tbuckley/cabot-search huggingface dataset:
MBRS-44. MODELLING THE BRAIN/CSF INTERFACE IN MEDULLOBLASTOMA
Authors: Macha Aldighieri, Franziska Linke, Anna M Grabowska, Ian D Kerr, Beth Coyle
Journal: Neuro-Oncology (2018)

The pathways involved in medulloblastoma dissemination and metastasis remain elusive. Invasive cells must travel from brain parenchyma to other regions in the brain/spine via the cerebrospinal fluid (CSF), where they can form laminar metastases on the surface of the leptomeninges, or nodular tumours. This project aims to develop a 3D culture model representing the basement membrane interface between the brain parenchyma and the CSF in order to isolate migrating cells, and identify gene expression changes that predict and control cell migration. Basement membrane extract (BME) or its major component collagen IV were used to model the basement membrane, and a hyaluronic acid gel was used to model the brain parenchyma. The 3D culture conditions in BME were optimised for a panel of group 3 and group 4 medulloblastoma cell lines. Laminar coating was observed when cells were seeded on top of BME, whereas embedded cells formed large nodules. This appeared to be induced by factors in the secretome of cell clusters, since cell clusters preferentially migrated towards each other rather than along a chemokine gradient. Trans-well migration assays across collagen IV, however, showed that cell lines migrated in response to serum, and a cell line-dependent response to soluble factors was observed. The aim of our model is to isolate RNA from cells as they migrate through the basement membrane interface, allowing the underlying mechanism to be studied by RNA Seq.
MBRS-23. EFFECT OF KNOCKDOWN OF KDM6A BY CRISPR/CAS9 EDITING IN MEDULLOBLASTOMA
Authors: Susan Fosmire, Molishree Joshi, Tim Smith, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2018)

KDM6A and EZH2 are epigenetic regulators that play a key role in embryogenesis and development. Presumably, EZH2 and KDM6A have opposite impact on H3K27me3. KDM6A functions as a demethylase of Histone3 lysine 27 trimethylation and is closely associated with the mixed lineage leukemia 2/3 in creating a transcriptionally active chromatin state through removal of methyl groups. EZH2, on the other hand, is a methyl transferase which catalyzes the trimethylation of Histone3 lysine 27. Several studies including ours have shown that KDM6A is genomically deleted in Group 4 medulloblastoma suggesting it may have a role as a tumor suppressor. The biological role of KDM6A in medulloblastoma is not clear. To better understand the role of KDM6A in MB, in our current study we used the Crispr/Cas9 system to knock out KDM6A in MB cell lines and to determine the effect of KDM6A on MB tumor cell stemness and proliferation. Increased expression of stemcell-associated genes including Nanog, Nestin and Oct4 were observed in cells depleted of KDM6A. Intriguingly, Crispr/Cas9-mediated deletion of KDM6A significantly abolished MB cell neurosphere formation and cell proliferation compared to control cells. As expected, in the knockdown cells there was a concomitant increase in H3K27me3 and decrease in H3K4me3 expression but the overall biological impact of KDM6A deletion was unexpected. This puzzling effect on cells with the knockdown of KDM6A opens a door to investigate the target genes that are affected by the depletion of KDM6A. This study will shine light on new epigenetic therapies in medulloblastoma.
The maximum tolerated dose and biologic effects of 3-amino-pyridine-2-carboxaldehyde thiosemicarbazone (T) in combination with irinotecan (I) for patients with refractory solid tumors
Authors: B. S. Choi, K. D. Holen, D. Alberti, W. Schelman, J. Kolesar, J. P. Thomas, W. Antholine, R. Marnocha, J. Eickhoff, G. Wilding
Journal: Journal of Clinical Oncology (2008)

