tbuckley/cabot-search huggingface dataset:
Stage I Sertoli-Leydig cell tumors: An interim report from the International PPB/<i>DICER1</i> &amp; OTST Registry.
Authors: Alexander Nelson, Anne Harris, Dave Watson, Sean Robin Pyper, Nathan Hall, Junne Kamihara, Douglas R Stewart, Louis P Dehner, D. Ashley Hill, Yoav H. Messinger, Lindsay Lindsay Frazier, Deborah F. Billmire, Dominik T. Schneider, Kris Ann Pinekenstein Schultz
Journal: Journal of Clinical Oncology (2021)

5547 Background: Sertoli-Leydig cell tumors (SLCT) are rare ovarian sex cord-stromal tumors which occur primarily in adolescents and young adults and are associated with DICER1 pathogenic variants. Methods: Informed consent for participation in the International PPB/ DICER1 or OTST Registry was obtained. When available, pathology was centrally reviewed. Staging was evaluated by Registry review using the International Federation of Gynecology and Obstetrics (FIGO) classification system. Results: Eighty-three patients with stage I SLCT were enrolled. Median age at diagnosis was 15 (range 1-60) years. Most (57/83) patients had germline DICER1 testing; 35/57 (61%) had germline pathogenic variants. Fifty-six patients had Ia and 27 had Ic SLCT. The distribution of patients receiving chemo based on histology and stage is displayed in Table. One patient with poorly differentiated stage Ia SLCT with sarcomatous elements and no chemo at diagnosis recurred 6 months after surgery and died of disease. Three patients with local diagnosis of stage Ia SLCT, with data unavailable for Registry confirmation of stage, developed a subsequent SLCT 33 to 74 months after diagnosis; of these, 2 died, and 1 remains in treatment for recurrence. Available records and molecular testing in these 3 cases have not provided a distinction between recurrent and metachronous disease. Excluding the latter 3 patients, 3-year overall survival was 97.3% for stage Ia SLCT. Six patients with stage Ic SLCT recurred (Stage Ic1=5 and Stage Ic2=1) with a median time to recurrence of 25 (range 3-53) months. In stage Ic1, 18% (2/11) recurred after upfront chemo compared to 33% (3/9) after surgery alone. Of the 5 patients with stage Ic1 disease that recurred, 4 had intermediate and 1 had poorly differentiated SLCT. One patient had sarcomatous elements and 2 received upfront chemo. Two of the 5 patients are alive, neither received upfront chemo. One patient with poorly differentiated stage Ic2 SLCT with sarcomatous elements and no upfront chemo recurred and died of disease. Three-year event free and overall survival were 86.9 and 88.6% for stage Ic SLCT. Four patients had metachronous SLCT in the contralateral ovary confirmed by clinical review or somatic testing at a median time from diagnosis of 33 (range 28-104) months. All 4 have germline pathogenic variants and no evidence of disease at last follow-up. Conclusions: Individuals with early stage SLCT generally fare well, however, ongoing surveillance for recurrence and metachronous disease is indicated. Novel therapies are needed to address recurrent SLCT.[Table: see text]
Gene targeting techniques for Huntington’s disease
Authors: Eric Fields, Erik Vaughan, Deepika Tripu, Isabelle Lim, Katherine Shrout, Jessica Conway, Nicole Salib, Yubin Lee, Akash Dhamsania, Michael Jacobsen, Ashley Woo, Huijing Xue, Kan Cao
Journal: Ageing Research Reviews (2021)

Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT's normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.
EPEN-09. SUPER ENHANCER GENES AS MOLECULAR TARGETS IN C11ORF95-RELA FUSION EPENDYMOMA
Authors: Kelsey Bertrand, Stephen Mack
Journal: Neuro-Oncology (2021)

