tbuckley/cabot-search huggingface dataset:
DIPG-10. OPTIMAL HDAC INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Nicholas Vitanza, Matt Biery, Carrie Myers, Eric Ferguson, Giulia Park, Alyssa Noll, Fiona Pakiam, Emily Girard, Shelli Morris, Bonnie Cole, Mi-Youn Brusniak, Andrew Mhyre, James Olson
Journal: Neuro-Oncology (2020)

Abstract As the majority of diffuse intrinsic pontine glioma (DIPG) have H3K27M mutations, epigenetic-targeting agents have been studied, though evaluations have been limited by their model systems, untranslatable drug concentrations, and/or evasive mechanisms of action. To develop a more translational model, we used biopsy samples from newly diagnosed DIPG patients to create treatment-naïve in vitro and in vivo models (molecular aberrations in parentheses), including PBT-09FH (H3FA3, PI3KCA), PBT-22FH (H3F3A, TP53), PBT-24FH (PMS2), and PBT-27FH (HIST1H3B, TP53, NTRK2). Models demonstrated radiation-resistance similar to the patient from whom the culture was generated, supporting the models’ relevance (e.g. cell viability after 8 Gy was 36%, 81%, 71%, and 61% in PBT-09FH, -22FH, -24FH, and -27FH, respectively, compared to 7% in the medulloblastoma model MED-411FH). We evaluated cell viability and apoptosis following treatment with a panel of HDAC inhibitors, identifying the low nanomolar IC50 of quisinostat (~50 nM) and romidepsin (~5 nM). While RNA expression changes induced by 100 nM panobinostat and quisinostat included shared overexpression of the top 20/25 genes (e.g. FSTL5, ITIH5) and shared downregulation of the top 22/25 (e.g. GPR37L1, HEPACAM), only 9/25 were downregulated by panobinostat, quisinostat, and romidepsin (e.g. C21orf62, IFIT2), identifying these as potential vulnerabilities or biomarkers of lethal HDAC inhibition. Mass-spectrometry (LC-MS) demonstrated panobinostat as the greatest acetylator of cortactin, potentially related to thrombocytopenia. While PBT-09 flank models demonstrated quisinostat’s on-target acetylation and efficacy, orthotopic xenograft models did not, supporting our model’s intact blood-brain barrier and emphasizing the need for CNS penetrant versions of potentially efficacious agents.
103P Temporospatial heterogeneity in metastatic colorectal cancer (mCRC)
Authors: C. Fountzilas, A. Witkiewicz, J. Muhitch, S. Abrams, E. Knudsen, S. Mukherjee, D. Bajor, J. Saltzman, K. Wang, R. Iyer, P. Kalinski, P. Boland
Journal: Annals of Oncology (2020)
QOLP-16. EFFICACY OF SCRAMBLER THERAPY (CALMARE®) FOR THE TREATMENT OF CHRONIC CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Authors: Neal Prakash, Rachel Tran, Elizabeth Strain
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious consequence of cancer treatment that, for up to 30% of patients, persists beyond six months of completing chemotherapy. Scrambler therapy (ST) is a therapeutic modality with emerging evidence supporting its ability to diminish CIPN symptoms. METHODS Data was from a convenience sample of 24 CIPN patients (with symptoms between 1-240 months after platinum-based, taxane, or combination chemotherapy) completing 10 sessions of ST using the Calmare® device in the City of Hope Outpatient Physical Therapy Department. Patients were treated for ~45 minutes per session over 10 sessions. Patients received a standardized assessment pre- and post ST that included: EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20), mono-filament testing, pain intensity numerical rating scale, numbness scale, extensor hallicus longus strength, Timed Up and Go, Romberg, and single leg balance. RESULTS Regardless of length of symptoms, significant changes were seen in post-treatment assessment of quality of life as measured by the QLQ-CIPN-20 and numbness scale. Post-treatment QLQ-CIPN-20 total scores decreased by an average of 7.1 points (n= 24, p&amp;lt; .01). Numbness in the left lower extremity decreased by an average of 1 point of the 0-4 point scale (n=24, p=.0007) and 1.09 points on the right lower extremity (n=24, p &amp;lt; .0004). There was a trend towards improvements in pain, monofilament testing, single leg balance, and Romberg test, though they did not reach a level of significance. Surprisingly, only 3 of 24 patients reported pain related to their CIPN at the start of treatment. CONCLUSION For patients with CIPN, scrambler therapy improves numbness and improves quality of life measures. This suggests an important role for this treatment modality in cancer patients suffering from this debilitating condition.
