tbuckley/cabot-search huggingface dataset:
NCMP-26. RECOGNITION OF PARANEOPLASTIC SYNDROMES TRIGGERED BY TRADITIONAL CYTOTOXIC CANCER TREATMENT, TUMOR RECURRENCE AND DEVELOPMENT OF SECOND CANCER
Authors: Sudhakar Tummala
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Paraneoplastic syndromes traditionally precede tumor diagnosis. With recent greater use of immune checkpoint blockade therapy there is ever-increasing recognition of various immune related adverse effects. This abstract highlights PCA 1 paraneoplastic syndrome triggered by non-immune based chemotherapy, surgery, tumor recurrence and prior to development of second cancer. METHODS This is retrospective case review of patients seen at MD Anderson Cancer Center who developed PCA 1 paraneoplastic syndrome. RESULTS 64 yr old female with ovarian cancer on ERK inhibitor develops lower extremity weakness, ataxia and difficulty ambulation. Serum and CSF showed positive PCA-1 antibody. 59 yr old female with ovarian serous carcinoma develops cerebellar dysfunction after receiving caroboplatin and doxil. Serum and CSF were positive for PCA-1 antibody. 57 yr old female with ovarian carcinoma develops tremors, progressive ataxia after second cycle of carboplatin,taxol and avastin. Serum was positive for PCA-1 antibody. 45 yr old female with ovarian carcinoma completes 6 cycles of taxol and carboplatin. 3 months later develops gait ataxia. CSF was positive for PCA-1 antibody. Workup showed progressive ovarian carcinoma. 59 yr old with invasive ductal breast cancer develops lower extremity weakness and ataxia. Serum and CSF were positive for PCA-1 antibody. Work up revealed ovarian carcinoma. 63 yr old female with newly diagnosed breast cancer undergoes mastectomy. In the immediate postoperative time period develops diplopia, gait ataxia. Serum and CSF were positive for PCA-A antibody. All patients were aggressively treated with steroids. Most received additional therapies including plasma exchange, IVIG, tacrolimus, Rituxan, Cytoxan. All patients remained with permanent cerebellar dysfunction. CONCLUSIONS Case series highlights the recognition of paraneoplastic syndrome following traditional cytotoxic chemotherapy. There is need for early recognition of this neurological urgency. Work up includes prompt LP, serum and CSF paraneoplastic antibody panel, and evaluation for primary tumor recurrence or development of second cancer.
Genomic Landscapes in Elderly AML
Authors: Franck Rapaport, Timour Baslan, Ling Wang, Caroline Sheridan, Tak Lee, Todd Hricik, Marc Robert de Massy, Leonid Telis, Yaseswini Neelamraju, Juan Medina, Larry D Cripe, Martin S. Tallman, Scott Lowe, Zhuoxin Sun, Yanming Zhang, Donna S. Neuberg, Elisabeth Paietta, Ari Melnick, Ross L. Levine, Maria Kleppe, Francine E. Garrett-Bakelman
Journal: Blood (2017)
Non-REM Apnea and Hypopnea Duration Varies across Population Groups and Physiologic Traits
Authors: Priya V. Borker, Michelle Reid, Tamar Sofer, Matthew P. Butler, Ali Azarbarzin, Heming Wang, Andrew Wellman, Scott A. Sands, Susan Redline
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Symptoms and morbidities associated with obstructive sleep apnea (OSA) vary across individuals and are not predicted by the apnea-hypopnea index (AHI). Respiratory event duration is a heritable trait associated with mortality that may further characterize OSA.Objectives: We evaluated how hypopnea and apnea durations in non-REM (NREM) sleep vary across demographic groups and quantified their associations with physiological traits (loop gain, arousal threshold, circulatory delay, and pharyngeal collapsibility).Methods: Data were analyzed from 1,546 participants from the Multi-Ethnic Study of Atherosclerosis with an AHI ≥5. Physiological traits were derived using a validated model fit to the polysomnographic airflow signal. Multiple linear regression models were used to evaluate associations of event duration with demographic and physiological factors.Measurements and Main Results: Participants had a mean age ± SD of 68.9 ± 9.2 years, mean NREM hypopnea duration of 21.73 ± 5.60, and mean NREM apnea duration of 23.87 ± 7.44 seconds. In adjusted analyses, shorter events were associated with younger age, female sex, higher body mass index (P < 0.01, all), and Black race (P < 0.05). Longer events were associated with Asian race (P < 0.01). Shorter event durations were associated with lower circulatory delay (2.53 ± 0.13 s, P < 0.01), lower arousal threshold (1.39 ± 0.15 s, P < 0.01), reduced collapsibility (-0.71 ± 0.16 s, P < 0.01), and higher loop gain (-0.27 ± 0.11 s, P < 0.05) per SD change. Adjustment for physiological traits attenuated age, sex, and obesity associations and eliminated racial differences in event duration.Conclusions: Average event duration varies across population groups and provides information on ventilatory features and airway collapsibility not captured by the AHI.
