tbuckley/cabot-search huggingface dataset:
MTHFR, TSER and DPYD gene mutation is associated with toxicity and response in pre-operative chemo-radiotherapy for local advanced rectal cancer
Authors: S. Mancarella, O. Potì, D. De Giorgi, M. Schirinzi
Journal: Annals of Oncology (2018)

Introduction: Radiotherapy and 5 FU based chemotherapy is the most common pre-operative regimen used for cT3-T4, N1 rectal cancer (RC). Evaluation of predictive markers of response and toxicity to radio-chemotherapy is a challenging approach for patients (pts) and drug selection. In the present experience we have analyzed the predictive role of the genetic polymorphisms (MTHFR, TSER and DPYD) on toxicity and response to pre-operative radio-chemotherapy. Methods: We have enrolled eighteen patients with locally advanced RC treated with pre-operative radiotherapy and fluoropyrimidines based chemotherapy. Genetic polymorphisms of MTHFR C677T, MTHFRA 1298C, DPYD IVS 14 + 1G>A, DPYDA 2846T, DPYD T 1679 G, TSER 28 bp VNTR were analyzed by PCR and pyrosequencing of genomic DNA extracted from peripheral blood samples. Genetic markers were correlated with toxicity to treatment (chemotherapy and radio-chemotherapy) and clinical response. Results: Patients characteristics were: male 15 pts, female 3 pts, median age 66 years, ECOG PS 0-1 all pts. We found DPYD IVS 14 + 1 G>A G/G homozygous wild type, DPYD A2846T, T/T homozygous wild type and DPYD T1679 g, T/T homozygous wild type in 100% of pts, homozygous wild type MTHFR C677T in 10% of pts, MTHFR C677T homozygous mutated in 50% of pts, heterozygous MTHFR A1298C in 60% of pts and homozygous wild type MTHFR A 1298C in 40% of pts. Adverse events G-3 (diarrhea, neutropenia, asthenia, mucositis) were observed in 60% of pts with heterozygous MTHFR A 1298C and in 10% of pts with homozygous mutated MTHFR C 677t treated with chemo radiotherapy combination. DPYD homozygous wild type was not associated with severe toxicity. Rectal surgery with TME/TEM will be performed 8 weeks after the end of pre-operative chemo-radiotherapy. We obtained 9 pathological complete response and 9 partial pathological response. Adjuvant chemotherapy was well tolerated without G3-G4 adverse events. Five pts with pathological complete response were treated with Transanal Endoscopic Microsurgery (TEM) and they are alive without recurrence to twelve months after surgery. Conclusion: Concomitant assessment of genetic polymorphisms of MTHFR and DPYD is promising to predict severe toxicity during preoperative chemo-radiotherapy approach for pts with locally advanced rectal cancer. This result does not exclude the need to consider other non-genetic factors that might influence the individual enzyme activities.
Nei Paesi Bassi l'incidenza della pertosse si è mantenuta alta dopo un'epidemia verificatasi nel 1996
Authors: S E Neppelenbroek, H de Melker, J. F.P Schellekens, M A E Conyn-Van Spaendonck
Journal: Eurosurveillance (1999)