2527 Background: T is a small molecule inhibitor of ribonucleotide reductase (RR) and has been postulated to act synergistically with I. This study was conducted to determine the toxicity and antitumor activity of T with I. Correlative studies included pharmacokinetics, ABCB1 polymorphisms, and the effects of T on cell cycle and electron paramagnetic resonance (EPR). Methods: This study used standard eligibility criteria; in addition, patients (pts) must have had no prior I and no G6PD deficiency. The treatment plan consisted of I on day 1 with T on days 1–3 of a 21-day cycle. Starting dose (level 1) was I 150 mg/m2 and T 85 mg/m2/d. Polymorphisms in ABCB1 were evaluated by pyrosequencing, T concentrations were evaluated in plasma and erythrocytes by HPLC, and Fe-T, Cu-T and cytochrome c release were evaluated by EPR. Results: 23 pts were enrolled, 10 men, 13 women. Tumor types: 7 pancreatic, 4 lung, 2 cholangio, 2 mesothelioma, 2 ovarian, and 1 each of esophageal, sarcoma, gastric, lymphoma, cervical, and unknown primary. The first pt at level 1 developed a DLT, hypoxia. Thus, I and T doses were reduced to 100 mg/m2 and 60 mg/m2/d. Only 1 of 6 pts had DLT (fatigue) at this dose. Three more pts were then enrolled at level 1, resulting in another DLT, leukopenia. The trial was then amended to evaluate escalating doses of I with a constant dose of T at 60 mg/m2/d. One DLT, infection, was seen at level 3a (I 200 mg/m2). Three of 4 pts at level 4a (I 250 mg/m2) experienced DLT (grade 3 platelets, dehydration, and ALT). Level 3a was determined to be the MTD. Other grade 3 or 4 toxicities included neutropenia, nausea, vomiting, and diarrhea. One PR (NSCLC) was seen. There was an increase in the Fe-T and Cu-T complexes and cytochrome c release observed by EPR 2 and 4 hours after T infusion. Genotyping suggests that pts with wild-type ABCB1 have increased hematologic toxicity. The dose adjusted AUC and Cmax were increased in erythrocytes when compared to plasma. Conclusions: MTD was T 60 mg/m2/d for three days and I 200 mg/m2 on day 1 every 21 days. EPR confirms the formation of Fe-T complexes, which may be a key step in deactivating RR. Antitumor activity in NSCLC was noted at level 1. This study was supported in part by grant UO1-CA062491, SAIC contract 24XS090 and NIH/CTRC grant 1UL1RR025011. No significant financial relationships to disclose.
Clinico epidemiological and therapeutic profile of GIST: Oran center's experience
Authors: F. Boudinar, Z. Sara, B. Larbaoui
Journal: Annals of Oncology (2018)

Introduction: A gastro-intestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastro-intestinal tract (1-3% of all gastro intestinal malignancies). Gastro intestinal stromal tumors are Kit – expressing and Kit (tyrosine kinase receptor – CD117) – signaling driven mesenchymal tumors. The most common location of GIST is stomach (50 – 60%) and small intestine (30 – 40%). Surgical resection of the local disease is the gold standard therapy, the mitotic count is a reliable parameter of prognosis. Imatinib mesylate has shown in main studies tumor control about 80% on metastatic GIST. Methods: A retrospective analysis was performed on 16 patients treated for locally advanced and metastatic GIST in medical oncology department of Oran center from 2013 to 2017. Results: Between January 2013 and December 2017, 16 patients (9 male/7 female) with GIST were diagnosed and treated in our center. Median age was 51 years with range (23- 71). All patients had performance status 0 -1. Diagnoses were based on traditional methods of examination and immunohistochemistry for determination expression C-KIT protein (CD117- CD34) in 100% of cases. There were gastric localization in 56%, mesenteric tumors in 6, 25%, jejunal tumors in 6, 25%, retroperitoneal tumors 6,25%, rectal tumors 6,25%, duodenal tumors 6,25%. Surgery performed in 68, 7%, total gastrectomy in 27%, 2/3 gastrectomy in 9%, abdoperineal resection in 9%, anterior resection in 9%, ileal resection in 9%. High grade tumors in 25%, intermediate grade, low grade tumors in 18,7%. Medication with imatinib was initiated in high grade tumors in adjuvant for 83%. In the locally advanced and metastatic GIST, 1st line by imatinib 800 mg in 37,5%, 2nd line by sunitinib 50 mg in 25%, 3rd line by regorafenib 160 mg in 6,25%. The 3 years survival was 80%, progression in 37,5%, stability in 31,5%, complete response in 31,5%, 1 case of death. Conclusion: A stromal intestinal stromal tumor (GIST) was rare. Diagnoses were based on traditional methods of examination and immunohistochemistry for determination C-KIT protein (CD117 – CD34). The surgical of GIST is the principle treatment. Imatinib indication in metastatic and unresectable forms.
Abstract 11139: Prevalence, Characteristics and Prognostic Associations of Carotid Plaque Among HIV-infected Subjects Free of Known Cerebrovascular Disease
Authors: Sumbal A Janjua, Pedro V Staziaki, Richard A Takx, Hamed Emami, Jakob Park, Alexander V Ivanov, Travis R Hallett, Brian B Ghoshhajra, Javier M Romero, Michael T Lu, Markella Zanni, Steven K Grinspoon, Udo Hoffmann, Tomas G Neilan
Journal: Circulation (2015)