GCT-13. THE TREATMENT OUTCOMES OF INTRACRANIAL GERM CELL TUMORS WITH KSPNO PROTOCOL: SINGLE CENTER RETROSPECTIVE ANALYSIS
Authors: Kyeong-O Go, Soyoung Ji, Kihwan Hwang, Jung Ho Han, Hyoung Soo Choi, You Jung Kim, Byung Se Choi, In Ah Kim, Gheeyoung Choe, Jin-Myung Jung, Yong-Kil Hong, Chae-Yong Kim
Journal: Neuro-Oncology (2020)

Abstract Dho et al. (BTRT, 2017) reported that 1.1% (127/11,827) of primary brain tumors are intracranial germ cell tumors (iGCT) in Korea. We analyzed the epidemiology and treatment results of germ cell tumors in our institution. From 2004 to 2019, among 6494 patients with intracranial neoplasms the 61 (0.9%) patients with iGCTs were enrolled: histologically diagnosed in 50 patients and clinically in 11 respectively. Pediatric patients underwent treatment according to the KSPNO protocol, and adult patients were treated with bleomycin, etoposide, and cisplatin regimens. The median age was 20 years (range: 1–42) and the follow-up period was 7.7 months (range: 10.0–203.4 months), respectively. The tumors arise most frequently in the pineal area (n=30, 49.2%). There were no significant differences in outcomes between protocols, but in KSPNO protocol group showed lower tumor recurrence rate (11.5% vs. 20%, p=0.494) and mortality (0% vs. 5.2%, p=0.503). According to the pathological subtype, the outcomes showed statistically significant differences between germinoma and non-germinomatous germ cell tumor (NGGCT) groups. The 10-year progression-free survival was 93.2% and 67.1% in the germinoma and the NGGCT group, respectively (p=0.009). The NGGCT pathological type (p=0.021) was a significant recurrence associated factor in multivariate analysis. Significant adverse events (CTCAE version 5.0 grade≥3) were showed in 14 patients (7 patients in both KSPNO and other treatment protocol groups). Pure germinoma has a higher survival rate and a lower recurrence rate than NGGCT. And KSPNO protocol might be safe and effective. For appropriate treatment for iGTCs, a multidisciplinary approach might be needed.
48P Impact of 12 months of immunotherapy for metastatic cancer patients on oncology workload
Authors: V.J. Andreotti, M. Cinausero, S.K. Garattini, L. Bortot, L. Palmero, F. Valent, C. Riosa, D. Iacono, M. Casagrande, K. Rihawi, M. Macerelli, A.M. Minisini, G. Fasola
Journal: Annals of Oncology (2020)
ETMR-09. THE ROLE OF RADIATION FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Akihide Kondo, Mario Suzuki, Junya Fujimura
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Embryonal tumor with multilayered rosettes (ETMR) is a challenging tumor. The prognosis of the patients suffering from this tumor is extremely poor. We have survival cases of more than 12 months. However, the status of illness is different. In order to clarify the cause of this difference, we reviewed our treatments in this study. TREATMENT COURSE: We have two cases. Both have relapsed after the same chemotherapy after the same radiation therapy. After the recurrence we used protocols that were included extended resection, second radiation therapy with bevacizumab. METHODS We compared molecular biological evaluations for the initial and recurrent tumors. The resection rate at the time of second removal and the intensity of radiation therapy intensity were compared. RESULTS We succeeded to remove the tumors with the confirmation of intraoperative MRI. No apparent differences could be seen in molecular biological characters of tumors before and after treatment. There was a difference between the period until radiation therapy and the irradiation methods. CONCLUSIONS This tumor is untreatable only by resection. We need the second radiation therapy with bevacizumab. It was presumed that tumor should be irradiated quickly with appropriate irradiation field and dose.