Su tutto il territorio dei Paesi Bassi, l'incidenza della pertosse, valutata sulla base delle notifiche, e improvvisamente aumentata nel 1996, in confronto con il valore medio di 2,3/100.000 mantenuto dal 1989 al 1995, raggiungendo i 27,2 casi ogni 100.000 abitanti. Gli aumenti precedenti, nel 1989-1990 e nel 1994, riflettevano le distribuzioni usuali gia osservate in altri paesi, con cicli epidemici compresi tra i tre e i cinque anni, quindi l'epidemia del 1996e stata inaspettata. Non si e potuto spiegarla con cambiamenti nella qualita del vaccino, con interferenze dovute all'introduzione della vaccinazione contro Haemophilus influenzae tipo b nel 1993 o con lacune nella copertura vaccinale (96% all'eta di 12 mesi) (1,2,3).
HOUT-29. COMORBIDITIES IN SURVIVAL OF ADULTS WITH A GLIOBLASTOMA
Authors: Jenny Firkins, Prakash Ambady, Edward Neuwelt
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. A wide range of patient comorbid conditions such as obesity, hypertension, hyperlipidemia and type II diabetes mellitus (DM) may impact treatment-related complications and outcomes. This retrospective, IRB-approved study included 140 adults with pathology-confirmed GBM (WHO grade IV) who initiated chemo-radiation as first line treatment from 2002 to 2016 at Oregon Health & Science University. A total of 140 subjects were included for analysis, 75 of these subjects were simultaneously enrolled in 1 of 3 prospective IRB-approved magnetic resonance imaging studies using ferumoxytol iron oxide nanoparticles as contrast agent. No grade 3 or 4 toxicities were seen with the administration of ferumoxytol, this is consistent with the results of a larger review of 671 administrations of ferumoxytol (Varallyay et al, AJNR in press). Body Mass Index (BMI) was calculated based on primary chemotherapy dose. Comorbidities were defined by American Heart association guidelines. Survival was correlated with comorbidities and adjusted with known predictors of survival: age at diagnosis, performance status at diagnosis, extent of tumor resection, and MGMT methylation status. No difference in survival was seen between subjects who received ferumoxytol and those who did not. Being overweight was associated with a 28% decrease in survival (p=0.039) and hypertension was associated with a 57% increase in survival (p=0.041). We conclude that a higher BMI at diagnosis may adversely impact survival in patients with glioblastoma. Future studies are needed to determine if BMI should be considered a variable for risk stratification and survival analysis for patients with GBM. In our cohort, hypertension was associated with an increase in survival; this could be due to initiation of aggressive monitoring and medical interventions to manage hypertension, though the exact mechanism for both of these results is yet to be determined.
RARE-02. PRIMARY SPINAL CORD EWING’S SARCOMA IN 50-YEAR-OLD WOMAN: A CASE REPORT
Authors: Satoshi Takahashi, Shunsaku Takayanagi, Masako Ikemura, Takahide Nejo, Masashi Nomura, Shunsuke Yanagisawa, Shota Tanaka, Akitake Mukasa, Nobuhito Saito
Journal: Neuro-Oncology (2017)

WHO classification of brain tumor was revised in 2016, with removal of primitive neuroectodermal tumor (PNET) from its classification entity. Thus, tumor previously diagnosed as PNET should be reclassified. In this report, we present a case, in which molecular diagnosis was useful to accurately classify the tumor that was previously diagnosed as PNET to spinal cord Ewing sarcoma. CASE REPORT: 50-year-old woman presented 3 months history of motor / sensory disturbance of both lower -extremities and lower back pain, as well as one week history of walking difficultly. Magnetic resonance imaging (MRI) of the spinal cord showed an intradural tumor that extended from the Th11-12 to cauda equina. She underwent subtotal removal of the tumor. Then postoperatively, she received 39.6 Gy of whole craniospinal irradiation, followed by 14.4 Gy of local irradiation, in combination with chemotherapy (Carboplatin + VP-16). The tumor showed partial response to the chemoradiotherapy. Histopathologic examination revealed malignant small round-cells with hyperchromatic nuclei that were immunoreactive for CD99, synaptophysin and NeuN. Thus, at first the tumor was diagnosed as PNET. However, further molecular investigation revealed EWS(exon7)-FLI1(exon6) fusion gene, that changed the diagnosis of this tumor to Ewing sarcoma. Intramedullary Ewing's sarcoma is extremely rare. Molecular diagnosis was useful to classify spinal cord Ewing sarcoma. The patient was treated following our protocol that had been used for adult medulloblastoma and a good therapeutic response has been obtained.
MS 07.04 Surgical Treatment for Neuroendocrine Tumors other than SCLC
Authors: A. Iyoda, Y. Azuma, T. Makino, H. Otsuka, S. Koezuka, N. Tochigi, K. Shibuya, T. Mikami, K. Isobe, S. Homma
Journal: Journal of Thoracic Oncology (2017)
Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient
Authors: Gwyneth Davies, Janet Stocks, Lena P. Thia, Ah-Fong Hoo, Andrew Bush, Paul Aurora, Lucy Brennan, Simon Lee, Sooky Lum, Philippa Cottam, Joanne Miles, Jane Chudleigh, Jane Kirkby, Ian M. Balfour-Lynn, Siobhán B. Carr, Colin Wallis, Hilary Wyatt, Angie Wade
Journal: European Respiratory Journal (2017)