Introduction: The risk of cerebrovascular events is increased among HIV-infected subjects; this risk is independent of conventional cardiovascular (CV) risk factors and may be related to persistent inflammation leading to accelerated carotid atherosclerosis. However, there are no data characterizing the prevalence, characteristics and prognostic associations of carotid plaque among subjects with HIV. Methods: From a clinical registry, we identified all HIV-infected subjects with a CT neck from 2005-2014. Data collection and CT analysis were performed by blinded independent teams and included CV and HIV specific risk factors. CT variables included presence of carotid plaque, plaque composition (calcified/non-calcified/mixed), degree of stenosis [≥ 50%] and high-risk plaque (HRP) features [low attenuation, spotty calcification]. The outcome was a cerebrovascular event (stroke, transient ischemic event) defined by ICD codes and independently adjudicated by a board certified physician. Association between plaque presence, characteristics and HRP with events was tested by Cox proportional hazard models. Results: Of 231 HIV-infected subjects, 32 had prior cerebrovascular disease,15 had poor image quality leaving an n=184 (46±10 yrs, 21% female,12% diabetics, 19% HTN, smoking in 31%, 14% on statins, average LDL of 90±39mg/dl). On CT, 36% had any carotid plaque and 23% had bilateral plaque. Of those with plaque,15% had a stenosis of ≥50% and 70% had any HRP feature. Both plaque and HRP were increased with age, duration of HIV and anti-retroviral therapy. Over a median of 4 yrs,13 (7%) cerebrovascular events occurred. After adjusting for the number of CV risk factors, a carotid plaque [HR: 3.5 (1.1-11) P =0.03, Fig 1A] and any HRP feature [HR: 3.2 (1.0-10) P =0.04, Fig 1B] were associated with incident cerebrovascular events. Conclusions: Among HIV-infected subjects, free of known cerebrovascular disease, carotid plaque and/or HRP predict cerebrovascular events.
MBCL-48. HEARING CHEMOPROTECTION WITH SODIUM THIOSULFATE (STS) IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH STANDARD RISK MEDULLOBLASTOMA
Authors: Edward Neuwelt, Susan Lindemulder, Kristin Knight, Rochelle Fu, Archie Bleyer, Penelope Brock
Journal: Neuro-Oncology (2018)

Platinum based chemotherapies are essential for treating certain pediatric cancers, but cause significant ototoxicity in many patients. While patients with localized medulloblastoma have an overall survival of more than 80%, many survivors develop hearing loss requiring lifelong use of hearing aids and have markedly decreased long term quality of life. In a series of 41 pediatric patients at OHSU treated for standard risk medulloblastoma, 7 (17%) developed ototoxicity after the second cisplatin cycle and 26 (63%) had hearing loss following the fourth cycle. Cisplatin dose reductions were required for 24 (59%) patients due to hearing loss. At the end of treatment 32/38 (84%) had hearing loss and 12 required hearing aids. Two randomized phase III trials, one conducted by the Children’s Oncology Group (COG ACCL0431) and the other by the Société Internationale d’Oncologie Pédiatrique - Epithelial Liver Tumor Study Group (SIOPEL 6), have demonstrated the efficacy of sodium thiosulfate (STS) in protecting children from cisplatin-induced hearing loss. Both studies showed no impact of STS on progression-free or overall survival in patients with localized disease (Freyer, 2017; Brock, 2017). In the COG study medulloblastoma subgroup, hearing loss was seen in 33% (3/9) of those treated with STS vs 100% (10/10) in the observation arm. We conclude that STS may safely and effectively protect against hearing loss in medulloblastoma patients with localized disease.
Impact of exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis: a systematic review of randomised controlled trials
Authors: Alessio Bricca, Carsten B Juhl, Martijn Steultjens, Wolfgang Wirth, Ewa M Roos
Journal: British Journal of Sports Medicine (2018)