Abstract 17029: Risk Stratification and Real World Incidence of Cardiac Toxicity With Immune Checkpoint Inhibitors
Authors: Jian Hu, Mina Shnoda, Nikos Pappan, Andreas Kyvernitakis, Indu G Poornima
Journal: Circulation (2020)

Introduction: Awareness of cardiac toxicity with immune checkpoint inhibitor (ICI) therapy is increasing with emerging data on the manifestations and diagnosis of cardiotoxicity. However, risk stratification of these patients remains undefined. Hypothesis: We examined associations of traditional cardiovascular risk factors with ICI cardiotoxicity and patterns of cardiac evaluation prior to and during ICI therapy within a quaternary integrated health network. Methods: We reviewed patients on ICIs for atherosclerotic cardiovascular disease (ASCVD) risk factors, cardiology office visits, patterns of screening for cardiac disease (ECG, echocardiogram, cardiac biomarkers), and correlated with the incident of cardiac adverse events. Results: We studied 344 patients receiving ICIs for lung cancer (50%), melanoma (15%), and other malignancies (34%). Smoking (75%), hypertension (71%), and hyperlipidemia (49%) were the most common ASCVD risk factors. Pre-ICI initiation cardiac evaluation included ECG in 60%, TTE in 37%, and 63% of patients had at least one ECG or TTE while on ICIs. Less than 20% were seen by Cardiology before ICI therapy, despite 81% having ≥2 ASCVD risk factors. Cardiac toxicity with ICIs was observed in 12% of patients and was significantly more common in those with more ASCVD risk factors (4.6% vs 9.7% vs 16.4% with 0-1 vs 2-3 vs ≥4 ASCVD risk factors, respectively; P= 0.03) and in patients with atrial fibrillation (AFib) before ICI initiation (26.5% vs 8.5% without AFib; P=0.0008). ICIs were discontinued in 87 patients, of which 15% were due to cardiac toxicity. Conclusions: The incidence of cardiac toxicity is high, especially in patients with multiple ASCVD risk factors or AFib, and is often the reason for ICI discontinuation, warranting close surveillance prior to and during therapy. Cardiac evaluation and monitoring for cardiotoxicity were infrequent in patients receiving ICI therapy, despite the high prevalence of ASCVD in this population.
Hematopoietic Stem Cell Transplantation May Lower the Risk of Leukemia in ELANE Neutropenia: Historical Trends from a French Severe Chronic Neutropenia Registry (FSCNR) Cohort
Authors: Jean Donadieu, Blandine Beaupain, Fanny Rialland, Catherine Paillard, Ouahiba Nachit, Claire Galambrun, Virginie Gandemer, Yves Bertrand, Benedicte Neven, Despina Moshous, Flore Sicre De Fontbrune, Regis peffault De La Tour, Marie Ouachee, Christine bellanne Chantelot, Jean-Hugues Dalle
Journal: Blood (2017)
GCT-75. ISOLATED PITUITARY STALK THICKENING
Authors: Julie Bennett, Liana Nobre, Eric Bouffet, Oussama Abla, Jonathan Wasserman, Birgit Ertl-Wagner, Ute Bartels
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Only few studies have examined the predictive factors and outcome of isolated pituitary stalk thickening (PST) in children. We aim to describe our institutional cohort to determine predictors of future malignancy. METHODS A search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with isolated PST diagnosed between January 2000 and June 2019. Clinical data was collected. A detailed radiology review of baseline and follow up magnetic resonance imaging (MRI) was undertaken in a blinded fashion by two examiners. RESULTS Forty-four patients were identified, with 37 meeting criteria for isolated PST and adequate imaging. Median age of baseline MRI was 9.9 years (range 0.9–17.5). Twenty-three were female (62%). Median follow up time was 5 (0.31–18.6) years. Indication for MRI was symptoms of diabetes insipidus (DI) in 28 patients with the remainder having other concerns for endocrine disturbance (7), headache (1) or visual impairment (1). Thirty-five subjects had pituitary dysfunction (95%), including 30 with diabetes insipidus (81%). Nine patients developed a malignancy (24%), with germinoma (5), Langerhans cell histiocytosis (3) and lymphoma (1) at a median of 0.36 years, 0.63 years and 1.1 years respectively. Elevated white blood cell count (&amp;gt;5 x 106/L) in initial cerebrospinal fluid analysis was predictive of future diagnosis of germinoma or lymphoma (p=0.027). CONCLUSION In this cohort 24% of children with PST were eventually diagnosed with a neoplasia after a median of 0.63 years. Pleocytosis in initial CSF samples was predictive for future development of germinoma or lymphoma.