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants. Forced expiratory volume in 0.5 s (FEV 0.5 ), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls. By 2 years there was no significant difference in FEV 0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45–1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV 0.5 on all test occasions, precluding the ability to identify “high-risk” infants in early life. In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.
P1.06-012 Non-Small Cell Lung Cancer (NSCLC) Patient Characteristics and Clinical Care Insights in Sweden: The SCAN-LEAF Study
Authors: M. Sandelin, M. Planck, J.B. Sørensen, O.T. Brustugun, J. Rockberg, A. Juarez-Garcia, D. Layton, M. Manley Daumont, H. Huang, M. Pereira, J. Svärd, M. Rosenlund, O. Chirita, L. Jørgensen, S. Ekman
Journal: Journal of Thoracic Oncology (2017)
CMET-37. SAFETY AND EFFICACY OF INTRAVENTRICULAR BIOLOGIC AGENTS AS PART OF A MULTI-AGENT INTRAVENTRICULAR TREATMENT REGIMEN FOR PATIENTS WITH NEOPLASTIC MENINGITIS
Authors: Aaron Bernstein, Oliver Mrowczynski, Roy E Strowd, Leah Cream, Roberta Rudà, Suriya Jeyapalan, Richard Eby, David Black, Anna Patrikidou, Silvia Hofer, Andres Ferreri, Michael Glantz
Journal: Neuro-Oncology (2017)

Neoplastic meningitis (NM) is a devastating and increasingly common complication of cancer. Despite multimodal therapy, prognosis is dismal with a median survival of 2–3 months, largely because of therapeutic nihilism and a paucity of treatments considered suitable for intra-CSF administration. Biologic agents represent one of the most active therapies for extra-CNS malignancies, but often have limited access to the CSF when administered systematically, and have not been widely used for intra-CSF administration. All data was obtained from an international neoplastic meningitis registry (NeMeRe). As part of a histology and molecular profile-adjusted multi-agent intraventricular chemotherapy treatment approach, we treated patients with solid tumor and lymphomatous meningitis with regimens including rituximab (45 patients, 193 cycles), trastuzumab (40 patients, 207 cycles in patients with malignant primary brain tumors, 13 patients and 138 cycles in patients with breast cancer), panitumumab (2 patients, 3 cycles), and alpha-interferon (3 patients, 10 cycles). Grade III toxicity occurred in 5.2% of rituximab, 3.1% of trastuzumab, and 0% of panitumumab and alpha-interferon-containing cycles. There was no grade IV or V toxicity. Median survival in patients with lymphomatous meningitis (304 days), solid tumor NM from primary brain tumors (243 days), and HER2-positive breast cancer (not reached, >315 days) was encouraging. A unique rituximab-related toxicity consisting of nausea, vomiting, ascending numbness and tingling, sometimes progressing to severe pain, and generalized malaise, was seen in 7 of 45 patients and was mitigated by dexamethasone and ondansetron prophylaxis. No difference in survival was seen between patients with and without treatment-related toxicity in any histologic group. This large patient series suggests that rituximab, trastuzumab, panitumumab, and alpha-interferon may be safely administered into the CSF, and, as part of a multi-agent intra-CSF treatment regimen, may result in improved survival. Prospective evaluation of this approach is warranted.
PATH-24. MOLECULAR SUBGROUPS OF ADULT EPENDYMAL TUMORS: AN ANALYSIS OF THE GERMAN GLIOMA NETWORK
Authors: Hendrik Witt, Dorothee Gramatzki, Bettina Hentschel, Kristian W Pajtler, Gabriele Schackert, David Capper, Felix Sahm, Andreas von Deimling, Manfred Westphal, Ulrich Herrlinger, Torsten Pietsch, Markus Löffler, Guido Reifenberger, Stefan M Pfister, Joerg-Christian Tonn, Michael Weller
Journal: Neuro-Oncology (2017)
Paving the Path toward Porcine Organs for Transplantation
Authors: Joachim Denner
Journal: New England Journal of Medicine (2017)

