tbuckley/cabot-search huggingface dataset:
ATIM-36. TEM-GBM-001 STUDY: AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2 &amp; ADMINISTERED TO PATIENTS WITH GLIOBLASTOMA &amp; AN UNMETHYLATED MGMT PROMOTER
Authors: Gaetano Finocchiaro, Bernhard Gentner, Fabio Ciceri, Francesco DiMeco, Federico Legnani, Marica Eoli, Bianca Pollo, Francesca Farina, Andrew Zambanini, Stefania Mazzoleni, Carlo Russo, Luigi Naldini
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Most patients with GBM &amp; an unmethylated O-6-methylguanine-DNA methylase (MGMT) gene promoter, have a poor prognosis with approximately 20% of patients surviving to 2 years. Poor prognosis is likely related to factors including a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) &amp; microglia. A subset of tumor-infiltrating macrophages characterized by expression of the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis &amp; are infrequently found in normal organs. Tie2 is significantly upregulated upon homing to tumors. Gene therapy technology has allowed TEMs to be used as carriers for the local and tumor restricted release of interferon-α (IFN). IFN has antitumor effects, inhibits angiogenesis &amp; modulates the immune system. Cell-based delivery of IFN into the TME by TEMs is expected to provide efficacy, taking advantage of pleiotropic anti-tumor effects &amp; avoiding tolerability issues associated with systemic IFN treatment. We are currently conducting a Phase I/IIa clinical study in Milan (INCB &amp; OSR) to evaluate this therapeutic approach (Temferon) in 21 patients with GBM &amp; unmethylated MGMT promoter (EudraCT Number 2018-001404-11). Eligible patients are identified immediately after first surgical resection. After screening, harvesting of HSPCs occurs followed by 6 weeks of radiotherapy. Non-myeloablative conditioning consists of BCNU &amp; thiotepa followed by administration of non-manipulated HSPCs and Temferon. RESULTS In Part A of the study, 3 cohorts of 3 patients will receive escalating doses of Temferon. After Part A, a single dose of Temferon will be studied in a further 12 patients (Part B). Criteria for study eligibility are the same for both Part A and Part B. Part A is ongoing with the first 2 patients recruited (June 2019) and Temferon is scheduled for administration. An update on the status and progress of the study will be provided.
CBMT-27. ABERRANT AMINO ACID METABOLISM EXPOSE NOVEL FUNCTIONAL VULNERABILITIES IN GLIOBLASTOMA
Authors: Antony Prabhu, Anthony Guastella, Shiva Kant, Pravin Kesarwani, Ichiro Nakano, Prakash Chinnaiyan
Journal: Neuro-Oncology (2019)

Abstract Despite advances in molecularly characterizing glioblastoma, metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant amino acid (AA) metabolism as a central node in glioblastoma. This metabolic phenotype was recapitulated in preclinical models and through a series of investigations designed to determine the biologic consequence of individual AA, we identified branched chain AA (BCAA) and glutamine as the only indispensable AA in glioblastoma, serving as the sole source of nucleotide pools and glutathione, respectively. Although molecularly and/or chemically perturbing these pathways resulted in cytotoxicity in glioblastoma, normal astrocytes demonstrated a similar response, suggesting therapeutic limitations in targeting these core metabolic pathways in cancer. As the glioblastoma microenvironment typically represents a nutrient-deprived state, we went on to determine the capacity of these cells to adapt to AA restricted conditions by only providing these cells with the above-identified indispensable AA. Intriguingly, glioblastoma cells had the unique ability to revert a state of metabolic dormancy. In addition to triggering a reversible proliferative arrest, this dormant phenotype displayed a near-complete shutdown of glycolysis that allowed these cells to adapt and maintain survival in glucose-deprived conditions and elicited profound resistance to ionizing radiation. Studies designed to systemically understand molecular underpinnings driving this unique metabolically dormant state uncovered a functional reliance upon mTOR/p21 signaling to maintain proliferative arrest in nutrient unfavorable conditions. Consistent with these findings, p21 expression was differentially expressed in the perinecrotic core of glioblastoma when compared to the peripheral edge in patient samples. Targeting this novel functional vulnerability through p21 inhibition, thereby, ‘forcing’ proliferation of these cells in nutrient unfavorable conditions, led to robust cytotoxicity specific to dormant cells and enhanced radiation response. Targeting functional vulnerabilities in otherwise therapeutically resistant cells represents a promising clinical strategy in glioblastoma.