Objective To investigate the impact of knee joint loading exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis (OA) by conducting a systematic review of randomised controlled trials (RCTs). Design We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data sources We performed a literature search with no restriction on publication year or language in MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials and Web of Science up to September 2017. Eligibility criteria RCTs investigating the impact of exercise on MRI-assessed articular cartilage in people over 18 years of age. Results We included nine trials, including a total of 14 comparisons of cartilage morphometry, morphology and composition outcomes, of which two included participants at increased risk of knee OA and 12 included participants with knee OA. In participants at increased risk, one study comparison reported no effect on cartilage defects and one had positive effects on glycosaminoglycans (GAG). In participants with OA, six study comparisons reported no effect on cartilage thickness, volume or defects; one reported a negative effect and one no effect on GAG; two reported a positive effect and two no effect on collagen. Conclusions Knee joint loading exercise seems to not be harmful for articular cartilage in people at increased risk of, or with, knee OA. However, the quality of evidence was low, including some interventions studying activities considered outside the therapeutic loading spectrum to promote cartilage health.
Treatment of hip osteoarthritis with glucocorticoids
Authors: Jian Zhou, Biao Liu, Chenxi Li, Yingquan Luo, Tang Liu, Wanchun Wang
Journal: Annals of the Rheumatic Diseases (2018)

Osteoarthritis (OA), also known as degenerative joint disease, hypertrophic arthritis, senile arthritis and articular cartilage osteoarthritis, is a common clinical disease. The common symptoms of OA include pain in affected joints, aggravation after exercise, remission after rest and a feeling of stiffness without activity for a long time.1 OA can occur in any joint, but mainly in the hip joint, knee joint, hand joint and spine facet joint. Recently, it was with great interest that we read the report entitled ‘Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12 week blinded randomised controlled trial’ by Dorleijn and colleagues published online in 7 March 2018 in Annals of the Rheumatic Diseases .2 Dorleijn et al  concluded that an intramuscular glucocorticoid injection showed effectiveness in patients with hip OA on one of the three primary outcomes at 2 weeks postinjection and all primary outcomes showed effectiveness from 4 to 6 weeks. Certainly, the study of Dorleijn et al will be important for …
Chemotherapy for patients with advanced or metastatic pancreatic cancer (AMPC)
Authors: B. Abdelkader El Hakim, F. Braneci, N. Caid, L. Saoudi, R. Ramoul, R. Benemla, S. Rekkache, F. Smaili
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways. Methods: The primary objective of this retrospective analysis is to evaluate overall survival; the secondary objective is to evaluate progression-free survival and toxicity of gemcitabine-cisplatin in AMPC after 4 cycles. Inclusion criteria were histologically proven pancreatic carcinoma, no prior chemotherapy (adjuvant chemotherapy allowed if more than 6 month before), no other serious concomitant illness ECOG PS < 2, adequate renal and liver function, good marrow reserve. Results: From 01/2010 to 12/2015, 90 patients were enrolled in this study. Median age 57.8 ± 1.5 years old (21-80), with a total 410 cycles were administrated, median = 4 (4- 8). All patients were evaluated for efficacy and toxicity. Median of overall survival was 7.1 months[3-17 months]; median of progression free survival was 3.4 months, the overall response rate was 10% and disease control rate was 32% including 10% partial response, 22% had stable disease. Grade ¾ toxicities evaluated were asthenia 3%, leucopenia 1%, neutropenia 2%, anemia 1.5%, vomiting 1.5%, thrombopenia 1%, mucositis 1%. Conclusion: Gemcitabine-cisplatin is moderately effective and well tolerated as first line treatment for AMPC with a correct quality of life. The results of chemotherapy in metastatic or advanced pancreatic cancer remain poor; they must be improved by other therapeutic combinations.
Quality of life by Karnofsky index in patients with gastrointestinal cancer subject to parenteral nutritional therapy
Authors: T. Pessoa, A. Pessoa, P. Aguiar, F. Moreira, R. Pessoa, C. Silva
Journal: Annals of Oncology (2018)