The pig heart is a candidate organ for xenotransplantation, but endogenous retroviruses (ERVs) in the pig genome can infect human cells in vitro, raising the specter of zoonotic infection. A recent report describes the generation of healthy pigs free of replication-competent ERVs.
P1.07-043 Barrier Molecule Overexpression is Associated with Increased CD8 T Cells and Decreased B/Treg Cells in Human Lung Cancer
Authors: Y.K. Chae, W. Choi, W. Bae, J. Anker, A. Davis, W. Iams, M. Cruz, M. Matsangou, F. Giles
Journal: Journal of Thoracic Oncology (2017)
Comparsa nella Repubblica Ceca di Salmonella typhimurium DT 104 con resistenza multipla ai farmaci
Authors: R Karpíšková, D Benes, D Dedicova
Journal: Eurosurveillance (1999)

La Repubblica Ceca e un paese dell'Europa Centrale con una popolazione di circa 10 milioni di abitanti. La salmonellosi e l'infezione intestinale notificata piu frequentemente. Fino al1989, sono stati notificati circa 10.000 casi all'anno e Salmonella enteritidis e S. typhimurium sono stati isolati in uguale misura. Dal 1989, i casi di salmonellosi umana sono aumentati rapidamente. Ogni anno, dal 1993 al 1997, sono stati riportati un numero di casi compreso tra 39.862 e 54.554, con un'incidenza compresa tra 386 e 518 casi ogni 100.000 abitanti che ha presentato un picco nel 1995. Il 95% dei casi era dovuto a S. enteritidis e il 3% a S. typhimurium.
PDCT-22. GENOME-WIDE DISCOVERY OF NOVEL SUSCEPTIBILITY POLYMORPHISMS FOR TREATMENT-ASSOCIATED HYPOTHYROIDISM IN PEDIATRIC MEDULLOBLASTOMA
Authors: Austin Brown, Kevin Bielamowicz, Rona Sonabend, Michael Scheurer, Philip Lupo, Arnold Paulino, Zoann Dreyer, Anita Mahajan, Murali Chintagumpala, M Fatih Okcu
Journal: Neuro-Oncology (2017)

Pediatric medulloblastoma patients are at high risk of developing hypothyroidism after craniospinal radiotherapy (CSI). We investigated the role of genetic variation on hypothyroidism susceptibility in children and adolescents with medullobastoma. We reviewed the medical records in 61 medulloblastoma patients treated at Texas Children’s Hospital between 1997 and 2013 who completed baseline and yearly follow-up thyroid function tests. Genome-wide genotyping was performed on Illumina HumanOmni1 and HumanOmni2.5 BeadChip single nucleotide polymorphism (SNP) arrays. Following standard quality control measures and exclusion of rare variants (minor allele frequency [MAF] <5%), 572,562 autosomal SNPs were included in our analyses. The association between each SNP and hypothyroidism was tested using Fisher’s exact test and logistic regression, assuming additive allelic effects. A total of 25 patients (41%) developed hypothyroidism over a median follow-up of 8.3 years from diagnosis (range: 1.8-17.2 years). Primary hypothyroidism was identified in 9 (36%) cases, while the remaining 16 (64%) cases developed central hypothyroidism. Hypothyroidism was detected in 13 of 40 (33%) individuals exposed to <30 Gy CSI and 12 of 21 (57%) individuals exposed to ≥30 Gy CSI (p=0.06). Genome-wide association analysis identified several risk loci, including 3 variants associated with hypothyroidism (p-value<1x10-5) at chromosome 2q11.2 (NPAS2 gene). The top overall SNP (MAF=27.5%, p-value=6.5x10-7) remained strongly associated with hypothyroidism after accounting for possible confounders, including CSI dose, CSI type (proton/photon), age, sex, and genetic ancestry. While these results require replication in an independent population, the preliminary findings suggest susceptibility to treatment-related hypothyroidism is strongly influenced by a common genetic variation in NPAS2. The NPAS2 gene, a central component of the circadian rhythm network, is a transcriptional activator and regulator of DNA damage response and DNA repair genes. Once validated screening strategies for hypothyroidism can be modified based on genetic susceptibility in patients receiving radiotherapy including the thyroid gland.
Abstract 20279: Signalosomes Orchestrate Ouabain-Induced Intracellular Inotropic Signaling
Authors: Anders O Garlid, Ding Wang, Peipei Ping, Keith D Garlid
Journal: Circulation (2016)

