAPSE IN NEUROFIBROMATOSIS TYPE 1 ASSOCIATED MALIGNANT PERIPHERAL NERVE SHEATH TUMORS
Authors: Daochun Sun, Sameer Farouk Sait, Zilai Wang, Luis Parada
Journal: Neuro-Oncology (2018)

The cancer stem cell (CSC) hypothesis proposes a hierarchy of tumor development, at the apex of which sits a unique set of stem-like cells that are responsible for giving rise to the rapidly proliferating tumor cells and which are the conveyors of drug resistance, tumor spread and reemergence following therapy. Neurofibromatosis type 1 (NF1) associated malignant peripheral nerve sheath tumors (MPNSTs) are malignant sarcomas occurring in 10-15% of NF1 patients. The mortality is high, and approaches 100% in patients with unresectable, metastatic or recurrent disease. Precisely how recurrence occurs is unknown. We developed a transgene, using components of the rat endogenous Nestin promoter and enhancer which contains the herpes simplex virus thymidine kinase gene and GFP (Nes-TK-GFP). This transgene enables labeling of neural stem/neural crest lineage cells plus the ability to specifically eliminate cycling and transgene-expressing cells by ganciclovir (GCV) toxicity. Using an MPNST genetically engineered mouse model (GEMM), we demonstrate that: 1. The transgene is specifically expressed in a subset of MPNST cells that are quiescent (Ki67-;BrdU-); 2. On arrest of tumour cell proliferation with Doxorubicin, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-TK-GFP transgene subpopulation; 3. Elimination of the GFP+ cells with chronic GCV administration significantly impeded tumour development and extended survival in allografts and a spontaneous mouse model of MPNST (cis NP;Nes-TK-GFP). Thus, a relatively quiescent subset of endogenous MPNST cells, with properties similar to CSCs, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.
EPEN-15. RETINOIDS AS POTENTIAL CHEMOTHERAPEUTIC OPTIONS FOR POSTERIOR FOSSA EPENDYMOMA OF CHILDHOOD
Authors: Vladimir Amani, Andrew Donson, Andrea Griesinger, Davis Witt, Jean Mulcahy Levy, Lindsey Hoffman, Todd Hankinson, Michael Handler, Rajeev Vibhakar, Kathleen Dorris, Nicholas Foreman
Journal: Neuro-Oncology (2018)

Chemotherapy has yet to show reproducible therapeutic benefit in ependymoma, and this is partly due to a lack of models for preclinical testing. Treatment of ependymoma has changed little over the last 40 years and is essentially limited to surgery and radiation. Our group has published establishing 2 posterior fossa 1q+ ependymoma cell lines which provides a model for high throughput testing of therapeutic treatments. With the goal of immediate clinical translation, we screened these cell lines for ependymoma-selective drug sensitivity across a panel of 124 FDA-approved oncology drugs. Treatment effect was measured using a tritiated-thymidine incorporation proliferation assay and ependymoma-selective sensitivity was determined by comparison to a panel of other pediatric brain tumor types (medulloblastoma, glioblastoma, DIPG and AT/RT). Upon screening we identified retinoids bexarotene, tretinoin and isotretinoin as effective and ependymoma-selective. Retinoid Acid Receptors alpha and beta (RARɑ and RARβ) and Retinoid X Receptor alpha (RXRɑ) were overexpressed in cell lines and primary samples versus other pediatric brain tumors and normal brain. We examined the effect of retinoids on ependymoma using transcriptomic analysis which revealed Retinoic Acid Receptor Responder 1 (RARRES1) as the most upregulated gene in bexarotene-treated EPN cell lines. RARRES1 is a known tumor suppressor gene described in a variety of human cancers and has been shown to repress mitogen-activated protein kinase (MAPK) activation. We aim to further investigate the mechanism by which retinoids inhibit ependymoma cell growth. These findings may support further clinical evaluation of retinoids as effective chemotherapeutics for ependymoma.
MBRS-09. EphA3 A NOVEL TUMOUR SPECIFIC THERAPEUTIC TARGET FOR MEDULLOBLASTOMA
Authors: Carolin Offenhauser, Benjamin Carrington, Kris Thurecht, Kathleen Ensbey, Zara Bruce, Paul Jamieson, Yi Chieh Lim, Seckin Akgul, Michelle Li, Brett Stringer, Simon Puttick, Adrian Fuchs, Daniel Picard, Wendy Ingram, Andrew Hallahan, Andrew Moore, Terrance Johns, Nicholas Gottardo, Marc Remke, Andrew Boyd, Bryan Day
Journal: Neuro-Oncology (2018)