Racial and Ethnic Differences in Parental Attitudes and Concerns About School Reopening During the COVID-19 Pandemic — United States, July 2020
Authors: Leah K. Gilbert, Tara W. Strine, Leigh E. Szucs, Tamara N. Crawford, Sharyn E. Parks, Danielle T. Barradas, Rashid Njai, Jean Y. Ko
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

In light of the disproportionate risk of hospitalization and death attributable to coronavirus disease 2019 (COVID-19) among racial and ethnic minority groups, parental attitudes and concerns regarding school reopening were assessed by race and ethnicity using data from three online CARAVAN omnibus surveys conducted during July 8-12, 2020, by ENGINE Insights.* Survey participants included 858 parents who had children and adolescents in kindergarten through grade 12 (school-aged children) living in their household. Overall, 56.5% of parents strongly or somewhat agreed that school should reopen this fall, with some differences by race/ethnicity: compared with 62.3% of non-Hispanic White (White) parents, 46.0% of non-Hispanic Black or African American (Black) parents (p = 0.007) and 50.2% of Hispanic parents (p = 0.014) agreed that school should reopen this fall. Fewer White parents (62.5%) than Hispanic (79.5%, p = 0.026) and non-Hispanic parents of other racial/ethnic groups (66.9%, p = 0.041) were supportive of a mask mandate for students and staff members. Understanding parental attitudes and concerns is critical to informing communication and messaging around COVID-19 mitigation. Families' concerns also highlight the need for flexible education plans and equitable resource provision so that youth education is not compromised.
RARE-25. RETINAL ASTROCYTOMA mTOR INHIBITOR THERAPY IN TUBEROUS SCLEROSIS MOSAICISM
Authors: Naomi Evans, Katherine Paton, Harinder Kaur Gill, Juliette Hukin
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Everolimus is an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), it is Health Canada and FDA approved for SEGA and renal angiomyolipoma in the setting of tuberous sclerosis complex (TSC). There is little data available in regards to this treatment of TSC associated retinal astrocytoma (RA). Although the behaviour of RA is often indolent or slowly progressive, aggressive behaviour with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients. Definite TSC diagnosis is established when either two major features or one major and two minor features are present. Probable TSC diagnosis is established when one major plus one minor feature is present. METHODS We report a child with probable TSC mosaicism, with negative serum NGS for TSC but RA and retinal achromic patch on the left. A left retinal peripapillary astrocytoma around optic nerve and very close to fovea was noted. There was concern that if it grew or there were to be any leakage it would cause visual impairment. This lead to therapy with everolimus 4.5 mg/m2/d aiming for level between 5 and 10 mcg/L. RESULTS This boy has had a gradual reduction of the RA over the last 29 months, with healthy retina in the region no longer occupied by the lesion and preserved vision. He has tolerated therapy well with occasional mouth ulcers. CONCLUSION mTORC1 inhibition is effective therapy to preserve vision in the setting of retinal astrocytoma and tuberous sclerosis mosaicism.