Introduction: Receptor-mediated, intracellular signaling leading to cardioprotection and inotropy is orchestrated by signalosome. The caveolar vesicles bud off the plasma membrane, move to mitochon...
EXTH-55. REPURPOSING THERAPEUTICS IN PATIENT-DERIVED GLIOMAS AND AN IDH1 MUTANT GLIOMA MODEL
Authors: Christin Schmidt, Steven Chen, Shirin IIkhanizadeh, Hanna Sabelstrom, Edith Yuan, Andy Ding, William Weiss, Mitchel S Berger, Michelle Arkin, Anders Persson
Journal: Neuro-Oncology (2017)

Malignant glioma is the most common primary brain tumor in adults, where ~70% of newly diagnosed cases represent glioblastoma. As a result, development of novel therapies has focused on this tumor rather than lower-grade gliomas. Mutations of isocitrate dehydrogenase (IDH) genes have been found in ~10% of glioblastomas and ~80% of grade II-III gliomas. Lack of pre-clinical animal models and patient-derived glioma cultures has prevented development of therapies targeting IDH mutant gliomas. Furthermore, IDH1 mutation is emerging as a poor therapeutic target. Instead of targeting highly expressed/amplified targets in glioma, hypermethylation resulting in down-regulation of proteins in IDH1 mutant glioma cells provides a unique opportunity to identify targets that are suppressed, and when inhibited, will sensitize tumors to therapies. To identify novel therapeutics targeting IDH1 mutant glioma cells, we have used the RCAS-Tva system to generate a pre-clinical glioma mouse model and patient-derived cultures displaying IDH1 mutation. We confirmed previous reports demonstrating that IDH1 mutant cells were sensitized to ionizing radiation and showed reduced DNA repair response compared to IDH1 wild-type cells. To repurpose existing therapeutics, we performed high-throughput screening of 2,177 approved compounds in IDH1 wild-type and mutant glioma cultures. We identified families of compounds that showed specificity in reducing cell viability of IDH1 mutant glioma cells, including topoisomerase, HDAC, ATM, BCL2, HSP90, and PI3K/mTOR inhibitors. In contrast, IDH1 wild-type glioma cells showed sensitivity to diverse families of compounds, including those targeting growth factor signaling pathways, PLK1, and HMG-CoA reductase. Identified candidate compounds are currently being validated in vitro and in pre-clinical glioma models. In conclusion, we have identified a number of approved compounds that can quickly be translated from bench to bedside to improve outcome for patients diagnosed with IDH mutant gliomas.
P2.08-003 An Audit of Concurrent Chemoradiotherapy for Non-Small Cell Lung Cancer at the Leeds Cancer Centre (LCC)
Authors: F. Sun, O. Coen, E. Appleton, A. Zeniou, K. Clarke, K. Franks, M. Snee, P. Dickinson, P. Jain
Journal: Journal of Thoracic Oncology (2017)
ANGI-03. THE MIGRATORY SWITCH – INVESTIGATING MESENCHYMAL-AMOEBOID TRANSITION (MAT) IN HIGH GRADE GLIOMAS
Authors: Sophie Taylor, Sabine Knipp, Arndt Rohwedder, Alistair Curd, Nina Struve, Michelle Peckham, John Ladbury, Susan C Short, Anke Brüning-Richardson
Journal: Neuro-Oncology (2017)