Introduction: The inaccessibility to early parenteral nutrition therapy (NPT) or delayed administration, by a large part of the Brazilian population with gastrointestinal cancer, has a disastrous consequence for the tertiary level of health and fundamentally for the patient due to worsening of its clinical state and tolerance to oncological treatment generating a functional and emotional dependence, reflected in a decrease in their Quality of Life. Currently, 20% of the deaths of cancer patients are secondary to malnutrition, since it influences energy expenditure in a heterogeneous manner. This study aimed to recognize the nutritional repercussions of NPT in patients with gastrointestinal cancer. Methods: This was a longitudinal and quantitative study performed in hospital institutions in Fortaleza, Brazil, comprising 212 patients with cancer of the gastrointestinal tract undergoing NPT. The research was carried out in three phases (I, II and III). In the phase I was performed Global Subjective Nutritional Assessment (ANSG), determination of the Karnofsky Performance Status Scale (KPS) to assess the quality of life, data referring to the fasting time from the prescription of the therapy to its initiation, type of NPT administered and intercurrent in its infusion, in addition to serum lymphocyte and albumin dosage for the evaluation of immunological competence. In Phase II a PPH (Health Promotion Program) was applied in the conscious and familiar patients, from educational actions on NPT. The phase III occurred after 10 uninterrupted TNP pockets where new KPS were determined and new data were collected. It was SPSS software, paired t-test and significance level (p < 0.05). Results: The results showed that 77.67% of the oncology patients had started the NPT severely malnourished and almost half of them still remained approximately 6 to 10 days without any nutritional support until the beginning of NPT. The NPT reduced the risk of complications in patients when it increased the immunological competence of 78.21% and improved the Quality of Life, in functional aspect, raising the KPS = 40 of 76.78% of the patients to KPS = 70, making them able to self-care. The lack of knowledge of NPT was reported by 79.41% of the conscious patients, who presented fear and sadness, replaced after educational actions, by feelings of hope and confidence associated with the improvement of thirst, hunger and weakness. The NPT indices with interruptions were 53.65%, followed by lack of data regarding nutritional status in patients' charts. Conclusion: It was concluded that NPT had a positive impact on patients with improvement in their clinical status and quality of life, but its use in Brazil has not yet been satisfactory and immediate even when the alarming numbers of malnutrition in patients with gastrointestinal cancer are confirmed and your need is essential.
MBCL-46. COMPOUND HETEROZYGOUS MUTATION OF THE PMS2 GENE IN AN INFANT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY AND MEDULLOBLASTOMA
Authors: Claudia Lukas, Melissa Crenshaw, Ignacio Gonzalez-Gomez, Joseph Potthast, Nir Shimony, George Jallo, Stacie Stapleton
Journal: Neuro-Oncology (2018)

Constitutional mismatch repair deficiency (CMMRD) is a rare inherited cancer predisposition syndrome caused by bi-allelic mutations in one of four mismatch repair genes.1 Individuals with CMMRD are at increased risk for childhood-onset brain tumors, hematologic malignancies, gastrointestinal tumors and often have café-au-lait macules (CALMS).2,3 Diagnosis is frequently delayed due to overlapping phenotype with neurofibromatosis 1 (NF1).4,5,6 Additionally, molecular diagnosis and medical management can be challenging when variants of uncertain significance (VUS) are found.7,8,9,10,11 We present an 11-month-old infant, initially evaluated at an outside facility for multiple CALMs and diagnosed with NF1. He subsequently presented with a posterior fossa mass and subtotal resection was performed. Final pathology was desmoplastic medulloblastoma (DM), SHH with P53 genotype. Following chemotherapy, he underwent near total resection. Pathology revealed gangliocytic/gangliomatous differentiation. He subsequently progressed and received radiation and chemotherapy. Due to patient and family history of CALMs, germline mutation analysis was performed and revealed pathogenic variant in one copy of PMS2 (deletion of exon 12) and a VUS in the other copy of PMS2 (p.Ser815Leu). The second copy was felt to be pathogenic based on review of databases and missense change causing a large change in a well conserved area of the gene, diagnostic of CMMRD. The VUS was confirmed paternal and consistent with father’s family history of colon cancer. The pathogenic variant was maternal. CALMs can be indicative of a cancer predisposition syndrome, thus when a child has multiple CALMs or has CALMs and malignancy, clinicians should consider testing for CMMRD and overlapping disorders.