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous findings, we hypothesized that mapping chromatin landscapes and super enhancers (SE) could uncover transcriptional dependencies as targets for therapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes. Our screen was performed in one C11ORF95-RELA-fusion model and two PF-EPN-A models as controls in biological triplicates. As an indication that our screen was successful, positive controls scored among lead hits including KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A models, thus revealing novel pathways that potentially govern subgroup-specific ependymoma cell growth. Further, several candidates detected across all ependymoma lines were also identified as pan-cancer dependencies or glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.
Toxicity, response, and survival in older adults with metastatic melanoma treated with checkpoint inhibitors.
Authors: Nienke A De Glas, Esther Bastiaannet, Frederiek van den Bos, Simon Mooijaart, Astrid Aplonia Maria Van Der Veldt, Karijn Suijkerbuijk, Maureen J.B. Aarts, Franchette van den Berkmortel, Christian U. Blank, Marye Boers-Sonderen, Alfonsus Johannes Maria van den Eertwegh, Jan Willem de Groot, Geke Hospers, John B. A. G. Haanen, Djura Piersma, Rozemarijn Van Rijn, A. J. Ten Tije, Michel W.J.M. Wouters, Johanna Elisabeth A. Portielje, Ellen Kapiteijn
Journal: Journal of Clinical Oncology (2021)

9544 Background: Checkpoint inhibitors have strongly improved survival of patients with metastatic melanoma. Trials suggest no differences in outcomes between older and younger patients, but only relatively young patients with a good performance status were included in these trials. The aim of this study was to describe treatment patterns and outcomes of older adults with metastatic melanoma, and to identify predictors of outcome. Methods: We included all patients aged ≥65 years with metastatic melanoma between 2013 and 2020 from the Dutch Melanoma Treatment registry (DMTR), in which detailed information on patients, treatments and outcomes is available. We assessed predictors of grade ≥3 toxicity and 6-months response using logistic regression models, and melanoma-specific and overall survival using Cox regression models. Additionally, we described reasons for hospital admissions and treatment discontinuation. Results: A total of 2216 patients were included. Grade ≥3 toxicity did not increase with age, comorbidity or WHO performance status, in patients treated with monotherapy (anti-PD1 or ipilimumab) or combination treatment. However, patients aged ≥75 were admitted more frequently and discontinued treatment due to toxicity more often. Six months-response rates were similar to previous randomized trials (40.3% and 43.6% in patients aged 65-75 and ≥75 respectively for anti-PD1 treatment) and were not affected by age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity, but age, comorbidity and WHO performance status were associated with overall survival in multivariate analyses. Conclusions: Toxicity, response and melanoma-specific survival were not associated with age or comorbidity status. Treatment with immunotherapy should therefore not be omitted solely based on age or comorbidity. However, the impact of grade I-II toxicity in older patients deserves further study as older patients discontinue treatment more frequently and receive less treatment cycles.[Table: see text]
A simulation model-based clinical decision tool to guide personalized treatment based on individual characteristics: Does 21-gene recurrence score assay testing change decisions?
Authors: Jinani Jayasekera, Joseph A. Sparano, Young Chandler, Claudine Isaacs, Allison W. Kurian, Lawrence H. Kushi, Suzanne C. O'Neill, Clyde B. Schechter, Jeanne S. Mandelblatt
Journal: Journal of Clinical Oncology (2021)

e12507 Background: There is a need for web-based decision tools that integrate clinicopathologic features and genomic information to guide breast cancer therapy for women with node-negative, hormone receptor positive, HER2 negative (“early-stage”) breast cancer. We developed a novel simulation model-based clinical decision tool that provides prognostic estimates of treatment outcomes based on age, tumor size, grade, and comorbidities with and without 21-gene recurrence scores (RS). Methods: We adapted an extant breast cancer simulation model developed within the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) to derive estimates for the 10-year risks of distant recurrence, breast cancer-specific mortality, other cause mortality and life-years gained with endocrine vs. chemo-endocrine therapy for individual women based on their age, tumor size, grade, and comorbidity-level with and without RS test results. The model used an empiric Bayesian analytical approach to combine information from clinical trials, registry and claims data to provide individual estimates. External validation of the model was performed by comparing model-based breast cancer mortality rates and observed rates in the Surveillance Epidemiology and End Results (SEER) registry. Results: Several exemplar profiles were selected to illustrate the clinical utility of the decision tool. For example, the absolute chemotherapy benefit for 10-year distant recurrence risk and life-years gained, without RS testing, and the outcomes if a woman got tested and had a RS 16-20 are provided below for a 40-44-year-old woman and a 65–69-year-old woman diagnosed with a small (≤2cm), intermediate grade tumor and mild comorbidities. Conclusions: Simulation modeling is useful for creating clinical decision tools to support shared decision making for early-stage breast cancer treatment.[Table: see text]
Inhibiting BRD4 to generate BETter T cell memory
Authors: Moujtaba Y. Kasmani, Weiguo Cui
Journal: The Journal of Experimental Medicine (2021)