One of the most devastating hallmarks of cancer is cell migration/invasion, a prerequisite for tumour metastasis. Targeting this cellular phenomenon offers an opportunity to improve the treatment of invasive and highly migratory tumours such as Glioblastoma multiforme, and to better understand the cellular mechanisms controlling cell migration. Previous work, using a range of migration assays and inhibitors targeting the actin polymerisation pathway, identified a compound, CCG-1423, that distinctively failed to halt migration in 3D invasion assays. We suggest that mesenchymal-amoeboid transition (MAT) is induced by CCG-1423 allowing the switch from one migratory modality to another. It is reported that CCG-1423 reduces the expression of CCN1; a key adhesion protein in mesenchymal migration, by blocking nuclear import of the transcriptional co-activator, MKL1. ELISA assays also confirm significantly reduced CCN1 levels following treatment with CCG-1423 in the established cell lines U251 and U87 compared to untreated controls. In addition, preliminary data using immunofluorescence and western blotting techniques, suggest an increase in MKL1 levels in the cytosol of CCG-1423 treated cells, which is consistent with the absence of MKL1 nuclear import, as previously reported. Phenotypically, CCG-1423 has been shown to induce MAT, visualised using Instant Structured Illuminated Microscopy (iSIM), a super-resolution microscope built and housed at Leeds University. With 150nm resolution and rapid acquisition of Z-stacks, this technology has allowed us to observe in detail a change in morphology from elongated to rounded in treated versus untreated cells detached from the core of U251 spheroids embedded in collagen. Detailed analysis of the iSIM images will allow us to understand the effect of CCG-1423 on MAT and the signalling pathways involved. This will facilitate pharmacological intervention by the development of combination treatments to target both mesenchymal and amoeboid cell migration and to fully prevent glioma cell migration and invasion.
P2.01-015 Longitudinal Assessment of Performance Status (PS) in Patients with NSCLC and ECOG PS 2 on Nab-Paclitaxel–Based Therapy
Authors: N. Abdel Karim, D. Mulford, M. Matrana, H. Ali, E. Santos, T.J. Ong, A. Sanford, K. Amiri, D. Spigel, A. Gajra
Journal: Journal of Thoracic Oncology (2017)
P1.09-004 YB-1 Suppresses miR-137 via a Feed Forward Loop, Increasing YB-1 Levels, Migration and Invasion in Malignant Mesothelioma
Authors: K. Schelch, T. Johnson, K. Sarun, A. Lasham, N. Van Zandwijk, G. Reid
Journal: Journal of Thoracic Oncology (2017)
PATH-50. UNDERSTANDING THE MECHANISM OF BENZODIAZEPINE MEDIATED CELL DEATH IN GABRA5 OVEREXPRESSING GROUP 3 MEDULLOBLASTOMAS
Authors: Laura Kallay, Alexandra Ross, Olivia Moody, Guanguan Li, James Cook, Tobey MacDonald, Andrew Jenkins, Daniel Pomeranz Krummel, Soma Sengupta
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is a common pediatric malignant primary brain tumor originating in the posterior fossa. MB is generally classified into one of four molecular subgroups: Wnt, Shh, Group 3, and Group 4. Group 3 is the most clinically aggressive of the four and exhibits a molecular signature that includes over-expression of the GABRA5 isoform of the GABAA neurotransmitter receptor. Paradoxically, we previously observed that by administration of a positive modulator of the GABAA neurotransmitter receptor, a benzodiazepine, Group 3 cells with a GABRA5 signature could be arrested. We subsequently reported on use of a novel microdevice to screen a broad range of benzodiazepine compounds that functioned as GABRA5 positive modulators. This study identified a new benzodiazepine compound (KRM-II-08) that was particularly efficacious and thus an attractive candidate as a therapeutic against Group 3 MB. Using KRM-II-08 we have examined how a benzodiazepine can effectively arrest Group 3 MB cells. We report on the mechanism underlying the cell cycle arrest.