EPID-26. CLINICAL AND HISTOLOGICAL CHARACTERIZATION OF PRIMARY CENTRAL NERVOUS SYSTEM SARCOMA IN PEDIATRICS. A SINGLE INSTITUTION EXPERIENCE IN A MIDDLE-INCOME COUNTRY
Authors: Edgar Cabrera, Nelson Aponte, Johnny Garcia, Fredy Salazar, Eric Bouffet, Ute Bartels, Lina Jaramillo, Adriana Fonseca
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Primary central nervous system (CNS) sarcomas are rare mesenchymal non-meningothelial tumors accounting for less than 0.2% of intracranial lesions. Diagnosis and management are challenging due to the current lack of substantive clinical, histological and molecular data. METHODS We retrospectively identified all patients with diagnosis of primary CNS sarcoma at the Hospital Fundación Pediatrico la Misericordia (HOMI) in Bogota, Colombia. We collected patient demographics, disease characteristics, and outcomes for analysis. RESULTS Between 2008 and 2020, twenty-four consecutive patients were diagnosed at the HOMI representing 6% of all CNS tumors diagnosed over the same time period. The median age at presentation was 9.48 years (range:1.6–13.4). The median time of symptoms prior to diagnosis was 2 weeks (0.1–24). The most common presentation was headache (21/24- 89%) and vomiting (19/24- 79%). The frontal lobe was involved in 63% of patients (15/24) and only one patient presented with a cerebellar lesion. Histologically, these tumors were characterized by a pleomorphic spindle cell architecture and high mitotic activity. All samples lacked immunoreactivity to GFAP, CD34, EMA, and S100 and all samples had strong nuclear immunopositivity for TLE-1; BCL-2 was reactive in eighteen cases. Gross total resection was attained in fifteen patients, most patients received focal radiation therapy and ICE chemotherapy. Progression-free survival at 12 and 24 months was 57% and 31% respectively. Overall survival was 77% at 12 months and 39% at 24 months. Thirteen patients relapsed, 11 presented with local failures, and 2 with intracranial recurrences outside of the radiation field. CONCLUSION Our study identifies TLE-1 as a diagnostic marker of primary CNS sarcoma, a highly malignant supratentorial tumor of childhood. Further molecular studies are urgently needed to elucidate the biology of this disease and the unusually high incidence observed in the Colombian pediatric population.
DIPG-16. COMBINATION OF ARGININE DEPLETION AND POLYAMINE INHIBITION AS AN ANTICANCER STRATEGY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Aaminah Khan, Laura Gamble, Ruby Pandher, Mark R Burns, Francis Mussai, Murray Norris, Michelle Haber, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2020)

Abstract DIPG is an aggressive pediatric brainstem tumor, with a median survival below 12 months. Tumor cells are dependent upon arginine, a semi-essential amino acid, metabolised by arginase enzymes into ornithine, a pivotal precursor to the polyamine pathway. Polyamines, frequently upregulated in cancer, are intracellular polycations controlling key biological processes – the inhibition of which we have previously shown to be highly efficacious in preclinical DIPG models. Pegylated arginase (BCT-100) has recently been shown to significantly delay tumor development, prolonging survival of neuroblastoma-prone Th-MYCN mice. This study investigated the effects of arginine depletion therapy as a single agent and in combination with polyamine pathway inhibitors in DIPG. We found that ARG2, the gene encoding for arginase II, is expressed significantly more highly in DIPG tumors compared to normal brain. Arginine depletion via BCT-100 reduced DIPG cell proliferation and colony formation in patient-derived cell lines. Using orthotopic patient-derived xenograft models of DIPG, we found that frequent dosing of BCT-100 (4x/week) significantly delayed tumor development and increased the survival of the mice (p&amp;lt;0.0001). DFMO is an FDA-approved inhibitor of the enzyme ornithine decarboxylase, a key driver of polyamine synthesis. The combination of BCT-100 with DFMO led to significant enhancement in DIPG survival (p&amp;lt;0.005 compared to single agent treatments). Triple combination therapy with addition of the polyamine transport inhibitor AMXT-1501 led to a potent and profound improvement in survival. These data show that arginine depletion therapy using BCT-100 combined with dual polyamine inhibitory agents represents a potentially exciting new approach for the treatment of DIPG.