RARE-08. ROSAI-DORFMAN-DESTOMBES DISEASE OF THE NERVOUS SYSTEM; A SYSTEMATIC LITERATURE REVIEW
Authors: Ruham Alshiekh Nasany, Anne Reiner, Katherine Panageas, Eli Diamond
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Rosai-Dorfman-Destombes disease (RDD) is a rare non–Langerhans cell histiocytosis with neurologic involvement in fewer than 5% of cases. Data about neurologic RDD is limited. Our objective was to synthesize the clinical literature about presentation, treatments, and outcomes of neurologic RDD. METHODS A multi-database English systematic review search using keywords related to (1) histiocytosis and (2) neurologic involvement. Candidate articles were screened for clinical content. Secondary literature and cases without treatment information were excluded. Sites of involvement, presenting symptoms, treatments, and therapeutic responses were reviewed. RESULTS Of 4768 screened, 153 articles presenting 223 patients were included. Mean age was 37.7 years (range 2–79; IQR 23.5–52.5). 149 patients (66.8%) were male and 74 (33.2%) were female. RDD lesions were located in the dura in 111 (49.8%) of cases, spine in 16.6%, brain parenchyma in 9.0%, orbit in 7.2%, calvarium in 2.7%, and in multiple sites in 13.5%. The most frequent presenting symptoms were headache in 101 (45.3%.), focal neurological deficits (32.7%), visual symptoms (31.8%), seizures (24.7%), cranial (11.7%), and cerebellar dysfunction (11.2%). Cognitive decline, masses were less common presentations. First-line treatments included resection, radiation, corticosteroids, chemotherapy, and combinations of these. First-line treatment led to complete (CR) or partial response (PR) in 153 (68.6%) of cases, stable disease in 30 (13.5%), and progressive disease in 40 (17.9%). CR or PR was observed in the calvarium in 5/6 (83.3%), dura in 82/111 (73.9%), spine in 29/37 (78.4%), orbit 8/16 (50.0%), parenchyma in 15/20 (75.0%), and multiple sites in 14/30 (46.7%). 47 (21.1%) of patients required second-line therapy. DISCUSSION Neurologic RDD is a rare form of histiocytosis with varying sites of involvement, clinical presentations, and responses to treatment. Further investigation of effective therapies for neurologic RDD may improve outcomes for this disease.
Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: Up to now and next steps
Authors: Rodrigo Cañada Trofo Surjan, Elizabeth Santana dos Santos, Sergio do Prado Silveira, Fabio Ferrari Makdissi, Marcel Autran Cesar Machado
Journal: Clinical and Molecular Hepatology (2019)

What is the cause of acute hepatic encephalopathy in a young patient?" regarding an 18-year-old patient with a large FLHCC has been answered, including its precise pathophysiology.Nevetheless, a few more steps must still be taken.First, the molecular basis of the proposed pathophysiology is needed to be proven.Second, there were more studies are warranted to demosntrate the efficacy and safety of these new treatment options.Third, this treatment regimen for hyperammonia may be useful for other causes of liver-related HAE such as portosystemic shunt, acute liver failure and cirrhosis.