Risk Factors Associated With In-Hospital Mortality in a US National Sample of Patients With COVID-19
Authors: Ning Rosenthal, Zhun Cao, Jake Gundrum, Jim Sianis, Stella Safo
Journal: JAMA Network Open (2020)

Coronavirus disease 2019 (COVID-19) has infected more than 8.1 million US residents and killed more than 221 000. There is a dearth of research on epidemiology and clinical outcomes in US patients with COVID-19.To characterize patients with COVID-19 treated in US hospitals and to examine risk factors associated with in-hospital mortality.This cohort study was conducted using Premier Healthcare Database, a large geographically diverse all-payer hospital administrative database including 592 acute care hospitals in the United States. Inpatient and hospital-based outpatient visits with a principal or secondary discharge diagnosis of COVID-19 (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code, U07.1) between April 1 and May 31, 2020, were included.Characteristics of patients were reported by inpatient/outpatient and survival status. Risk factors associated with death examined included patient characteristics, acute complications, comorbidities, and medications.In-hospital mortality, intensive care unit (ICU) admission, use of invasive mechanical ventilation, total hospital length of stay (LOS), ICU LOS, acute complications, and treatment patterns.Overall, 64 781 patients with COVID-19 (29 479 [45.5%] outpatients; 35 302 [54.5%] inpatients) were analyzed. The median (interquartile range [IQR]) age was 46 (33-59) years for outpatients and 65 (52-77) years for inpatients; 31 968 (49.3%) were men, 25 841 (39.9%) were White US residents, and 14 340 (22.1%) were Black US residents. In-hospital mortality was 20.3% among inpatients (7164 patients). A total of 5625 inpatients (15.9%) received invasive mechanical ventilation, and 6849 (19.4%) were admitted to the ICU. Median (IQR) inpatient LOS was 6 (3-10) days. Median (IQR) ICU LOS was 5 (2-10) days. Common acute complications among inpatients included acute respiratory failure (19 706 [55.8%]), acute kidney failure (11 971 [33.9%]), and sepsis (11 910 [33.7%]). Older age was the risk factor most strongly associated with death (eg, age ≥80 years vs 18-34 years: odds ratio [OR], 16.20; 95% CI, 11.58-22.67; P < .001). Receipt of statins (OR, 0.60; 95% CI, 0.56-0.65; P < .001), angiotensin-converting enzyme inhibitors (OR, 0.53; 95% CI, 0.46-0.60; P < .001), and calcium channel blockers (OR, 0.73; 95% CI, 0.68-0.79; P < .001) was associated with decreased odds of death. Compared with patients with no hydroxychloroquine or azithromycin, patients with both azithromycin and hydroxychloroquine had increased odds of death (OR, 1.21; 95% CI, 1.11-1.31; P < .001).In this cohort study of patients with COVID-19 infection in US acute care hospitals, COVID-19 was associated with high ICU admission and in-hospital mortality rates. Use of statins, angiotensin-converting enzyme inhibitors, and calcium channel blockers were associated with decreased odds of death. Understanding the potential benefits of unproven treatments will require future randomized trials.
Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy
Authors: Sophie Knipper, Luigi Ascalone, Benjamin Ziegler, Jan L. Hohenhorst, Ricarda Simon, Christoph Berliner, Fijs W.B. van Leeuwen, Henk van der Poel, Frederik Giesel, Markus Graefen, Matthias Eiber, Matthias M. Heck, Thomas Horn, Tobias Maurer
Journal: European Urology (2020)
PATH-43. TARGETED GENOMIC ANALYSIS OF PRIMARY ADULT BRAIN TUMORS: A SINGLE INSTITUTIONAL EXPERIENCE OF 26 CASES
Authors: Samina Hirani, Aswani Thurlapati, Shahzeem Bhayani, Adam Greer, Glenn Mills
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND In the United States, primary brain tumors comprise 2% of all cancers with an alarming 5-year survival rate of 35% [1,2]. To aid histopathological diagnosis, genomic profiling of tumors using next generation sequencing (NGS) has allowed more accurate molecular subclassification of tumors and identification of novel, subtype specific therapies in management [3]. We present single institutional data of molecular gene profiles in patients with adult primary brain tumors. Understanding the genetic landscape of these tumors will help determine molecular targets for currently available drugs and open new avenues for further drug development [4]. METHODS We retrospectively reviewed all primary brain tumor patients seen at LSU Health Science Center Shreveport who underwent NGS from July, 2017 to July, 2019. After reviewing a total of 44 patient charts, 26 were identified to have all the data required for our analysis. Standardized genetic sequencing reports made by molecular pathologists were used. Genetic mapping was performed and descriptive analysis was done using Statistical Analysis System (SAS). RESULTS Demographic characteristics of our patients consist of 50% males, 15% African American with an average age of diagnosis 59. The histopathological types diagnosed include 65% glioblastoma-multiforme and others comprising of gliosarcoma, pilocytic astrocytoma, ganglioma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic ganglioma, meningioma, hemangiopericytoma, and astroblastoma. In 23% of patients, the results of gene sequencing in addition to histopathology impacted the clinical management by improving subclassification and in identifying targetable mutations. 42% of our patients found to have targetable mutations. CONCLUSION In the era of precision oncology, targeted gene sequencing of adult primary brain tumors may aid in diagnosis beyond histopathology by identifying the genetic landscape of tumors and molecular targets for individualized therapies.
Abstract 15978: Acetyl-coa Catalysis by Atp-citrate Lyase is Essential for Myofibroblast Differentiation and Persistence
Authors: Michael P Lazaropoulos, Andrew A Gibb, Anh Huynh, Kathryn Wellen, John W Elrod
Journal: Circulation (2020)

A feature of heart failure (HF) is excessive extracellular matrix deposition and cardiac remodeling by a differentiated fibroblast population known as myofibroblasts. Identifying mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel therapeutic targets to delay or reverse HF. Recent evidence suggests that myofibroblast differentiation requires metabolic reprogramming for transcriptional activation of the myofibroblast gene program by chromatin-dependent mechanisms. We previously reported that inhibition of histone demethylation blocks myofibroblast formation, however, whether histone acetylation (e.g., H3K27ac, a prominent mark associated with gene transcription) is involved in fibroblast reprogramming remains unclear. ATP-citrate lyase (ACLY) synthesizes acetyl-CoA and therein supplies acetyl-CoA to the nucleus, where it is used as a substrate by histone acetyltransferases (HATs). To define the role of acetyl-CoA metabolism in myofibroblast differentiation, we stimulated differentiation in mouse embryonic fibroblasts (MEFs) and adult mouse cardiac fibroblasts (ACFs) with the pro-fibrotic agonist transforming growth factor β (TGFβ) and treated cells with a pharmacological inhibitor of ACLY. ACLY inhibition decreased myofibroblast gene expression in ACF and MEFs in TGFβ-stimulated myofibroblast differentiation, in addition to decreasing the population of αSMA positive MEFs. Genetic deletion of ACLY in MEFs recapitulated the results observed with pharmacological inhibition. Encouragingly, the ACLY inhibitor was sufficient to revert fully differentiated myofibroblasts under continuous TGFβ stimulation to a quiescent, non-fibrotic phenotype. Altogether, our data indicate that ACLY activity is necessary for myofibroblast differentiation and persistence. We hypothesize that ACLY-dependent acetyl-CoA synthesis is necessary for histone acetylation and transcriptional activation of the myofibroblast gene program. Currently, we are examining mechanisms of ACLY-dependent chromatin remodeling in fibroblasts and the in vivo relevance of this mechanism in mutant mice. In summary, ACLY is a potential target to reverse cardiac fibrosis and lessen HF.
LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH <i>BRAF</i> V600-MUTANT LOW-GRADE GLIOMA (LGG)
Authors: Eric Bouffet, James A Whitlock, Christopher Moertel, Birgit Geoerger, Isabelle Aerts, Darren Hargrave, Kenneth J Cohen, Lindsay B Kilburn, Santhosh A Upadhyaya, Cynthia Wetmore, Karen D Wright, Jeea Choi, Eduard Gasal, Mark W Russo, Elizabeth Fox
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (&amp;lt;18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.