Device Therapy in Heart Failure: Has CRT Changed “the Sickest Benefit the Most” to “the Healthiest Benefit the Most?”**Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Maurizio Gasparini, Paola Galimberti
Journal: Journal of the American College of Cardiology (2013)
EPCO-39. DICER1 SYNDROME WITH PRIMITIVE NEUROECTODERMAL TUMOR FROM SCREENING MUTATIONS OF DICER1 GENE
Authors: Anhua Wu, Zhitao Jing, Wen Cheng, Chen Zhu, Chao Song, Huijuan Qin, Xing Zhang, Yuhang Ji, Minqi Tian, Xiaomin Li, Yong Ren
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND DICER1 syndrome is a rare disorder of tumor predisposition. The DICER1 gene encodes the Dicer protein of the ribonuclease Ⅲ family and plays a critical role in miRNA creation. Patients with DICER1 syndrome-related cancer commonly harbor an additional somatic variant in exon24 or 25 of DICER1 involving one of the hotspots including p.E1705, p.D1709, p.G1809, p.D1810, or p.E1813. Herein, we firstly report the presence of hotspot missence mutation in a patient with primitive neuroectodermal tumor (PNET). METHODS The mutations in DIRCER1 were searched in the tumor tissue or peripheral blood from 4,349 patients with different types of cancer via next generation sequencing. Among them, comprehensive genomic profiling (CGP) with 131 CNS cancer-related genes and 4 brain tumor-related chromosome structure variations was performed in 230 cases, and CGP with 539 cancer-related genes was administrated in 4,119 cases. The histopathology diagnosis of each case was confirmed via hematoxylin and eosin staining. RESULTS A number of 99 mutations in the exon and intron regions of DICER1 gene were observed from 88 patients in 4,349 cases. The ratio of somatic variants located on exon 24 and 25 where both encoded the RNase Ⅲb cleavage domain to all mutations was 9.09% (9/99). There were 3 and 6 somatic variants in the exon 24 and 25, respectively. Among the 9 mutations, 4 of them were p.E1813, one class of hotspots located on exon 25 leading to DICER1 syndrome, and the other 4 hotspots were not observed. Among 4 cases of DICER1 syndrom, pleuropulmenary blastoma was common, rhabdomyosarcomas arisen in two cases were also reported before, and the last one was patient with PNET. CONCLUSIONS In this study, we analyze the mutation distribution of DICER1 in cancer patients, report firstly a patient with PNET harbors a hotspot, and widen and deepen the understanding of DICER1 syndrome.
Pivotal role of PD-1/PD-L1 immune checkpoints in immune escape and cancer progression: Their interplay with platelets and FOXP3+Tregs related molecules, clinical implications and combinational potential with phytochemicals
Authors: Dae Young Lee, Eunji Im, Dahye Yoon, Young-Seob Lee, Geum-Soog Kim, Donghwi Kim, Sung-Hoon Kim
Journal: Seminars in Cancer Biology (2020)
THER-05. GENETICALLY STABLE POLIOVIRUS VECTOR CARRYING H3.3K27M ANTIGEN FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA BY INTRAMUSCULAR INJECTION
Authors: Mubeen Mosaheb, Daniel Landi, Elena Dobrikova, Michael Brown, Yuanfan Yang, Jana Cable, Hideho Okada, Smita Nair, Darell Bigner, David Ashley, Matthias Gromeier
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma (DMG) is invariably lethal. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses, in particular, are uniquely tropic for dendritic cells (DC) and potently activate DC, inducing Th1-dominant cytokine profiles, CD8 T cell immunity, and enhanced epitope presentation. Thus, poliovirus is ideally suited for vectored delivery of signature tumor neoantigens, e.g. the H3 K27M feature of DMG. However, poliovirus vector design is inherently limited by genetic instability and the underlying neuropathogenicity of poliovirus. METHODS We created a genetically stable, polio:rhinovirus chimera vector devoid of neuropathogenicity and modified for stable expression of the HLA-A2 restricted H3.3 K27M antigen (RIPO (H3.3)). RESULTS RIPO(H3.3) infects, activates, and induces H3.3K27M antigen presentation in DCs in vitro. Given intramuscularly in vivo, RIPO(H3.3) recruits and activates DCs with Th1-dominant cytokine profiles, efficiently primes H3.3K27M-specific CD8 T cells, induces antigen-specific CD8 T cell migration to the tumor site, delays tumor growth, and enhances survival in murine tumor models. CONCLUSION This novel approach leverages the unique ability of polioviruses to activate DCs while simultaneously introducing the H3.3 K27M antigen. In this way, DCs are activated optimally in situ, while being simultaneously infected to express/present tumor antigen. RIPO(H3.3), given by intramuscular injection, will be evaluated in a clinical trial for children with H3 K27M-mutant diffuse midline glioma.
