tbuckley/cabot-search huggingface dataset:
DIPG-08. ELECTRONIC SEQUENCING PROVIDES OPTIMIZED QUANTIFICATION OF SERIAL, MULTI-GENE MOLECULAR RESPONSE IN THE CSF OF CHILDREN WITH HIGH-GRADE GLIOMA
Authors: Amy Bruzek, Ashwath Muruganand, Karthik Ravi, Jack Wadden, Clarissa Babila, Leo Tunkle, Kyle Wierzbicki, Stefanie Stallard, Evan Cantor, Tingting Qin, Ian Wolfe, Rajen Mody, Karin Muraszko, Andrea Franson, Patrica Robertson, Cormac Maher, Hugh Garton, Carl Koschmann
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND For pediatric high-grade glioma (pHGG), non-invasive methods for diagnosis and surveillance are needed. Tumors release DNA (tDNA) into cerebrospinal fluid (CSF), allowing for detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of tDNA with a novel, hand-held platform (Oxford Nanopore MinION) could quantify patient-specific CSF tDNA variant allele fraction (VAF) with improved speed and limit of detection compared to established methods. METHODS We integrated required multi-timepoint (0, 2, and 6 months) correlate lumbar punctures (LP) in two ongoing pHGG clinical trials. Using Nanopore technology, we performed amplicon-based PCR on CSF tDNA for recurrent mutations from patient samples (n=19) and normal controls. VAF were determined via MinKNOW, Guppy, MiniMap2, and Integrated Genome Browser. RESULTS Nanopore CSF tDNA demonstrated improved sensitivity (91%) when compare to NGS sequencing (50%). Nanopore analysis of serially diluted CSF sample demonstrated significantly lower limit of detection (attomolar) than typical NGS sample requirement (nanomolar). H3K27M mutation was reliably detected with 1,000x depth sequencing, which was achieved in less than 15 minutes of sequencing after amplification. Multiplexed Nanopore analysis of H3F3A and HIST1H3B was employed when H3 status was unknown. Serial CSF tDNA analysis confirmed multi-gene (H3F3A K27M, PIK3CA, and TP53) molecular remission in a 17-year-old with thalamic diffuse midline glioma that correlated with sustained clinical response to ONC201 (14 months and ongoing). CONCLUSIONS Use of a hand-held, electronic DNA analysis platform allows quantification of multi-gene molecular response with improved speed and limit of detection in the CSF of children with high-grade glioma.
TAMI-62. ANGIOGENESIS INHIBITORS STRONGLY SYNERGIZE WITH THERAPEUTICS TARGETING TUMOR METABOLISM
Authors: Sunada Khadka, Yu-Hsi Lin, Jeffrey Ackroyd, Kenisha Arthur, Yasaman Barekatain, Anton Poral, Theresa Tran, Dimitra Georgiou, John de Groot, Jason Huse, John Asara, Florian Muller
Journal: Neuro-Oncology (2020)

Abstract Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates as state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the OxPhos inhibitor IACS-010759 and the angiogenesis tyrosine kinase inhibitor, Tivozanib. The same results were recapitulated with the anti-VEGFA antibody, Avastin, and the OxPhos inhibitor could be substituted with the Enolase inhibitor HEX, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that Angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.
NIMG-24. GLYCINE AND GLUTAMINE BY MR SPECTROSCOPY ARE IMAGING BIOMARKERS OF GLIOMA AGGRESSIVENESS
Authors: Changho Choi, Pegah Askari, Elena Daoud, Kimmo Hatanpaa, Jack Raisanen, Cheryl Lewis, Michael Levy, Toral Patel, Edward Pan, Bruce Mickey, Elizabeth Maher
Journal: Neuro-Oncology (2020)