CSIG-21. DE-ORPHANIZING GPR133 - AN ADHESION GPCR REQUIRED FOR GLIOBLASTOMA PROGRESSION
Authors: Joshua Frenster, Hediye Erdjument-Bromage, Gabriele Stephan, Shravanthi Chidambaram, Abdulhakeem Alghamdi, Devin Bready, Norbert Straeter, Ines Liebscher, Torsten Schoeneberg, Thomas Neubert, Dimitris Placantonakis
Journal: Neuro-Oncology (2019)

Abstract We previously found GPR133 (ADGRD1), an orphan adhesion GPCR, is de novo expressed in glioblastoma (GBM) and enriched in patient-derived glioblastoma stem cells (GSCs). Knockdown of GPR133 reduces GBM cell proliferation and tumorsphere formation, and abolishes orthotopic tumor initiation in vivo in mice. Analysis of TCGA data indicates that increased GPR133 transcription inversely correlates with patient survival in GBM. While these findings underscore the importance of GPR133 in GBM and suggest an essential role in tumor growth, its ligand and mechanism of activation remain unknown. Toward identifying GPR133 ligands, we used GPR133’s N-terminal ectodomain as bait and performed affinity co-immunoprecipitation (CoIP) followed by mass spectrometry as an unbiased screening approach. We identified 490 extracellular proteins with enriched binding to GPR133 compared to control. Reverse CoIP using the 15 most abundant candidate ligands as bait to purify the receptor confirmed this interaction reproducibly in 4 candidates. Despite this binding, overexpression of these candidate ligands, or addition of purified recombinant protein, is not sufficient to increase receptor signaling as assessed by cAMP levels in HEK293 cells. This suggests that ligand binding to the GPR133 ectodomain may not be sufficient by itself to induce receptor activation. We hypothesize receptor activation requires mechanical forces in addition to ligand binding. Consistent with this hypothesis, the GPR133 binding proteins we have identified may be anchored to the extracellular matrix, mediating such mechanical force. To test whether mechanical shearing of the extracellular domain is sufficient for receptor activation, we used Dynabeads coupled to antibody against GPR133’s N-terminal ectodomain, and indeed observed receptor activation leading to elevated cAMP levels. No activation was observed when Dynabeads devoid of antibody were used. This mode of GPR133 activation might indicate a role in sensing mechanical/viscoelastic properties of GBM extracellular matrix, which may be relevant to tumor cell migration and invasion.
RARE-53. THE ROLE OF RADIATION AND CHEMOTHERAPY IN ADULT PATIENTS WITH HIGH-GRADE BRAINSTEM GLIOMAS
Authors: Panagiotis Kerezoudis, Victor Lu, Mohammed Alvi, Anshit Goyal, Mohamad Bydon, Sani Kizilbash, Terry Burns
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND High-grade gliomas (HGGs) of the brainstem represent a rarer subtype of central nervous system tumors compared to their supratentorial counterpart. Predictors of survival and patterns of care have not yet been established on a national, multi-institutional scale. METHODS The National Cancer Database was queried for adult cases surgically diagnosed with brainstem high-grade glioma. An array of patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Predictors of survival were investigated using multivariable Cox proportional hazards regression analysis adjusting for age, insurance status, Charlson comorbidity score, tumor grade, tumor size and type of treatment. RESULTS A total of 422 patients (median 51 years, 60% males) were analyzed. Two hundred eighty one received postoperative radiation with chemotherapy (66.6%), thirty-nine had radiation alone (9.2%), while the remaining had no adjuvant treatment (24.2%). Median radiation dosage was 54Gy. Overall median survival was 9.8 months (95% CI 8.8–12). Survival was significantly longer (p&lt; .001) in the chemotherapy+radiation group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no adjuvant treatment (median:1.8 months, 95% CI 1.4–4). In multivariable analysis, increasing age (HR 1.87, 95% CI 1.47–2.37, p&lt; .001) was associated with worse survival, whereas radiation with chemotherapy (HR 0.67, 95% CI 0.46–0.98, p=0.038) were associated with lower hazards of death compared to radiation alone. In subgroup analysis, the effect of adjuvant chemotherapy with radiation remained significant for grade IV (HR 0.46, 95% CI 0.28–0.76, p=0.003), but not for grade III tumors (HR 0.87, 95% CI 0.48–1.58, p=0.65). CONCLUSION Findings of the present analysis demonstrate the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should aim on identifying specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.