Targeted tumour specific therapies for children with medulloblastoma are required to improve survival and reduce the significant long-term side effects associated with current treatment protocols. Our study identifies the receptor tyrosine kinase EphA3 as a tumour specific novel therapeutic target for medulloblastoma and demonstrates safety and efficacy of EphA3-targeting antibody-drug conjugates (ADCs) in preclinical primary medulloblastoma xenograft models. Analysis of published medulloblastoma gene expression datasets shows a significant proportion of medulloblastoma samples across all subtypes have elevated expression of EphA3. Immunohistochemistry staining confirmed positive EphA3 expression in medulloblastoma specimens particularly in the perivascular region, a known stem cell niche. Thus, to target EphA3 in medulloblastoma we developed EphA3-ADCs by conjugating our EphA3-targeting monoclonal antibody IIIA4 to the tubulin-inhibitor maytansine. These EphA3-ADCs were highly effective in vitro and, more importantly, showed significant anti-tumour activity while being well tolerated in vivo in primary orthotopic xenograft models of medulloblastoma. Using intravital bioluminescence imaging we found that treatment with EphA3-ADCs reduced tumour burden of established tumours and, as a corollary, significantly improved survival of these tumour-bearing mice, with a commensurate drop in EphA3 tumour expression levels. We propose that combining EphA3-ADCs with current treatment modalities has the potential to improve outcome and may allow de-escalation of current therapies.
NURS-17. PROSPECTIVE SYMPTOM ASSESSMENT IN CHILDREN WITH PROGRESSIVE BRAIN TUMORS
Authors: Elizabeth Gilger, Molly Hemenway, Jennifer Raybin, Chelsea Balian, Jessica Ward, Kathleen Montgomery
Journal: Neuro-Oncology (2018)

Children with brain tumors may have unique symptoms at end of life (EOL) compared to other cancers. Most of the pediatric oncology literature regarding symptoms during palliative care or EOL is retrospective. The study purpose was to prospectively describe symptom frequency, severity, and distress level in children/adolescents with advanced cancer using patient self-report and parent proxy. A data subset of subjects with brain tumors was analyzed. The multi-institutional study used a prospective cohort design. Eligibility included 7-18 years, English-speaking, and advanced cancer diagnosis (2-week history of progressive, recurrent, non-responsive disease, or a decision not to pursue curative-focused therapy). A modified Memorial Symptom Assessment Scale (MSAS) version was used. Symptoms were measured electronically biweekly. Disease status and current treatment were recorded. Data was analyzed using descriptive statistics and univariate logistic regression analysis. Out of 47 patient/parent dyads, 15 [WJ1] had a brain tumor. The most frequently reported symptoms by all subjects were pain (n=195/562, 34.70%), lack of energy (n=186/561, 33.16%), and nausea (n=156/560, 27.86%). However, children with brain tumors reported fatigue (94/185=50.81%), irritation (n=43/130, 33.08%), and pain (n=61/185, 32.97%) most frequently. Disease presence (P=0.0006), recent disease progression (P=0.029),[WJ2] receiving cancer therapy (P=0.0045), and high intensity cancer therapy (P=0.0822) were significant factors related to fatigue. Collecting symptom assessment data prospectively in this population is feasible. Although pain was the most frequently reported symptom overall, fatigue and irritability were more prevalent in brain tumor patients. This finding warrants further investigation and potential intervention.