BRD4 is a bromodomain-containing protein that binds acetylated histones to regulate transcription. In this issue of JEM, Milner et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202512) show that BRD4 plays a critical role in the effector function of CD8 T cells responding to infection and cancer.
HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia
Authors: Xinyan Li, Mengshen Wang, Su Li, Yuqiong Chen, Mozhi Wang, Zhonghua Wu, Xiangyu Sun, Litong Yao, Haoran Dong, Yongxi Song, Yingying Xu
Journal: Theranostics (2021)

Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.
Phase IIa study of BVAC-C in HPV type 16 or 18 positive recurrent cervical carcinoma.
Authors: Chel Hun Choi, Byoung-Gie Kim, Jeong-Won Lee, Duk-Soo Bae, Eun-Suk Kang, Yong-Man Kim, Kidong Kim, Jae-Weon Kim, Young-Tae Kim, Myong Cheol Lim, Taegwon Oh, Chang-Yuil Kang, Duck Cho, JUNG-YUN LEE, Hee Seung Kim
Journal: Journal of Clinical Oncology (2021)

5512 Background: BVAC-C is a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, which was well tolerated in HPV positive recurrent cervical carcinoma in phase I study (J Clin Med. 2020 Jan 5;9(1):147). This phase IIa study sought to determine the antitumor activity of BVAC-C. Methods: Twenty-one patients with HPV 16 or 18 positive recurrent cervical cancer who had experienced recurrence after one prior platinum-based combination chemotherapy were enrolled. They were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks (1x10 8 cells/dose); Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks (5x10 7 cells/dose); Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks (5x10 7 cells/dose) with topotecan at 2, 6, 10, 14 weeks (0.75 mg/m2 for 3 days). Results: The overall response rate was 21% (Arm 1: 29% (2/7), Arm 2: 25% (1/4), Arm 3 : 0 % (0/3)) among the evaluable patients (N = 14), and the median duration of response was 18 months (range, 9 – 26 months). The disease control rate was 43% (Arm 1: 29% (2/7), Arm 2: 50% (2/4), Arm 3 : 67 % (2/3)) and the median duration of stable disease were 12 months (range, 6 - 26 months). The median progression-free survival in all patients was 4 months (95% CI, 2 to Infinite months). Immune responses of patients after vaccination were shown to be correlated with clinical responses of them. Consistent with Phase I study, all evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α), which might be mediated by the activation of natural killer cells and natural killer T cells, but also potent E6/E7-specific T cell responses upon vaccinations. Conclusions: BVAC-C demonstrated a durable antitumor activity with an immune response in HPV 16- or 18-positive recurrent cervical carcinoma patients who failed 1 st line platinum based chemotherapy. Clinical trial information: NCT02866006.
Association of Polygenic Liability for Autism With Face-Sensitive Cortical Responses From Infancy
Authors: Anna Gui, Emma L. Meaburn, Charlotte Tye, Tony Charman, Mark H. Johnson, Emily J. H. Jones
Journal: JAMA Pediatrics (2021)

This cohort study investigates whether N290 latency to faces vs nonfaces is associated with autism polygenic scores and cross-disorder polygenic scores in infants with and without a family history of autism.
EPCT-09. CNS LEVELS OF PANOBINOSTAT IN A NON-HUMAN PRIMATE MODEL: COMPARISON OF BLOOD AND CEREBROSPINAL FLUID PHARMACOKINETIC METHODS AND MALDI MSI
Authors: Katherine Warren, Cynthia Lester McCully, Rafael Cruz Garcia, Sylwia Stopka, Michael Regan, Thet Aye, Sara Zimmerman, Cody Peer, Josh Kramer, Matthew Breed, W Douglas Figg, Nathalie Agar
Journal: Neuro-Oncology (2021)