Assessing PD-L1 expression in non-small cell lung cancer and predicting responses to immune checkpoint inhibitors using deep learning on computed tomography images
Authors: Panwen Tian, Bingxi He, Wei Mu, Kunqin Liu, Li Liu, Hao Zeng, Yujie Liu, Lili Jiang, Ping Zhou, Zhipei Huang, Di Dong, Weimin Li
Journal: Theranostics (2020)

Rationale: This study aimed to use computed tomography (CT) images to assess PD-L1 expression in non-small cell lung cancer (NSCLC) and predict response to immunotherapy. Methods: We retrospectively analyzed a PD-L1 expression dataset that consisted of 939 consecutive stage IIIB-IV NSCLC patients with pretreatment CT images. A deep convolutional neural network was trained and optimized with CT images from the training cohort (n = 750) and validation cohort (n = 93) to obtain a PD-L1 expression signature (PD-L1ES), which was evaluated using the test cohort (n = 96). Finally, a separate immunotherapy cohort (n = 94) was used to assess the prognostic value of PD-L1ES with respect to clinical outcome. Results: PD-L1ES was able to predict high PD-L1 expression (PD-L1 ≥ 50%) with areas under the receiver operating characteristic curve (AUC) of 0.78 (95% confidence interval (CI): 0.75~0.80), 0.71 (95% CI: 0.59~0.81), and 0.76 (95% CI: 0.66~0.85) in the training, validation, and test cohorts, respectively. In patients treated with anti-PD-1 antibody, low PD-L1ES was associated with improved progression-free survival (PFS) (median PFS 363 days in low score group vs 183 days in high score group; hazard ratio [HR]: 2.57, 95% CI: 1.22~5.44; P = 0.010). Additionally, when PD-L1ES was combined with a clinical model that was trained using age, sex, smoking history and family history of malignancy, the response to immunotherapy could be better predicted compared to either PD-L1ES or the clinical model alone. Conclusions: The deep learning model provides a noninvasive method to predict high PD-L1 expression of NSCLC and to infer clinical outcomes in response to immunotherapy. Additionally, this deep learning model combined with clinical models demonstrated improved stratification capabilities.
TAMI-61. TUMOR-ASSOCIATED MACROPHAGES ARE INDEPENDENT PROGNOSTIC MARKERS IN MENINGIOMAS
Authors: Fang Liu, Gerhard Jungwirth, Rolf Warta, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2020)

Abstract Tumor-associated macrophages (TAMs) play an emerging role in tumor progression by creating an immunosuppressive tumor microenvironment. Therefore, we investigated TAM numbers and their activation (M1/2) in primary (p-) and recurrent (r-) meningiomas and evaluated their impact on survival. Presence of TAMs was analyzed in 195 clinically well-annotated cases (WHO°I n = 43, WHO°II n = 95, WHO°III n = 57; pMGM n = 120, rMGM n = 75). TAMs were quantified by a semiautomated analysis on whole tissue sections stained by multicolor immunofluorescence for CD68 as general TAM marker, and for CD163 and CD204 as M2 marker. CD68+ macrophages positive for either CD163 or CD204 were regarded as M2-polarized TAMs. Furthermore, concentration of 27 immune-relevant cytokines and chemokines from meningioma tissue samples (n = 46) were assessed by Luminex analysis. Median TAM infiltration accounted for 2.47% per total cell count in pMGM and 3.22% in rMGMs. Although no significant WHO°-dependent changes regarding TAM numbers were observed, high numbers of TAMs were associated with shorter progression-free survival (PFS) independent of prognostic confounding variables such as WHO, sex and age. In pMGMs, proportion of M2-polarized TAMs was significantly increased in WHO°II and WHO°III tumors compared to WHO°I (P = 0.001 and P = 0.03, respectively). Luminex data revealed a WHO°-dependent increase of IL-8, IL-10, and IL-12p70. Tissue samples containing higher numbers of TAMs demonstrated significant elevated concentrations of interleukin-1 family members (IL-1β, IL-1Ra), and G-CSF. Furthermore, upregulation of IL-1β and IL-1Ra resulted in shorter overall survival of patients (P = 0.049, P = 0.006, respectively). Taken together, we identified higher numbers of TAMs as an independent prognostic factor for shorter progression-free survival in meningioma patients. This was associated with increased levels of the interleukin-1 family members IL-1β and IL-1Ra and a shorter overall survival, indicating an important function in the tumor microenvironment.
Predicting Radiation-Induced Heart Disease and Survival—Is Location the Key?
Authors: Carmen Bergom, David Rayan, Sherry-Ann Brown
Journal: JAMA Oncology (2020)

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