The Innate Immune Sensor Sting Promotes Donor CD8+ T Cell Activation and Recipient APC Death Early after Preclinical Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Cameron S. Bader, Henry Barreras, Casey O. Lightbourn, Sabrina N. Copsel, Dietlinde Wolf, Jingjing Meng, Jeonghyun Ahn, Krishna V Komanduri, Bruce R. Blazar, Lei Jin, Glen N. Barber, Sabita Roy, Robert B. Levy
Journal: Blood (2019)
Lung Cancer Among White South Africans
Authors: G. Myddelton
Journal: BMJ (1965)

MEDIALORThis patient, a woman 20 years old, pre- sented at this Department on 20 July 1964 with a lesion on the left cheek below the left eye.This was erythematous, slightly scaly, somewhat raised, and circumscribed by a ring of vesicles.It measured 4.25 cm. in diameter, and was of six weeks' duration.The patient's history was not contributory.Scrapings from the lesion revealed mycelium, and on culture yielded T. megninii.The maproscopical and microscopical morphology was typical of the species.Further- more, this strain demonstrated clearly, in two successive cultural tests, its absolute requirement for histidine on the synthetic basal medium de- vised by Georg for this purpose.'On this medium it is unable to produce any growth in the absence of histidine, whereas T. rubrum, which in many other respects it resembles, is able to grow well on this medium, irrespective of the presence or absence of histidine.This strain of T. megninii was sensitive in vitro at 27' C.to 10 jug./ml. of griseofulvin in Sabouraud glucose broth.For comparison with this strain, one of the isolates of T. megninii obtained by Dr. I. Sarkany and his colleagues at the Royal Free Hospital, London, was used in parallel series in these tests, and they were found to be similar in all respects.Treatment of the patient was begun with fine- particle griseofulvin, in the dosage of 125 mg.four times daily.-The lesion responded well at first to this drug, which was stopped only when the erythematous reaction had almost cleared, and scrapings were microscopically negative.Instead, ung.betnovate was prescribed.One week later, on 11 August 1964, the patient re- turned with three discrete circumscribed lesions within the area of the initial lesion (see Fig. ) and scrapings from them were not only positive microscopically, but also on culture yielded T. megmnii for the second time.Accordingly, fear- ing that the ung.bemnovate had been responsible for its exacerbation, this drug was promptly withdrawn and griseofulvin prescribed again twice daily.However, despite these measures, the lesion remained active for another 22 weeks, during which period T. megnrnii was isolated from it for the third, fourth, and fifth times, respectively on 29 September and 30 November 1964, and on 26 January 1965.Then at three subsequent examinations, the last on 16 March 1965, scrapings were negative microscopically and on culture.By this date also, about eight months after the patient's first visit to this clinic, the lesion had completely cleared and she was accordingly discharged.
Long-Term Hypoxic/Hypocapnic Storage of Red Blood Cells Results in Amelioration of Lesion Hallmarks and Increased In Vivorecovery at 24 Hours Post-Transfusion
Authors: Jose A Cancelas, F. Bernadette West, Matthew Karaffin, Tatsuro Yoshida, Neeta Rugg, Pamela Whitley, Michael Dioguardi, Scott Brooks, Michael Wellington, William Iselin, Andrew Dunham
Journal: Blood (2019)
Noninvasive Detection and Localization of Genitourinary Cancers Using Urinary Sediment DNA Methylomes and Copy Number Profiles
Authors: Zhengzheng Xu, Guangzhe Ge, Bao Guan, Zhentao Lei, Xueyu Hao, Yuanyuan Zhou, Yue Shi, Huan Lu, Jilu Wang, Ding Peng, XiKang Wu, Huiying He, Bao Zhang, Xuesong Li, Liqun Zhou, Weimin Ci
Journal: European Urology (2019)
Dissecting the Transcriptomic Basis of Phenotypic Evolution in an Aquatic Keystone Grazer
Authors: Dagmar Frisch, Dörthe Becker, Marcin W Wojewodzic
Journal: Molecular Biology and Evolution (2019)

Knowledge of the molecular basis of phenotypic responses to environmental cues is key to understanding the process of adaptation. Insights to adaptation at an evolutionary time scale can be gained by observing organismal responses before and after a shift in environmental conditions, but such observations can rarely be made. Using the ecological and genomic model Daphnia, we linked transcriptomic responses and phosphorus (P)-related phenotypic traits under high and low P availability. We mapped weighted gene coexpression networks to traits previously assessed in resurrected ancient (600 years old) and modern Daphnia pulicaria from a lake with a historic shift in P-enrichment. Subsequently, we assessed evolutionary conservation or divergence in transcriptional networks of the same isolates. We discovered highly preserved gene networks shared between ancient genotypes and their modern descendants, but also detected clear evidence of transcriptional divergence between these evolutionarily separated genotypes. Our study highlights that phenotypic evolution is a result of molecular fine-tuning on different layers ranging from basic cellular responses to higher order phenotypes. In a broader context, these findings advance our understanding how populations are able to persist throughout major environmental shifts.