Abstract Adequate exposure (effective concentration over time) of a therapeutic agent at its site of action is essential for antitumor efficacy. Given constraints of repeat tissue sampling, non-human primate models predictive of pharmacokinetics in pediatric patients have been utilized to assess central nervous system (CNS) exposure. Assessment of cerebrospinal fluid (CSF) drug levels have been used to extrapolate CNS penetration but the relationship of CSF drug levels with tissue distribution is unclear. Utilizing microdialysis, we previously demonstrated geographic variability of drug permeability across the blood:brain barrier (BBB), but this technique is complex and has a high standard deviation. We, therefore, explored a novel technique, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), to compare plasma, CSF, and tissue drug levels in a terminal non-human primate model. Panobinostat, an HDAC inhibitor in clinical trials for DIPG/DMG, was selected for study as it has previously demonstrated poor CNS tissue penetration but suggested modest clinical activity. Methods Panobinostat (p.o., dose 1.6 mg/kg) was administered to non-tumor bearing primates (n=2). One hour following administration (Tmax), blood and CSF were collected, the animal euthanized, brain and spinal cord extracted, and immediately frozen at -80. Panobinostat distribution was mapped on ex vivo sagittal tissue sections using MALDI MSI. To provide specificity and degree of permeability, anatomical structures were segmented for analysis to determine drug concentrations. Blood, CSF and tissue levels of panobinostat were measured via LC-MS/MS. Results Segmentation analysis revealed quantifiable panobinostat, particularly in the lateral ventricles and choroid plexus, and also in the subventricular zone and brainstem, although the overall panobinostat concentration was below the limit of quantitation in these areas. Conclusions Although not reflected in CSF PK, panobinostat is widely distributed in brain tissue. MALDI MSI allows regional assessment of panobinostat penetration and complements CSF pharmacokinetics.
Phenotypes and prognostic factors in adults with Langerhans cell histiocytosis.
Authors: Gaurav Goyal, Aldo A. Acosta-Medina, Marie Hu, Jithma P. Abeykoon, Aishwarya Ravindran, N. Nora Bennani, Caroline Davidge-Pitts, Mithun Vinod Shah, W. Oliver Tobin, Jason R. Young, Jay H. Ryu, Robert Vassallo, Karen Rech, Ronald S. Go
Journal: Journal of Clinical Oncology (2021)

7049 Background: Langerhans cell histiocytosis (LCH) can manifest as single system (SS) disease, multisystem (MS) disease, or pulmonary LCH (smoking-related). There is a paucity of data on prognostic factors including risk organ (RO) involvement (liver, spleen, and bone marrow) in adult LCH, which we sought to address in this study. Methods: Single-center retrospective study of patients ≥18y diagnosed with LCH from 1998 to 2020. Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were conducted using age, sex, organ involvement, LCH subtype, year of diagnosis, BRAF V600E status, and treatments. Results: We included 219 patients with LCH; median age 43y (range 19-88), females 51%, SS unifocal (23%), SS multifocal (6%), pulmonary (31%) and MS (40%). Commonly involved organs included lung (53%), bone (42%), skin (24%), pituitary (16%), and CNS (12%). BRAF V600E was positive in 40/88 (46%). Median follow-up duration was 6.1y (95% CI, 5.1- 7.1). On univariate analysis, factors associated with worse PFS were bone LCH, RO involvement, multifocal/MS LCH, and radiation therapy alone; those with worse OS included RO involvement, MS disease, BRAF V600E+, and age ≥45y at diagnosis. In multivariate analysis, BRAF V600E and age ≥45y at diagnosis were associated with worse mortality (Table). Median PFS was not reached (NR-NR) for SS unifocal LCH, 5mo (0-12.7) for SS multifocal LCH, 110mo (84.7-135.3) for pulmonary LCH, and 27mo (17.2-36.8) for MS LCH. 5-year OS was 97.4% for SS unifocal LCH, 100% for SS multifocal LCH, 96.1% for pulmonary LCH, and 79.9% for MS LCH. 41 (18.7%) developed a second primary malignancy (SPM), of which 11 were hematologic neoplasms. There was a trend towards a higher prevalence of SPMs in patients with BRAF V600E (28% vs. 17%; p = 0.22). Conclusions: In our large single-center study, PFS for multifocal and MS LCH was worse than SS unifocal or pulmonary LCH. RO involvement was not associated with outcomes in multivariate analysis. Overall prognosis was excellent for all subtypes except MS LCH. BRAF V600E and older age were associated with worse OS. The prevalence of SPMs was very high and needs to be explored further.[Table: see text]