Abstract Cancers reprogram their metabolism and the resulting alterations in metabolite concentrations may be closely related to the clinical behavior of the tumors. We evaluated glycine, glutamine and 2-hydroxyglutarate (2HG) in 16 adult subjects with glioblastomas (9 male and 7 female; age 43-64 years, median 58) noninvasively using proton magnetic resonance spectroscopy and examined their association with the cell proliferation rate (MIB-1 labeling index) and overall survival. MRS was acquired using point-resolved spectroscopy (PRESS TE 97ms) at 3T. Metabolite levels were quantified with reference to water. The concentrations of glycine and glutamine were both positively correlated with MIB-1 (p=.002 and .0008 respectively). The sum of glycine and glutamine levels showed stronger association with MIB-1 (p&amp;lt; .0001). In the Kaplan-Meier overall survival analysis, the median survival was significantly shorter in patients with glycine levels higher than 2.3 mM than those with concentrations less than 2.3 mM. For glutamine, the patients with higher than 5.7 mM showed association with poor survival. The log-rank p value was substantially smaller in glutamine compared to glycine (p=.008 vs .04). The sum of glycine and glutamine levels showed stronger association with overall survival. 2HG level greater than 1 mM was associated with long survival, which was as expected since elevation of 2HG represents IDH mutant tumors and IDH mutation carries favorable prognosis. Given the association of low 2HG with poor survival, we tested metabolic ratios to 2HG, in which 2HG estimates &amp;lt; 1 mM were put as 1 mM. The glycine/2HG, glutamine/2HG, and (glycine+glutamine)/2HG showed stronger association with overall survival, compared to glycine, glutamine, and glycine+glutamine. Our data suggested that increased metabolism of glycine and glutamine is closely associated with rapid cell proliferation and poor clinical outcome, suggesting the metabolites as an MRS imaging biomarker of glioma aggressiveness.
Radiation-sensitization in the absence of Bax/Bak
Authors: Bo Lu
Journal: Cancer Research (2006)

4953  Abstract Bax and Bak act as a mitochondrial gateway for various apoptotic signals. However, cells lacking both Bax and Bak are resistant to apoptosis induced by various apoptotic stimuli. Instead, they undergo autophagic cell death. Resistance to apoptosis has been associated with radiation resistance, although little is known regarding the relationship between Bax/Bak -/- and irradiation-induced autophagy. In the present study, we investigated radiation-induced autophagy in the presence or absence of Bax and Bak. We found that mouse embryonic fibroblasts (MEFs) lacking both Bax and Bak are much more sensitive to radiation than the wild-type (WT) MEFs as demonstrated by clonogenic assay. Following radiation, increased levels of cleaved caspase 3 and higher apoptotic index were detected in the WT cells, but not in the Bax/Bak -/- double knockout (DKO) cells. Punctate fluorescence of GFP-LC3, characteristic of autophagy, was significantly increased in the irradiated DKO cells. Electron microscopy revealed that these cells had numerous autophagosomes and lysosomes. Inhibition of autophagy by 3-methyl adenine (3MA) increased the radiation resistance of Bax/Bak-/- MEF cells. In addition, expression of the pro-autophagic proteins APG5 and Beclin 1 was induced by radiation in the DKO cells. These results indicate that deficiency of Bax and Bak sensitized MEF cells to radiation and upregulated non-apoptotic cell death in response to radiation.
DDEL-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS
Authors: Stergios Zacharoulis, Luca Szalontay, Dominic Higgins, Zachary Englander, ZhenZhen Jin, James Garvin, Rebecca Zylber, Eileen Stark, Alexis Maddocks, Chankrit Sethi, Peter Canoll, Steve Dammnett, Craig Cook, Neil Feldstein, Jeffrey Bruce
Journal: Neuro-Oncology (2020)

Abstract Convection-enhanced delivery (CED, the infusion of drugs under controlled pressure to the brain parenchyma via targeted micro-catheters, allows accurate anatomical targeting and delivery of higher (therapeutic) drug concentrations through clinically relevant volumes of brain tissue or tumor. Histone deacetylase inhibitors have been found in vitro to be the most active agents against Diffuse Midline Gliomas (DMGs) Using a novel device (implantable subcutaneous pump connected with catheter directly implanted into the pons/thalamus) we are performing a Phase I safety study of repeated infusions of MTX110 (MTX110, Midatech) in a dose escalation manner. Eligible patients include 3–18 years of age with newly diagnosed DMGs following radiation therapy without evidence of hemorrhage or cysts with intact organ function. Patients undergo a tumor biopsy and a single catheter (Spetzler lumbar shunt catheter, Integra, Plainsboro, NJ) is placed stereotactically into the geometric center of the tumor. A second catheter is inserted subcutaneously with the distal tubing connected to the infusion pump, (SynchroMed II (Medtronic)), also inserted subcutaneously. The infusion pump is prefilled with MTX110 and administered using wireless N’Vison Clinical programmer into two 24-hour infusions, consisting of 20 hours of drug infusions at 0.2mL/hr. The pulse is completed 7 days later. This is a dose escalation study with the infusate consisting of gadolinium and MTX110 (30, 60, or 90 microM). The study describing the first use in children of this device for direct-to-tumor drug delivery is open to recruitment (January 2020) and the preliminary data will be available for presentation by June 2020.
Development and aging of the lymphatic vascular system
Authors: Alejandra González-Loyola, Tatiana V. Petrova
Journal: Advanced Drug Delivery Reviews (2020)