Impact of mouse contamination in genomic profiling of patient-derived models and best practice for robust analysis
Authors: Se-Young Jo, Eunyoung Kim, Sangwoo Kim
Journal: Genome biology (2019)

Patient-derived xenograft and cell line models are popular models for clinical cancer research. However, the inevitable inclusion of a mouse genome in a patient-derived model is a remaining concern in the analysis. Although multiple tools and filtering strategies have been developed to account for this, research has yet to demonstrate the exact impact of the mouse genome and the optimal use of these tools and filtering strategies in an analysis pipeline.We construct a benchmark dataset of 5 liver tissues from 3 mouse strains using human whole-exome sequencing kit. Next-generation sequencing reads from mouse tissues are mappable to 49% of the human genome and 409 cancer genes. In total, 1,207,556 mouse-specific alleles are aligned to the human genome reference, including 467,232 (38.7%) alleles with high sensitivity to contamination, which are pervasive causes of false cancer mutations in public databases and are signatures for predicting global contamination. Next, we assess the performance of 8 filtering methods in terms of mouse read filtration and reduction of mouse-specific alleles. All filtering tools generally perform well, although differences in algorithm strictness and efficiency of mouse allele removal are observed. Therefore, we develop a best practice pipeline that contains the estimation of contamination level, mouse read filtration, and variant filtration.The inclusion of mouse cells in patient-derived models hinders genomic analysis and should be addressed carefully. Our suggested guidelines improve the robustness and maximize the utility of genomic analysis of these models.
Experience of Generic Imatinib As a First Line Therapy for Patients with Chronic Myeloid Leukemia in a Single Reference Institution
Authors: Gabriel Carvalho Pereira, Fernanda B da Silva, Luisa Espirito Santo Oliveira, Pedro Marques Garibaldi, Lorena Lobo Figueiredo-Pontes, Belinda Pinto Simões, Leonardo Carvalho Palma, Fabiola Traina
Journal: Blood (2019)
RARE-33. LEPTOMENINGEAL DISEASE IN PATIENTS WITH MIDLINE GLIOMAS HARBORING HISTONE H3 K27M MUTATIONS
Authors: Carlos Eduardo Silva Correia, Elena Pentsova, Andrew Lin, Alexandra Miller
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION The 2016 WHO classification describes a specific subtype of midline gliomas harboring histone 3 (H3) K27M mutations which compromise 15–40% of gliomas in children and young adults. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the true incidence and the clinical behavior of this group has not been well-defined. METHODS This is a retrospective study of patients with H3K27M/I diffuse midline gliomas at MSKCC from 01/2012 to 01/2019. Mutations were identified through next-generation sequencing (NGS). RESULTS We identified 24 patients. Median age was 21 (6–70) and 13 were male. Thirteen tumors were in the thalamus, 6 in the brainstem, 4 in the spinal cord, and 1 in the pineal region. H3K27M mutations were detected by NGS from tumor tissue in 21 patients, from cerebral spinal fluid (CSF) circulating tumor DNA (ctDNA) in 2 and from tissue and CSF ctDNA in one. LMD was diagnosed in 17/24 (71%) patients radiographically. Of these, 8 underwent LP: CSF cytology was positive in 2/8 and CSF ctDNA was detected in 3/3. All patients received RT and one or more lines of chemotherapy. At analysis, thirteen patients remain alive. Median time to last follow up for all patients was 14.2 months. Median time from diagnosis to LMD was 13.2 months (0–45.1), with median OS of 6.5 months (0.3–27) after diagnosis of LMD. CONCLUSION Our study showed that more than two-thirds of the patients with H3 K27M diffuse midline developed LMD. Neuroaxis imaging should be performed in conjunction with CSF studies to diagnose LMD. Besides, CSF ctDNA represents an important tool to identify molecular profile of tumors when biopsy is not feasible or limited for the analysis.