The lymphatic vasculature has a pivotal role in regulating body fluid homeostasis, immune surveillance and dietary fat absorption. The increasing number of in vitro and in vivo studies in the last decades has shed light on the processes of lymphatic vascular development and function. Here, we will discuss the current progress in lymphatic vascular biology such as the mechanisms of lymphangiogenesis, lymphatic vascular maturation and maintenance and the emerging mechanisms of lymphatic vascular aging.
LINC-39. PERFORMANCE STATUS OF PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS TREATED IN MEXICO, A SINGLE-CENTER EXPERIENCE
Authors: Claudia Madrigal-Avila, Alfonso Perez-Bañuelos, Rafael Ruvalcaba-Sanchez, Lourdes Vega-Vega, Gabriela Escamilla-Asiain
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age, they comprise about a quarter of all cancers at this age. Little is known about the specific epidemiology of this group in Mexico and there are no reports of results focused on the Performance Status of patients who are treated in a multidisciplinary setting. OBJECTIVE To describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center. METHODS We report a retrospective chart review of all pediatric patients who presented to the Neuro-Oncology Clinic at Teleton Pediatric Oncology Hospital in Queretaro, Mexico, from December 2014 to January 2020. We analyzed age, gender, the extent of surgical resection and histopathology. Performance Status was assessed using ECOG and Karnofsky/Lansky scores during every patient’s last follow-up visit. RESULTS A total of 56 patients were treated, epidemiology and histopathology variants are similar to those described in the international literature. With a median follow-up of 33 months, 35 patients are alive (62.5%), 28 of them (74.2%) have an excellent Performance Status (ECOG score 0 or Lansky/Karnofsky ≥ 90), 5 (14.2%) scored ECOG 1–2 and only 4 (11.4%) scored ECOG 3–4. CONCLUSIONS A multidisciplinary approach with a focus on Performance Status and the potential for neurological recovery is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term.
The face of CPR
Authors: Stephanie Loke, SL McKernon
Journal: BMJ (2020)

She is known by many names—L’Inconnue de la Seine (Unknown Woman of Seine), the Mona Lisa of Seine, Resusci Annie, and The Most Kissed Girl in the World. She might not have lived to tell the tale, but she has transformed training for medical emergencies and saved many lives. She is the face that we have all kissed during practice for cardiopulmonary resuscitation (CPR), but do we ever stop and wonder about the story behind this mesmerising face?
Does medicine run in the family—evidence from three generations of physicians in Sweden: retrospective observational study
Authors: Maria Polyakova, Petra Persson, Katja Hofmann, Anupam B Jena
Journal: BMJ (2020)

Abstract Objective To examine occupational heritability in medicine and changes in heritability over time, with Swedish population wide administrative data that allowed mapping family trees of physicians spanning up to three generations. Design Retrospective observational study. Setting Individual level administrative registry data from Sweden. Participants Physicians born in 1950-90 and living in Sweden at some time during 2001-16 (n=47 400). Main outcome measures The proportion of individuals with a completed medical degree with at least one parent who also trained in medicine, and the change in this proportion across birth cohorts. Additional analyses were conducted among other relatives (grandparents, aunts and uncles, and siblings) and for individuals with a law degree. Results For 27 788 physicians, where the educational background for both parents was known, 14% had a parent who was also a physician and 2% had two parents who were physicians. The proportion of physicians with at least one physician parent increased significantly over time, from 6% for physicians born in 1950-59 to 20% for physicians born in 1980-90 (P&lt;0.001). The same pattern of increasing occupational heritability was not seen for individuals with law degrees. Conclusions In recent cohorts of physicians in Sweden, one in five had a parent who was also a physician, more than triple the proportion seen for physicians born three decades earlier. A similar pattern was not seen in lawyers, suggesting that increasing occupational heritability in medicine does not reflect intergenerational persistence of high paying degrees alone. Rather, for physicians in Sweden, medicine might increasingly run in families.
Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species
Authors: Ufuk Karakus, Dilara Sahin, Peer R. E. Mittl, Petra Mooij, Gerrit Koopman, Onur Boyman
Journal: Science Translational Medicine (2020)

Stimulation of regulatory T (Treg) cells holds great promise for the treatment of autoimmune, chronic inflammatory, and certain metabolic diseases. Recent clinical trials with low-dose interleukin-2 (IL-2) to expand Treg cells led to beneficial results in autoimmunity, but IL-2 immunotherapy can activate both Treg cells and pathogenic T cells. Use of IL-2 receptor α (IL-2Rα, CD25)-biased IL-2/anti-IL-2 antibody complexes improves IL-2 selectivity for Treg cells; however, the mechanism of action of such IL-2 complexes is incompletely understood, thus hampering their translation into clinical trials. Using a cell-based and dynamic IL-2R platform, we identified a particular anti-human IL-2 antibody, termed UFKA-20. When bound to UFKA-20, IL-2 failed to stimulate cells expressing IL-2Rβ (CD122) and IL-2Rγ (CD132), unless these cells also expressed high amounts of CD25. CD25 allowed IL-2/UFKA-20 complexes to bind, and binding to CD25 in the presence of CD122 and CD132 was followed by rapid dissociation of UFKA-20 from IL-2, delivery of IL-2 to CD122 and CD132, and intracellular signaling. IL-2/UFKA-20 complexes efficiently and preferentially stimulated CD4+ Treg cells in freshly isolated human T cells ex vivo and in mice and rhesus macaques in vivo. The crystal structure of the IL-2/UFKA-20 complex demonstrated that UFKA-20 interfered with IL-2 binding to CD122 and, to a lesser extent, also CD25. Together, we translated CD25-biased IL-2 complexes from mice to nonhuman primates and extended our mechanistic understanding of how CD25-biasing anti-human IL-2 antibodies work, which paves the way to clinical trials of CD25-biased IL-2 complexes.
RARE-19. PEDIATRIC HIGH GRADE GLIOMA WITH DNA REPAIR PATHWAY ABERRATIONS, CLINICAL CHARACTERISTICS AND OUTCOME
Authors: Muhammad Baig, David McCall, Tyler Moss, David Sandberg, Gregory Fuller, Susan McGovern, Arnold Paulino, Amer Najjar, Joya Chandra, Soumen Khatua, Wafik Zaky
Journal: Neuro-Oncology (2020)

Abstract DNA mismatch repair machinery is an integral part of the human genome and its defect has been involved in tumorigenesis and treatment resistance. Heterozygous monoallelic germline loss of function in MLH-1, MSH-2, MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is associated with hematologic malignancies and glioblastoma. We report here the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients had a clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had a known family history of Lynch syndrome upon their diagnosis of glioma. Three patients with high-grade glioma and negative family history, 2 had germline mutations in MMR genes, and one had numerous mutations including MMR genes with microsatellite instability. Patients were initially treated with chemotherapy and radiation for high-grade gliomas (HGG); 5/7 had progression. Median time to progression was 12 months (range: 5–52), and median time from progression to death was 7 months (range: 2–25). One patient had low-grade glioma initially but progressed to HGG and is currently on therapy. Another patient treated with temozolomide and radiation is currently receiving maintenance therapy without any disease recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas are treatment-resistant and have a dismal outcome. Collaborative efforts are needed to better understand this subgroup of pediatric HGG and to define optimal treatment strategy.
INNV-10. EFFECTS OF TTFIELDS USAGE AND DURATION OF USAGE ON CELLULARITY AND Ki67 DISTRIBUTIONS AT AUTOPSY
Authors: Samuel Bobholz, Allison Lowman, Jennifer Connelly, Elizabeth Cochran, Wade Mueller, Sean McGarry, Michael Brehler, Peter LaViolette
Journal: Neuro-Oncology (2020)

Abstract This study used autopsy tissue samples taken from patients with glioblastoma who had undergone Tumor-Treating Fields (TTFields) therapy to examine the effects of treatment usage and duration on cellular and mitotic activity distributions. We hypothesized that treatment duration and percent compliance would be associated with a change in cellularity. Three tissue samples were collected from 10 patients with glioblastoma at autopsy. These samples were specifically collected in regions that demonstrated clear contrast enhancement on the patients’ last clinical imaging, in order to capture regions of suspected active tumor. Samples were stained with both hematoxylin and eosin (HE) and Ki67 immuno-histochemistry (IHC) and digitized at 40X resolution using a digital microscope. A color deconvolution algorithm was used to separate stains, which allowed nuclei segmentation. Number of cells and percent of Ki67 positive cells were computed across 100x100 superpixels. Spearman’s correlations were used to examine the association between TTFields usage (measured as a percent) and duration of use (in days) and signatures of active tumor proliferation, measured as median cellularity and proportion of Ki67 positive cells across each patients’ three samples. Trending negative associations with median cellularity were observed for both TTFields usage (R=-0.60, p=0.065) and duration (R=-0.61,p=0.063). The magnitude of the treatment duration effect increased when controlling for time between diagnosis and death, despite a p-value drop due to the lost statistical degree of freedom (R=-0.62, p=0.073). No significant effects were observed for Ki67 positive staining. These results generally suggest a possible effect of TTFields therapy duration, where longer treatments and increased compliance lead to lower tumor proliferation. However, these results should be interpreted with caution, as larger, more statistically powerful studies will be better suited to assess the generalizability of the preliminary trends seen in these RESULTS: